Researchers from University College London in the United Kingdom and University of Amsterdam in the Netherlands who conducted a systematic review of available research found a “striking” lack of evidence, considering the vast interest in the potential of the treatment and the “overwhelming demand by veterans.”

The researchers wanted to conduct a “fine-grained evaluation” of cannabinoid effectiveness in posttraumatic stress disorder (PTSD). They identified 10 studies investigating medicinal cannabinoids for patients with PTSD who were experiencing symptoms that were measured by a clinical psychometric, such as the Clinician-Administered PTSD Scale. Only 1 was a randomized, double-blind, placebo-controlled crossover clinical trial. Three studies used nabilone, a synthetic delta9-tetrahydrocannabinol (THC) analog; 1 used oral THC; 2 used cannabidiol (CBD) oil, and 4 used smoked herbal preparations of cannabis.

In line with previous reviews, the researchers found insufficient evidence to support the use of cannabinoids as a psychopharmacologic treatment for PTSD. In fact, they suggest that the lack of evidence poses a public health risk. However, the researchers say, this is mainly because the available support so far has been limited to small, “low-quality” studies, anecdotal reports, and some experimental evidence. There are reasons to keep investigating the possibilities, they conclude.

For instance, there is concurrence among studies that medicinal cannabinoids can help with sleep disturbances, and thus may be more effective, with less risk of addiction than benzodiazepines or opiate-based medications. Self-reports, anecdotal accounts, and case reports suggest that medical cannabis can dramatically reduce not only sleep symptoms, such as insomnia and nightmares, but may help with traumatic intrusions, hyperarousal, stress, anxiety, and depression.

The researchers also cite a study that found veterans who use cannabis believe it to be more effective and less complicated by adverse effects (AEs) than are alcohol and other psychopharmaceuticals. The AEs are generally mild to moderate, such as dry mouth and feeling “stoned,” but compared with the AEs of currently prescribed drugs are considered less burdensome.

Safety concerns are particularly critical in this population, though. Some research has shown that rates of cannabis use disorder are greater among patients who have PTSD compared with those who do not. A study of veterans admitted to US Department of Veterans Affairs treatment programs found recreational cannabis users with PTSD had poorer outcomes on severity of symptoms, violent behavior, and other drug use. Cannabinoids have also been associated with severe AEs in people with a history of psychosis—a consideration in combat veterans who have hallucinations or delusions.

Although they used strict inclusion criteria, the researchers say the studies they used still had “significant” limitations. Future well-controlled, randomized, double-blind clinical trials are highly warranted, they add, to address the “large unmet need” for effective PTSD treatments.

Researchers from University College London in the United Kingdom and University of Amsterdam in the Netherlands who conducted a systematic review of available research found a “striking” lack of evidence, considering the vast interest in the potential of the treatment and the “overwhelming demand by veterans.”

The researchers wanted to conduct a “fine-grained evaluation” of cannabinoid effectiveness in posttraumatic stress disorder (PTSD). They identified 10 studies investigating medicinal cannabinoids for patients with PTSD who were experiencing symptoms that were measured by a clinical psychometric, such as the Clinician-Administered PTSD Scale. Only 1 was a randomized, double-blind, placebo-controlled crossover clinical trial. Three studies used nabilone, a synthetic delta9-tetrahydrocannabinol (THC) analog; 1 used oral THC; 2 used cannabidiol (CBD) oil, and 4 used smoked herbal preparations of cannabis.

In line with previous reviews, the researchers found insufficient evidence to support the use of cannabinoids as a psychopharmacologic treatment for PTSD. In fact, they suggest that the lack of evidence poses a public health risk. However, the researchers say, this is mainly because the available support so far has been limited to small, “low-quality” studies, anecdotal reports, and some experimental evidence. There are reasons to keep investigating the possibilities, they conclude.

For instance, there is concurrence among studies that medicinal cannabinoids can help with sleep disturbances, and thus may be more effective, with less risk of addiction than benzodiazepines or opiate-based medications. Self-reports, anecdotal accounts, and case reports suggest that medical cannabis can dramatically reduce not only sleep symptoms, such as insomnia and nightmares, but may help with traumatic intrusions, hyperarousal, stress, anxiety, and depression.

The researchers also cite a study that found veterans who use cannabis believe it to be more effective and less complicated by adverse effects (AEs) than are alcohol and other psychopharmaceuticals. The AEs are generally mild to moderate, such as dry mouth and feeling “stoned,” but compared with the AEs of currently prescribed drugs are considered less burdensome.

Safety concerns are particularly critical in this population, though. Some research has shown that rates of cannabis use disorder are greater among patients who have PTSD compared with those who do not. A study of veterans admitted to US Department of Veterans Affairs treatment programs found recreational cannabis users with PTSD had poorer outcomes on severity of symptoms, violent behavior, and other drug use. Cannabinoids have also been associated with severe AEs in people with a history of psychosis—a consideration in combat veterans who have hallucinations or delusions.

Although they used strict inclusion criteria, the researchers say the studies they used still had “significant” limitations. Future well-controlled, randomized, double-blind clinical trials are highly warranted, they add, to address the “large unmet need” for effective PTSD treatments.

Researchers from University College London in the United Kingdom and University of Amsterdam in the Netherlands who conducted a systematic review of available research found a “striking” lack of evidence, considering the vast interest in the potential of the treatment and the “overwhelming demand by veterans.”

The researchers wanted to conduct a “fine-grained evaluation” of cannabinoid effectiveness in posttraumatic stress disorder (PTSD). They identified 10 studies investigating medicinal cannabinoids for patients with PTSD who were experiencing symptoms that were measured by a clinical psychometric, such as the Clinician-Administered PTSD Scale. Only 1 was a randomized, double-blind, placebo-controlled crossover clinical trial. Three studies used nabilone, a synthetic delta9-tetrahydrocannabinol (THC) analog; 1 used oral THC; 2 used cannabidiol (CBD) oil, and 4 used smoked herbal preparations of cannabis.

In line with previous reviews, the researchers found insufficient evidence to support the use of cannabinoids as a psychopharmacologic treatment for PTSD. In fact, they suggest that the lack of evidence poses a public health risk. However, the researchers say, this is mainly because the available support so far has been limited to small, “low-quality” studies, anecdotal reports, and some experimental evidence. There are reasons to keep investigating the possibilities, they conclude.

For instance, there is concurrence among studies that medicinal cannabinoids can help with sleep disturbances, and thus may be more effective, with less risk of addiction than benzodiazepines or opiate-based medications. Self-reports, anecdotal accounts, and case reports suggest that medical cannabis can dramatically reduce not only sleep symptoms, such as insomnia and nightmares, but may help with traumatic intrusions, hyperarousal, stress, anxiety, and depression.

The researchers also cite a study that found veterans who use cannabis believe it to be more effective and less complicated by adverse effects (AEs) than are alcohol and other psychopharmaceuticals. The AEs are generally mild to moderate, such as dry mouth and feeling “stoned,” but compared with the AEs of currently prescribed drugs are considered less burdensome.

Safety concerns are particularly critical in this population, though. Some research has shown that rates of cannabis use disorder are greater among patients who have PTSD compared with those who do not. A study of veterans admitted to US Department of Veterans Affairs treatment programs found recreational cannabis users with PTSD had poorer outcomes on severity of symptoms, violent behavior, and other drug use. Cannabinoids have also been associated with severe AEs in people with a history of psychosis—a consideration in combat veterans who have hallucinations or delusions.

Although they used strict inclusion criteria, the researchers say the studies they used still had “significant” limitations. Future well-controlled, randomized, double-blind clinical trials are highly warranted, they add, to address the “large unmet need” for effective PTSD treatments.

Antimalarial retinal complications occurred in about 5% of patients with systemic lupus erythematosus (SLE) exposed to hydroxychloroquine or chloroquine during an average of nearly 13 years of follow-up, without any cases of retinal toxicity occurring within the first 5 years of use, according to findings from a case-control study.

The rate of retinal complications observed in the study is slightly lower or within the range reported in other studies of antimalarial use by patients with SLE, first author Elvis-Raymond Mukwikwi of the University of Montreal and coauthors from McGill University, Montreal, reported in the Journal of Rheumatology.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are commonly used to treat SLE and rheumatoid arthritis, and they are being investigated for use in diabetes, cancer, and cardiovascular disease. However, in rare cases, the drugs can lead to irreversible retinopathy.

To better understand the factors associated with retinopathy, the researchers analyzed data from 326 records obtained from the McGill University Health Center Lupus Clinic Registry. A total of 18 patients (5.5%) had confirmed retinal toxicity, and the investigators matched each of these patients to 3 control patients with SLE and exposure to HCQ/CQ who did not develop retinopathy and had the same duration of SLE and age at SLE diagnosis.

The minimum number of years of HCQ/CQ exposure before retinopathy developed was 8 years, and the maximum number was 33 years. Overall, 17 retinopathy cases had exposure to HCQ, and 12 of those cases (71%) received average doses higher than current recommendations. Eight patients were exposed to average daily doses of HCQ higher than 5 mg/kg and four to average daily doses of CQ above 2.3 mg/kg. Exposure to an average dose higher than currently recommended occurred in 49% of controls. The exposure to doses higher than current recommendations was “not surprising given that these were issued in 2016 and most of our patients had been taking HCQ for longer than this,” the authors wrote.

High-dose exposure was common, with 83% of controls and all retinopathy cases having been exposed to HCQ/CQ doses above recommendations, as determined during at least one annual assessment.

Among patients with retinopathy, exposure to CQ was three times more frequent than it was for those without the condition (39% vs. 13%; 95% confidence interval, 1.8%-52%), although all of the patients exposed to CQ also were exposed to long periods of HCQ, making it impossible to determine retinopathy risk to CQ exposure alone.

The researchers also found gaps in monitoring. In the 5 years before discontinuation of medication, 53% of cases had missed one or more annual ophthalmologic assessments to screen for retinal damage, compared with 75% of controls.

Concomitant renal damage, believed to be a risk factor for retinal toxicity, occurred more often in the retinopathy group, though the difference failed to meet statistical significance (23% versus 15%). Patients with retinopathy were less likely to be Caucasian (61% versus 74%), but this also did not reach statistical significance.

The authors did not disclose information on funding or conflicts of interest.

SOURCE: Mukwikwi ER et al. J Rheumatol. 2019 Sep 1. doi: 10.3899/jrheum.181102

Antimalarial retinal complications occurred in about 5% of patients with systemic lupus erythematosus (SLE) exposed to hydroxychloroquine or chloroquine during an average of nearly 13 years of follow-up, without any cases of retinal toxicity occurring within the first 5 years of use, according to findings from a case-control study.

The rate of retinal complications observed in the study is slightly lower or within the range reported in other studies of antimalarial use by patients with SLE, first author Elvis-Raymond Mukwikwi of the University of Montreal and coauthors from McGill University, Montreal, reported in the Journal of Rheumatology.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are commonly used to treat SLE and rheumatoid arthritis, and they are being investigated for use in diabetes, cancer, and cardiovascular disease. However, in rare cases, the drugs can lead to irreversible retinopathy.

To better understand the factors associated with retinopathy, the researchers analyzed data from 326 records obtained from the McGill University Health Center Lupus Clinic Registry. A total of 18 patients (5.5%) had confirmed retinal toxicity, and the investigators matched each of these patients to 3 control patients with SLE and exposure to HCQ/CQ who did not develop retinopathy and had the same duration of SLE and age at SLE diagnosis.

The minimum number of years of HCQ/CQ exposure before retinopathy developed was 8 years, and the maximum number was 33 years. Overall, 17 retinopathy cases had exposure to HCQ, and 12 of those cases (71%) received average doses higher than current recommendations. Eight patients were exposed to average daily doses of HCQ higher than 5 mg/kg and four to average daily doses of CQ above 2.3 mg/kg. Exposure to an average dose higher than currently recommended occurred in 49% of controls. The exposure to doses higher than current recommendations was “not surprising given that these were issued in 2016 and most of our patients had been taking HCQ for longer than this,” the authors wrote.

High-dose exposure was common, with 83% of controls and all retinopathy cases having been exposed to HCQ/CQ doses above recommendations, as determined during at least one annual assessment.

Among patients with retinopathy, exposure to CQ was three times more frequent than it was for those without the condition (39% vs. 13%; 95% confidence interval, 1.8%-52%), although all of the patients exposed to CQ also were exposed to long periods of HCQ, making it impossible to determine retinopathy risk to CQ exposure alone.

The researchers also found gaps in monitoring. In the 5 years before discontinuation of medication, 53% of cases had missed one or more annual ophthalmologic assessments to screen for retinal damage, compared with 75% of controls.

Concomitant renal damage, believed to be a risk factor for retinal toxicity, occurred more often in the retinopathy group, though the difference failed to meet statistical significance (23% versus 15%). Patients with retinopathy were less likely to be Caucasian (61% versus 74%), but this also did not reach statistical significance.

The authors did not disclose information on funding or conflicts of interest.

SOURCE: Mukwikwi ER et al. J Rheumatol. 2019 Sep 1. doi: 10.3899/jrheum.181102

Antimalarial retinal complications occurred in about 5% of patients with systemic lupus erythematosus (SLE) exposed to hydroxychloroquine or chloroquine during an average of nearly 13 years of follow-up, without any cases of retinal toxicity occurring within the first 5 years of use, according to findings from a case-control study.

The rate of retinal complications observed in the study is slightly lower or within the range reported in other studies of antimalarial use by patients with SLE, first author Elvis-Raymond Mukwikwi of the University of Montreal and coauthors from McGill University, Montreal, reported in the Journal of Rheumatology.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are commonly used to treat SLE and rheumatoid arthritis, and they are being investigated for use in diabetes, cancer, and cardiovascular disease. However, in rare cases, the drugs can lead to irreversible retinopathy.

To better understand the factors associated with retinopathy, the researchers analyzed data from 326 records obtained from the McGill University Health Center Lupus Clinic Registry. A total of 18 patients (5.5%) had confirmed retinal toxicity, and the investigators matched each of these patients to 3 control patients with SLE and exposure to HCQ/CQ who did not develop retinopathy and had the same duration of SLE and age at SLE diagnosis.

The minimum number of years of HCQ/CQ exposure before retinopathy developed was 8 years, and the maximum number was 33 years. Overall, 17 retinopathy cases had exposure to HCQ, and 12 of those cases (71%) received average doses higher than current recommendations. Eight patients were exposed to average daily doses of HCQ higher than 5 mg/kg and four to average daily doses of CQ above 2.3 mg/kg. Exposure to an average dose higher than currently recommended occurred in 49% of controls. The exposure to doses higher than current recommendations was “not surprising given that these were issued in 2016 and most of our patients had been taking HCQ for longer than this,” the authors wrote.

High-dose exposure was common, with 83% of controls and all retinopathy cases having been exposed to HCQ/CQ doses above recommendations, as determined during at least one annual assessment.

Among patients with retinopathy, exposure to CQ was three times more frequent than it was for those without the condition (39% vs. 13%; 95% confidence interval, 1.8%-52%), although all of the patients exposed to CQ also were exposed to long periods of HCQ, making it impossible to determine retinopathy risk to CQ exposure alone.

The researchers also found gaps in monitoring. In the 5 years before discontinuation of medication, 53% of cases had missed one or more annual ophthalmologic assessments to screen for retinal damage, compared with 75% of controls.

Concomitant renal damage, believed to be a risk factor for retinal toxicity, occurred more often in the retinopathy group, though the difference failed to meet statistical significance (23% versus 15%). Patients with retinopathy were less likely to be Caucasian (61% versus 74%), but this also did not reach statistical significance.

The authors did not disclose information on funding or conflicts of interest.

SOURCE: Mukwikwi ER et al. J Rheumatol. 2019 Sep 1. doi: 10.3899/jrheum.181102

To the Editor:

A 55-year-old man with a history of Graves disease treated with radioactive iodine and Graves ophthalmopathy was referred to our dermatology clinic by his endocrinologist with a 2-year history of severe pretibial myxedema (PM) that had failed treatment with systemic immunosuppressants after diagnosis by an outside dermatologist in the United Kingdom approximately 2 years prior. In addition to burning pain and difficulty walking associated with progressive “enlarging” of the lower legs and feet (Figure, A and B), the patient reported that he consistently had to find larger shoes (size 13 at the current presentation). His medications included gabapentin for foot pain and levothyroxine for hypothyroidism.

Physical examination revealed diffuse, waxy, indurated, flesh-colored and erythematous plaques and nodules with a peau d’orange appearance on the dorsal feet, ankles, and lower legs. Laboratory evaluation revealed a thyroid stimulating immunoglobulin level of 617% (reference range, <140%) and mild anemia. His thyroid stimulating hormone and free T4 levels, a comprehensive metabolic panel, and lipid panel were all within reference range.

Treatment with oral, intravenous, and intralesional steroids; cyclosporine; and azathioprine were tried prior to presentation to our clinic with no improvement. The patient was started on pentoxifylline (400 mg 3 times daily), intralesional triamcinolone acetonide (5 mg/mL every 3–4 weeks), clobetasol propionate ointment 0.05% under occlusion twice daily, short-stretch bandages, and compression stockings (20–30 mm Hg). The baseline circumference of the extremities also were measured (right ankle, 12 in; left ankle, 11.5 in; right and left mid-plantar feet, 12 in).

At 3-week follow-up, the lesions had flattened with softening of the skin. The patient reported his legs were smaller and he had bought a new pair of shoes at size 8.5 (Figure, C). He noted less pain and difficulty with walking. The circumference of the extremities was measured again (right ankle, 10.2 in; left ankle, 10 in; right and left mid-plantar feet, 10.5 in). The patient continued treatment and was followed for 3 months. At each visit, clinical improvement was noted as well as report of decreased pain while walking (Figure, D).

Pretibial myxedema is a known manifestation of Graves disease that almost always occurs in the presence of Graves ophthalmopathy. Pretibial myxedema occurs in 0.5% to 4.3% of patients with Graves disease and variably manifests as diffuse nonpitting edema or localized, waxy, indurated plaques or nodules.^1,2

The proposed pathogenesis of PM is that autoantibodies directed against the thyroid receptors cross-react with the fibroblasts of the skin,^2,3 which stimulates the fibroblasts to produce high amounts of glycosaminoglycans, especially hyaluronic acid, in the dermis and subcutis of the pretibial area. It is not known why there is a predilection for the anterior shins, but mechanical factors and dependent position (ie, leg position is lower than the level of the heart) may be involved.⁴

The mainstay of treatment for PM is topical and intralesional corticosteroids, which may have a benefit in mild to moderate disease; however, in cases of severe disease that is refractory to intralesional and topical corticosteroids under occlusion, more aggressive treatment is required. Systemic immunosuppressants such as cyclosporine, azathioprine, and corticosteroids have proven useful in some but not all cases.^5,6

Our patient did not respond to treatment with systemic and intralesional corticosteroids, cyclosporine, or azathioprine before he presented to our clinic; however, the lesions were dramatically improved after 3 weeks of treatment with pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression stockings.

Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves ophthalmology and PM.⁷ It has been shown to reduce thickness of skin lesions when used in combination with topical or intralesional steroids.^3,8 Corticosteroids are thought to block fibroblast-mediated glycosaminoglycan production.^3,9 The deposition of mucin, which is comprised of glycosaminoglycans, expands the dermal tissue and causes fluid to accumulate; it also causes compression of dermal lymphatics, worsening the dermal edema. Because fluid accumulates, the use of short-stretch bandages and compression stockings may provide additional benefit, as was seen in our patient, whose shoe size decreased from a 13 to an 8.5 within 3 weeks of treatment.

In conclusion, the combination of pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression garments can cause substantial improvement in severe PM refractory to systemic immunosuppressants.

To the Editor:

A 55-year-old man with a history of Graves disease treated with radioactive iodine and Graves ophthalmopathy was referred to our dermatology clinic by his endocrinologist with a 2-year history of severe pretibial myxedema (PM) that had failed treatment with systemic immunosuppressants after diagnosis by an outside dermatologist in the United Kingdom approximately 2 years prior. In addition to burning pain and difficulty walking associated with progressive “enlarging” of the lower legs and feet (Figure, A and B), the patient reported that he consistently had to find larger shoes (size 13 at the current presentation). His medications included gabapentin for foot pain and levothyroxine for hypothyroidism.

Physical examination revealed diffuse, waxy, indurated, flesh-colored and erythematous plaques and nodules with a peau d’orange appearance on the dorsal feet, ankles, and lower legs. Laboratory evaluation revealed a thyroid stimulating immunoglobulin level of 617% (reference range, <140%) and mild anemia. His thyroid stimulating hormone and free T4 levels, a comprehensive metabolic panel, and lipid panel were all within reference range.

Treatment with oral, intravenous, and intralesional steroids; cyclosporine; and azathioprine were tried prior to presentation to our clinic with no improvement. The patient was started on pentoxifylline (400 mg 3 times daily), intralesional triamcinolone acetonide (5 mg/mL every 3–4 weeks), clobetasol propionate ointment 0.05% under occlusion twice daily, short-stretch bandages, and compression stockings (20–30 mm Hg). The baseline circumference of the extremities also were measured (right ankle, 12 in; left ankle, 11.5 in; right and left mid-plantar feet, 12 in).

At 3-week follow-up, the lesions had flattened with softening of the skin. The patient reported his legs were smaller and he had bought a new pair of shoes at size 8.5 (Figure, C). He noted less pain and difficulty with walking. The circumference of the extremities was measured again (right ankle, 10.2 in; left ankle, 10 in; right and left mid-plantar feet, 10.5 in). The patient continued treatment and was followed for 3 months. At each visit, clinical improvement was noted as well as report of decreased pain while walking (Figure, D).

Pretibial myxedema is a known manifestation of Graves disease that almost always occurs in the presence of Graves ophthalmopathy. Pretibial myxedema occurs in 0.5% to 4.3% of patients with Graves disease and variably manifests as diffuse nonpitting edema or localized, waxy, indurated plaques or nodules.^1,2

The proposed pathogenesis of PM is that autoantibodies directed against the thyroid receptors cross-react with the fibroblasts of the skin,^2,3 which stimulates the fibroblasts to produce high amounts of glycosaminoglycans, especially hyaluronic acid, in the dermis and subcutis of the pretibial area. It is not known why there is a predilection for the anterior shins, but mechanical factors and dependent position (ie, leg position is lower than the level of the heart) may be involved.⁴

The mainstay of treatment for PM is topical and intralesional corticosteroids, which may have a benefit in mild to moderate disease; however, in cases of severe disease that is refractory to intralesional and topical corticosteroids under occlusion, more aggressive treatment is required. Systemic immunosuppressants such as cyclosporine, azathioprine, and corticosteroids have proven useful in some but not all cases.^5,6

Our patient did not respond to treatment with systemic and intralesional corticosteroids, cyclosporine, or azathioprine before he presented to our clinic; however, the lesions were dramatically improved after 3 weeks of treatment with pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression stockings.

Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves ophthalmology and PM.⁷ It has been shown to reduce thickness of skin lesions when used in combination with topical or intralesional steroids.^3,8 Corticosteroids are thought to block fibroblast-mediated glycosaminoglycan production.^3,9 The deposition of mucin, which is comprised of glycosaminoglycans, expands the dermal tissue and causes fluid to accumulate; it also causes compression of dermal lymphatics, worsening the dermal edema. Because fluid accumulates, the use of short-stretch bandages and compression stockings may provide additional benefit, as was seen in our patient, whose shoe size decreased from a 13 to an 8.5 within 3 weeks of treatment.

In conclusion, the combination of pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression garments can cause substantial improvement in severe PM refractory to systemic immunosuppressants.

To the Editor:

A 55-year-old man with a history of Graves disease treated with radioactive iodine and Graves ophthalmopathy was referred to our dermatology clinic by his endocrinologist with a 2-year history of severe pretibial myxedema (PM) that had failed treatment with systemic immunosuppressants after diagnosis by an outside dermatologist in the United Kingdom approximately 2 years prior. In addition to burning pain and difficulty walking associated with progressive “enlarging” of the lower legs and feet (Figure, A and B), the patient reported that he consistently had to find larger shoes (size 13 at the current presentation). His medications included gabapentin for foot pain and levothyroxine for hypothyroidism.

Physical examination revealed diffuse, waxy, indurated, flesh-colored and erythematous plaques and nodules with a peau d’orange appearance on the dorsal feet, ankles, and lower legs. Laboratory evaluation revealed a thyroid stimulating immunoglobulin level of 617% (reference range, <140%) and mild anemia. His thyroid stimulating hormone and free T4 levels, a comprehensive metabolic panel, and lipid panel were all within reference range.

Treatment with oral, intravenous, and intralesional steroids; cyclosporine; and azathioprine were tried prior to presentation to our clinic with no improvement. The patient was started on pentoxifylline (400 mg 3 times daily), intralesional triamcinolone acetonide (5 mg/mL every 3–4 weeks), clobetasol propionate ointment 0.05% under occlusion twice daily, short-stretch bandages, and compression stockings (20–30 mm Hg). The baseline circumference of the extremities also were measured (right ankle, 12 in; left ankle, 11.5 in; right and left mid-plantar feet, 12 in).

At 3-week follow-up, the lesions had flattened with softening of the skin. The patient reported his legs were smaller and he had bought a new pair of shoes at size 8.5 (Figure, C). He noted less pain and difficulty with walking. The circumference of the extremities was measured again (right ankle, 10.2 in; left ankle, 10 in; right and left mid-plantar feet, 10.5 in). The patient continued treatment and was followed for 3 months. At each visit, clinical improvement was noted as well as report of decreased pain while walking (Figure, D).

Pretibial myxedema is a known manifestation of Graves disease that almost always occurs in the presence of Graves ophthalmopathy. Pretibial myxedema occurs in 0.5% to 4.3% of patients with Graves disease and variably manifests as diffuse nonpitting edema or localized, waxy, indurated plaques or nodules.^1,2

The proposed pathogenesis of PM is that autoantibodies directed against the thyroid receptors cross-react with the fibroblasts of the skin,^2,3 which stimulates the fibroblasts to produce high amounts of glycosaminoglycans, especially hyaluronic acid, in the dermis and subcutis of the pretibial area. It is not known why there is a predilection for the anterior shins, but mechanical factors and dependent position (ie, leg position is lower than the level of the heart) may be involved.⁴

The mainstay of treatment for PM is topical and intralesional corticosteroids, which may have a benefit in mild to moderate disease; however, in cases of severe disease that is refractory to intralesional and topical corticosteroids under occlusion, more aggressive treatment is required. Systemic immunosuppressants such as cyclosporine, azathioprine, and corticosteroids have proven useful in some but not all cases.^5,6

Our patient did not respond to treatment with systemic and intralesional corticosteroids, cyclosporine, or azathioprine before he presented to our clinic; however, the lesions were dramatically improved after 3 weeks of treatment with pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression stockings.

Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves ophthalmology and PM.⁷ It has been shown to reduce thickness of skin lesions when used in combination with topical or intralesional steroids.^3,8 Corticosteroids are thought to block fibroblast-mediated glycosaminoglycan production.^3,9 The deposition of mucin, which is comprised of glycosaminoglycans, expands the dermal tissue and causes fluid to accumulate; it also causes compression of dermal lymphatics, worsening the dermal edema. Because fluid accumulates, the use of short-stretch bandages and compression stockings may provide additional benefit, as was seen in our patient, whose shoe size decreased from a 13 to an 8.5 within 3 weeks of treatment.

In conclusion, the combination of pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression garments can cause substantial improvement in severe PM refractory to systemic immunosuppressants.

AUSTIN, TEX. – If a child presents with acute photosensitivity at a young age, onset of freckling before the age of 2 years, and severe sun damage of the lips and eyes, think xeroderma pigmentosum (XP), a rare autosomal recessive disorder.

Doug Brunk/MDedge News

Other telltale symptoms of XP include the presence of skin cancer at an early age and a large number of skin cancers.

At the annual meeting of the Society for Pediatric Dermatology, John J. DiGiovanna, MD, described XP as a disorder of genomic instability, which has no cure. It’s caused by a mutation in genes XPA through XPG and the XP variant (XPV) gene. “The genome controls our genes, and UV rays damage DNA,” said Dr. DiGiovanna, who is a senior research physician at the National Cancer Institute’s Laboratory of Cancer and Biology and Genetics, Bethesda, Md. “This damage from UV radiation is similar to damage from chemical agents that form DNA adducts, such as cigarette smoke and certain chemotherapy agents such as cisplatinum.”

XP patients present with or without acute burning after minimal sun exposure, while children with both subtypes develop “freckling” by the time they reach 2 years of age. Dr. DiGiovanna pointed out that lentigo maligna lesions associated with XP resemble freckles at first glance, yet they vary in size, intensity, and border. Meanwhile, freckles in healthy patients are similar in size, are light tan in color, and have a regular border.

“The burning with minimal sun exposure that occurs during childhood leads to pigmentary changes, atrophy, xerosis, and telangiectasias,” he said. A follow-up analysis of 106 XP patients admitted to the National Institutes of Health between 1971 and 2009 found that patients were diagnosed with their first nonmelanoma skin cancer at a median age of 9 years, compared with age 67 among those in the general population (J Med Genet 2011 Mar;48[3]:168-76). “This is a 58-year decrease in age at risk, which is a 10,000-fold increase in skin cancer,” said Dr. DiGiovanna, who was one of the study authors.

Melanoma also occurs at an earlier age among XP patients – a median age of 22 years, compared with a median of 55 years in the general population. “In the general population, melanoma occurs at a younger age than nonmelanoma skin cancer, while in the XP population, melanoma occurs at an older age,” he said. “This is giving us a good biologic lesson that the melanoma induction mechanism must be different from nonmelanoma skin cancer.”

He recalled one XP patient who was followed by NIH researchers for 4 decades. She worked in a doctor’s office and drove a car, but developed progressive neurologic degeneration and died at the age of 40. “This was not due to unrepaired UV damage, but there are other agents which damage other neurons,” Dr. DiGiovanna explained. “Over time, what you get is a decrease in brain volume, an increase in the brain ventricles, and a loss of brain tissue. At postmortem examination, her brain was of infantile size, compared with that of an equivalent 40-year-old. This is a disease of neuronal loss, and it’s progressive. Only about 20%-25% of XP patients experience neural degeneration.”

Management of XP involves strict sun avoidance, including use of a portable UV meter and many layers of UV protection, including application of sunscreen, wearing protective clothing, sunglasses, hats, and face shields, and the use of UV-blocking window film, LED lights, and a vitamin D diet or oral supplementation. Affected individuals also require frequent skin monitoring by the patients and their family members, frequent dermatologic exams by clinicians, biopsy of suspicious lesions, removal of any skin cancers found, field treatments with agents such as 5-fluorouracil and imiquimod, and chemoprevention with oral retinoids for patients who are actively developing large numbers of new lesions (N Engl J Med. 1988 Jun23;318[25]:1633-7).

“Probably the most important thing you can do is refer them to patient support groups,” Dr. DiGiovanna said. “They are present in many countries and can help them manage the day-to-day issues of their condition.” Support groups based in North America include the XP Family Support Group, XP Society, and XP Grupo Luz De Esperanza.

Dr. DiGiovanna reported having no financial disclosures.

[email protected]

AUSTIN, TEX. – If a child presents with acute photosensitivity at a young age, onset of freckling before the age of 2 years, and severe sun damage of the lips and eyes, think xeroderma pigmentosum (XP), a rare autosomal recessive disorder.

Doug Brunk/MDedge News

Other telltale symptoms of XP include the presence of skin cancer at an early age and a large number of skin cancers.

At the annual meeting of the Society for Pediatric Dermatology, John J. DiGiovanna, MD, described XP as a disorder of genomic instability, which has no cure. It’s caused by a mutation in genes XPA through XPG and the XP variant (XPV) gene. “The genome controls our genes, and UV rays damage DNA,” said Dr. DiGiovanna, who is a senior research physician at the National Cancer Institute’s Laboratory of Cancer and Biology and Genetics, Bethesda, Md. “This damage from UV radiation is similar to damage from chemical agents that form DNA adducts, such as cigarette smoke and certain chemotherapy agents such as cisplatinum.”

XP patients present with or without acute burning after minimal sun exposure, while children with both subtypes develop “freckling” by the time they reach 2 years of age. Dr. DiGiovanna pointed out that lentigo maligna lesions associated with XP resemble freckles at first glance, yet they vary in size, intensity, and border. Meanwhile, freckles in healthy patients are similar in size, are light tan in color, and have a regular border.

“The burning with minimal sun exposure that occurs during childhood leads to pigmentary changes, atrophy, xerosis, and telangiectasias,” he said. A follow-up analysis of 106 XP patients admitted to the National Institutes of Health between 1971 and 2009 found that patients were diagnosed with their first nonmelanoma skin cancer at a median age of 9 years, compared with age 67 among those in the general population (J Med Genet 2011 Mar;48[3]:168-76). “This is a 58-year decrease in age at risk, which is a 10,000-fold increase in skin cancer,” said Dr. DiGiovanna, who was one of the study authors.

Melanoma also occurs at an earlier age among XP patients – a median age of 22 years, compared with a median of 55 years in the general population. “In the general population, melanoma occurs at a younger age than nonmelanoma skin cancer, while in the XP population, melanoma occurs at an older age,” he said. “This is giving us a good biologic lesson that the melanoma induction mechanism must be different from nonmelanoma skin cancer.”

He recalled one XP patient who was followed by NIH researchers for 4 decades. She worked in a doctor’s office and drove a car, but developed progressive neurologic degeneration and died at the age of 40. “This was not due to unrepaired UV damage, but there are other agents which damage other neurons,” Dr. DiGiovanna explained. “Over time, what you get is a decrease in brain volume, an increase in the brain ventricles, and a loss of brain tissue. At postmortem examination, her brain was of infantile size, compared with that of an equivalent 40-year-old. This is a disease of neuronal loss, and it’s progressive. Only about 20%-25% of XP patients experience neural degeneration.”

Management of XP involves strict sun avoidance, including use of a portable UV meter and many layers of UV protection, including application of sunscreen, wearing protective clothing, sunglasses, hats, and face shields, and the use of UV-blocking window film, LED lights, and a vitamin D diet or oral supplementation. Affected individuals also require frequent skin monitoring by the patients and their family members, frequent dermatologic exams by clinicians, biopsy of suspicious lesions, removal of any skin cancers found, field treatments with agents such as 5-fluorouracil and imiquimod, and chemoprevention with oral retinoids for patients who are actively developing large numbers of new lesions (N Engl J Med. 1988 Jun23;318[25]:1633-7).

“Probably the most important thing you can do is refer them to patient support groups,” Dr. DiGiovanna said. “They are present in many countries and can help them manage the day-to-day issues of their condition.” Support groups based in North America include the XP Family Support Group, XP Society, and XP Grupo Luz De Esperanza.

Dr. DiGiovanna reported having no financial disclosures.

[email protected]

AUSTIN, TEX. – If a child presents with acute photosensitivity at a young age, onset of freckling before the age of 2 years, and severe sun damage of the lips and eyes, think xeroderma pigmentosum (XP), a rare autosomal recessive disorder.

Doug Brunk/MDedge News

Other telltale symptoms of XP include the presence of skin cancer at an early age and a large number of skin cancers.

At the annual meeting of the Society for Pediatric Dermatology, John J. DiGiovanna, MD, described XP as a disorder of genomic instability, which has no cure. It’s caused by a mutation in genes XPA through XPG and the XP variant (XPV) gene. “The genome controls our genes, and UV rays damage DNA,” said Dr. DiGiovanna, who is a senior research physician at the National Cancer Institute’s Laboratory of Cancer and Biology and Genetics, Bethesda, Md. “This damage from UV radiation is similar to damage from chemical agents that form DNA adducts, such as cigarette smoke and certain chemotherapy agents such as cisplatinum.”

XP patients present with or without acute burning after minimal sun exposure, while children with both subtypes develop “freckling” by the time they reach 2 years of age. Dr. DiGiovanna pointed out that lentigo maligna lesions associated with XP resemble freckles at first glance, yet they vary in size, intensity, and border. Meanwhile, freckles in healthy patients are similar in size, are light tan in color, and have a regular border.

“The burning with minimal sun exposure that occurs during childhood leads to pigmentary changes, atrophy, xerosis, and telangiectasias,” he said. A follow-up analysis of 106 XP patients admitted to the National Institutes of Health between 1971 and 2009 found that patients were diagnosed with their first nonmelanoma skin cancer at a median age of 9 years, compared with age 67 among those in the general population (J Med Genet 2011 Mar;48[3]:168-76). “This is a 58-year decrease in age at risk, which is a 10,000-fold increase in skin cancer,” said Dr. DiGiovanna, who was one of the study authors.

Melanoma also occurs at an earlier age among XP patients – a median age of 22 years, compared with a median of 55 years in the general population. “In the general population, melanoma occurs at a younger age than nonmelanoma skin cancer, while in the XP population, melanoma occurs at an older age,” he said. “This is giving us a good biologic lesson that the melanoma induction mechanism must be different from nonmelanoma skin cancer.”

He recalled one XP patient who was followed by NIH researchers for 4 decades. She worked in a doctor’s office and drove a car, but developed progressive neurologic degeneration and died at the age of 40. “This was not due to unrepaired UV damage, but there are other agents which damage other neurons,” Dr. DiGiovanna explained. “Over time, what you get is a decrease in brain volume, an increase in the brain ventricles, and a loss of brain tissue. At postmortem examination, her brain was of infantile size, compared with that of an equivalent 40-year-old. This is a disease of neuronal loss, and it’s progressive. Only about 20%-25% of XP patients experience neural degeneration.”

Management of XP involves strict sun avoidance, including use of a portable UV meter and many layers of UV protection, including application of sunscreen, wearing protective clothing, sunglasses, hats, and face shields, and the use of UV-blocking window film, LED lights, and a vitamin D diet or oral supplementation. Affected individuals also require frequent skin monitoring by the patients and their family members, frequent dermatologic exams by clinicians, biopsy of suspicious lesions, removal of any skin cancers found, field treatments with agents such as 5-fluorouracil and imiquimod, and chemoprevention with oral retinoids for patients who are actively developing large numbers of new lesions (N Engl J Med. 1988 Jun23;318[25]:1633-7).

“Probably the most important thing you can do is refer them to patient support groups,” Dr. DiGiovanna said. “They are present in many countries and can help them manage the day-to-day issues of their condition.” Support groups based in North America include the XP Family Support Group, XP Society, and XP Grupo Luz De Esperanza.

Dr. DiGiovanna reported having no financial disclosures.

[email protected]

Combination metformin and epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) therapy improved progression-free survival in patients with EGFR-mutated lung adenocarcinoma, according to results from a phase 2 trial.

“This is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS [progression-free survival],” wrote Oscar Arrieta, MD, of the Instituto Nacional de Cancerología, Mexico, and colleagues in JAMA Oncology.

The open-label, randomized study included 139 patients, 69 of whom were randomly assigned to receive metformin plus EGFR-TKI therapy and 70 of whom received EGFR-TKI monotherapy.

EGFR-TKI therapy was selected based on physician choice and consisted of either afatinib dimaleate, gefitinib, or erlotinib hydrochloride at regular doses. Study patients in the combination arm received metformin 500 mg twice daily.

The primary endpoint was PFS (intent-to-treat population). Secondary endpoints included overall survival (OS), objective response rate, and safety.

After analysis, the researchers found that the median PFS was 13.1 months with metformin-EGFR-TKI combination therapy and 9.9 months with EGFR-TKI monotherapy (hazard ratio, 0.60; P = .03).

In addition, the median OS was also significantly prolonged for patients receiving combined treatment (31.7 months vs. 17.5 months; P = .02).

“Multivariable analysis showed that treatment with metformin is independently associated with longer PFS and OS,” the researchers wrote.

With respect to safety, no significant rise in adverse events was observed, and toxicities were comparable across both treatment groups.

The researchers acknowledged that a key limitation of the study was the absence of a double-blinded design. As a result, various biases could have influenced the results.

“The results from this phase 2 study warrant the design of a larger, phase 3, placebo-controlled study to draw more robust conclusions,” they said.

The study was funded by the National Council for Science and Technology in Mexico. The authors reported financial affiliations with AbbVie, AstraZeneca, Boehringer Ingelheim, Lilly, Bristol-Myers Squibb, Merck, Pfizer, Roche, and several others.

SOURCE: Arrieta O et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.2553.

Combination metformin and epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) therapy improved progression-free survival in patients with EGFR-mutated lung adenocarcinoma, according to results from a phase 2 trial.

“This is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS [progression-free survival],” wrote Oscar Arrieta, MD, of the Instituto Nacional de Cancerología, Mexico, and colleagues in JAMA Oncology.

The open-label, randomized study included 139 patients, 69 of whom were randomly assigned to receive metformin plus EGFR-TKI therapy and 70 of whom received EGFR-TKI monotherapy.

EGFR-TKI therapy was selected based on physician choice and consisted of either afatinib dimaleate, gefitinib, or erlotinib hydrochloride at regular doses. Study patients in the combination arm received metformin 500 mg twice daily.

The primary endpoint was PFS (intent-to-treat population). Secondary endpoints included overall survival (OS), objective response rate, and safety.

After analysis, the researchers found that the median PFS was 13.1 months with metformin-EGFR-TKI combination therapy and 9.9 months with EGFR-TKI monotherapy (hazard ratio, 0.60; P = .03).

In addition, the median OS was also significantly prolonged for patients receiving combined treatment (31.7 months vs. 17.5 months; P = .02).

“Multivariable analysis showed that treatment with metformin is independently associated with longer PFS and OS,” the researchers wrote.

With respect to safety, no significant rise in adverse events was observed, and toxicities were comparable across both treatment groups.

The researchers acknowledged that a key limitation of the study was the absence of a double-blinded design. As a result, various biases could have influenced the results.

“The results from this phase 2 study warrant the design of a larger, phase 3, placebo-controlled study to draw more robust conclusions,” they said.

The study was funded by the National Council for Science and Technology in Mexico. The authors reported financial affiliations with AbbVie, AstraZeneca, Boehringer Ingelheim, Lilly, Bristol-Myers Squibb, Merck, Pfizer, Roche, and several others.

SOURCE: Arrieta O et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.2553.

Combination metformin and epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) therapy improved progression-free survival in patients with EGFR-mutated lung adenocarcinoma, according to results from a phase 2 trial.

“This is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS [progression-free survival],” wrote Oscar Arrieta, MD, of the Instituto Nacional de Cancerología, Mexico, and colleagues in JAMA Oncology.

The open-label, randomized study included 139 patients, 69 of whom were randomly assigned to receive metformin plus EGFR-TKI therapy and 70 of whom received EGFR-TKI monotherapy.

EGFR-TKI therapy was selected based on physician choice and consisted of either afatinib dimaleate, gefitinib, or erlotinib hydrochloride at regular doses. Study patients in the combination arm received metformin 500 mg twice daily.

The primary endpoint was PFS (intent-to-treat population). Secondary endpoints included overall survival (OS), objective response rate, and safety.

After analysis, the researchers found that the median PFS was 13.1 months with metformin-EGFR-TKI combination therapy and 9.9 months with EGFR-TKI monotherapy (hazard ratio, 0.60; P = .03).

In addition, the median OS was also significantly prolonged for patients receiving combined treatment (31.7 months vs. 17.5 months; P = .02).

“Multivariable analysis showed that treatment with metformin is independently associated with longer PFS and OS,” the researchers wrote.

With respect to safety, no significant rise in adverse events was observed, and toxicities were comparable across both treatment groups.

The researchers acknowledged that a key limitation of the study was the absence of a double-blinded design. As a result, various biases could have influenced the results.

“The results from this phase 2 study warrant the design of a larger, phase 3, placebo-controlled study to draw more robust conclusions,” they said.

The study was funded by the National Council for Science and Technology in Mexico. The authors reported financial affiliations with AbbVie, AstraZeneca, Boehringer Ingelheim, Lilly, Bristol-Myers Squibb, Merck, Pfizer, Roche, and several others.

SOURCE: Arrieta O et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.2553.

Hospitalized patients with inflammatory bowel diseases (IBD) are most likely to be readmitted for venous thromboembolism (VTE) within 60 days of discharge, according to a new study that analyzed 5 years of U.S. readmissions data.

“Given increased thrombotic risk postdischarge, as well as overall safety of VTE prophylaxis, extending prophylaxis for those at highest risk may have significant benefits,” wrote Adam S. Faye, MD, of Columbia University, and coauthors. The study was published in Clinical Gastroenterology and Hepatology.

To determine which IBD patients would be most in need of postdischarge VTE prophylaxis, as well as when to administer it, the researchers analyzed 2010-2014 data from the Nationwide Readmissions Database (NRD). They found a total of 872,122 index admissions for IBD patients; 4% of those patients had a prior VTE. Of the index admissions, 1,160 led to a VTE readmission within 90 days. Readmitted patients had a relatively equal proportion of ulcerative colitis (n = 522) and Crohn’s disease (n = 638).

More than 90% of VTE readmissions occurred within 60 days of discharge; the risk was highest over the first 10 days and then decreased in each ensuing 10-day period until a slight increase at the 81- to 90-day period. All patients over age 30 had higher rates of readmission than those of patients under age 18, with the highest risk in patients between the ages of 66 and 80 years (risk ratio 4.04; 95% confidence interval, 2.54-6.44, P less than .01). Women were at lower risk (RR 0.82; 95% CI, 0.73-0.92, P less than .01). Higher risks of readmission were also associated with being on Medicare (RR 1.39; 95% CI, 1.23-1.58, P less than .01) compared with being on private insurance and being cared for at a large hospital (RR 1.26; 95% CI, 1.04-1.52, P = .02) compared with a small hospital.

The highest risk of VTE readmission was associated with a prior history of VTE (RR 2.89; 95% CI, 2.40-3.48, P less than .01), having two or more comorbidities (RR 2.57; 95% CI, 2.11-3.12, P less than .01) and having a Clostridioides difficile infection as of index admission (RR 1.90; 95% CI, 1.51-2.38, P less than .01). In addition, increased risk was associated with being discharged to a nursing or care facility (RR 1.85; 95% CI, 1.56-2.20, P less than .01) or home with health services (RR 2.05; 95% CI, 1.78-2.38, P less than .01) compared with a routine discharge.

In their multivariable analysis, similar factors such as a history of VTE (adjusted RR 2.41; 95% CI, 1.99-2.90, P less than .01), two or more comorbidities (aRR 1.78; 95% CI, 1.44-2.20, P less than .01) and C. difficile infection (aRR 1.47; 95% CI, 1.17-1.85, P less than.01) continued to be associated with higher risk of VTE readmission.

SOURCE: Faye AS et al. Clin Gastroenterol Hepatol. 2019 July 20. doi: 10.1016/j.cgh.2019.07.028.

Hospitalized patients with inflammatory bowel diseases (IBD) are most likely to be readmitted for venous thromboembolism (VTE) within 60 days of discharge, according to a new study that analyzed 5 years of U.S. readmissions data.

“Given increased thrombotic risk postdischarge, as well as overall safety of VTE prophylaxis, extending prophylaxis for those at highest risk may have significant benefits,” wrote Adam S. Faye, MD, of Columbia University, and coauthors. The study was published in Clinical Gastroenterology and Hepatology.

To determine which IBD patients would be most in need of postdischarge VTE prophylaxis, as well as when to administer it, the researchers analyzed 2010-2014 data from the Nationwide Readmissions Database (NRD). They found a total of 872,122 index admissions for IBD patients; 4% of those patients had a prior VTE. Of the index admissions, 1,160 led to a VTE readmission within 90 days. Readmitted patients had a relatively equal proportion of ulcerative colitis (n = 522) and Crohn’s disease (n = 638).

More than 90% of VTE readmissions occurred within 60 days of discharge; the risk was highest over the first 10 days and then decreased in each ensuing 10-day period until a slight increase at the 81- to 90-day period. All patients over age 30 had higher rates of readmission than those of patients under age 18, with the highest risk in patients between the ages of 66 and 80 years (risk ratio 4.04; 95% confidence interval, 2.54-6.44, P less than .01). Women were at lower risk (RR 0.82; 95% CI, 0.73-0.92, P less than .01). Higher risks of readmission were also associated with being on Medicare (RR 1.39; 95% CI, 1.23-1.58, P less than .01) compared with being on private insurance and being cared for at a large hospital (RR 1.26; 95% CI, 1.04-1.52, P = .02) compared with a small hospital.

The highest risk of VTE readmission was associated with a prior history of VTE (RR 2.89; 95% CI, 2.40-3.48, P less than .01), having two or more comorbidities (RR 2.57; 95% CI, 2.11-3.12, P less than .01) and having a Clostridioides difficile infection as of index admission (RR 1.90; 95% CI, 1.51-2.38, P less than .01). In addition, increased risk was associated with being discharged to a nursing or care facility (RR 1.85; 95% CI, 1.56-2.20, P less than .01) or home with health services (RR 2.05; 95% CI, 1.78-2.38, P less than .01) compared with a routine discharge.

In their multivariable analysis, similar factors such as a history of VTE (adjusted RR 2.41; 95% CI, 1.99-2.90, P less than .01), two or more comorbidities (aRR 1.78; 95% CI, 1.44-2.20, P less than .01) and C. difficile infection (aRR 1.47; 95% CI, 1.17-1.85, P less than.01) continued to be associated with higher risk of VTE readmission.

SOURCE: Faye AS et al. Clin Gastroenterol Hepatol. 2019 July 20. doi: 10.1016/j.cgh.2019.07.028.

Hospitalized patients with inflammatory bowel diseases (IBD) are most likely to be readmitted for venous thromboembolism (VTE) within 60 days of discharge, according to a new study that analyzed 5 years of U.S. readmissions data.

“Given increased thrombotic risk postdischarge, as well as overall safety of VTE prophylaxis, extending prophylaxis for those at highest risk may have significant benefits,” wrote Adam S. Faye, MD, of Columbia University, and coauthors. The study was published in Clinical Gastroenterology and Hepatology.

To determine which IBD patients would be most in need of postdischarge VTE prophylaxis, as well as when to administer it, the researchers analyzed 2010-2014 data from the Nationwide Readmissions Database (NRD). They found a total of 872,122 index admissions for IBD patients; 4% of those patients had a prior VTE. Of the index admissions, 1,160 led to a VTE readmission within 90 days. Readmitted patients had a relatively equal proportion of ulcerative colitis (n = 522) and Crohn’s disease (n = 638).

More than 90% of VTE readmissions occurred within 60 days of discharge; the risk was highest over the first 10 days and then decreased in each ensuing 10-day period until a slight increase at the 81- to 90-day period. All patients over age 30 had higher rates of readmission than those of patients under age 18, with the highest risk in patients between the ages of 66 and 80 years (risk ratio 4.04; 95% confidence interval, 2.54-6.44, P less than .01). Women were at lower risk (RR 0.82; 95% CI, 0.73-0.92, P less than .01). Higher risks of readmission were also associated with being on Medicare (RR 1.39; 95% CI, 1.23-1.58, P less than .01) compared with being on private insurance and being cared for at a large hospital (RR 1.26; 95% CI, 1.04-1.52, P = .02) compared with a small hospital.

The highest risk of VTE readmission was associated with a prior history of VTE (RR 2.89; 95% CI, 2.40-3.48, P less than .01), having two or more comorbidities (RR 2.57; 95% CI, 2.11-3.12, P less than .01) and having a Clostridioides difficile infection as of index admission (RR 1.90; 95% CI, 1.51-2.38, P less than .01). In addition, increased risk was associated with being discharged to a nursing or care facility (RR 1.85; 95% CI, 1.56-2.20, P less than .01) or home with health services (RR 2.05; 95% CI, 1.78-2.38, P less than .01) compared with a routine discharge.

In their multivariable analysis, similar factors such as a history of VTE (adjusted RR 2.41; 95% CI, 1.99-2.90, P less than .01), two or more comorbidities (aRR 1.78; 95% CI, 1.44-2.20, P less than .01) and C. difficile infection (aRR 1.47; 95% CI, 1.17-1.85, P less than.01) continued to be associated with higher risk of VTE readmission.

SOURCE: Faye AS et al. Clin Gastroenterol Hepatol. 2019 July 20. doi: 10.1016/j.cgh.2019.07.028.

NEW YORK – Inpatient dermatology consults can make all the difference when a serious dermatology complication is suspected, said Lucia Seminario-Vidal, MD, PhD, speaking at a hospital dermatology–focused session of the summer meeting of the American Academy of Dermatology.

Even before histopathologic results are available, dermatologists can help take some of the panic out of the room when Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN) is first on the differential diagnosis for the referring physician, she said. Physical findings, a careful review of systems, and past history – especially the introduction of any new medications – can go a long way toward ruling out SJS/TEN among many patients.

In a recent study coauthored by Dr. Seminario-Vidal, of the University of South Florida, Tampa, 208 inpatients with suspected SJS/TEN, 72% were given another diagnosis after a dermatologist consultation (J Am Acad Dermatol. 2019 Sep;81[3]:749-57). The study’s authors, led by Allison Weinkle, MD, a dermatology resident at the University of South Florida, performed a retrospective chart review of 208 patients suspected of having SJS/TEN and received inpatient dermatology consultations.

One surprising finding from the review is that “known risk factors for SJS/TEN such as drug exposure, malignancy, and HIV/AIDS are not helpful to differentiate it from its mimickers,” Dr. Seminario-Vidal said.

However, close attention to the clinical presentation is helpful in differentiating the mimickers from true SJS/TEN. Fever, painful skin, Nikolsky sign, and mucosal involvement were all more common in patients with SJS/TEN. “This was something that was really helpful to discuss with the primary teams at our institutions,” Dr. Seminario-Vidal said.

The most common mimickers in the cases she and her colleagues reviewed were severe cutaneous adverse drug reactions (SCARs) and erythema multiforme; in general, the mimickers were conditions that have severe mucocutaneous involvement.

Patients with SJS/TEN will have fever and pain, typically, and the primary lesions are atypical targets with a positive Nikolsky sign. Hepatic enzyme elevation is seen in 15% of patients, and lymphopenia may be present. Common drugs provoking SJS/TEN include antibiotics, anticonvulsants, NSAIDs, allopurinol, and – importantly – programmed cell death protein 1 (PD-1) inhibitors. Because PD-1s are being used for an ever-expanding range of oncology indications, the rate of SJS/TEN may be expected to rise, Dr. Seminario-Vidal noted.

Other common mimics can include a florid generalized fixed drug eruption, which can also be painful and have atypical targets and a positive Nikolsky sign. Here, large, dusky patches may be present, with perioral, genital, and hand/foot involvement common, but fever is absent. Lesions are sharply localized, round or oval, and they recur at the same site with reexposure to the provoking agent. “Histopathologic studies are diagnostic in these patients, but many times, if you have a good clinical history, you don’t need histopathology,” Dr. Seminario-Vidal said.

As with SJS/TEN, mucosal involvement can be present with fixed drug eruptions. However, hepatic enzymes and the complete blood count will not show abnormalities related to the fixed drug eruption.

Sulfonamides have been associated with up to 75% of fixed drug eruptions reported in some case series, she said, noting that common over-the-counter medications such as nonprescription analgesics, loratadine, and pseudoephedrine can also provoke fixed drug eruptions.

Bullous conditions that can mimic SJS/TEN include linear Immunoglobulin A bullous dermatosis. “We know that the classic presentation is the beautiful ‘string of pearls’ sign, but most patients won’t have this,” Dr. Seminario-Vidal said. The condition often appears in intertriginous locations, and Koebnerization can be a strong clue to this diagnosis, she added.

This painful condition rarely has an associated fever, and will occasionally involve the mucosa, but it doesn’t cause alterations in laboratory values. About 70% of cases of drug-induced linear IgA bullous dermatosis are caused by vancomycin, a consideration when patients may be on several antibiotics. “When I first started, I used to stop everything,” said Dr. Seminario-Vidal. Now, she first discontinues vancomycin and rechecks the patient the next day. In the absence of progression, vancomycin can be presumed to be the culprit, she said.

In bullous pemphigoid, mucosal involvement has been reported in up to 30% of patients, which can initially confuse the diagnosis. “A clue is the presence of tense bullae that initially are very pruritic, but they can become painful over time,” Dr. Seminario-Vidal said. “With tense bullae, with no specific primary lesion, but the patient is very itchy, think bullous pemphigoid.” Pain is sometimes present, but fever is rare. Eosinophilia occurs about 50% of the time, offering an additional diagnostic clue.

Furosemide is a common culprit in drug-induced bullous pemphigoid, as is its cousin bumetanide. Certain analgesics, amoxicillin, ciprofloxacin, and angiotensin converting enzyme inhibitors have also been implicated, said Dr. Seminario-Vidal, though most cases are not drug induced. “Go over the drug history of the patients. It’s something that I cannot emphasize enough … because if you find the drug that causes this disease, you can avoid lengthy systemic treatment.”

Pemphigus foliaceus has a characteristic crusting scale that forms with the rupture of flaccid bullae. Nikolsky’s sign is positive. Mucosal involvement is rare, but is sometimes seen on the occasions when the condition is drug-induced, and laboratory values are usually normal, she said. “The clues to diagnosis of these patients are involvement in the seborrheic areas, including the face; there’s a lot of crust in pemphigus foliaceus.”

Drug-induced pemphigus foliaceus is associated with drugs that have a thiol group, or with sulfur groups that are converted to thiol (–SH) groups. These include both angiotensin converting enzyme inhibitors and angiotensin receptor blockers, penicillins, cephalosporins, and piroxicam. However, said Dr. Seminario-Vidal, penicillamine alone accounts for 50% of drug-induced pemphigus foliaceus.

Dr. Seminario-Vidal reported financial relationships with Eli Lilly, Soligenix, Helsinn, Eisai, Boehringer Ingelheim, Corrona, Akros, Novartis, AbbVie, BMS, Celgene, Glenmark, and Kyowa Kirin.
 

[email protected]

SOURCE: Seminario-Vidal L. Summer AAD 2019, Session F-025.

NEW YORK – Inpatient dermatology consults can make all the difference when a serious dermatology complication is suspected, said Lucia Seminario-Vidal, MD, PhD, speaking at a hospital dermatology–focused session of the summer meeting of the American Academy of Dermatology.

Even before histopathologic results are available, dermatologists can help take some of the panic out of the room when Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN) is first on the differential diagnosis for the referring physician, she said. Physical findings, a careful review of systems, and past history – especially the introduction of any new medications – can go a long way toward ruling out SJS/TEN among many patients.

In a recent study coauthored by Dr. Seminario-Vidal, of the University of South Florida, Tampa, 208 inpatients with suspected SJS/TEN, 72% were given another diagnosis after a dermatologist consultation (J Am Acad Dermatol. 2019 Sep;81[3]:749-57). The study’s authors, led by Allison Weinkle, MD, a dermatology resident at the University of South Florida, performed a retrospective chart review of 208 patients suspected of having SJS/TEN and received inpatient dermatology consultations.

One surprising finding from the review is that “known risk factors for SJS/TEN such as drug exposure, malignancy, and HIV/AIDS are not helpful to differentiate it from its mimickers,” Dr. Seminario-Vidal said.

However, close attention to the clinical presentation is helpful in differentiating the mimickers from true SJS/TEN. Fever, painful skin, Nikolsky sign, and mucosal involvement were all more common in patients with SJS/TEN. “This was something that was really helpful to discuss with the primary teams at our institutions,” Dr. Seminario-Vidal said.

The most common mimickers in the cases she and her colleagues reviewed were severe cutaneous adverse drug reactions (SCARs) and erythema multiforme; in general, the mimickers were conditions that have severe mucocutaneous involvement.

Patients with SJS/TEN will have fever and pain, typically, and the primary lesions are atypical targets with a positive Nikolsky sign. Hepatic enzyme elevation is seen in 15% of patients, and lymphopenia may be present. Common drugs provoking SJS/TEN include antibiotics, anticonvulsants, NSAIDs, allopurinol, and – importantly – programmed cell death protein 1 (PD-1) inhibitors. Because PD-1s are being used for an ever-expanding range of oncology indications, the rate of SJS/TEN may be expected to rise, Dr. Seminario-Vidal noted.

Other common mimics can include a florid generalized fixed drug eruption, which can also be painful and have atypical targets and a positive Nikolsky sign. Here, large, dusky patches may be present, with perioral, genital, and hand/foot involvement common, but fever is absent. Lesions are sharply localized, round or oval, and they recur at the same site with reexposure to the provoking agent. “Histopathologic studies are diagnostic in these patients, but many times, if you have a good clinical history, you don’t need histopathology,” Dr. Seminario-Vidal said.

As with SJS/TEN, mucosal involvement can be present with fixed drug eruptions. However, hepatic enzymes and the complete blood count will not show abnormalities related to the fixed drug eruption.

Sulfonamides have been associated with up to 75% of fixed drug eruptions reported in some case series, she said, noting that common over-the-counter medications such as nonprescription analgesics, loratadine, and pseudoephedrine can also provoke fixed drug eruptions.

Bullous conditions that can mimic SJS/TEN include linear Immunoglobulin A bullous dermatosis. “We know that the classic presentation is the beautiful ‘string of pearls’ sign, but most patients won’t have this,” Dr. Seminario-Vidal said. The condition often appears in intertriginous locations, and Koebnerization can be a strong clue to this diagnosis, she added.

This painful condition rarely has an associated fever, and will occasionally involve the mucosa, but it doesn’t cause alterations in laboratory values. About 70% of cases of drug-induced linear IgA bullous dermatosis are caused by vancomycin, a consideration when patients may be on several antibiotics. “When I first started, I used to stop everything,” said Dr. Seminario-Vidal. Now, she first discontinues vancomycin and rechecks the patient the next day. In the absence of progression, vancomycin can be presumed to be the culprit, she said.

In bullous pemphigoid, mucosal involvement has been reported in up to 30% of patients, which can initially confuse the diagnosis. “A clue is the presence of tense bullae that initially are very pruritic, but they can become painful over time,” Dr. Seminario-Vidal said. “With tense bullae, with no specific primary lesion, but the patient is very itchy, think bullous pemphigoid.” Pain is sometimes present, but fever is rare. Eosinophilia occurs about 50% of the time, offering an additional diagnostic clue.

Furosemide is a common culprit in drug-induced bullous pemphigoid, as is its cousin bumetanide. Certain analgesics, amoxicillin, ciprofloxacin, and angiotensin converting enzyme inhibitors have also been implicated, said Dr. Seminario-Vidal, though most cases are not drug induced. “Go over the drug history of the patients. It’s something that I cannot emphasize enough … because if you find the drug that causes this disease, you can avoid lengthy systemic treatment.”

Pemphigus foliaceus has a characteristic crusting scale that forms with the rupture of flaccid bullae. Nikolsky’s sign is positive. Mucosal involvement is rare, but is sometimes seen on the occasions when the condition is drug-induced, and laboratory values are usually normal, she said. “The clues to diagnosis of these patients are involvement in the seborrheic areas, including the face; there’s a lot of crust in pemphigus foliaceus.”

Drug-induced pemphigus foliaceus is associated with drugs that have a thiol group, or with sulfur groups that are converted to thiol (–SH) groups. These include both angiotensin converting enzyme inhibitors and angiotensin receptor blockers, penicillins, cephalosporins, and piroxicam. However, said Dr. Seminario-Vidal, penicillamine alone accounts for 50% of drug-induced pemphigus foliaceus.

Dr. Seminario-Vidal reported financial relationships with Eli Lilly, Soligenix, Helsinn, Eisai, Boehringer Ingelheim, Corrona, Akros, Novartis, AbbVie, BMS, Celgene, Glenmark, and Kyowa Kirin.
 

[email protected]

SOURCE: Seminario-Vidal L. Summer AAD 2019, Session F-025.

NEW YORK – Inpatient dermatology consults can make all the difference when a serious dermatology complication is suspected, said Lucia Seminario-Vidal, MD, PhD, speaking at a hospital dermatology–focused session of the summer meeting of the American Academy of Dermatology.

Even before histopathologic results are available, dermatologists can help take some of the panic out of the room when Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN) is first on the differential diagnosis for the referring physician, she said. Physical findings, a careful review of systems, and past history – especially the introduction of any new medications – can go a long way toward ruling out SJS/TEN among many patients.

In a recent study coauthored by Dr. Seminario-Vidal, of the University of South Florida, Tampa, 208 inpatients with suspected SJS/TEN, 72% were given another diagnosis after a dermatologist consultation (J Am Acad Dermatol. 2019 Sep;81[3]:749-57). The study’s authors, led by Allison Weinkle, MD, a dermatology resident at the University of South Florida, performed a retrospective chart review of 208 patients suspected of having SJS/TEN and received inpatient dermatology consultations.

One surprising finding from the review is that “known risk factors for SJS/TEN such as drug exposure, malignancy, and HIV/AIDS are not helpful to differentiate it from its mimickers,” Dr. Seminario-Vidal said.

However, close attention to the clinical presentation is helpful in differentiating the mimickers from true SJS/TEN. Fever, painful skin, Nikolsky sign, and mucosal involvement were all more common in patients with SJS/TEN. “This was something that was really helpful to discuss with the primary teams at our institutions,” Dr. Seminario-Vidal said.

The most common mimickers in the cases she and her colleagues reviewed were severe cutaneous adverse drug reactions (SCARs) and erythema multiforme; in general, the mimickers were conditions that have severe mucocutaneous involvement.

Patients with SJS/TEN will have fever and pain, typically, and the primary lesions are atypical targets with a positive Nikolsky sign. Hepatic enzyme elevation is seen in 15% of patients, and lymphopenia may be present. Common drugs provoking SJS/TEN include antibiotics, anticonvulsants, NSAIDs, allopurinol, and – importantly – programmed cell death protein 1 (PD-1) inhibitors. Because PD-1s are being used for an ever-expanding range of oncology indications, the rate of SJS/TEN may be expected to rise, Dr. Seminario-Vidal noted.

Other common mimics can include a florid generalized fixed drug eruption, which can also be painful and have atypical targets and a positive Nikolsky sign. Here, large, dusky patches may be present, with perioral, genital, and hand/foot involvement common, but fever is absent. Lesions are sharply localized, round or oval, and they recur at the same site with reexposure to the provoking agent. “Histopathologic studies are diagnostic in these patients, but many times, if you have a good clinical history, you don’t need histopathology,” Dr. Seminario-Vidal said.

As with SJS/TEN, mucosal involvement can be present with fixed drug eruptions. However, hepatic enzymes and the complete blood count will not show abnormalities related to the fixed drug eruption.

Sulfonamides have been associated with up to 75% of fixed drug eruptions reported in some case series, she said, noting that common over-the-counter medications such as nonprescription analgesics, loratadine, and pseudoephedrine can also provoke fixed drug eruptions.

Bullous conditions that can mimic SJS/TEN include linear Immunoglobulin A bullous dermatosis. “We know that the classic presentation is the beautiful ‘string of pearls’ sign, but most patients won’t have this,” Dr. Seminario-Vidal said. The condition often appears in intertriginous locations, and Koebnerization can be a strong clue to this diagnosis, she added.

This painful condition rarely has an associated fever, and will occasionally involve the mucosa, but it doesn’t cause alterations in laboratory values. About 70% of cases of drug-induced linear IgA bullous dermatosis are caused by vancomycin, a consideration when patients may be on several antibiotics. “When I first started, I used to stop everything,” said Dr. Seminario-Vidal. Now, she first discontinues vancomycin and rechecks the patient the next day. In the absence of progression, vancomycin can be presumed to be the culprit, she said.

In bullous pemphigoid, mucosal involvement has been reported in up to 30% of patients, which can initially confuse the diagnosis. “A clue is the presence of tense bullae that initially are very pruritic, but they can become painful over time,” Dr. Seminario-Vidal said. “With tense bullae, with no specific primary lesion, but the patient is very itchy, think bullous pemphigoid.” Pain is sometimes present, but fever is rare. Eosinophilia occurs about 50% of the time, offering an additional diagnostic clue.

Furosemide is a common culprit in drug-induced bullous pemphigoid, as is its cousin bumetanide. Certain analgesics, amoxicillin, ciprofloxacin, and angiotensin converting enzyme inhibitors have also been implicated, said Dr. Seminario-Vidal, though most cases are not drug induced. “Go over the drug history of the patients. It’s something that I cannot emphasize enough … because if you find the drug that causes this disease, you can avoid lengthy systemic treatment.”

Pemphigus foliaceus has a characteristic crusting scale that forms with the rupture of flaccid bullae. Nikolsky’s sign is positive. Mucosal involvement is rare, but is sometimes seen on the occasions when the condition is drug-induced, and laboratory values are usually normal, she said. “The clues to diagnosis of these patients are involvement in the seborrheic areas, including the face; there’s a lot of crust in pemphigus foliaceus.”

Drug-induced pemphigus foliaceus is associated with drugs that have a thiol group, or with sulfur groups that are converted to thiol (–SH) groups. These include both angiotensin converting enzyme inhibitors and angiotensin receptor blockers, penicillins, cephalosporins, and piroxicam. However, said Dr. Seminario-Vidal, penicillamine alone accounts for 50% of drug-induced pemphigus foliaceus.

Dr. Seminario-Vidal reported financial relationships with Eli Lilly, Soligenix, Helsinn, Eisai, Boehringer Ingelheim, Corrona, Akros, Novartis, AbbVie, BMS, Celgene, Glenmark, and Kyowa Kirin.
 

[email protected]

SOURCE: Seminario-Vidal L. Summer AAD 2019, Session F-025.

For patients with acute myeloid leukemia (AML) in need of allogeneic hematopoietic cell transplantation (alloHCT), reduced-intensity/nonmyeloablative conditioning (RIC/NMA) offers a lower risk of infection than myeloablative conditioning (MAC), based on a retrospective study involving more than 1,700 patients.

OlegMalyshev/Getty Images

Within 100 days of treatment, patients who underwent MAC were significantly more likely to develop a bacterial infection, and develop it at an earlier date, than patients who had undergone RIC/NMA, reported lead author Celalettin Ustun, MD, of Rush University in Chicago, and colleagues.

“The incidence of infections, a common and often severe complication of alloHCT, is expected to be lower after RIC/NMA compared with MAC and thus contribute to the decreased [nonrelapse mortality],” the investigators wrote in Blood Advances, noting that this hypothesis has previously lacked supporting data, prompting the present study.

The retrospective analysis involved 1,755 patients with AML who were in first complete remission. Data were drawn from the Center for International Blood and Marrow Transplant Research (CIBMTR). The primary end point was incidence of infection within 100 days after T-cell replete alloHCT in patients receiving MAC (n = 978) versus those who underwent RIC/NMA (n = 777). Secondary end points included comparisons of infection types and infection density.

Patients who received RIC/NMA were generally older and more likely to have myelodysplastic syndrome than patients in the MAC group; the groups were otherwise similar, based on comorbidities, cytogenetic risks, and Karnofsky performance scores.

The proportion of patients who developed at least one infection was comparable between groups: 61% of MAC patients versus 58% of RIC/NMA patients (P = .21), but further analysis showed that MAC was in fact associated with some relatively increased risks. For instance, patients in the MAC group tended to develop infections sooner than patients treated with RIC/NMA (21 vs. 15 days), and more patients treated with MAC had at least one bacterial infection by day 100 (46% vs. 37%).

Although the proportion of patients developing at least one viral infection was slightly lower in the MAC group than the RIC/NMA group (34% vs. 39%), overall infection density was higher, which takes into account multiple infections.

The increased bacterial infections after MAC were caused by gram-positive bacteria, while the increased viral infections with RIC/NMA were caused by cytomegalovirus, the investigators reported.

“RIC/NMA alloHCT is associated with a decreased risk of any infection and particularly early bacterial infections,” the investigators wrote. “The risk of viral and fungal infections per days at risk is similar.”

The Center for International Blood and Marrow Transplant Research is supported by grants from the U.S. government and several pharmaceutical companies. The investigators reported having no conflicts of interest.

SOURCE: Ustun C et al. Blood Adv. 2019 Sep 10;3(17):2525-36.

For patients with acute myeloid leukemia (AML) in need of allogeneic hematopoietic cell transplantation (alloHCT), reduced-intensity/nonmyeloablative conditioning (RIC/NMA) offers a lower risk of infection than myeloablative conditioning (MAC), based on a retrospective study involving more than 1,700 patients.

OlegMalyshev/Getty Images

Within 100 days of treatment, patients who underwent MAC were significantly more likely to develop a bacterial infection, and develop it at an earlier date, than patients who had undergone RIC/NMA, reported lead author Celalettin Ustun, MD, of Rush University in Chicago, and colleagues.

“The incidence of infections, a common and often severe complication of alloHCT, is expected to be lower after RIC/NMA compared with MAC and thus contribute to the decreased [nonrelapse mortality],” the investigators wrote in Blood Advances, noting that this hypothesis has previously lacked supporting data, prompting the present study.

The retrospective analysis involved 1,755 patients with AML who were in first complete remission. Data were drawn from the Center for International Blood and Marrow Transplant Research (CIBMTR). The primary end point was incidence of infection within 100 days after T-cell replete alloHCT in patients receiving MAC (n = 978) versus those who underwent RIC/NMA (n = 777). Secondary end points included comparisons of infection types and infection density.

Patients who received RIC/NMA were generally older and more likely to have myelodysplastic syndrome than patients in the MAC group; the groups were otherwise similar, based on comorbidities, cytogenetic risks, and Karnofsky performance scores.

The proportion of patients who developed at least one infection was comparable between groups: 61% of MAC patients versus 58% of RIC/NMA patients (P = .21), but further analysis showed that MAC was in fact associated with some relatively increased risks. For instance, patients in the MAC group tended to develop infections sooner than patients treated with RIC/NMA (21 vs. 15 days), and more patients treated with MAC had at least one bacterial infection by day 100 (46% vs. 37%).

Although the proportion of patients developing at least one viral infection was slightly lower in the MAC group than the RIC/NMA group (34% vs. 39%), overall infection density was higher, which takes into account multiple infections.

The increased bacterial infections after MAC were caused by gram-positive bacteria, while the increased viral infections with RIC/NMA were caused by cytomegalovirus, the investigators reported.

“RIC/NMA alloHCT is associated with a decreased risk of any infection and particularly early bacterial infections,” the investigators wrote. “The risk of viral and fungal infections per days at risk is similar.”

The Center for International Blood and Marrow Transplant Research is supported by grants from the U.S. government and several pharmaceutical companies. The investigators reported having no conflicts of interest.

SOURCE: Ustun C et al. Blood Adv. 2019 Sep 10;3(17):2525-36.

For patients with acute myeloid leukemia (AML) in need of allogeneic hematopoietic cell transplantation (alloHCT), reduced-intensity/nonmyeloablative conditioning (RIC/NMA) offers a lower risk of infection than myeloablative conditioning (MAC), based on a retrospective study involving more than 1,700 patients.

OlegMalyshev/Getty Images

Within 100 days of treatment, patients who underwent MAC were significantly more likely to develop a bacterial infection, and develop it at an earlier date, than patients who had undergone RIC/NMA, reported lead author Celalettin Ustun, MD, of Rush University in Chicago, and colleagues.

“The incidence of infections, a common and often severe complication of alloHCT, is expected to be lower after RIC/NMA compared with MAC and thus contribute to the decreased [nonrelapse mortality],” the investigators wrote in Blood Advances, noting that this hypothesis has previously lacked supporting data, prompting the present study.

The retrospective analysis involved 1,755 patients with AML who were in first complete remission. Data were drawn from the Center for International Blood and Marrow Transplant Research (CIBMTR). The primary end point was incidence of infection within 100 days after T-cell replete alloHCT in patients receiving MAC (n = 978) versus those who underwent RIC/NMA (n = 777). Secondary end points included comparisons of infection types and infection density.

Patients who received RIC/NMA were generally older and more likely to have myelodysplastic syndrome than patients in the MAC group; the groups were otherwise similar, based on comorbidities, cytogenetic risks, and Karnofsky performance scores.

The proportion of patients who developed at least one infection was comparable between groups: 61% of MAC patients versus 58% of RIC/NMA patients (P = .21), but further analysis showed that MAC was in fact associated with some relatively increased risks. For instance, patients in the MAC group tended to develop infections sooner than patients treated with RIC/NMA (21 vs. 15 days), and more patients treated with MAC had at least one bacterial infection by day 100 (46% vs. 37%).

Although the proportion of patients developing at least one viral infection was slightly lower in the MAC group than the RIC/NMA group (34% vs. 39%), overall infection density was higher, which takes into account multiple infections.

The increased bacterial infections after MAC were caused by gram-positive bacteria, while the increased viral infections with RIC/NMA were caused by cytomegalovirus, the investigators reported.

“RIC/NMA alloHCT is associated with a decreased risk of any infection and particularly early bacterial infections,” the investigators wrote. “The risk of viral and fungal infections per days at risk is similar.”

The Center for International Blood and Marrow Transplant Research is supported by grants from the U.S. government and several pharmaceutical companies. The investigators reported having no conflicts of interest.

SOURCE: Ustun C et al. Blood Adv. 2019 Sep 10;3(17):2525-36.

COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.

Bruce Jancin/MDedge News

Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.

SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.

For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).

His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).

At a symposium on repurposing statins as antidepressants held at ECNP 2019, Dr. Otte was joined by other researchers who have made key contributions in this area. All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.

Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.

Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).

Bruce Jancin/MDedge News

He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.

The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.

Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).

Bruce Jancin/MDedge News

Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).

Bruce Jancin/MDedge News

“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.

All speakers reported having no financial conflicts of interest.

[email protected]

COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.

Bruce Jancin/MDedge News

Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.

SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.

For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).

His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).

At a symposium on repurposing statins as antidepressants held at ECNP 2019, Dr. Otte was joined by other researchers who have made key contributions in this area. All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.

Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.

Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).

Bruce Jancin/MDedge News

He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.

The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.

Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).

Bruce Jancin/MDedge News

Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).

Bruce Jancin/MDedge News

“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.

All speakers reported having no financial conflicts of interest.

[email protected]

COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.

Bruce Jancin/MDedge News

Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.

SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.

For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).

His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).

At a symposium on repurposing statins as antidepressants held at ECNP 2019, Dr. Otte was joined by other researchers who have made key contributions in this area. All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.

Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.

Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).

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He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.

The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.

Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).

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Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).

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“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.

All speakers reported having no financial conflicts of interest.

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Background: Acute hospitalization has been associated with functional and cognitive decline, particularly in elderly adults. This decline is associated with increased morbidity and mortality.

Patients who received the exercise intervention had significantly higher scores on functional and cognitive assessments at discharge, compared with patients who received standard hospital care alone. Specifically, the study demonstrated a mean increase of 2.2 points (95% CI, 1.7-2.6 points) on the Short Physical Performance Battery, 6.9 points (95% CI, 4.4-9.5 points) on the Barthel Index, and 1.8 points (95% CI, 1.3-2.3 points) on a cognitive assessment, compared with those who received standard hospital care.

Bottom line: An individualized, multicomponent exercise intervention can help reverse functional and cognitive decline associated with acute hospitalization in elderly patients.

Citation: Martinez-Velilla N et al. Effect of exercise intervention on functional decline in very elderly adults during acute hospitalization. JAMA Intern Med. 2019;179(1):28-36.

Dr. Chace is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: Acute hospitalization has been associated with functional and cognitive decline, particularly in elderly adults. This decline is associated with increased morbidity and mortality.

Patients who received the exercise intervention had significantly higher scores on functional and cognitive assessments at discharge, compared with patients who received standard hospital care alone. Specifically, the study demonstrated a mean increase of 2.2 points (95% CI, 1.7-2.6 points) on the Short Physical Performance Battery, 6.9 points (95% CI, 4.4-9.5 points) on the Barthel Index, and 1.8 points (95% CI, 1.3-2.3 points) on a cognitive assessment, compared with those who received standard hospital care.

Bottom line: An individualized, multicomponent exercise intervention can help reverse functional and cognitive decline associated with acute hospitalization in elderly patients.

Citation: Martinez-Velilla N et al. Effect of exercise intervention on functional decline in very elderly adults during acute hospitalization. JAMA Intern Med. 2019;179(1):28-36.

Dr. Chace is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: Acute hospitalization has been associated with functional and cognitive decline, particularly in elderly adults. This decline is associated with increased morbidity and mortality.

Patients who received the exercise intervention had significantly higher scores on functional and cognitive assessments at discharge, compared with patients who received standard hospital care alone. Specifically, the study demonstrated a mean increase of 2.2 points (95% CI, 1.7-2.6 points) on the Short Physical Performance Battery, 6.9 points (95% CI, 4.4-9.5 points) on the Barthel Index, and 1.8 points (95% CI, 1.3-2.3 points) on a cognitive assessment, compared with those who received standard hospital care.

Bottom line: An individualized, multicomponent exercise intervention can help reverse functional and cognitive decline associated with acute hospitalization in elderly patients.

Citation: Martinez-Velilla N et al. Effect of exercise intervention on functional decline in very elderly adults during acute hospitalization. JAMA Intern Med. 2019;179(1):28-36.

Dr. Chace is an associate physician in the division of hospital medicine at the University of California, San Diego.