Key clinical point: Metabolic syndrome (MetS) is associated with an increased risk for low bone mineral density (BMD) in women examined by dual-energy X-ray absorptiometry (DXA) for suspected osteoporosis.

Major finding: MetS was associated with an increased risk for low BMD (odds ratio [OR], 1.19; P = .001). Among MetS components, hypertension significantly correlated with an increased risk for low BMD (OR, 1.23; P = .002), whereas high fasting glucose level/diabetes correlated with a reduced occurrence of low BMD (OR, 0.84; P = .003).

Study details: The data come from a cross-sectional study of 13,182 free-living Caucasian women in Italy (mean age, 62.8 years) who underwent diagnostic assessment of BMD by DXA and of all MetS constitutive elements.

Disclosures: This study received no external funding. The authors declared no conflicts of interest.

Citation: Rendina D et al. J Endocrinol Invest. 2020 Sep 22. doi: 10.1007/s40618-020-01428-w.

Key clinical point: Metabolic syndrome (MetS) is associated with an increased risk for low bone mineral density (BMD) in women examined by dual-energy X-ray absorptiometry (DXA) for suspected osteoporosis.

Major finding: MetS was associated with an increased risk for low BMD (odds ratio [OR], 1.19; P = .001). Among MetS components, hypertension significantly correlated with an increased risk for low BMD (OR, 1.23; P = .002), whereas high fasting glucose level/diabetes correlated with a reduced occurrence of low BMD (OR, 0.84; P = .003).

Study details: The data come from a cross-sectional study of 13,182 free-living Caucasian women in Italy (mean age, 62.8 years) who underwent diagnostic assessment of BMD by DXA and of all MetS constitutive elements.

Disclosures: This study received no external funding. The authors declared no conflicts of interest.

Citation: Rendina D et al. J Endocrinol Invest. 2020 Sep 22. doi: 10.1007/s40618-020-01428-w.

Key clinical point: Metabolic syndrome (MetS) is associated with an increased risk for low bone mineral density (BMD) in women examined by dual-energy X-ray absorptiometry (DXA) for suspected osteoporosis.

Major finding: MetS was associated with an increased risk for low BMD (odds ratio [OR], 1.19; P = .001). Among MetS components, hypertension significantly correlated with an increased risk for low BMD (OR, 1.23; P = .002), whereas high fasting glucose level/diabetes correlated with a reduced occurrence of low BMD (OR, 0.84; P = .003).

Study details: The data come from a cross-sectional study of 13,182 free-living Caucasian women in Italy (mean age, 62.8 years) who underwent diagnostic assessment of BMD by DXA and of all MetS constitutive elements.

Disclosures: This study received no external funding. The authors declared no conflicts of interest.

Citation: Rendina D et al. J Endocrinol Invest. 2020 Sep 22. doi: 10.1007/s40618-020-01428-w.

Key clinical point: Higher serum vitamin K1 (phylloquinone) concentration is associated with a reduced risk for fracture in women with postmenopausal osteoporosis (PMO).

Major finding: Serum vitamin K1 was significantly lower in women with prevalent fractures vs. those without (0.53 μg/L vs. 0.65 μg/L; P = .04). Vitamin K1 inversely correlated with fracture risk (adjusted odds ratio per μg/L increase in serum vitamin K1, 0.550; P = .042). Hip geometry and mechanical strength parameters including cross-sectional area, cross-sectional moment of inertia, and section modulus ‘Z’ at the narrow neck of femur were positively associated with vitamin K1.

Study details: The data come from a cross-sectional study of 374 women with PMO (mean age, 68.7 years).

Disclosures: The study was funded, in part, by the Royal Osteoporosis Society, U.K. The authors declared no conflicts of interest.

Citation: Moore AE et al. Bone. 2020 Sep 10. doi: 10.1016/j.bone.2020.115630.

Key clinical point: Higher serum vitamin K1 (phylloquinone) concentration is associated with a reduced risk for fracture in women with postmenopausal osteoporosis (PMO).

Major finding: Serum vitamin K1 was significantly lower in women with prevalent fractures vs. those without (0.53 μg/L vs. 0.65 μg/L; P = .04). Vitamin K1 inversely correlated with fracture risk (adjusted odds ratio per μg/L increase in serum vitamin K1, 0.550; P = .042). Hip geometry and mechanical strength parameters including cross-sectional area, cross-sectional moment of inertia, and section modulus ‘Z’ at the narrow neck of femur were positively associated with vitamin K1.

Study details: The data come from a cross-sectional study of 374 women with PMO (mean age, 68.7 years).

Disclosures: The study was funded, in part, by the Royal Osteoporosis Society, U.K. The authors declared no conflicts of interest.

Citation: Moore AE et al. Bone. 2020 Sep 10. doi: 10.1016/j.bone.2020.115630.

Key clinical point: Higher serum vitamin K1 (phylloquinone) concentration is associated with a reduced risk for fracture in women with postmenopausal osteoporosis (PMO).

Major finding: Serum vitamin K1 was significantly lower in women with prevalent fractures vs. those without (0.53 μg/L vs. 0.65 μg/L; P = .04). Vitamin K1 inversely correlated with fracture risk (adjusted odds ratio per μg/L increase in serum vitamin K1, 0.550; P = .042). Hip geometry and mechanical strength parameters including cross-sectional area, cross-sectional moment of inertia, and section modulus ‘Z’ at the narrow neck of femur were positively associated with vitamin K1.

Study details: The data come from a cross-sectional study of 374 women with PMO (mean age, 68.7 years).

Disclosures: The study was funded, in part, by the Royal Osteoporosis Society, U.K. The authors declared no conflicts of interest.

Citation: Moore AE et al. Bone. 2020 Sep 10. doi: 10.1016/j.bone.2020.115630.

Key clinical point: Patients with osteoporosis with age-related macular degeneration (AMD) are at a significantly higher risk of developing spine and hip fractures.

Major finding: The AMD vs. non-AMD group had a significantly higher risk for spine and hip fractures (hazard ratio [HR], 1.09; P less than .001 and HR, 1.18; P = .001; respectively). The risk for mortality was significantly higher in patients with osteoporosis with older age, male sex, and all types of comorbidities (P less than .05), except for hyperthyroidism (P = .200).

Study details: This Taiwanese nationwide study included 1,206,247 patients with osteoporosis using insurance claims data. After propensity score matching, 13,548 and 54,336 patients were analyzed in the AMD and non-AMD groups, respectively.

Disclosures: The study was supported by Chang Gung Medical Research Foundation. The authors declared no conflicts of interest.

Citation: Sun CC et al. BMJ Open. 2020 Sep 17. doi: 10.1136/bmjopen-2020-037028.

Key clinical point: Patients with osteoporosis with age-related macular degeneration (AMD) are at a significantly higher risk of developing spine and hip fractures.

Major finding: The AMD vs. non-AMD group had a significantly higher risk for spine and hip fractures (hazard ratio [HR], 1.09; P less than .001 and HR, 1.18; P = .001; respectively). The risk for mortality was significantly higher in patients with osteoporosis with older age, male sex, and all types of comorbidities (P less than .05), except for hyperthyroidism (P = .200).

Study details: This Taiwanese nationwide study included 1,206,247 patients with osteoporosis using insurance claims data. After propensity score matching, 13,548 and 54,336 patients were analyzed in the AMD and non-AMD groups, respectively.

Disclosures: The study was supported by Chang Gung Medical Research Foundation. The authors declared no conflicts of interest.

Citation: Sun CC et al. BMJ Open. 2020 Sep 17. doi: 10.1136/bmjopen-2020-037028.

Key clinical point: Patients with osteoporosis with age-related macular degeneration (AMD) are at a significantly higher risk of developing spine and hip fractures.

Major finding: The AMD vs. non-AMD group had a significantly higher risk for spine and hip fractures (hazard ratio [HR], 1.09; P less than .001 and HR, 1.18; P = .001; respectively). The risk for mortality was significantly higher in patients with osteoporosis with older age, male sex, and all types of comorbidities (P less than .05), except for hyperthyroidism (P = .200).

Study details: This Taiwanese nationwide study included 1,206,247 patients with osteoporosis using insurance claims data. After propensity score matching, 13,548 and 54,336 patients were analyzed in the AMD and non-AMD groups, respectively.

Disclosures: The study was supported by Chang Gung Medical Research Foundation. The authors declared no conflicts of interest.

Citation: Sun CC et al. BMJ Open. 2020 Sep 17. doi: 10.1136/bmjopen-2020-037028.

Routinely collected clinical data help identify men with high-risk prostate cancer most likely to benefit from a gallium-68 prostate-specific membrane antigen (PSMA) PET/CT scan, according to a study reported at the American Society for Radiation Oncology Annual Meeting 2020.

Courtesy of University of California Los Angeles

“PSMA PET/CT is a novel molecular and functional imaging modality specific for prostate cancer cells that has good sensitivity and outstanding specificity in detecting metastasis,” noted study investigator T. Martin Ma, MD, PhD, of the University of California, Los Angeles.

The proPSMA trial, published in The Lancet earlier this year, found PSMA PET/CT to be superior to conventional imaging for primary staging of high-risk prostate cancer.

“These findings carry significant clinical implications and can affect treatment decision-making,” Dr. Ma noted.

With the current study, Dr. Ma and colleagues set out to assess the impact of PSMA PET/CT in nodal and metastatic upstaging in patients with high-risk prostate cancer and explore predictors of upstaging.

The researchers conducted a post hoc analysis of a single-center, prospective study of 262 patients with high-risk prostate cancer (cN1 or cN0 on conventional imaging) undergoing primary staging. Patients who had received 3 or more months of androgen deprivation therapy before their scan were excluded.
 

Study results

PSMA PET/CT led to nodal upstaging – from N0 to N1 – in 19.7% of patients and metastasis upstaging – from M0 to M1a, b, or c – in 9.4%.

“It is worth pointing out that the percentage of upstaging at the PSMA scan in our study is very similar to that in the proPSMA study,” Dr. Ma noted, with that trial finding nodal upstaging in 18% of patients and metastasis upstaging in 8%.

In multivariate analysis, independent predictors of nodal upstaging with PSMA PET/CT were higher percentage of positive cores at biopsy (odds ratio per decile, 1.21; P = .001) and higher Gleason grade (OR, 1.61; P = .025).

Similarly, independent predictors of metastasis upstaging were higher percentage of positive cores at biopsy (OR per decile, 1.19; P = .013) and higher Gleason grade (OR, 2.13; P = .024).

Other factors – clinical T stage and N stage, initial prostate-specific antigen level, and presence of two or more high-risk features – did not independently predict these outcomes.

When various combinations were assessed, the incidence of nodal upstaging was highest for patients who had a Gleason grade of 4 or 5 plus at least 50% positive cores (27.5% vs. 13.1% among all others). Similarly, incidence of metastasis upstaging was highest for those who had a Gleason grade of 5 plus at least 50% positive cores (20.6% vs. 5.9% among all others).

“Patients with percent-positive cores of 50% or more and Gleason grade group 4 or 5 will benefit the most from a PSMA PET/CT scan,” Dr. Ma concluded. “Future studies should validate the importance of these factors and identify whether changing treatment leads to improved outcomes.”

“The beauty of percent-positive cores is that it is an objective and routinely available piece of clinical information from systematic biopsy,” he added. “It may aid in the selection of patients in resource-limited settings and consideration of treatment intensification. We may also consider incorporation of percent positive cores into clinical risk stratification schemes for clinical use.”
 

A game changer

“PSMA PET has been a real game changer in high-risk prostate cancer and has implications in the various stages of prostate cancer management from diagnosis and staging to theranostics,” said Renu Eapen, MBBS, of Peter MacCallum Cancer Centre in Melbourne, who was not involved in this study.

“PSMA PET/CT has challenged conventional imaging in staging before curative intent surgery or radiotherapy,” Dr. Eapen added.

Accuracy of PSMA PET/CT was 27% higher than that of conventional imaging in the proPSMA trial, she noted in an interview. This superior accuracy can ultimately have management impact, while the imaging has additional benefits of lower radiation dose and reproducibility with high reporter agreement, potentially making it a “one-stop-shop” scan.

“This prospective study by Ma et al. is a great adjunct to the proPSMA results, with the aims of further stratifying patients who are likely to be upstaged on PSMA PET/CT,” Dr. Eapen said. “As the availability of PSMA PET/CT increases and more centers adopt this technology, we need studies like these to risk-stratify patients and select those who would benefit.”

The study did not receive any specific funding. Dr. Ma and Dr. Eapen disclosed no conflicts of interest.

SOURCE: Ma TM et al. ASTRO 2020, Abstract 58.

Routinely collected clinical data help identify men with high-risk prostate cancer most likely to benefit from a gallium-68 prostate-specific membrane antigen (PSMA) PET/CT scan, according to a study reported at the American Society for Radiation Oncology Annual Meeting 2020.

Courtesy of University of California Los Angeles

“PSMA PET/CT is a novel molecular and functional imaging modality specific for prostate cancer cells that has good sensitivity and outstanding specificity in detecting metastasis,” noted study investigator T. Martin Ma, MD, PhD, of the University of California, Los Angeles.

The proPSMA trial, published in The Lancet earlier this year, found PSMA PET/CT to be superior to conventional imaging for primary staging of high-risk prostate cancer.

“These findings carry significant clinical implications and can affect treatment decision-making,” Dr. Ma noted.

With the current study, Dr. Ma and colleagues set out to assess the impact of PSMA PET/CT in nodal and metastatic upstaging in patients with high-risk prostate cancer and explore predictors of upstaging.

The researchers conducted a post hoc analysis of a single-center, prospective study of 262 patients with high-risk prostate cancer (cN1 or cN0 on conventional imaging) undergoing primary staging. Patients who had received 3 or more months of androgen deprivation therapy before their scan were excluded.
 

Study results

PSMA PET/CT led to nodal upstaging – from N0 to N1 – in 19.7% of patients and metastasis upstaging – from M0 to M1a, b, or c – in 9.4%.

“It is worth pointing out that the percentage of upstaging at the PSMA scan in our study is very similar to that in the proPSMA study,” Dr. Ma noted, with that trial finding nodal upstaging in 18% of patients and metastasis upstaging in 8%.

In multivariate analysis, independent predictors of nodal upstaging with PSMA PET/CT were higher percentage of positive cores at biopsy (odds ratio per decile, 1.21; P = .001) and higher Gleason grade (OR, 1.61; P = .025).

Similarly, independent predictors of metastasis upstaging were higher percentage of positive cores at biopsy (OR per decile, 1.19; P = .013) and higher Gleason grade (OR, 2.13; P = .024).

Other factors – clinical T stage and N stage, initial prostate-specific antigen level, and presence of two or more high-risk features – did not independently predict these outcomes.

When various combinations were assessed, the incidence of nodal upstaging was highest for patients who had a Gleason grade of 4 or 5 plus at least 50% positive cores (27.5% vs. 13.1% among all others). Similarly, incidence of metastasis upstaging was highest for those who had a Gleason grade of 5 plus at least 50% positive cores (20.6% vs. 5.9% among all others).

“Patients with percent-positive cores of 50% or more and Gleason grade group 4 or 5 will benefit the most from a PSMA PET/CT scan,” Dr. Ma concluded. “Future studies should validate the importance of these factors and identify whether changing treatment leads to improved outcomes.”

“The beauty of percent-positive cores is that it is an objective and routinely available piece of clinical information from systematic biopsy,” he added. “It may aid in the selection of patients in resource-limited settings and consideration of treatment intensification. We may also consider incorporation of percent positive cores into clinical risk stratification schemes for clinical use.”
 

A game changer

“PSMA PET has been a real game changer in high-risk prostate cancer and has implications in the various stages of prostate cancer management from diagnosis and staging to theranostics,” said Renu Eapen, MBBS, of Peter MacCallum Cancer Centre in Melbourne, who was not involved in this study.

“PSMA PET/CT has challenged conventional imaging in staging before curative intent surgery or radiotherapy,” Dr. Eapen added.

Accuracy of PSMA PET/CT was 27% higher than that of conventional imaging in the proPSMA trial, she noted in an interview. This superior accuracy can ultimately have management impact, while the imaging has additional benefits of lower radiation dose and reproducibility with high reporter agreement, potentially making it a “one-stop-shop” scan.

“This prospective study by Ma et al. is a great adjunct to the proPSMA results, with the aims of further stratifying patients who are likely to be upstaged on PSMA PET/CT,” Dr. Eapen said. “As the availability of PSMA PET/CT increases and more centers adopt this technology, we need studies like these to risk-stratify patients and select those who would benefit.”

The study did not receive any specific funding. Dr. Ma and Dr. Eapen disclosed no conflicts of interest.

SOURCE: Ma TM et al. ASTRO 2020, Abstract 58.

Routinely collected clinical data help identify men with high-risk prostate cancer most likely to benefit from a gallium-68 prostate-specific membrane antigen (PSMA) PET/CT scan, according to a study reported at the American Society for Radiation Oncology Annual Meeting 2020.

Courtesy of University of California Los Angeles

“PSMA PET/CT is a novel molecular and functional imaging modality specific for prostate cancer cells that has good sensitivity and outstanding specificity in detecting metastasis,” noted study investigator T. Martin Ma, MD, PhD, of the University of California, Los Angeles.

The proPSMA trial, published in The Lancet earlier this year, found PSMA PET/CT to be superior to conventional imaging for primary staging of high-risk prostate cancer.

“These findings carry significant clinical implications and can affect treatment decision-making,” Dr. Ma noted.

With the current study, Dr. Ma and colleagues set out to assess the impact of PSMA PET/CT in nodal and metastatic upstaging in patients with high-risk prostate cancer and explore predictors of upstaging.

The researchers conducted a post hoc analysis of a single-center, prospective study of 262 patients with high-risk prostate cancer (cN1 or cN0 on conventional imaging) undergoing primary staging. Patients who had received 3 or more months of androgen deprivation therapy before their scan were excluded.
 

Study results

PSMA PET/CT led to nodal upstaging – from N0 to N1 – in 19.7% of patients and metastasis upstaging – from M0 to M1a, b, or c – in 9.4%.

“It is worth pointing out that the percentage of upstaging at the PSMA scan in our study is very similar to that in the proPSMA study,” Dr. Ma noted, with that trial finding nodal upstaging in 18% of patients and metastasis upstaging in 8%.

In multivariate analysis, independent predictors of nodal upstaging with PSMA PET/CT were higher percentage of positive cores at biopsy (odds ratio per decile, 1.21; P = .001) and higher Gleason grade (OR, 1.61; P = .025).

Similarly, independent predictors of metastasis upstaging were higher percentage of positive cores at biopsy (OR per decile, 1.19; P = .013) and higher Gleason grade (OR, 2.13; P = .024).

Other factors – clinical T stage and N stage, initial prostate-specific antigen level, and presence of two or more high-risk features – did not independently predict these outcomes.

When various combinations were assessed, the incidence of nodal upstaging was highest for patients who had a Gleason grade of 4 or 5 plus at least 50% positive cores (27.5% vs. 13.1% among all others). Similarly, incidence of metastasis upstaging was highest for those who had a Gleason grade of 5 plus at least 50% positive cores (20.6% vs. 5.9% among all others).

“Patients with percent-positive cores of 50% or more and Gleason grade group 4 or 5 will benefit the most from a PSMA PET/CT scan,” Dr. Ma concluded. “Future studies should validate the importance of these factors and identify whether changing treatment leads to improved outcomes.”

“The beauty of percent-positive cores is that it is an objective and routinely available piece of clinical information from systematic biopsy,” he added. “It may aid in the selection of patients in resource-limited settings and consideration of treatment intensification. We may also consider incorporation of percent positive cores into clinical risk stratification schemes for clinical use.”
 

A game changer

“PSMA PET has been a real game changer in high-risk prostate cancer and has implications in the various stages of prostate cancer management from diagnosis and staging to theranostics,” said Renu Eapen, MBBS, of Peter MacCallum Cancer Centre in Melbourne, who was not involved in this study.

“PSMA PET/CT has challenged conventional imaging in staging before curative intent surgery or radiotherapy,” Dr. Eapen added.

Accuracy of PSMA PET/CT was 27% higher than that of conventional imaging in the proPSMA trial, she noted in an interview. This superior accuracy can ultimately have management impact, while the imaging has additional benefits of lower radiation dose and reproducibility with high reporter agreement, potentially making it a “one-stop-shop” scan.

“This prospective study by Ma et al. is a great adjunct to the proPSMA results, with the aims of further stratifying patients who are likely to be upstaged on PSMA PET/CT,” Dr. Eapen said. “As the availability of PSMA PET/CT increases and more centers adopt this technology, we need studies like these to risk-stratify patients and select those who would benefit.”

The study did not receive any specific funding. Dr. Ma and Dr. Eapen disclosed no conflicts of interest.

SOURCE: Ma TM et al. ASTRO 2020, Abstract 58.

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.
 

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.
 

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.
 

Having a low threshold to biopsy atypical pigmented lesions on the vulva may identify melanoma early, according to a lecture at virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.

Pigmented brown or black vulvar lesions occur in approximately 10% of women, and they may be normal and benign.

“Often we will see a pigmented lesion on the vulva and think that there is nothing to worry about,” said Melissa Mauskar, MD.

Lesions could be angiokeratomas, petechiae, purpura, melanosis, and nevi, for example. Seborrheic keratoses can mimic melanoma. “If it looks odd, don’t be afraid to biopsy it,” said Dr. Mauskar, assistant professor of dermatology and obstetrics and gynecology at the University of Texas Southwestern Medical Center in Dallas.

Characteristics of melanoma, covered by the mnemonic ABCDE, include asymmetry, borders that are irregular, coloring that is uneven, diameter greater than 7 mm, and evolution over time.

When biopsying a lesion because of concerns about melanoma, the goal is to remove the whole lesion at once, Dr. Mauskar said.

In a recent U.S. population-based study of more than 1,800 patients with malignant melanoma of the vulva or vagina (including 1,400 patients with vulvar melanoma and 463 patients with vaginal melanoma), median disease-specific survival was 99 months for vulvar melanoma and 19 months for vaginal melanoma.

Patients with vaginal melanoma were more likely than patients with vulvar melanoma to have nodular lesions. The American Joint Committee on Cancer staging system predicts vulvar melanoma outcomes, the researchers found. In addition, lymph node status and mitotic rate were important predictors of survival.

A wide local excision is the mainstay of therapy for melanoma. Other therapeutic advances are “changing the survival curves for these patients, especially when we can find things early,” Dr. Mauskar said.

Photographing lesions can help doctors monitor them over time, she added.

It is important for dermatologists to include the vulva in skin exams and for gynecologists to have a low threshold to biopsy atypical pigmented lesions, Dr. Mauskar said. “Having a very low threshold for biopsy ... will increase our chances of finding these lesions when they are more at the superficial spreading phase as opposed to the nodular phase,” she said.

Capturing the depth of a tumor within the confines of a biopsy may help accurately stage malignant melanoma, Jason Reutter, MD, a pathologist in Hickory, N.C., said in a separate presentation. He suggested trying to get around the lesion with a punch biopsy if possible. A shave biopsy may be advantageous for larger macular lesions. To diagnose one melanoma, doctors may have to biopsy many lesions, Dr. Reutter noted.

At one institution, the number of skin biopsies needed to diagnose skin cancer ranged from 2.82 to 6.55, depending on the type of clinician, according to a recent study. The number of biopsies needed to detect one melanoma was greater – between 14 and 54 – depending on type of clinician.

For larger lesions, scouting biopsies of different areas may be the best approach, Dr. Reutter said.

Dr. Mauskar and Dr. Reutter had no relevant financial conflicts of interest.
 

[email protected]

Having a low threshold to biopsy atypical pigmented lesions on the vulva may identify melanoma early, according to a lecture at virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.

Pigmented brown or black vulvar lesions occur in approximately 10% of women, and they may be normal and benign.

“Often we will see a pigmented lesion on the vulva and think that there is nothing to worry about,” said Melissa Mauskar, MD.

Lesions could be angiokeratomas, petechiae, purpura, melanosis, and nevi, for example. Seborrheic keratoses can mimic melanoma. “If it looks odd, don’t be afraid to biopsy it,” said Dr. Mauskar, assistant professor of dermatology and obstetrics and gynecology at the University of Texas Southwestern Medical Center in Dallas.

Characteristics of melanoma, covered by the mnemonic ABCDE, include asymmetry, borders that are irregular, coloring that is uneven, diameter greater than 7 mm, and evolution over time.

When biopsying a lesion because of concerns about melanoma, the goal is to remove the whole lesion at once, Dr. Mauskar said.

In a recent U.S. population-based study of more than 1,800 patients with malignant melanoma of the vulva or vagina (including 1,400 patients with vulvar melanoma and 463 patients with vaginal melanoma), median disease-specific survival was 99 months for vulvar melanoma and 19 months for vaginal melanoma.

Patients with vaginal melanoma were more likely than patients with vulvar melanoma to have nodular lesions. The American Joint Committee on Cancer staging system predicts vulvar melanoma outcomes, the researchers found. In addition, lymph node status and mitotic rate were important predictors of survival.

A wide local excision is the mainstay of therapy for melanoma. Other therapeutic advances are “changing the survival curves for these patients, especially when we can find things early,” Dr. Mauskar said.

Photographing lesions can help doctors monitor them over time, she added.

It is important for dermatologists to include the vulva in skin exams and for gynecologists to have a low threshold to biopsy atypical pigmented lesions, Dr. Mauskar said. “Having a very low threshold for biopsy ... will increase our chances of finding these lesions when they are more at the superficial spreading phase as opposed to the nodular phase,” she said.

Capturing the depth of a tumor within the confines of a biopsy may help accurately stage malignant melanoma, Jason Reutter, MD, a pathologist in Hickory, N.C., said in a separate presentation. He suggested trying to get around the lesion with a punch biopsy if possible. A shave biopsy may be advantageous for larger macular lesions. To diagnose one melanoma, doctors may have to biopsy many lesions, Dr. Reutter noted.

At one institution, the number of skin biopsies needed to diagnose skin cancer ranged from 2.82 to 6.55, depending on the type of clinician, according to a recent study. The number of biopsies needed to detect one melanoma was greater – between 14 and 54 – depending on type of clinician.

For larger lesions, scouting biopsies of different areas may be the best approach, Dr. Reutter said.

Dr. Mauskar and Dr. Reutter had no relevant financial conflicts of interest.
 

[email protected]

Having a low threshold to biopsy atypical pigmented lesions on the vulva may identify melanoma early, according to a lecture at virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.

Pigmented brown or black vulvar lesions occur in approximately 10% of women, and they may be normal and benign.

“Often we will see a pigmented lesion on the vulva and think that there is nothing to worry about,” said Melissa Mauskar, MD.

Lesions could be angiokeratomas, petechiae, purpura, melanosis, and nevi, for example. Seborrheic keratoses can mimic melanoma. “If it looks odd, don’t be afraid to biopsy it,” said Dr. Mauskar, assistant professor of dermatology and obstetrics and gynecology at the University of Texas Southwestern Medical Center in Dallas.

Characteristics of melanoma, covered by the mnemonic ABCDE, include asymmetry, borders that are irregular, coloring that is uneven, diameter greater than 7 mm, and evolution over time.

When biopsying a lesion because of concerns about melanoma, the goal is to remove the whole lesion at once, Dr. Mauskar said.

In a recent U.S. population-based study of more than 1,800 patients with malignant melanoma of the vulva or vagina (including 1,400 patients with vulvar melanoma and 463 patients with vaginal melanoma), median disease-specific survival was 99 months for vulvar melanoma and 19 months for vaginal melanoma.

Patients with vaginal melanoma were more likely than patients with vulvar melanoma to have nodular lesions. The American Joint Committee on Cancer staging system predicts vulvar melanoma outcomes, the researchers found. In addition, lymph node status and mitotic rate were important predictors of survival.

A wide local excision is the mainstay of therapy for melanoma. Other therapeutic advances are “changing the survival curves for these patients, especially when we can find things early,” Dr. Mauskar said.

Photographing lesions can help doctors monitor them over time, she added.

It is important for dermatologists to include the vulva in skin exams and for gynecologists to have a low threshold to biopsy atypical pigmented lesions, Dr. Mauskar said. “Having a very low threshold for biopsy ... will increase our chances of finding these lesions when they are more at the superficial spreading phase as opposed to the nodular phase,” she said.

Capturing the depth of a tumor within the confines of a biopsy may help accurately stage malignant melanoma, Jason Reutter, MD, a pathologist in Hickory, N.C., said in a separate presentation. He suggested trying to get around the lesion with a punch biopsy if possible. A shave biopsy may be advantageous for larger macular lesions. To diagnose one melanoma, doctors may have to biopsy many lesions, Dr. Reutter noted.

At one institution, the number of skin biopsies needed to diagnose skin cancer ranged from 2.82 to 6.55, depending on the type of clinician, according to a recent study. The number of biopsies needed to detect one melanoma was greater – between 14 and 54 – depending on type of clinician.

For larger lesions, scouting biopsies of different areas may be the best approach, Dr. Reutter said.

Dr. Mauskar and Dr. Reutter had no relevant financial conflicts of interest.
 

[email protected]

About one-third of patients with chronic hepatitis B maintained a profile consistent with inactive disease 1 year after withdrawal from treatment in the randomized HBRN trial, which compared tenofovir with and without pegylated interferon (PEG-IFN). The two treatment groups, however, had similarly low rates of hepatitis B surface antigen (HBsAg) loss, the trial’s primary end point.

The successful withdrawals could inform discussions with patients who are “very motivated to have a finite treatment course,” said investigator Norah Terrault, MD, from the University of Southern California, Los Angeles. The results might “help patients in talking about expectations,” she said, because “there’s a one in three chance they won’t go back on treatment” if they meet specific metrics.

In HBRN, the metrics for withdrawal from treatment after 192 weeks included low levels of viral DNA (<1,000 IU/mL) for at least 24 weeks, no cirrhosis, negative week 144 test results for the hepatitis B envelope antigen (HBeAg), and week 180 conversion to anti-HBe positivity.

Of 102 patients who received tenofovir monotherapy for 192 weeks and who completed the trial, 51 met these criteria. After withdrawal from treatment, 30% still had DNA levels below 1,000 IU/mL and normal ALT at week 240, which is consistent with inactive chronic hepatitis B.

Of the 99 participants in the combination group – who received PEG-IFN for the first 24 of 192 weeks in addition to tenofovir – 60 met the withdrawal criteria at 192 weeks. At week 240, 39% of this withdrawal group still had DNA and ALT values consistent with inactive disease.

Rates of HBsAg loss, which signals functional cure, were low in the two groups, however. At week 240, fewer patients in the tenofovir monotherapy group tested negative for HBsAg than in the tenofovir plus PEG-IFN combination group, but the difference was not significant (4.5% vs. 5.7%).

The timing of HBsAg loss differed between the groups. In the combination group, the loss largely occurred before treatment withdrawal, likely because of the antiviral effects of interferon, Dr. Terrault said in an interview. In the monotherapy group, the loss occurred after 192 weeks, possibly reflecting the immunologic consequences of treatment withdrawal.

The timing of ALT flares also differed between groups. In the combination group, 58% of flares occurred during the 24-week PEG-IFN period. In the monotherapy group, 70% of flares occurred after tenofovir was stopped at 192 weeks.

The flare picture is a tricky one, said Dr. Terrault. The episodes might be a positive factor in HBsAg loss, but severe flares carry a risk for decompensation. Good predictors of the severity of flares are lacking, and “that is the hurdle” to finding a balance with these trade-offs.
 

‘Partially a failure and partially a success’

The findings are “partially a failure and partially a success,” said Robert Gish, MD, from Loma Linda (Calif.) University of Health, who was not involved in the study.

The low rates of HBsAg loss and the similarity between the two treatment groups represent the failure, he explained. The success is for the patients who were HBeAg-positive when the study began because they had high HBeAg loss rates in both the monotherapy and combination groups (41% vs. 61%; P = .06).

Loss of HBeAg was numerically higher in the combination group because of the interferon effect. That could be viewed as a “subjective benefit” of PEG-IFN, even though the difference wasn’t statistically significant, said Dr. Gish.

The low rates of HBsAg loss could relate to two features of the patient profile, he explained. At study entry, the participants had moderately high levels of quantitative HBsAg and were predominately of Asian ancestry, which are predisposing factors for limited HBsAg loss.

Previous studies have suggested that peak HBsAg loss could take 2-3 years to develop after treatment withdrawal in a trial population. In the HBRN trial, rates almost 1 year after withdrawal are similar to 1-year rates from other studies, Dr. Terrault said. How these results for HBsAg loss in the two treatment groups will look at the 3-year mark is not known.

The trial design standardized withdrawal protocol and the length of time patients were on treatment before withdrawal was attempted, which are strengths of this study, said Dr. Terrault. And “a triumph of this study is execution of a standard for nucleic acid treatment in a protocolized way, followed by withdrawal. That is something we are happy about.”

Dr. Terrault reported receiving institutional grant support from Roche/Genentech and Gilead Sciences. Dr. Gish reported receiving research support from Gilead Sciences and serving as a consultant and on advisory boards for several pharmaceutical companies.

This article first appeared on Medscape.com.

About one-third of patients with chronic hepatitis B maintained a profile consistent with inactive disease 1 year after withdrawal from treatment in the randomized HBRN trial, which compared tenofovir with and without pegylated interferon (PEG-IFN). The two treatment groups, however, had similarly low rates of hepatitis B surface antigen (HBsAg) loss, the trial’s primary end point.

The successful withdrawals could inform discussions with patients who are “very motivated to have a finite treatment course,” said investigator Norah Terrault, MD, from the University of Southern California, Los Angeles. The results might “help patients in talking about expectations,” she said, because “there’s a one in three chance they won’t go back on treatment” if they meet specific metrics.

In HBRN, the metrics for withdrawal from treatment after 192 weeks included low levels of viral DNA (<1,000 IU/mL) for at least 24 weeks, no cirrhosis, negative week 144 test results for the hepatitis B envelope antigen (HBeAg), and week 180 conversion to anti-HBe positivity.

Of 102 patients who received tenofovir monotherapy for 192 weeks and who completed the trial, 51 met these criteria. After withdrawal from treatment, 30% still had DNA levels below 1,000 IU/mL and normal ALT at week 240, which is consistent with inactive chronic hepatitis B.

Of the 99 participants in the combination group – who received PEG-IFN for the first 24 of 192 weeks in addition to tenofovir – 60 met the withdrawal criteria at 192 weeks. At week 240, 39% of this withdrawal group still had DNA and ALT values consistent with inactive disease.

Rates of HBsAg loss, which signals functional cure, were low in the two groups, however. At week 240, fewer patients in the tenofovir monotherapy group tested negative for HBsAg than in the tenofovir plus PEG-IFN combination group, but the difference was not significant (4.5% vs. 5.7%).

The timing of HBsAg loss differed between the groups. In the combination group, the loss largely occurred before treatment withdrawal, likely because of the antiviral effects of interferon, Dr. Terrault said in an interview. In the monotherapy group, the loss occurred after 192 weeks, possibly reflecting the immunologic consequences of treatment withdrawal.

The timing of ALT flares also differed between groups. In the combination group, 58% of flares occurred during the 24-week PEG-IFN period. In the monotherapy group, 70% of flares occurred after tenofovir was stopped at 192 weeks.

The flare picture is a tricky one, said Dr. Terrault. The episodes might be a positive factor in HBsAg loss, but severe flares carry a risk for decompensation. Good predictors of the severity of flares are lacking, and “that is the hurdle” to finding a balance with these trade-offs.
 

‘Partially a failure and partially a success’

The findings are “partially a failure and partially a success,” said Robert Gish, MD, from Loma Linda (Calif.) University of Health, who was not involved in the study.

The low rates of HBsAg loss and the similarity between the two treatment groups represent the failure, he explained. The success is for the patients who were HBeAg-positive when the study began because they had high HBeAg loss rates in both the monotherapy and combination groups (41% vs. 61%; P = .06).

Loss of HBeAg was numerically higher in the combination group because of the interferon effect. That could be viewed as a “subjective benefit” of PEG-IFN, even though the difference wasn’t statistically significant, said Dr. Gish.

The low rates of HBsAg loss could relate to two features of the patient profile, he explained. At study entry, the participants had moderately high levels of quantitative HBsAg and were predominately of Asian ancestry, which are predisposing factors for limited HBsAg loss.

Previous studies have suggested that peak HBsAg loss could take 2-3 years to develop after treatment withdrawal in a trial population. In the HBRN trial, rates almost 1 year after withdrawal are similar to 1-year rates from other studies, Dr. Terrault said. How these results for HBsAg loss in the two treatment groups will look at the 3-year mark is not known.

The trial design standardized withdrawal protocol and the length of time patients were on treatment before withdrawal was attempted, which are strengths of this study, said Dr. Terrault. And “a triumph of this study is execution of a standard for nucleic acid treatment in a protocolized way, followed by withdrawal. That is something we are happy about.”

Dr. Terrault reported receiving institutional grant support from Roche/Genentech and Gilead Sciences. Dr. Gish reported receiving research support from Gilead Sciences and serving as a consultant and on advisory boards for several pharmaceutical companies.

This article first appeared on Medscape.com.

About one-third of patients with chronic hepatitis B maintained a profile consistent with inactive disease 1 year after withdrawal from treatment in the randomized HBRN trial, which compared tenofovir with and without pegylated interferon (PEG-IFN). The two treatment groups, however, had similarly low rates of hepatitis B surface antigen (HBsAg) loss, the trial’s primary end point.

The successful withdrawals could inform discussions with patients who are “very motivated to have a finite treatment course,” said investigator Norah Terrault, MD, from the University of Southern California, Los Angeles. The results might “help patients in talking about expectations,” she said, because “there’s a one in three chance they won’t go back on treatment” if they meet specific metrics.

In HBRN, the metrics for withdrawal from treatment after 192 weeks included low levels of viral DNA (<1,000 IU/mL) for at least 24 weeks, no cirrhosis, negative week 144 test results for the hepatitis B envelope antigen (HBeAg), and week 180 conversion to anti-HBe positivity.

Of 102 patients who received tenofovir monotherapy for 192 weeks and who completed the trial, 51 met these criteria. After withdrawal from treatment, 30% still had DNA levels below 1,000 IU/mL and normal ALT at week 240, which is consistent with inactive chronic hepatitis B.

Of the 99 participants in the combination group – who received PEG-IFN for the first 24 of 192 weeks in addition to tenofovir – 60 met the withdrawal criteria at 192 weeks. At week 240, 39% of this withdrawal group still had DNA and ALT values consistent with inactive disease.

Rates of HBsAg loss, which signals functional cure, were low in the two groups, however. At week 240, fewer patients in the tenofovir monotherapy group tested negative for HBsAg than in the tenofovir plus PEG-IFN combination group, but the difference was not significant (4.5% vs. 5.7%).

The timing of HBsAg loss differed between the groups. In the combination group, the loss largely occurred before treatment withdrawal, likely because of the antiviral effects of interferon, Dr. Terrault said in an interview. In the monotherapy group, the loss occurred after 192 weeks, possibly reflecting the immunologic consequences of treatment withdrawal.

The timing of ALT flares also differed between groups. In the combination group, 58% of flares occurred during the 24-week PEG-IFN period. In the monotherapy group, 70% of flares occurred after tenofovir was stopped at 192 weeks.

The flare picture is a tricky one, said Dr. Terrault. The episodes might be a positive factor in HBsAg loss, but severe flares carry a risk for decompensation. Good predictors of the severity of flares are lacking, and “that is the hurdle” to finding a balance with these trade-offs.
 

‘Partially a failure and partially a success’

The findings are “partially a failure and partially a success,” said Robert Gish, MD, from Loma Linda (Calif.) University of Health, who was not involved in the study.

The low rates of HBsAg loss and the similarity between the two treatment groups represent the failure, he explained. The success is for the patients who were HBeAg-positive when the study began because they had high HBeAg loss rates in both the monotherapy and combination groups (41% vs. 61%; P = .06).

Loss of HBeAg was numerically higher in the combination group because of the interferon effect. That could be viewed as a “subjective benefit” of PEG-IFN, even though the difference wasn’t statistically significant, said Dr. Gish.

The low rates of HBsAg loss could relate to two features of the patient profile, he explained. At study entry, the participants had moderately high levels of quantitative HBsAg and were predominately of Asian ancestry, which are predisposing factors for limited HBsAg loss.

Previous studies have suggested that peak HBsAg loss could take 2-3 years to develop after treatment withdrawal in a trial population. In the HBRN trial, rates almost 1 year after withdrawal are similar to 1-year rates from other studies, Dr. Terrault said. How these results for HBsAg loss in the two treatment groups will look at the 3-year mark is not known.

The trial design standardized withdrawal protocol and the length of time patients were on treatment before withdrawal was attempted, which are strengths of this study, said Dr. Terrault. And “a triumph of this study is execution of a standard for nucleic acid treatment in a protocolized way, followed by withdrawal. That is something we are happy about.”

Dr. Terrault reported receiving institutional grant support from Roche/Genentech and Gilead Sciences. Dr. Gish reported receiving research support from Gilead Sciences and serving as a consultant and on advisory boards for several pharmaceutical companies.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

To the Editor:

Oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV)–mediated mucocutaneous disease that often involves the lingual epithelium. The lateral portions of the tongue are the most commonly affected sites. The lesions often are described as asymptomatic, white, corrugated patches or plaques that are unable to be scraped off.¹ Oral hairy leukoplakia was first identified in 1984 and was considered to be associated with AIDS.² An association between the presence of OHL and the degree of immunosuppression as well as the severity of human immunodeficiency virus (HIV) has been reported.³ Although OHL initially was considered to be pathognomonic for HIV, it has since been described in multiple other immunosuppressive conditions.⁴ Numerous medical conditions and combinations of immunosuppressive medications have been associated with OHL in patients who were HIV negative.⁵

Adalimumab is an injectable human IgG1 recombinant antibody to tumor necrosis factor α (TNF-α).⁶ It currently is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn disease, ulcerative colitis, noninfectious uveitis, hidradenitis suppurativa, and plaque psoriasis.⁷ We report a case of OHL associated with the use of adalimumab.

A 47-year-old woman initially presented with chronic plaque-type psoriasis. Her medical history was notable for bipolar disorder, migraines, hypertension, and tobacco use. The patient’s psoriasis initially was well controlled on a regimen of topical steroids and methotrexate; however, methotrexate was stopped after 2.5 years due to a mildly elevated alanine aminotransferase level, as well as an abnormal liver biopsy showing mildly active (grade 1 of 3) steatohepatitis with portal chronic inflammation, pericellular fibrosis, and portal and focal periportal fibrosis (stage 1-2 of 4). The patient and her dermatologist were uncomfortable continuing methotrexate with these findings. After baseline screening including a negative purified protein derivative skin test, adalimumab was initiated. A loading dose of 80 mg subcutaneously (SQ) was given, followed by adalimumab 40 mg SQ 1 week later and 40 mg every other week as maintenance.

The patient’s psoriasis was well controlled with adalimumab for 22 months, but she then developed a thin white plaque on the right lateral tongue (Figure 1). An incisional biopsy of the tongue performed by an oral surgeon revealed hyperkeratosis with Candida colonization and viral cytopathic effect (Figure 2). An EBV DNA in situ hybridization stain revealed focal positivity within these cells (Figure 3), leading to a diagnosis of OHL. Laboratory evaluation demonstrated a normal complete blood cell count with differential and liver panel as well as a negative HIV test. The patient otherwise felt well and denied fevers, lymphadenopathy, and weight loss.

Oral hairy leukoplakia is associated with upregulated EBV replication and EBV-encoded proteins such as latent membrane protein 1.² It often presents as white or gray patches on the lateral lingual margins with prominent folds and/or projections, giving a shaggy appearance. Oral hairy leukoplakia often is specific for HIV infection and rarely is associated with other immunodeficiencies.² Prasad and Bilodeau⁵ performed a literature review of medical conditions and immunosuppressive medications associated with OHL in patients without HIV. Allogeneic transplant was associated with the highest incidence of OHL in HIV-negative patients (59.2% [45/76]).⁵ Various combinations of immunosuppressive medications (eg, prednisone, cyclosporine, azathioprine) also may be implicated in cases of HIV-negative patients with OHL. A case of OHL also has been reported with long-standing use of inhaled corticosteroids in an immunocompetent, HIV-negative patient.⁶ Another case was reported with long-term use of the aromatic antiepileptic lamotrigine, which resolved once stopping the medication.⁸ Although EBV is an oncovirus and has been associated with lymphoproliferative disorders and nasopharyngeal carcinoma, OHL is not considered to be a premalignant lesion.⁷ Despite the strong association between OHL and HIV, our patient was HIV negative. The only immunocompromising factor in our patient was the use of adalimumab to treat psoriasis. We did not conduct further testing for immunodeficiency states because the OHL spontaneously resolved when the adalimumab was discontinued.

PubMed and Ovid searches of articles indexed for MEDLINE using the terms adalimumab and oral hairy leukoplakia as well as TNF-alpha inhibitor and oral hairy leukoplakia with humans and English language as limitations revealed that no cases have been reported in the literature demonstrating an association between OHL and adalimumab or any other TNF-α inhibitor. However, Cetkovska et al⁹ reported a case of EBV hepatitis and subsequently chronic hepatitis as a complication of infliximab used for the treatment of chronic psoriasis. Because TNF-α and IFN-γ play an important role in controlling viral infections, there is an increased risk for reactivating a viral illness when depleting TNF through pharmacologic measures (ie, adalimumab, infliximab).⁸ Another case of EBV-associated plasmablastic lymphoma was reported after 1 year of adalimumab use in a patient with Crohn disease. The plasmablastic lymphoma resolved after 4 rounds of chemotherapy.¹⁰

The only contraindication for the use of adalimumab is a known hypersensitivity to the drug. Relative contraindications for use of adalimumab include active tuberculosis, demyelinating disease, hematologic diseases (ie, thrombocytopenia, pancytopenia), lymphoma, hepatitis C, and hepatitis B.¹¹ The most common adverse effect of adalimumab is an injection-site reaction. Additional reported adverse effects of TNF-α inhibitors as a class are lymphoma, melanoma, nonmelanoma skin cancer, reactivation of latent tuberculosis, congestive heart failure, autoimmunity, and hematologic toxicity.¹¹

This case demonstrates an association between adalimumab and OHL in an HIV-negative patient. Although the mechanism behind OHL and immunosuppression remains to be elucidated, this association is important to keep in mind when using adalimumab or other TNF-α inhibitors for the treatment of psoriasis or other medical conditions.

To the Editor:

Oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV)–mediated mucocutaneous disease that often involves the lingual epithelium. The lateral portions of the tongue are the most commonly affected sites. The lesions often are described as asymptomatic, white, corrugated patches or plaques that are unable to be scraped off.¹ Oral hairy leukoplakia was first identified in 1984 and was considered to be associated with AIDS.² An association between the presence of OHL and the degree of immunosuppression as well as the severity of human immunodeficiency virus (HIV) has been reported.³ Although OHL initially was considered to be pathognomonic for HIV, it has since been described in multiple other immunosuppressive conditions.⁴ Numerous medical conditions and combinations of immunosuppressive medications have been associated with OHL in patients who were HIV negative.⁵

Adalimumab is an injectable human IgG1 recombinant antibody to tumor necrosis factor α (TNF-α).⁶ It currently is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn disease, ulcerative colitis, noninfectious uveitis, hidradenitis suppurativa, and plaque psoriasis.⁷ We report a case of OHL associated with the use of adalimumab.

A 47-year-old woman initially presented with chronic plaque-type psoriasis. Her medical history was notable for bipolar disorder, migraines, hypertension, and tobacco use. The patient’s psoriasis initially was well controlled on a regimen of topical steroids and methotrexate; however, methotrexate was stopped after 2.5 years due to a mildly elevated alanine aminotransferase level, as well as an abnormal liver biopsy showing mildly active (grade 1 of 3) steatohepatitis with portal chronic inflammation, pericellular fibrosis, and portal and focal periportal fibrosis (stage 1-2 of 4). The patient and her dermatologist were uncomfortable continuing methotrexate with these findings. After baseline screening including a negative purified protein derivative skin test, adalimumab was initiated. A loading dose of 80 mg subcutaneously (SQ) was given, followed by adalimumab 40 mg SQ 1 week later and 40 mg every other week as maintenance.

The patient’s psoriasis was well controlled with adalimumab for 22 months, but she then developed a thin white plaque on the right lateral tongue (Figure 1). An incisional biopsy of the tongue performed by an oral surgeon revealed hyperkeratosis with Candida colonization and viral cytopathic effect (Figure 2). An EBV DNA in situ hybridization stain revealed focal positivity within these cells (Figure 3), leading to a diagnosis of OHL. Laboratory evaluation demonstrated a normal complete blood cell count with differential and liver panel as well as a negative HIV test. The patient otherwise felt well and denied fevers, lymphadenopathy, and weight loss.

Oral hairy leukoplakia is associated with upregulated EBV replication and EBV-encoded proteins such as latent membrane protein 1.² It often presents as white or gray patches on the lateral lingual margins with prominent folds and/or projections, giving a shaggy appearance. Oral hairy leukoplakia often is specific for HIV infection and rarely is associated with other immunodeficiencies.² Prasad and Bilodeau⁵ performed a literature review of medical conditions and immunosuppressive medications associated with OHL in patients without HIV. Allogeneic transplant was associated with the highest incidence of OHL in HIV-negative patients (59.2% [45/76]).⁵ Various combinations of immunosuppressive medications (eg, prednisone, cyclosporine, azathioprine) also may be implicated in cases of HIV-negative patients with OHL. A case of OHL also has been reported with long-standing use of inhaled corticosteroids in an immunocompetent, HIV-negative patient.⁶ Another case was reported with long-term use of the aromatic antiepileptic lamotrigine, which resolved once stopping the medication.⁸ Although EBV is an oncovirus and has been associated with lymphoproliferative disorders and nasopharyngeal carcinoma, OHL is not considered to be a premalignant lesion.⁷ Despite the strong association between OHL and HIV, our patient was HIV negative. The only immunocompromising factor in our patient was the use of adalimumab to treat psoriasis. We did not conduct further testing for immunodeficiency states because the OHL spontaneously resolved when the adalimumab was discontinued.

PubMed and Ovid searches of articles indexed for MEDLINE using the terms adalimumab and oral hairy leukoplakia as well as TNF-alpha inhibitor and oral hairy leukoplakia with humans and English language as limitations revealed that no cases have been reported in the literature demonstrating an association between OHL and adalimumab or any other TNF-α inhibitor. However, Cetkovska et al⁹ reported a case of EBV hepatitis and subsequently chronic hepatitis as a complication of infliximab used for the treatment of chronic psoriasis. Because TNF-α and IFN-γ play an important role in controlling viral infections, there is an increased risk for reactivating a viral illness when depleting TNF through pharmacologic measures (ie, adalimumab, infliximab).⁸ Another case of EBV-associated plasmablastic lymphoma was reported after 1 year of adalimumab use in a patient with Crohn disease. The plasmablastic lymphoma resolved after 4 rounds of chemotherapy.¹⁰

The only contraindication for the use of adalimumab is a known hypersensitivity to the drug. Relative contraindications for use of adalimumab include active tuberculosis, demyelinating disease, hematologic diseases (ie, thrombocytopenia, pancytopenia), lymphoma, hepatitis C, and hepatitis B.¹¹ The most common adverse effect of adalimumab is an injection-site reaction. Additional reported adverse effects of TNF-α inhibitors as a class are lymphoma, melanoma, nonmelanoma skin cancer, reactivation of latent tuberculosis, congestive heart failure, autoimmunity, and hematologic toxicity.¹¹

This case demonstrates an association between adalimumab and OHL in an HIV-negative patient. Although the mechanism behind OHL and immunosuppression remains to be elucidated, this association is important to keep in mind when using adalimumab or other TNF-α inhibitors for the treatment of psoriasis or other medical conditions.

To the Editor:

Oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV)–mediated mucocutaneous disease that often involves the lingual epithelium. The lateral portions of the tongue are the most commonly affected sites. The lesions often are described as asymptomatic, white, corrugated patches or plaques that are unable to be scraped off.¹ Oral hairy leukoplakia was first identified in 1984 and was considered to be associated with AIDS.² An association between the presence of OHL and the degree of immunosuppression as well as the severity of human immunodeficiency virus (HIV) has been reported.³ Although OHL initially was considered to be pathognomonic for HIV, it has since been described in multiple other immunosuppressive conditions.⁴ Numerous medical conditions and combinations of immunosuppressive medications have been associated with OHL in patients who were HIV negative.⁵

Adalimumab is an injectable human IgG1 recombinant antibody to tumor necrosis factor α (TNF-α).⁶ It currently is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn disease, ulcerative colitis, noninfectious uveitis, hidradenitis suppurativa, and plaque psoriasis.⁷ We report a case of OHL associated with the use of adalimumab.

A 47-year-old woman initially presented with chronic plaque-type psoriasis. Her medical history was notable for bipolar disorder, migraines, hypertension, and tobacco use. The patient’s psoriasis initially was well controlled on a regimen of topical steroids and methotrexate; however, methotrexate was stopped after 2.5 years due to a mildly elevated alanine aminotransferase level, as well as an abnormal liver biopsy showing mildly active (grade 1 of 3) steatohepatitis with portal chronic inflammation, pericellular fibrosis, and portal and focal periportal fibrosis (stage 1-2 of 4). The patient and her dermatologist were uncomfortable continuing methotrexate with these findings. After baseline screening including a negative purified protein derivative skin test, adalimumab was initiated. A loading dose of 80 mg subcutaneously (SQ) was given, followed by adalimumab 40 mg SQ 1 week later and 40 mg every other week as maintenance.

The patient’s psoriasis was well controlled with adalimumab for 22 months, but she then developed a thin white plaque on the right lateral tongue (Figure 1). An incisional biopsy of the tongue performed by an oral surgeon revealed hyperkeratosis with Candida colonization and viral cytopathic effect (Figure 2). An EBV DNA in situ hybridization stain revealed focal positivity within these cells (Figure 3), leading to a diagnosis of OHL. Laboratory evaluation demonstrated a normal complete blood cell count with differential and liver panel as well as a negative HIV test. The patient otherwise felt well and denied fevers, lymphadenopathy, and weight loss.

Oral hairy leukoplakia is associated with upregulated EBV replication and EBV-encoded proteins such as latent membrane protein 1.² It often presents as white or gray patches on the lateral lingual margins with prominent folds and/or projections, giving a shaggy appearance. Oral hairy leukoplakia often is specific for HIV infection and rarely is associated with other immunodeficiencies.² Prasad and Bilodeau⁵ performed a literature review of medical conditions and immunosuppressive medications associated with OHL in patients without HIV. Allogeneic transplant was associated with the highest incidence of OHL in HIV-negative patients (59.2% [45/76]).⁵ Various combinations of immunosuppressive medications (eg, prednisone, cyclosporine, azathioprine) also may be implicated in cases of HIV-negative patients with OHL. A case of OHL also has been reported with long-standing use of inhaled corticosteroids in an immunocompetent, HIV-negative patient.⁶ Another case was reported with long-term use of the aromatic antiepileptic lamotrigine, which resolved once stopping the medication.⁸ Although EBV is an oncovirus and has been associated with lymphoproliferative disorders and nasopharyngeal carcinoma, OHL is not considered to be a premalignant lesion.⁷ Despite the strong association between OHL and HIV, our patient was HIV negative. The only immunocompromising factor in our patient was the use of adalimumab to treat psoriasis. We did not conduct further testing for immunodeficiency states because the OHL spontaneously resolved when the adalimumab was discontinued.

PubMed and Ovid searches of articles indexed for MEDLINE using the terms adalimumab and oral hairy leukoplakia as well as TNF-alpha inhibitor and oral hairy leukoplakia with humans and English language as limitations revealed that no cases have been reported in the literature demonstrating an association between OHL and adalimumab or any other TNF-α inhibitor. However, Cetkovska et al⁹ reported a case of EBV hepatitis and subsequently chronic hepatitis as a complication of infliximab used for the treatment of chronic psoriasis. Because TNF-α and IFN-γ play an important role in controlling viral infections, there is an increased risk for reactivating a viral illness when depleting TNF through pharmacologic measures (ie, adalimumab, infliximab).⁸ Another case of EBV-associated plasmablastic lymphoma was reported after 1 year of adalimumab use in a patient with Crohn disease. The plasmablastic lymphoma resolved after 4 rounds of chemotherapy.¹⁰

The only contraindication for the use of adalimumab is a known hypersensitivity to the drug. Relative contraindications for use of adalimumab include active tuberculosis, demyelinating disease, hematologic diseases (ie, thrombocytopenia, pancytopenia), lymphoma, hepatitis C, and hepatitis B.¹¹ The most common adverse effect of adalimumab is an injection-site reaction. Additional reported adverse effects of TNF-α inhibitors as a class are lymphoma, melanoma, nonmelanoma skin cancer, reactivation of latent tuberculosis, congestive heart failure, autoimmunity, and hematologic toxicity.¹¹

This case demonstrates an association between adalimumab and OHL in an HIV-negative patient. Although the mechanism behind OHL and immunosuppression remains to be elucidated, this association is important to keep in mind when using adalimumab or other TNF-α inhibitors for the treatment of psoriasis or other medical conditions.

“What do you think of all this election stuff?” I froze. Sitting on the exam table was a 50-something-year-old woman. Her hair was long, but not gray. She was wearing a mask without distinctive markings, such as Trump lips or #BLM to identify the political leanings of the owner. She had a subtle New York accent, perhaps dating back to the Giuliani years. It was hard to know her intention. “It’s a trap!” I could hear Admiral Ackbar’s voice in my head. “Don’t engage.” We all know nothing erodes trust faster than showing your blue or red colors before you know which your patient identifies.

Instead, I replied that indeed it has been a stressful year for us all. Then I paused. She shifted a bit and tugged at the gown sleeves and admitted this was the most stress she felt in years. She was seeing me for lichen sclerosus et atrophicus, a terribly itchy, sometimes-disfiguring eruption that can occur in the vulva. She was dealing with COVID-19, kids, divorce, a new partner, working from home, parents, and now the election drama. 

At this point in the visit, I knew I could help her. First, the treatment for lichen sclerosus is straightforward and mostly effective. Second, I knew I’d have 7 minutes to spare to just listen. It was a lucky break, as often no such gift of time presents itself while seeing patients in a busy clinic. We take vitals, history (typing), do an exam, make a diagnosis (more typing), and maybe a procedure (yet more typing). All of this is necessary, but sometimes not what our patient needs. Some really need just to connect and share their burden with someone who isn’t a friend or family. As physicians, we have a unique opportunity to see and hear people without judgment.

This reminds me of a recent episode from Sam Harris’s podcast, “Making Sense.” Mr. Harris, a philosopher (and “blue” all the way through) revealed his insight into Presidents Trump’s appeal. Leaving policy aside, Mr. Harris notes that people are drawn to the President because he never judges you. He is incapable of being sanctimonious, Mr. Harris argues, and therefore creates a safe space for people to continue their lives, however flawed, without expectation that they improve. 

I’m unsure just how much of this theory explains the devotion of his supporters, but it resonated with me. We doctors are sanctimonious by nature. The better part of my day is spent prodding people to be better: Wear more sunscreen, exercise more, stop believing in conspiracy theories, get your flu shot, and above all, stop scratching! In doing so, I’m in a way judging them. Finger wagging: You’re lazy or poor or dumb or stubborn. “You aren’t as good as me,” is what they might feel after 15 minutes of my pep talk.

But what if that’s wrong? What if they are just fine exactly the way they are? Perhaps what my lichen sclerosis patient needs more than anything is unconditional attention? She, like most of our patients, is well aware of how her shortcomings might contribute to her own anxiety or difficulties. And now she has this rash and that’s probably somehow her fault too, she thinks. 

How can I best help her? Betamethasone dipropionate b.i.d. for 2 weeks and spend the last 7 minutes just sitting and listening without judgment or advice. I don’t know who she wanted to win the election. It didn’t matter, she was exactly right to believe what she believed, either way.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

“What do you think of all this election stuff?” I froze. Sitting on the exam table was a 50-something-year-old woman. Her hair was long, but not gray. She was wearing a mask without distinctive markings, such as Trump lips or #BLM to identify the political leanings of the owner. She had a subtle New York accent, perhaps dating back to the Giuliani years. It was hard to know her intention. “It’s a trap!” I could hear Admiral Ackbar’s voice in my head. “Don’t engage.” We all know nothing erodes trust faster than showing your blue or red colors before you know which your patient identifies.

Instead, I replied that indeed it has been a stressful year for us all. Then I paused. She shifted a bit and tugged at the gown sleeves and admitted this was the most stress she felt in years. She was seeing me for lichen sclerosus et atrophicus, a terribly itchy, sometimes-disfiguring eruption that can occur in the vulva. She was dealing with COVID-19, kids, divorce, a new partner, working from home, parents, and now the election drama. 

At this point in the visit, I knew I could help her. First, the treatment for lichen sclerosus is straightforward and mostly effective. Second, I knew I’d have 7 minutes to spare to just listen. It was a lucky break, as often no such gift of time presents itself while seeing patients in a busy clinic. We take vitals, history (typing), do an exam, make a diagnosis (more typing), and maybe a procedure (yet more typing). All of this is necessary, but sometimes not what our patient needs. Some really need just to connect and share their burden with someone who isn’t a friend or family. As physicians, we have a unique opportunity to see and hear people without judgment.

This reminds me of a recent episode from Sam Harris’s podcast, “Making Sense.” Mr. Harris, a philosopher (and “blue” all the way through) revealed his insight into Presidents Trump’s appeal. Leaving policy aside, Mr. Harris notes that people are drawn to the President because he never judges you. He is incapable of being sanctimonious, Mr. Harris argues, and therefore creates a safe space for people to continue their lives, however flawed, without expectation that they improve. 

I’m unsure just how much of this theory explains the devotion of his supporters, but it resonated with me. We doctors are sanctimonious by nature. The better part of my day is spent prodding people to be better: Wear more sunscreen, exercise more, stop believing in conspiracy theories, get your flu shot, and above all, stop scratching! In doing so, I’m in a way judging them. Finger wagging: You’re lazy or poor or dumb or stubborn. “You aren’t as good as me,” is what they might feel after 15 minutes of my pep talk.

But what if that’s wrong? What if they are just fine exactly the way they are? Perhaps what my lichen sclerosis patient needs more than anything is unconditional attention? She, like most of our patients, is well aware of how her shortcomings might contribute to her own anxiety or difficulties. And now she has this rash and that’s probably somehow her fault too, she thinks. 

How can I best help her? Betamethasone dipropionate b.i.d. for 2 weeks and spend the last 7 minutes just sitting and listening without judgment or advice. I don’t know who she wanted to win the election. It didn’t matter, she was exactly right to believe what she believed, either way.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

“What do you think of all this election stuff?” I froze. Sitting on the exam table was a 50-something-year-old woman. Her hair was long, but not gray. She was wearing a mask without distinctive markings, such as Trump lips or #BLM to identify the political leanings of the owner. She had a subtle New York accent, perhaps dating back to the Giuliani years. It was hard to know her intention. “It’s a trap!” I could hear Admiral Ackbar’s voice in my head. “Don’t engage.” We all know nothing erodes trust faster than showing your blue or red colors before you know which your patient identifies.

Instead, I replied that indeed it has been a stressful year for us all. Then I paused. She shifted a bit and tugged at the gown sleeves and admitted this was the most stress she felt in years. She was seeing me for lichen sclerosus et atrophicus, a terribly itchy, sometimes-disfiguring eruption that can occur in the vulva. She was dealing with COVID-19, kids, divorce, a new partner, working from home, parents, and now the election drama. 

At this point in the visit, I knew I could help her. First, the treatment for lichen sclerosus is straightforward and mostly effective. Second, I knew I’d have 7 minutes to spare to just listen. It was a lucky break, as often no such gift of time presents itself while seeing patients in a busy clinic. We take vitals, history (typing), do an exam, make a diagnosis (more typing), and maybe a procedure (yet more typing). All of this is necessary, but sometimes not what our patient needs. Some really need just to connect and share their burden with someone who isn’t a friend or family. As physicians, we have a unique opportunity to see and hear people without judgment.

This reminds me of a recent episode from Sam Harris’s podcast, “Making Sense.” Mr. Harris, a philosopher (and “blue” all the way through) revealed his insight into Presidents Trump’s appeal. Leaving policy aside, Mr. Harris notes that people are drawn to the President because he never judges you. He is incapable of being sanctimonious, Mr. Harris argues, and therefore creates a safe space for people to continue their lives, however flawed, without expectation that they improve. 

I’m unsure just how much of this theory explains the devotion of his supporters, but it resonated with me. We doctors are sanctimonious by nature. The better part of my day is spent prodding people to be better: Wear more sunscreen, exercise more, stop believing in conspiracy theories, get your flu shot, and above all, stop scratching! In doing so, I’m in a way judging them. Finger wagging: You’re lazy or poor or dumb or stubborn. “You aren’t as good as me,” is what they might feel after 15 minutes of my pep talk.

But what if that’s wrong? What if they are just fine exactly the way they are? Perhaps what my lichen sclerosis patient needs more than anything is unconditional attention? She, like most of our patients, is well aware of how her shortcomings might contribute to her own anxiety or difficulties. And now she has this rash and that’s probably somehow her fault too, she thinks. 

How can I best help her? Betamethasone dipropionate b.i.d. for 2 weeks and spend the last 7 minutes just sitting and listening without judgment or advice. I don’t know who she wanted to win the election. It didn’t matter, she was exactly right to believe what she believed, either way.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].