Medical Center

WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.

In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.

There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.

However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.

The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).

“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.

“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”

Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.

In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

Trial interventions

GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).

The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).

They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.

For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.

Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.

The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.

Results

The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).

The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.

There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.

“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”

“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”

Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.

Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.

Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.

“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.

Medical Center

WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.

In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.

There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.

However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.

The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).

“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.

“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”

Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.

In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

Trial interventions

GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).

The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).

They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.

For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.

Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.

The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.

Results

The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).

The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.

There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.

“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”

“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”

Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.

Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.

Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.

“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.

Medical Center

WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.

In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.

There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.

However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.

The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).

“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.

“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”

Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.

In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

Trial interventions

GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).

The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).

They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.

For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.

Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.

The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.

Results

The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).

The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.

There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.

“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”

“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”

Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.

Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.

Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.

“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.

Photo courtesy of the FDA

The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.

However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.

The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.

The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.

Background and MDRs

The FDA first identified a possible association between ALCL and breast implants in 2011.

The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.

The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.

The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.

Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.

Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.

Recommendations

The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.

Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.

Patients with suspected BIA-ALCL should be referred to an appropriate specialist.

When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.

Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.

When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.

Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).

Photo courtesy of the FDA

The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.

However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.

The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.

The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.

Background and MDRs

The FDA first identified a possible association between ALCL and breast implants in 2011.

The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.

The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.

The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.

Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.

Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.

Recommendations

The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.

Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.

Patients with suspected BIA-ALCL should be referred to an appropriate specialist.

When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.

Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.

When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.

Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).

Photo courtesy of the FDA

The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.

However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.

The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.

The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.

Background and MDRs

The FDA first identified a possible association between ALCL and breast implants in 2011.

The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.

The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.

The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.

Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.

Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.

Recommendations

The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.

Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.

Patients with suspected BIA-ALCL should be referred to an appropriate specialist.

When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.

Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.

When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.

Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).

Attention-deficit/hyperactivity disorder (ADHD) is common; it affects 5% to 7% of children^1,2 and 4% to 5% of all adults.^3,4 Pediatric ADHD often persists into adulthood, as 65% of individuals diagnosed as children retain impairing symptoms by age 25.⁴

The prevalence of ADHD in childhood is 2 to 3 times greater among boys than girls, but more comparable between the sexes in adulthood.² Symptoms could be more easily overlooked in women because of the greater prominence of hyperactivity and impulsivity-type symptoms in men.⁵

Untreated ADHD is associated with significant costs. Adults with ADHD have increased unemployment rates, poor work performance, and comparatively lower educational performance.^6,7 Compared with non-ADHD adults, those with ADHD have:

• more traffic violations and accidents and a higher rate of criminal convictions and incarcerations^8,9
• a mortality rate almost 2 times higher, with the greatest differences seen in deaths by suicide and accidents.^10,11

Adults with ADHD also are more likely to have a comorbid psychiatric disorder—in particular, substance use¹¹—and often are in treatment for other mental or substance use disorders. Among adults who meet diagnostic criteria for ADHD, approximately only 10% are receiving treatment for ADHD symptoms.^3,12

Changes in DSM-5

Revisions within DSM-5 simplify ADHD’s diagnosis—and make it more difficult to ignore in

DSM-5 also provides examples of behaviors more commonly found in adults, such as “feelings of restlessness,” compared with DSM-IV’s “often runs about or climbs excessively in situations in which it is inappropriate.” Finally, ADHD now may be diagnosed in a person with an autism spectrum disorder who meets diagnostic criteria for both disorders.^13,14

Identifying ADHD in adults

ADHD diagnosis in adults is made through careful clinical interviewing. For example, ask about what factors motivated an individual to seek evaluation for ADHD. Often, patients present after a change in responsibility at work or at home, such as a promotion or birth/adoption of a new child.

Consider incorporating a brief screen for adult ADHD in all new outpatient evaluations (Table 2).¹⁵ Screen for other psychiatric disorders as well; comorbidity with ADHD is high, and hyperactivity and inattention symptoms may result from anxiety, depression, or substance use.

Screen for learning disorders, which can present with ADHD symptoms (such as poor concentration) when the individual attempts difficult tasks. Evaluate for risk factors associated with ADHD medications, such as a history of cardiac problems, hypertension, or tachycardia. A family history of ADHD is found in approximately 80% of cases.^16,17 Determine the presence of ADHD symptoms in childhood. A careful review of the educational history often reveals long-term underachievement and struggles in school. Patients may report a chronic history of poor attention or feelings of restlessness in school. Sometimes problems do not become apparent until high school or college; some individuals, especially those with high intelligence, compensate for deficits and show fewer overt symptoms of impairment until later in their education.¹⁸Occupational history also may be revealing:

• How are they performing at work?
• Have they changed jobs multiple times in a short period?
• Do they have difficulty organizing tasks?

Subtle ADHD signs include time of arrival to appointments (eg, late or extremely early), missing data on intake paperwork, and a history of losing keys or phones.

Neuropsychological testing. Some clinicians routinely include neuropsychological testing in an adult ADHD evaluation, but these studies have shown inconsistent cognitive deficits in people with ADHD.^19,20 No distinct psychometric cognitive test or profile is diagnostic of ADHD or its subtypes.²¹

Treatment and follow-up care

Four general categories of medications are used to treat ADHD in children and adults:

After starting a patient on medication, at each follow-up appointment ask about new cardiac symptoms or diagnoses, new family history of cardiac problems, or new medications. Measure pulse and blood pressure every 1 to 3 months. Measure vital signs more frequently during titration and weaning periods.²³

Stimulant medications

Amphetamines have dual action: they block the reuptake of dopamine and noradrenaline by competitive inhibition of the transporters and promote the release of dopamine and noradrenaline by competitive inhibition of the intraneuronal vesicular monoamine transporter.²⁴

For most amphetamine products, including dextroamphetamine and amphetamine mixed salts, the target dosage is approximately 0.5 mg/kg. Start at a lower dosage, however, and rapidly titrate weekly so patients can adjust to the medication while not becoming frustrated with a lack of efficacy. Some patients may require short-acting forms with dosing 3 times per day, and twice daily dosing is not uncommon with extended-release (ER) formulations.

Metabolism of most amphetamine products—with the exception of lisdexamfetamine—involves the cytochrome P450 (CYP) enzyme CYP2D6, leading to the formation of the metabolite 4-hydroxyamphetamine.²⁵ The pharmacokinetics of lisdexamfetamine in slow or ultra-rapid CYP2D6 metabolizers has not been evaluated (Shire US Inc., written communication, July 2014).

Agents that alter urinary pH can affect blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels.²⁶

Lisdexamfetamine contains L-lysine, an essential amino acid, covalently bound to d-amphetamine via an amide linking group.²⁷ After absorption, lisdexamfetamine is metabolized by rate-limited, enzymatic hydrolysis to yield d-amphetamine and L-lysine.^24,28,29 A starting dose of 40 mg is advised; twice-daily dosing rarely is required.

A meta-analysis of 5 randomized, controlled trials in the treatment of adult ADHD showed a response rate of 70% for lisdexamfetamine compared with 37% for placebo. Trial duration ranged from 4 to 14 weeks, with dosages of 30 to 70 mg/d.³⁰ Another analysis of data from lisdexamfetamine trials predicted an effect size of 1.07 for European adults, which is larger than the 0.8 threshold for large effect sizes.³¹

Methylphenidate products. Methyl­phenidate’s main action is through enhancement of dopamine signaling by blockade of the dopamine transporter, leading to increases in extracellular dopamine as well as norepinephrine.^22,32 Optimized dosing is generally 1 mg/kg per day, and dosing up to 80 to 120 mg/d is not unusual.³³

Dexmethylphenidate is the more pharmacologically active enantiomer of racemic methylphenidate and is twice as potent.^34-36 Target dosing of dexmethylphenidate should be one-half as much (ie, 0.5 mg/kg per day) as other methylphenidate products.³⁷

Managing stimulants’ side effects

Amphetamines’ side effects may include insomnia, dry mouth, decreased appetite, weight loss, headaches, and anxiety. To help minimize sleep problems, advise patients to take a second immediate-release dose at noon, rather than later in the afternoon. The longer-acting formulation taken once per day in the morning may be offered as an alternative. Some patients may experience improved sleep because of diminished bedtime ruminations.

Oral rinses, such as Biotène, could help reduce discomfort associated with dry mouth. Pilocarpine, which stimulates saliva production, is another option if rinses are not effective. To address decreased appetite, advise patients to take their medication after they eat. Switching from an immediate-release amphetamine to a longer-acting formulation also may lessen symptoms. Lisdexamfetamine might be a good choice for adults with ADHD who have undergone bariatric surgeries because it is absorbed in the small bowel.³⁸

Methylphenidate has no interactions with CYP enzymes, making it an attractive option for patients taking CYP inhibiting or stimulating medications.³⁹ The most common side effects of methylphenidate products include appetite loss, insomnia, irritability, and tachycardia. Some side effects will abate after 1 to 2 weeks of treatment, but persistence of insomnia and appetite loss may require a decrease in dosage. In rare cases, methylphenidate may produce tics, exacerbate an existing tic disorder, or produce mania or psychosis.^40,41 Methylphenidate inhibits the metabolism of tricyclic antidepressants; use methylphenidate with caution in patients taking monoamine oxidase inhibitors.^42,43Cardiovascular risks. Possible cardiovascular risks associated with stimulant use have gained widespread attention, although research has not demonstrated an increased risk of serious cardiovascular events in young and middle-aged adults receiving stimulant medications for ADHD.⁴⁴ Nonetheless, obtain a thorough medical history in adult patients, including cardiac history, family history of cardiac disease, history of any cardiac symptoms, and a medication history. Baseline ECG is not required.⁴⁵

Screen for a family history of sudden death in a young person, sudden death during exercise, cardiac arrhythmia, cardiomyopathies (including hypertrophic cardiomyopathy, dilated cardiomyopathy, and right ventricular cardiomyopathy), prolonged QT interval, short QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, Marfan syndrome, and an event requiring resuscitation in a family member younger than 35, including syncope requiring rescuscitation.²³ If fainting spells, palpitations, chest pain, or other symptoms suggest preexisting cardiovascular disease, refer the patient promptly to a cardiologist.

Peripheral vasculopathy, including Raynaud’s phenomenon, is a lesser known side effect associated with stimulants.⁴⁶ Symptoms are usually mild, but in rare instances stimulants are associated with digital ulceration or soft tissue breakdown.⁴⁷ Advise patients to tell you if they experience any new symptoms of numbness, pain, skin color changes, or sensitivity to temperature in fingers and toes. Signs and symptoms generally improve after dosage reduction or discontinuation of the stimulant medication.⁴⁶ Referral to a rheumatologist might be appropriate if symptoms persist.

A noradrenergic medication

Atomoxetine is a potent, selective inhibitor of the presynaptic noradrenaline transporter that increases the availability of extracellular noradrenaline in the prefrontal cortex.^48,49 Atomoxetine may be a good alternative for adult patients with ADHD and comorbid anxiety.⁵⁰

For adults, the optimal starting dosage is 40 mg in the morning for 1 week, followed by an increase to 80 mg. Insufficient dosing is common with atomoxetine, and the dosage could be increased to 100 mg/d.⁵¹ Dosing twice per day may be associated with higher rates of insomnia.

Atomoxetine’s efficacy for managing ADHD in adults has been consistently demonstrated by 6 placebo-controlled trials of 10 to 16 weeks, 3 placebo-controlled 6-month trials, and a 1-year maintenance-of-response trial.⁵² Atomoxetine was found to have an effect size of 0.45 (medium) (number needed to treat [NNT] = 5).^53-55The most common adverse effects include nausea, dry mouth, insomnia, and erectile dysfunction. Small increases in heart rate and blood pressure have been reported, so use this medication with caution in patients for whom this might be problematic. Atomoxetine is metabolized by CYP2D6; 7% of white individuals have a genotype corresponding to a nonfunctional CYP2D6 enzyme.^56-58

Alpha-2 adrenergic agonists

Clonidine and guanfacine are antihypertensive drugs that induce peripheral sympathoinhibition via the stimulation of receptors. Clonidine binds equally to adrenergic receptor subtypes α-2A, α-2B, and α-2C (as well as to α-1 and β subtypes, histamine receptors, and possibly dopamine receptors).^59,60 Guanfacine binds preferentially to postsynaptic α-2A adrenoceptors in the prefrontal cortex, which have been implicated in attentional and organizational functions.^61,62

ER guanfacine and ER clonidine are FDA-approved as monotherapy for ADHD in children and adolescents.

Efficacy in adults. A small (N = 17), double-blind, placebo-controlled, crossover study comparing immediate-release guanfacine and dextroamphetamine found that both medications significantly reduced adult ADHD symptoms, as measured with the DSM-IV Adult Behavior Checklist for Adults.⁶³

No trials have been published regarding the efficacy of ER clonidine in adults with ADHD; adverse effects including sedation, bradycardia, and hypotension may limit its use. One study compared the supplemental use of ER guanfacine (1 to 6 mg/d) or a matching placebo in 26 adults with ADHD who had suboptimal response to stimulant-only treatment. After 10 weeks, both the guanfacine ER and placebo groups showed statistically significant improvements in ADHD symptoms and general functioning. The treatments did not differ in efficacy, safety, or tolerability.⁶⁴

Adverse events. Compared with clonidine, guanfacine has less CNS depressant and hypotensive activity.⁵⁸ A phase I trial of ER guanfacine in healthy adults found its single-dose pharmacokinetic properties in 1-, 2-, and 4-mg tablets appeared to be statistically linear. Somnolence—the most common treatment-emergent adverse effect—occurred in 33 of 52 participants (63.5%). All mean vital-sign measurements and ECG parameters remained within normal limits after dosing, and no marked changes from baseline measurements were noted.⁶⁵

Antidepressants

Antidepressants used in ADHD treatment include bupropion and tricyclic antidepressants.
Bupropion is a noradrenaline and dopamine reuptake inhibitor and is considered to be a mild psychostimulant because of its amphetamine-derived chemical structure.^66,67 It generally is considered a third-line medication when stimulants have not improved ADHD symptoms or are not tolerated.

A 2011 meta-analysis examined 5 randomized, controlled trials including 175 adults treated with bupropion for ADHD. Bupropion was found to be more effective than placebo (NNT = 5), although bupropion’s therapeutic benefits were not observed until weeks 5 and 6. Its effects were less pronounced than those of methylphenidate. Mean daily dosages were 362 mg for the bupropion SR trials and 393 mg for the bupropion XL trial.⁶⁸

Tricyclics. Desipramine and nortriptyline have been found to be efficacious in childhood ADHD,^69,70 although cardiovascular risk and toxicity in overdose limit their use.⁷¹

Attention-deficit/hyperactivity disorder (ADHD) is common; it affects 5% to 7% of children^1,2 and 4% to 5% of all adults.^3,4 Pediatric ADHD often persists into adulthood, as 65% of individuals diagnosed as children retain impairing symptoms by age 25.⁴

The prevalence of ADHD in childhood is 2 to 3 times greater among boys than girls, but more comparable between the sexes in adulthood.² Symptoms could be more easily overlooked in women because of the greater prominence of hyperactivity and impulsivity-type symptoms in men.⁵

Untreated ADHD is associated with significant costs. Adults with ADHD have increased unemployment rates, poor work performance, and comparatively lower educational performance.^6,7 Compared with non-ADHD adults, those with ADHD have:

• more traffic violations and accidents and a higher rate of criminal convictions and incarcerations^8,9
• a mortality rate almost 2 times higher, with the greatest differences seen in deaths by suicide and accidents.^10,11

Adults with ADHD also are more likely to have a comorbid psychiatric disorder—in particular, substance use¹¹—and often are in treatment for other mental or substance use disorders. Among adults who meet diagnostic criteria for ADHD, approximately only 10% are receiving treatment for ADHD symptoms.^3,12

Changes in DSM-5

Revisions within DSM-5 simplify ADHD’s diagnosis—and make it more difficult to ignore in

DSM-5 also provides examples of behaviors more commonly found in adults, such as “feelings of restlessness,” compared with DSM-IV’s “often runs about or climbs excessively in situations in which it is inappropriate.” Finally, ADHD now may be diagnosed in a person with an autism spectrum disorder who meets diagnostic criteria for both disorders.^13,14

Identifying ADHD in adults

ADHD diagnosis in adults is made through careful clinical interviewing. For example, ask about what factors motivated an individual to seek evaluation for ADHD. Often, patients present after a change in responsibility at work or at home, such as a promotion or birth/adoption of a new child.

Consider incorporating a brief screen for adult ADHD in all new outpatient evaluations (Table 2).¹⁵ Screen for other psychiatric disorders as well; comorbidity with ADHD is high, and hyperactivity and inattention symptoms may result from anxiety, depression, or substance use.

Screen for learning disorders, which can present with ADHD symptoms (such as poor concentration) when the individual attempts difficult tasks. Evaluate for risk factors associated with ADHD medications, such as a history of cardiac problems, hypertension, or tachycardia. A family history of ADHD is found in approximately 80% of cases.^16,17 Determine the presence of ADHD symptoms in childhood. A careful review of the educational history often reveals long-term underachievement and struggles in school. Patients may report a chronic history of poor attention or feelings of restlessness in school. Sometimes problems do not become apparent until high school or college; some individuals, especially those with high intelligence, compensate for deficits and show fewer overt symptoms of impairment until later in their education.¹⁸Occupational history also may be revealing:

• How are they performing at work?
• Have they changed jobs multiple times in a short period?
• Do they have difficulty organizing tasks?

Subtle ADHD signs include time of arrival to appointments (eg, late or extremely early), missing data on intake paperwork, and a history of losing keys or phones.

Neuropsychological testing. Some clinicians routinely include neuropsychological testing in an adult ADHD evaluation, but these studies have shown inconsistent cognitive deficits in people with ADHD.^19,20 No distinct psychometric cognitive test or profile is diagnostic of ADHD or its subtypes.²¹

Treatment and follow-up care

Four general categories of medications are used to treat ADHD in children and adults:

After starting a patient on medication, at each follow-up appointment ask about new cardiac symptoms or diagnoses, new family history of cardiac problems, or new medications. Measure pulse and blood pressure every 1 to 3 months. Measure vital signs more frequently during titration and weaning periods.²³

Stimulant medications

Amphetamines have dual action: they block the reuptake of dopamine and noradrenaline by competitive inhibition of the transporters and promote the release of dopamine and noradrenaline by competitive inhibition of the intraneuronal vesicular monoamine transporter.²⁴

For most amphetamine products, including dextroamphetamine and amphetamine mixed salts, the target dosage is approximately 0.5 mg/kg. Start at a lower dosage, however, and rapidly titrate weekly so patients can adjust to the medication while not becoming frustrated with a lack of efficacy. Some patients may require short-acting forms with dosing 3 times per day, and twice daily dosing is not uncommon with extended-release (ER) formulations.

Metabolism of most amphetamine products—with the exception of lisdexamfetamine—involves the cytochrome P450 (CYP) enzyme CYP2D6, leading to the formation of the metabolite 4-hydroxyamphetamine.²⁵ The pharmacokinetics of lisdexamfetamine in slow or ultra-rapid CYP2D6 metabolizers has not been evaluated (Shire US Inc., written communication, July 2014).

Agents that alter urinary pH can affect blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels.²⁶

Lisdexamfetamine contains L-lysine, an essential amino acid, covalently bound to d-amphetamine via an amide linking group.²⁷ After absorption, lisdexamfetamine is metabolized by rate-limited, enzymatic hydrolysis to yield d-amphetamine and L-lysine.^24,28,29 A starting dose of 40 mg is advised; twice-daily dosing rarely is required.

A meta-analysis of 5 randomized, controlled trials in the treatment of adult ADHD showed a response rate of 70% for lisdexamfetamine compared with 37% for placebo. Trial duration ranged from 4 to 14 weeks, with dosages of 30 to 70 mg/d.³⁰ Another analysis of data from lisdexamfetamine trials predicted an effect size of 1.07 for European adults, which is larger than the 0.8 threshold for large effect sizes.³¹

Methylphenidate products. Methyl­phenidate’s main action is through enhancement of dopamine signaling by blockade of the dopamine transporter, leading to increases in extracellular dopamine as well as norepinephrine.^22,32 Optimized dosing is generally 1 mg/kg per day, and dosing up to 80 to 120 mg/d is not unusual.³³

Dexmethylphenidate is the more pharmacologically active enantiomer of racemic methylphenidate and is twice as potent.^34-36 Target dosing of dexmethylphenidate should be one-half as much (ie, 0.5 mg/kg per day) as other methylphenidate products.³⁷

Managing stimulants’ side effects

Amphetamines’ side effects may include insomnia, dry mouth, decreased appetite, weight loss, headaches, and anxiety. To help minimize sleep problems, advise patients to take a second immediate-release dose at noon, rather than later in the afternoon. The longer-acting formulation taken once per day in the morning may be offered as an alternative. Some patients may experience improved sleep because of diminished bedtime ruminations.

Oral rinses, such as Biotène, could help reduce discomfort associated with dry mouth. Pilocarpine, which stimulates saliva production, is another option if rinses are not effective. To address decreased appetite, advise patients to take their medication after they eat. Switching from an immediate-release amphetamine to a longer-acting formulation also may lessen symptoms. Lisdexamfetamine might be a good choice for adults with ADHD who have undergone bariatric surgeries because it is absorbed in the small bowel.³⁸

Methylphenidate has no interactions with CYP enzymes, making it an attractive option for patients taking CYP inhibiting or stimulating medications.³⁹ The most common side effects of methylphenidate products include appetite loss, insomnia, irritability, and tachycardia. Some side effects will abate after 1 to 2 weeks of treatment, but persistence of insomnia and appetite loss may require a decrease in dosage. In rare cases, methylphenidate may produce tics, exacerbate an existing tic disorder, or produce mania or psychosis.^40,41 Methylphenidate inhibits the metabolism of tricyclic antidepressants; use methylphenidate with caution in patients taking monoamine oxidase inhibitors.^42,43Cardiovascular risks. Possible cardiovascular risks associated with stimulant use have gained widespread attention, although research has not demonstrated an increased risk of serious cardiovascular events in young and middle-aged adults receiving stimulant medications for ADHD.⁴⁴ Nonetheless, obtain a thorough medical history in adult patients, including cardiac history, family history of cardiac disease, history of any cardiac symptoms, and a medication history. Baseline ECG is not required.⁴⁵

Screen for a family history of sudden death in a young person, sudden death during exercise, cardiac arrhythmia, cardiomyopathies (including hypertrophic cardiomyopathy, dilated cardiomyopathy, and right ventricular cardiomyopathy), prolonged QT interval, short QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, Marfan syndrome, and an event requiring resuscitation in a family member younger than 35, including syncope requiring rescuscitation.²³ If fainting spells, palpitations, chest pain, or other symptoms suggest preexisting cardiovascular disease, refer the patient promptly to a cardiologist.

Peripheral vasculopathy, including Raynaud’s phenomenon, is a lesser known side effect associated with stimulants.⁴⁶ Symptoms are usually mild, but in rare instances stimulants are associated with digital ulceration or soft tissue breakdown.⁴⁷ Advise patients to tell you if they experience any new symptoms of numbness, pain, skin color changes, or sensitivity to temperature in fingers and toes. Signs and symptoms generally improve after dosage reduction or discontinuation of the stimulant medication.⁴⁶ Referral to a rheumatologist might be appropriate if symptoms persist.

A noradrenergic medication

Atomoxetine is a potent, selective inhibitor of the presynaptic noradrenaline transporter that increases the availability of extracellular noradrenaline in the prefrontal cortex.^48,49 Atomoxetine may be a good alternative for adult patients with ADHD and comorbid anxiety.⁵⁰

For adults, the optimal starting dosage is 40 mg in the morning for 1 week, followed by an increase to 80 mg. Insufficient dosing is common with atomoxetine, and the dosage could be increased to 100 mg/d.⁵¹ Dosing twice per day may be associated with higher rates of insomnia.

Atomoxetine’s efficacy for managing ADHD in adults has been consistently demonstrated by 6 placebo-controlled trials of 10 to 16 weeks, 3 placebo-controlled 6-month trials, and a 1-year maintenance-of-response trial.⁵² Atomoxetine was found to have an effect size of 0.45 (medium) (number needed to treat [NNT] = 5).^53-55The most common adverse effects include nausea, dry mouth, insomnia, and erectile dysfunction. Small increases in heart rate and blood pressure have been reported, so use this medication with caution in patients for whom this might be problematic. Atomoxetine is metabolized by CYP2D6; 7% of white individuals have a genotype corresponding to a nonfunctional CYP2D6 enzyme.^56-58

Alpha-2 adrenergic agonists

Clonidine and guanfacine are antihypertensive drugs that induce peripheral sympathoinhibition via the stimulation of receptors. Clonidine binds equally to adrenergic receptor subtypes α-2A, α-2B, and α-2C (as well as to α-1 and β subtypes, histamine receptors, and possibly dopamine receptors).^59,60 Guanfacine binds preferentially to postsynaptic α-2A adrenoceptors in the prefrontal cortex, which have been implicated in attentional and organizational functions.^61,62

ER guanfacine and ER clonidine are FDA-approved as monotherapy for ADHD in children and adolescents.

Efficacy in adults. A small (N = 17), double-blind, placebo-controlled, crossover study comparing immediate-release guanfacine and dextroamphetamine found that both medications significantly reduced adult ADHD symptoms, as measured with the DSM-IV Adult Behavior Checklist for Adults.⁶³

No trials have been published regarding the efficacy of ER clonidine in adults with ADHD; adverse effects including sedation, bradycardia, and hypotension may limit its use. One study compared the supplemental use of ER guanfacine (1 to 6 mg/d) or a matching placebo in 26 adults with ADHD who had suboptimal response to stimulant-only treatment. After 10 weeks, both the guanfacine ER and placebo groups showed statistically significant improvements in ADHD symptoms and general functioning. The treatments did not differ in efficacy, safety, or tolerability.⁶⁴

Adverse events. Compared with clonidine, guanfacine has less CNS depressant and hypotensive activity.⁵⁸ A phase I trial of ER guanfacine in healthy adults found its single-dose pharmacokinetic properties in 1-, 2-, and 4-mg tablets appeared to be statistically linear. Somnolence—the most common treatment-emergent adverse effect—occurred in 33 of 52 participants (63.5%). All mean vital-sign measurements and ECG parameters remained within normal limits after dosing, and no marked changes from baseline measurements were noted.⁶⁵

Antidepressants

Antidepressants used in ADHD treatment include bupropion and tricyclic antidepressants.
Bupropion is a noradrenaline and dopamine reuptake inhibitor and is considered to be a mild psychostimulant because of its amphetamine-derived chemical structure.^66,67 It generally is considered a third-line medication when stimulants have not improved ADHD symptoms or are not tolerated.

A 2011 meta-analysis examined 5 randomized, controlled trials including 175 adults treated with bupropion for ADHD. Bupropion was found to be more effective than placebo (NNT = 5), although bupropion’s therapeutic benefits were not observed until weeks 5 and 6. Its effects were less pronounced than those of methylphenidate. Mean daily dosages were 362 mg for the bupropion SR trials and 393 mg for the bupropion XL trial.⁶⁸

Tricyclics. Desipramine and nortriptyline have been found to be efficacious in childhood ADHD,^69,70 although cardiovascular risk and toxicity in overdose limit their use.⁷¹

Attention-deficit/hyperactivity disorder (ADHD) is common; it affects 5% to 7% of children^1,2 and 4% to 5% of all adults.^3,4 Pediatric ADHD often persists into adulthood, as 65% of individuals diagnosed as children retain impairing symptoms by age 25.⁴

The prevalence of ADHD in childhood is 2 to 3 times greater among boys than girls, but more comparable between the sexes in adulthood.² Symptoms could be more easily overlooked in women because of the greater prominence of hyperactivity and impulsivity-type symptoms in men.⁵

Untreated ADHD is associated with significant costs. Adults with ADHD have increased unemployment rates, poor work performance, and comparatively lower educational performance.^6,7 Compared with non-ADHD adults, those with ADHD have:

• more traffic violations and accidents and a higher rate of criminal convictions and incarcerations^8,9
• a mortality rate almost 2 times higher, with the greatest differences seen in deaths by suicide and accidents.^10,11

Adults with ADHD also are more likely to have a comorbid psychiatric disorder—in particular, substance use¹¹—and often are in treatment for other mental or substance use disorders. Among adults who meet diagnostic criteria for ADHD, approximately only 10% are receiving treatment for ADHD symptoms.^3,12

Changes in DSM-5

Revisions within DSM-5 simplify ADHD’s diagnosis—and make it more difficult to ignore in

DSM-5 also provides examples of behaviors more commonly found in adults, such as “feelings of restlessness,” compared with DSM-IV’s “often runs about or climbs excessively in situations in which it is inappropriate.” Finally, ADHD now may be diagnosed in a person with an autism spectrum disorder who meets diagnostic criteria for both disorders.^13,14

Identifying ADHD in adults

ADHD diagnosis in adults is made through careful clinical interviewing. For example, ask about what factors motivated an individual to seek evaluation for ADHD. Often, patients present after a change in responsibility at work or at home, such as a promotion or birth/adoption of a new child.

Consider incorporating a brief screen for adult ADHD in all new outpatient evaluations (Table 2).¹⁵ Screen for other psychiatric disorders as well; comorbidity with ADHD is high, and hyperactivity and inattention symptoms may result from anxiety, depression, or substance use.

Screen for learning disorders, which can present with ADHD symptoms (such as poor concentration) when the individual attempts difficult tasks. Evaluate for risk factors associated with ADHD medications, such as a history of cardiac problems, hypertension, or tachycardia. A family history of ADHD is found in approximately 80% of cases.^16,17 Determine the presence of ADHD symptoms in childhood. A careful review of the educational history often reveals long-term underachievement and struggles in school. Patients may report a chronic history of poor attention or feelings of restlessness in school. Sometimes problems do not become apparent until high school or college; some individuals, especially those with high intelligence, compensate for deficits and show fewer overt symptoms of impairment until later in their education.¹⁸Occupational history also may be revealing:

• How are they performing at work?
• Have they changed jobs multiple times in a short period?
• Do they have difficulty organizing tasks?

Subtle ADHD signs include time of arrival to appointments (eg, late or extremely early), missing data on intake paperwork, and a history of losing keys or phones.

Neuropsychological testing. Some clinicians routinely include neuropsychological testing in an adult ADHD evaluation, but these studies have shown inconsistent cognitive deficits in people with ADHD.^19,20 No distinct psychometric cognitive test or profile is diagnostic of ADHD or its subtypes.²¹

Treatment and follow-up care

Four general categories of medications are used to treat ADHD in children and adults:

After starting a patient on medication, at each follow-up appointment ask about new cardiac symptoms or diagnoses, new family history of cardiac problems, or new medications. Measure pulse and blood pressure every 1 to 3 months. Measure vital signs more frequently during titration and weaning periods.²³

Stimulant medications

Amphetamines have dual action: they block the reuptake of dopamine and noradrenaline by competitive inhibition of the transporters and promote the release of dopamine and noradrenaline by competitive inhibition of the intraneuronal vesicular monoamine transporter.²⁴

For most amphetamine products, including dextroamphetamine and amphetamine mixed salts, the target dosage is approximately 0.5 mg/kg. Start at a lower dosage, however, and rapidly titrate weekly so patients can adjust to the medication while not becoming frustrated with a lack of efficacy. Some patients may require short-acting forms with dosing 3 times per day, and twice daily dosing is not uncommon with extended-release (ER) formulations.

Metabolism of most amphetamine products—with the exception of lisdexamfetamine—involves the cytochrome P450 (CYP) enzyme CYP2D6, leading to the formation of the metabolite 4-hydroxyamphetamine.²⁵ The pharmacokinetics of lisdexamfetamine in slow or ultra-rapid CYP2D6 metabolizers has not been evaluated (Shire US Inc., written communication, July 2014).

Agents that alter urinary pH can affect blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels.²⁶

Lisdexamfetamine contains L-lysine, an essential amino acid, covalently bound to d-amphetamine via an amide linking group.²⁷ After absorption, lisdexamfetamine is metabolized by rate-limited, enzymatic hydrolysis to yield d-amphetamine and L-lysine.^24,28,29 A starting dose of 40 mg is advised; twice-daily dosing rarely is required.

A meta-analysis of 5 randomized, controlled trials in the treatment of adult ADHD showed a response rate of 70% for lisdexamfetamine compared with 37% for placebo. Trial duration ranged from 4 to 14 weeks, with dosages of 30 to 70 mg/d.³⁰ Another analysis of data from lisdexamfetamine trials predicted an effect size of 1.07 for European adults, which is larger than the 0.8 threshold for large effect sizes.³¹

Methylphenidate products. Methyl­phenidate’s main action is through enhancement of dopamine signaling by blockade of the dopamine transporter, leading to increases in extracellular dopamine as well as norepinephrine.^22,32 Optimized dosing is generally 1 mg/kg per day, and dosing up to 80 to 120 mg/d is not unusual.³³

Dexmethylphenidate is the more pharmacologically active enantiomer of racemic methylphenidate and is twice as potent.^34-36 Target dosing of dexmethylphenidate should be one-half as much (ie, 0.5 mg/kg per day) as other methylphenidate products.³⁷

Managing stimulants’ side effects

Amphetamines’ side effects may include insomnia, dry mouth, decreased appetite, weight loss, headaches, and anxiety. To help minimize sleep problems, advise patients to take a second immediate-release dose at noon, rather than later in the afternoon. The longer-acting formulation taken once per day in the morning may be offered as an alternative. Some patients may experience improved sleep because of diminished bedtime ruminations.

Oral rinses, such as Biotène, could help reduce discomfort associated with dry mouth. Pilocarpine, which stimulates saliva production, is another option if rinses are not effective. To address decreased appetite, advise patients to take their medication after they eat. Switching from an immediate-release amphetamine to a longer-acting formulation also may lessen symptoms. Lisdexamfetamine might be a good choice for adults with ADHD who have undergone bariatric surgeries because it is absorbed in the small bowel.³⁸

Methylphenidate has no interactions with CYP enzymes, making it an attractive option for patients taking CYP inhibiting or stimulating medications.³⁹ The most common side effects of methylphenidate products include appetite loss, insomnia, irritability, and tachycardia. Some side effects will abate after 1 to 2 weeks of treatment, but persistence of insomnia and appetite loss may require a decrease in dosage. In rare cases, methylphenidate may produce tics, exacerbate an existing tic disorder, or produce mania or psychosis.^40,41 Methylphenidate inhibits the metabolism of tricyclic antidepressants; use methylphenidate with caution in patients taking monoamine oxidase inhibitors.^42,43Cardiovascular risks. Possible cardiovascular risks associated with stimulant use have gained widespread attention, although research has not demonstrated an increased risk of serious cardiovascular events in young and middle-aged adults receiving stimulant medications for ADHD.⁴⁴ Nonetheless, obtain a thorough medical history in adult patients, including cardiac history, family history of cardiac disease, history of any cardiac symptoms, and a medication history. Baseline ECG is not required.⁴⁵

Screen for a family history of sudden death in a young person, sudden death during exercise, cardiac arrhythmia, cardiomyopathies (including hypertrophic cardiomyopathy, dilated cardiomyopathy, and right ventricular cardiomyopathy), prolonged QT interval, short QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, Marfan syndrome, and an event requiring resuscitation in a family member younger than 35, including syncope requiring rescuscitation.²³ If fainting spells, palpitations, chest pain, or other symptoms suggest preexisting cardiovascular disease, refer the patient promptly to a cardiologist.

Peripheral vasculopathy, including Raynaud’s phenomenon, is a lesser known side effect associated with stimulants.⁴⁶ Symptoms are usually mild, but in rare instances stimulants are associated with digital ulceration or soft tissue breakdown.⁴⁷ Advise patients to tell you if they experience any new symptoms of numbness, pain, skin color changes, or sensitivity to temperature in fingers and toes. Signs and symptoms generally improve after dosage reduction or discontinuation of the stimulant medication.⁴⁶ Referral to a rheumatologist might be appropriate if symptoms persist.

A noradrenergic medication

Atomoxetine is a potent, selective inhibitor of the presynaptic noradrenaline transporter that increases the availability of extracellular noradrenaline in the prefrontal cortex.^48,49 Atomoxetine may be a good alternative for adult patients with ADHD and comorbid anxiety.⁵⁰

For adults, the optimal starting dosage is 40 mg in the morning for 1 week, followed by an increase to 80 mg. Insufficient dosing is common with atomoxetine, and the dosage could be increased to 100 mg/d.⁵¹ Dosing twice per day may be associated with higher rates of insomnia.

Atomoxetine’s efficacy for managing ADHD in adults has been consistently demonstrated by 6 placebo-controlled trials of 10 to 16 weeks, 3 placebo-controlled 6-month trials, and a 1-year maintenance-of-response trial.⁵² Atomoxetine was found to have an effect size of 0.45 (medium) (number needed to treat [NNT] = 5).^53-55The most common adverse effects include nausea, dry mouth, insomnia, and erectile dysfunction. Small increases in heart rate and blood pressure have been reported, so use this medication with caution in patients for whom this might be problematic. Atomoxetine is metabolized by CYP2D6; 7% of white individuals have a genotype corresponding to a nonfunctional CYP2D6 enzyme.^56-58

Alpha-2 adrenergic agonists

Clonidine and guanfacine are antihypertensive drugs that induce peripheral sympathoinhibition via the stimulation of receptors. Clonidine binds equally to adrenergic receptor subtypes α-2A, α-2B, and α-2C (as well as to α-1 and β subtypes, histamine receptors, and possibly dopamine receptors).^59,60 Guanfacine binds preferentially to postsynaptic α-2A adrenoceptors in the prefrontal cortex, which have been implicated in attentional and organizational functions.^61,62

ER guanfacine and ER clonidine are FDA-approved as monotherapy for ADHD in children and adolescents.

Efficacy in adults. A small (N = 17), double-blind, placebo-controlled, crossover study comparing immediate-release guanfacine and dextroamphetamine found that both medications significantly reduced adult ADHD symptoms, as measured with the DSM-IV Adult Behavior Checklist for Adults.⁶³

No trials have been published regarding the efficacy of ER clonidine in adults with ADHD; adverse effects including sedation, bradycardia, and hypotension may limit its use. One study compared the supplemental use of ER guanfacine (1 to 6 mg/d) or a matching placebo in 26 adults with ADHD who had suboptimal response to stimulant-only treatment. After 10 weeks, both the guanfacine ER and placebo groups showed statistically significant improvements in ADHD symptoms and general functioning. The treatments did not differ in efficacy, safety, or tolerability.⁶⁴

Adverse events. Compared with clonidine, guanfacine has less CNS depressant and hypotensive activity.⁵⁸ A phase I trial of ER guanfacine in healthy adults found its single-dose pharmacokinetic properties in 1-, 2-, and 4-mg tablets appeared to be statistically linear. Somnolence—the most common treatment-emergent adverse effect—occurred in 33 of 52 participants (63.5%). All mean vital-sign measurements and ECG parameters remained within normal limits after dosing, and no marked changes from baseline measurements were noted.⁶⁵

Antidepressants

Antidepressants used in ADHD treatment include bupropion and tricyclic antidepressants.
Bupropion is a noradrenaline and dopamine reuptake inhibitor and is considered to be a mild psychostimulant because of its amphetamine-derived chemical structure.^66,67 It generally is considered a third-line medication when stimulants have not improved ADHD symptoms or are not tolerated.

A 2011 meta-analysis examined 5 randomized, controlled trials including 175 adults treated with bupropion for ADHD. Bupropion was found to be more effective than placebo (NNT = 5), although bupropion’s therapeutic benefits were not observed until weeks 5 and 6. Its effects were less pronounced than those of methylphenidate. Mean daily dosages were 362 mg for the bupropion SR trials and 393 mg for the bupropion XL trial.⁶⁸

Tricyclics. Desipramine and nortriptyline have been found to be efficacious in childhood ADHD,^69,70 although cardiovascular risk and toxicity in overdose limit their use.⁷¹

Photo by Rhoda Baer

A new study indicates that adolescent and young adult (AYA) cancer survivors continue to face social difficulties for more than 2 years after their diagnosis.

The research, published in Cancer, suggests these patients may see some improvement in their social lives during the first year after diagnosis.

However, their social functioning tends to remain constant after that, leaving them socially impaired relative to their cancer-free peers.

Previous studies have shown that AYAs with cancer experience greater challenges in social functioning than their cancer-free peers or even compared to older cancer patients.

But few studies have examined this phenomenon by following the same patients over time.

Olga Husson, PhD, of the Radboud University Medical Center in The Netherlands, and her colleagues set out to examine changes in social functioning among AYAs in the early years after a cancer diagnosis.

The researchers asked AYA cancer patients at 5 US medical institutions to complete a survey about social functioning within 4 months of their diagnosis, 12 months later, and 24 months later.

There were 141 patients (ages 14 to 39 at diagnosis) who completed the surveys.

The researchers found that, when compared to population norms, the cancer patients had inferior social functioning at all the time points studied.

Among the cancer patients, the mean social functioning score from the Medical Outcomes Study Short Form 36 Health Survey (version 2) was 52.0 around the time of cancer diagnosis, 73.1 at the 12-month follow-up, and 69.2 at the 24-month follow-up. In comparison, the population norm (for people ages 18 to 44) is 85.1 (P<0.001 for all time points).

The researchers did note that cancer patients experienced significant improvements in social functioning from baseline to the 12-month follow-up, but there was no further improvement after that.

The researchers also examined the different trajectories of social functioning over time. They found that social functioning improved over time for 47% of the cancer patients but worsened for 13%. In addition, 32% of patients had consistently low social functioning, and 9% had consistently high social functioning.

The cancer patients with consistently low social functioning were more likely to be off treatment at the time of follow-up, report more physical symptoms and higher levels of psychological distress (at both baseline and follow-up), and perceive themselves to receive less social support.

“Reducing physical symptoms and psychological distress and enhancing social support by interventions in the period after treatment may potentially help these young survivors to better reintegrate into society,” Dr Husson said.

Photo by Rhoda Baer

A new study indicates that adolescent and young adult (AYA) cancer survivors continue to face social difficulties for more than 2 years after their diagnosis.

The research, published in Cancer, suggests these patients may see some improvement in their social lives during the first year after diagnosis.

However, their social functioning tends to remain constant after that, leaving them socially impaired relative to their cancer-free peers.

Previous studies have shown that AYAs with cancer experience greater challenges in social functioning than their cancer-free peers or even compared to older cancer patients.

But few studies have examined this phenomenon by following the same patients over time.

Olga Husson, PhD, of the Radboud University Medical Center in The Netherlands, and her colleagues set out to examine changes in social functioning among AYAs in the early years after a cancer diagnosis.

The researchers asked AYA cancer patients at 5 US medical institutions to complete a survey about social functioning within 4 months of their diagnosis, 12 months later, and 24 months later.

There were 141 patients (ages 14 to 39 at diagnosis) who completed the surveys.

The researchers found that, when compared to population norms, the cancer patients had inferior social functioning at all the time points studied.

Among the cancer patients, the mean social functioning score from the Medical Outcomes Study Short Form 36 Health Survey (version 2) was 52.0 around the time of cancer diagnosis, 73.1 at the 12-month follow-up, and 69.2 at the 24-month follow-up. In comparison, the population norm (for people ages 18 to 44) is 85.1 (P<0.001 for all time points).

The researchers did note that cancer patients experienced significant improvements in social functioning from baseline to the 12-month follow-up, but there was no further improvement after that.

The researchers also examined the different trajectories of social functioning over time. They found that social functioning improved over time for 47% of the cancer patients but worsened for 13%. In addition, 32% of patients had consistently low social functioning, and 9% had consistently high social functioning.

The cancer patients with consistently low social functioning were more likely to be off treatment at the time of follow-up, report more physical symptoms and higher levels of psychological distress (at both baseline and follow-up), and perceive themselves to receive less social support.

“Reducing physical symptoms and psychological distress and enhancing social support by interventions in the period after treatment may potentially help these young survivors to better reintegrate into society,” Dr Husson said.

Photo by Rhoda Baer

A new study indicates that adolescent and young adult (AYA) cancer survivors continue to face social difficulties for more than 2 years after their diagnosis.

The research, published in Cancer, suggests these patients may see some improvement in their social lives during the first year after diagnosis.

However, their social functioning tends to remain constant after that, leaving them socially impaired relative to their cancer-free peers.

Previous studies have shown that AYAs with cancer experience greater challenges in social functioning than their cancer-free peers or even compared to older cancer patients.

But few studies have examined this phenomenon by following the same patients over time.

Olga Husson, PhD, of the Radboud University Medical Center in The Netherlands, and her colleagues set out to examine changes in social functioning among AYAs in the early years after a cancer diagnosis.

The researchers asked AYA cancer patients at 5 US medical institutions to complete a survey about social functioning within 4 months of their diagnosis, 12 months later, and 24 months later.

There were 141 patients (ages 14 to 39 at diagnosis) who completed the surveys.

The researchers found that, when compared to population norms, the cancer patients had inferior social functioning at all the time points studied.

Among the cancer patients, the mean social functioning score from the Medical Outcomes Study Short Form 36 Health Survey (version 2) was 52.0 around the time of cancer diagnosis, 73.1 at the 12-month follow-up, and 69.2 at the 24-month follow-up. In comparison, the population norm (for people ages 18 to 44) is 85.1 (P<0.001 for all time points).

The researchers did note that cancer patients experienced significant improvements in social functioning from baseline to the 12-month follow-up, but there was no further improvement after that.

The researchers also examined the different trajectories of social functioning over time. They found that social functioning improved over time for 47% of the cancer patients but worsened for 13%. In addition, 32% of patients had consistently low social functioning, and 9% had consistently high social functioning.

The cancer patients with consistently low social functioning were more likely to be off treatment at the time of follow-up, report more physical symptoms and higher levels of psychological distress (at both baseline and follow-up), and perceive themselves to receive less social support.

“Reducing physical symptoms and psychological distress and enhancing social support by interventions in the period after treatment may potentially help these young survivors to better reintegrate into society,” Dr Husson said.

CLINICAL QUESTION: For patients with advanced dementia, does a goals-of-care intervention improve communication and care outcomes?

BACKGROUND: Patients with advanced dementia are frequently admitted from nursing homes for acute conditions. Prior research demonstrates deficits in documentation of advanced directives.

STUDY DESIGN: Single-blind cluster randomized trial.

SETTING: Twenty-two nursing homes in North Carolina.

Dr. Cumbler is the associate chief of hospital medicine, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

CLINICAL QUESTION: For patients with advanced dementia, does a goals-of-care intervention improve communication and care outcomes?

BACKGROUND: Patients with advanced dementia are frequently admitted from nursing homes for acute conditions. Prior research demonstrates deficits in documentation of advanced directives.

STUDY DESIGN: Single-blind cluster randomized trial.

SETTING: Twenty-two nursing homes in North Carolina.

Dr. Cumbler is the associate chief of hospital medicine, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

CLINICAL QUESTION: For patients with advanced dementia, does a goals-of-care intervention improve communication and care outcomes?

BACKGROUND: Patients with advanced dementia are frequently admitted from nursing homes for acute conditions. Prior research demonstrates deficits in documentation of advanced directives.

STUDY DESIGN: Single-blind cluster randomized trial.

SETTING: Twenty-two nursing homes in North Carolina.

Dr. Cumbler is the associate chief of hospital medicine, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

CLINICAL QUESTION: Do antipsychotics provide symptomatic benefit for delirium in palliative care?

BACKGROUND: Antipsychotics are frequently used for the treatment of delirium and guideline recommended for delirium-associated distress. However, a 2016 meta-analysis found antipsychotics are not associated with change in delirium duration or severity. Antipsychotics for palliative management of delirium at end of life is not well studied.

Dr. Cumbler is the associate chief of hospital medicine, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

CLINICAL QUESTION: Do antipsychotics provide symptomatic benefit for delirium in palliative care?

BACKGROUND: Antipsychotics are frequently used for the treatment of delirium and guideline recommended for delirium-associated distress. However, a 2016 meta-analysis found antipsychotics are not associated with change in delirium duration or severity. Antipsychotics for palliative management of delirium at end of life is not well studied.

Dr. Cumbler is the associate chief of hospital medicine, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

CLINICAL QUESTION: Do antipsychotics provide symptomatic benefit for delirium in palliative care?

BACKGROUND: Antipsychotics are frequently used for the treatment of delirium and guideline recommended for delirium-associated distress. However, a 2016 meta-analysis found antipsychotics are not associated with change in delirium duration or severity. Antipsychotics for palliative management of delirium at end of life is not well studied.

Dr. Cumbler is the associate chief of hospital medicine, Division of Hospital Medicine, University of Colorado School of Medicine, Aurora.

If you work on the front lines of medical care, treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, which cover a variety of the major hepatitis viruses.

Sequential therapy with pegylated interferon after long-term–nucleoside/nucleotide analog therapy enhances the reduction of hepatitis B surface antigen and may represent a treatment option to promote HBsAg loss, a recent study revealed.

©vchal/Thinkstock

[email protected]

On Twitter @richpizzi

If you work on the front lines of medical care, treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, which cover a variety of the major hepatitis viruses.

Sequential therapy with pegylated interferon after long-term–nucleoside/nucleotide analog therapy enhances the reduction of hepatitis B surface antigen and may represent a treatment option to promote HBsAg loss, a recent study revealed.

©vchal/Thinkstock

[email protected]

On Twitter @richpizzi

If you work on the front lines of medical care, treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, which cover a variety of the major hepatitis viruses.

Sequential therapy with pegylated interferon after long-term–nucleoside/nucleotide analog therapy enhances the reduction of hepatitis B surface antigen and may represent a treatment option to promote HBsAg loss, a recent study revealed.

©vchal/Thinkstock

[email protected]

On Twitter @richpizzi

Question: Recent developments in malpractice include the following:

A. Severity and frequency rates continue to rise.

B. Apology laws appear to be very effective in reducing claims.

C. Litigation surrounds whether an assistant may obtain a patient’s informed consent on behalf of the doctor.

D. A and B.

E. A, B, and C.

Answer: C. Over the past decade, malpractice claims have in fact diminished, accompanied by a leveling or reduction in premiums.¹ Rates have plummeted to roughly half of previous levels, averaging six claims per 100 doctors in 2016.

According to The Doctors Company, internists paid an average premium of $15,853, compared with an average of $19,900 in 2006, general surgeons $52,905 instead of $68,186, and obstetricians $72,999, a drop from $93,230. Even claims-plagued Florida’s Dade County has seen a dramatic drop in internist premiums by some $27,000, down to $47,707.²

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from my earlier columns in Internal Medicine News. For additional information, readers may contact the author at [email protected].

References

1. JAMA. 2014 Nov 26;312(20):2146-55.

2. “Malpractice 2017: Do We Need Reform?” Internal Medicine News, March 1, 2017, page 1.

3. Fein v. Permanente, 38 Cal.3d 137 (1985).

4. Chan v. Curran, 237 CA 4th 601 (2015).

5. Estate of Johnson v. Randall Smith, Inc., 135 Ohio St.3d 440 (2013).

6. Available at https://papers.ssrn.com/sol3/papers2.cfm?abstract_id=2883693.

7. Shinal v. Toms, 122 A. 3d 1066 (Pa. Super. Ct. 2015).

8. Q J Econ. (1996) 111 (2): 353-390.

9. Available at www.jacksonhealthcare.com/media/8968/defensivemedicine_ebook_final.pdf.

Question: Recent developments in malpractice include the following:

A. Severity and frequency rates continue to rise.

B. Apology laws appear to be very effective in reducing claims.

C. Litigation surrounds whether an assistant may obtain a patient’s informed consent on behalf of the doctor.

D. A and B.

E. A, B, and C.

Answer: C. Over the past decade, malpractice claims have in fact diminished, accompanied by a leveling or reduction in premiums.¹ Rates have plummeted to roughly half of previous levels, averaging six claims per 100 doctors in 2016.

According to The Doctors Company, internists paid an average premium of $15,853, compared with an average of $19,900 in 2006, general surgeons $52,905 instead of $68,186, and obstetricians $72,999, a drop from $93,230. Even claims-plagued Florida’s Dade County has seen a dramatic drop in internist premiums by some $27,000, down to $47,707.²

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from my earlier columns in Internal Medicine News. For additional information, readers may contact the author at [email protected].

References

1. JAMA. 2014 Nov 26;312(20):2146-55.

2. “Malpractice 2017: Do We Need Reform?” Internal Medicine News, March 1, 2017, page 1.

3. Fein v. Permanente, 38 Cal.3d 137 (1985).

4. Chan v. Curran, 237 CA 4th 601 (2015).

5. Estate of Johnson v. Randall Smith, Inc., 135 Ohio St.3d 440 (2013).

6. Available at https://papers.ssrn.com/sol3/papers2.cfm?abstract_id=2883693.

7. Shinal v. Toms, 122 A. 3d 1066 (Pa. Super. Ct. 2015).

8. Q J Econ. (1996) 111 (2): 353-390.

9. Available at www.jacksonhealthcare.com/media/8968/defensivemedicine_ebook_final.pdf.

Question: Recent developments in malpractice include the following:

A. Severity and frequency rates continue to rise.

B. Apology laws appear to be very effective in reducing claims.

C. Litigation surrounds whether an assistant may obtain a patient’s informed consent on behalf of the doctor.

D. A and B.

E. A, B, and C.

Answer: C. Over the past decade, malpractice claims have in fact diminished, accompanied by a leveling or reduction in premiums.¹ Rates have plummeted to roughly half of previous levels, averaging six claims per 100 doctors in 2016.

According to The Doctors Company, internists paid an average premium of $15,853, compared with an average of $19,900 in 2006, general surgeons $52,905 instead of $68,186, and obstetricians $72,999, a drop from $93,230. Even claims-plagued Florida’s Dade County has seen a dramatic drop in internist premiums by some $27,000, down to $47,707.²

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from my earlier columns in Internal Medicine News. For additional information, readers may contact the author at [email protected].

References

1. JAMA. 2014 Nov 26;312(20):2146-55.

2. “Malpractice 2017: Do We Need Reform?” Internal Medicine News, March 1, 2017, page 1.

3. Fein v. Permanente, 38 Cal.3d 137 (1985).

4. Chan v. Curran, 237 CA 4th 601 (2015).

5. Estate of Johnson v. Randall Smith, Inc., 135 Ohio St.3d 440 (2013).

6. Available at https://papers.ssrn.com/sol3/papers2.cfm?abstract_id=2883693.

7. Shinal v. Toms, 122 A. 3d 1066 (Pa. Super. Ct. 2015).

8. Q J Econ. (1996) 111 (2): 353-390.

9. Available at www.jacksonhealthcare.com/media/8968/defensivemedicine_ebook_final.pdf.

Case Report

A 39-year-old woman with a 20-year history of rheumatoid arthritis (RA) presented to a university-affiliated tertiary care hospital with painful ulcerations on the bilateral dorsal feet that started as bullae 16 weeks prior to presentation. Initial skin biopsy performed by an outside dermatologist 8 weeks prior to presentation showed vasculitis and culture was positive for methicillin-sensitive Staphylococcus aureus. She was started on a prednisone taper and cephalexin, which did not improve the lower extremity ulcerations and the pain became progressively worse. At the time of presentation to our dermatology department, the patient was taking prednisone, hydroxychloroquine, hydrocodone-acetaminophen, and gabapentin. Prior therapy with sulfasalazine failed; etanercept and methotrexate were discontinued years prior due to side effects. The patient had no history of deep vein thrombosis, pulmonary embolism, or miscarriage.

At presentation, the patient was afebrile and her vital signs were stable. Physical examination showed multiple ulcers and erosions on the bilateral dorsal feet with a few scattered retiform red-purple patches (Figure). One bulla was present on the right dorsal foot. All lesions were tender to the touch and edema was present on the bilateral feet. No oral ulcerations were present and no focal neuropathies or palpable cords were appreciated in the lower extremities. There were no other cutaneous abnormalities.

Laboratory studies showed a white blood cell count of 9.54×10³/µL (reference range, 4.16-9.95×10³/µL), hemoglobin count of 12.4 g/dL (reference range, 11.6-15.2 g/dL), and a platelet count of 175×10³/µL (reference range, 143-398×10³/µL). A basic metabolic panel was normal except for an elevated glucose level of 185 mg/dL (reference range, 65-100 mg/dL). Urinalysis was normal. Erythrocyte sedimentation rate and C-reactive protein level were not elevated. Antinuclear antibodies and double-stranded DNA antibodies were normal. Prothrombin time was 10.4 seconds (reference range, 9.2-11.5 seconds) and dilute viper's venom time was negative. Rheumatoid factor level was elevated at 76 IU/mL (reference range, <25 IU/mL) and anti-citrullinated peptide antibody was moderately elevated at 42 U/mL (negative, <20 U/mL; weak positive, 20-39 U/mL; moderate positive, 40-59 U/mL; strong positive, >59 U/mL). The cardiolipin antibodies IgG, IgM, and IgA were within reference range. Results of β₂-glycoprotein I IgG and IgM antibody tests were normal, but IgA was elevated at 34 µg/mL (reference range, <20 µg/mL). Wound cultures grew moderate Enterobacter cloacae and Staphylococcus lugdunensis.

Slides from 2 prior punch biopsies obtained by an outside hospital approximately 8 weeks prior from the right and left dorsal foot lesions were reviewed. Both biopsies were histologically similar. Postcapillary venules showed extensive vasculitis with numerous fibrin thrombi in the lumens in both biopsy specimens. The biopsy from the right foot showed prominent ulceration of the epidermis, with a few of the affected vessels showing minimal accompanying nuclear dust; however, the predominant pattern was not that of leukocytoclastic vasculitis. Biopsy from the left foot showed prominent epidermal necrosis with focal reepithelialization and scattered eosinophils. The pathologist felt that a vasculitis secondary to coagulopathy was most likely but that a drug reaction and rheumatoid vasculitis would be other entities to consider in the differential. A review of the laboratory findings from the outside hospital from approximately 12 weeks prior to presentation showed IgM was normal but IgG was elevated at 28 U/mL (reference range, 0-15 U/mL) and IgA was elevated at 8 U/mL (reference range, 0-7 U/mL); β₂-glycoprotein I IgG antibodies were elevated at 37 mg/dL (reference range, 0-25.0 mg/dL) and β₂-glycoprotein I IgA antibodies were elevated at 5 mg/dL (reference range, 0-4.0 mg/dL).

The clinical suspicion of a thrombotic event on the dorsal feet, which was confirmed histologically, and the persistently positive antiphospholipid (aPL) antibody titers helped to establish the diagnosis of antiphospholipid syndrome (APS) in the setting of RA. The dose of prednisone was increased from 10 mg daily on admission to 40 mg daily. The patient was started on enoxaparin 60 mg subcutaneously twice daily at initial presentation and was bridged to oral warfarin 2 mg daily after the diagnosis of APS was established. Oral doxycycline 100 mg twice daily was started for wound infection. The ulcerations gradually improved over the course of her 7-day hospitalization. She was continued on prednisone, hydroxychloroquine, and warfarin as an outpatient and has had no recurrence of lesions after 3 years of follow-up on this regimen.

Comment

Antiphospholipid syndrome is an autoimmune condition defined by a venous and/or arterial thrombotic event and/or pregnancy morbidity in the presence of persistently elevated aPL antibody titers. The most frequently detected subgroups of aPL are anticardiolipin (aCL) antibodies, anti-β₂-glycoprotein I antibodies, and lupus anticoagulants.¹ Primary APS occurs as an isolated entity, whereas secondary APS occurs in the setting of a preexisting autoimmune disease, infection, malignancy, or medication.² The diagnostic criteria for APS requires positive aPL titers at least 12 weeks apart and a clinically confirmed thrombotic event or pregnancy morbidity.³

About one-third to half of patients with APS exhibit cutaneous manifestations.^4,5 Livedo reticularis is most commonly observed and represents the first clinical sign of APS in 17.5% of cases.6 Cutaneous findings of APS also include anetoderma, cutaneous ulceration and necrosis, necrotizing vasculitis, livedoid vasculitis, thrombophlebitis, purpura, ecchymoses, painful skin nodules, and subungual hemorrhages.⁷ The various cutaneous manifestations of APS are associated with a range of histopathologic findings, but noninflammatory thrombosis in small arteries and/or veins in the dermis and subcutaneous fat tissue is the most common histologic feature.⁴ Our patient exhibited cutaneous ulceration and necrosis, and biopsy clearly showed the presence of vasculitis and fibrin thrombi within postcapillary venules. These findings along with the persistently elevated β₂-glycoprotein I IgA solidified the diagnosis of APS.

The most common cutaneous manifestations of RA are nodules (32%), Raynaud phenomenon (10%), and vasculitis (3%).⁸ The mean prevalence of aPL antibodies in patients with RA is 28%, though reports range from 5% to 75%.¹ The presence of aPL or aCL does not predict the development of thrombosis and/or thrombocytopenia in RA patients^9,10; however, aCL antibodies in RA patients are associated with a higher risk for developing rheumatoid nodules. It is hypothesized that the majority of aCL antibodies identified in RA patients have different specificities than those identified in other diseases that are associated with thrombotic events.¹

Anticoagulation has been proven to decrease the risk for recurrent thrombotic events in patients with APS.¹¹ Patients should discontinue the use of estrogen-containing oral contraceptives; avoid smoking cigarettes; and treat hypertension, hyperlipidemia, and diabetes mellitus, if present. The type and duration of anticoagulation therapy, especially for the treatment of the cutaneous manifestations of APS, is less well defined. Antiplatelet therapies such as low-dose aspirin or dipyridamole often are used for less severe cutaneous manifestations such as livedoid vasculopathy. Warfarin with a target international normalized ratio of 2.0 to 3.0 is most commonly used following major thrombotic events, including cutaneous necrosis and digital gangrene. The role of corticosteroids and immunosuppressants is unclear; one study showed that these therapies did not prevent further thrombotic events in patients with systemic lupus erythematosus.⁴

Conclusion

Although aPL antibodies are most prevalent in patients with systemic lupus erythematosus, an estimated 28% of patients with RA have elevated aPL titers. The aPL antibodies recognized in RA patients are thought to have a different specificity than those recognized in other APS-associated diseases because elevated aPL antibody titers are not associated with an increased incidence of thrombotic events in RA patients; however, larger studies are needed to clarify this phenomenon. It remains to be determined if this case of APS and RA represents a coincidence or a true disease association, but the recognition of the cutaneous and histological features of APS is crucial for establishing a diagnosis and initiating anticoagulation therapy to prevent further morbidity and mortality.

Case Report

A 39-year-old woman with a 20-year history of rheumatoid arthritis (RA) presented to a university-affiliated tertiary care hospital with painful ulcerations on the bilateral dorsal feet that started as bullae 16 weeks prior to presentation. Initial skin biopsy performed by an outside dermatologist 8 weeks prior to presentation showed vasculitis and culture was positive for methicillin-sensitive Staphylococcus aureus. She was started on a prednisone taper and cephalexin, which did not improve the lower extremity ulcerations and the pain became progressively worse. At the time of presentation to our dermatology department, the patient was taking prednisone, hydroxychloroquine, hydrocodone-acetaminophen, and gabapentin. Prior therapy with sulfasalazine failed; etanercept and methotrexate were discontinued years prior due to side effects. The patient had no history of deep vein thrombosis, pulmonary embolism, or miscarriage.

At presentation, the patient was afebrile and her vital signs were stable. Physical examination showed multiple ulcers and erosions on the bilateral dorsal feet with a few scattered retiform red-purple patches (Figure). One bulla was present on the right dorsal foot. All lesions were tender to the touch and edema was present on the bilateral feet. No oral ulcerations were present and no focal neuropathies or palpable cords were appreciated in the lower extremities. There were no other cutaneous abnormalities.

Laboratory studies showed a white blood cell count of 9.54×10³/µL (reference range, 4.16-9.95×10³/µL), hemoglobin count of 12.4 g/dL (reference range, 11.6-15.2 g/dL), and a platelet count of 175×10³/µL (reference range, 143-398×10³/µL). A basic metabolic panel was normal except for an elevated glucose level of 185 mg/dL (reference range, 65-100 mg/dL). Urinalysis was normal. Erythrocyte sedimentation rate and C-reactive protein level were not elevated. Antinuclear antibodies and double-stranded DNA antibodies were normal. Prothrombin time was 10.4 seconds (reference range, 9.2-11.5 seconds) and dilute viper's venom time was negative. Rheumatoid factor level was elevated at 76 IU/mL (reference range, <25 IU/mL) and anti-citrullinated peptide antibody was moderately elevated at 42 U/mL (negative, <20 U/mL; weak positive, 20-39 U/mL; moderate positive, 40-59 U/mL; strong positive, >59 U/mL). The cardiolipin antibodies IgG, IgM, and IgA were within reference range. Results of β₂-glycoprotein I IgG and IgM antibody tests were normal, but IgA was elevated at 34 µg/mL (reference range, <20 µg/mL). Wound cultures grew moderate Enterobacter cloacae and Staphylococcus lugdunensis.

Slides from 2 prior punch biopsies obtained by an outside hospital approximately 8 weeks prior from the right and left dorsal foot lesions were reviewed. Both biopsies were histologically similar. Postcapillary venules showed extensive vasculitis with numerous fibrin thrombi in the lumens in both biopsy specimens. The biopsy from the right foot showed prominent ulceration of the epidermis, with a few of the affected vessels showing minimal accompanying nuclear dust; however, the predominant pattern was not that of leukocytoclastic vasculitis. Biopsy from the left foot showed prominent epidermal necrosis with focal reepithelialization and scattered eosinophils. The pathologist felt that a vasculitis secondary to coagulopathy was most likely but that a drug reaction and rheumatoid vasculitis would be other entities to consider in the differential. A review of the laboratory findings from the outside hospital from approximately 12 weeks prior to presentation showed IgM was normal but IgG was elevated at 28 U/mL (reference range, 0-15 U/mL) and IgA was elevated at 8 U/mL (reference range, 0-7 U/mL); β₂-glycoprotein I IgG antibodies were elevated at 37 mg/dL (reference range, 0-25.0 mg/dL) and β₂-glycoprotein I IgA antibodies were elevated at 5 mg/dL (reference range, 0-4.0 mg/dL).

The clinical suspicion of a thrombotic event on the dorsal feet, which was confirmed histologically, and the persistently positive antiphospholipid (aPL) antibody titers helped to establish the diagnosis of antiphospholipid syndrome (APS) in the setting of RA. The dose of prednisone was increased from 10 mg daily on admission to 40 mg daily. The patient was started on enoxaparin 60 mg subcutaneously twice daily at initial presentation and was bridged to oral warfarin 2 mg daily after the diagnosis of APS was established. Oral doxycycline 100 mg twice daily was started for wound infection. The ulcerations gradually improved over the course of her 7-day hospitalization. She was continued on prednisone, hydroxychloroquine, and warfarin as an outpatient and has had no recurrence of lesions after 3 years of follow-up on this regimen.

Comment

Antiphospholipid syndrome is an autoimmune condition defined by a venous and/or arterial thrombotic event and/or pregnancy morbidity in the presence of persistently elevated aPL antibody titers. The most frequently detected subgroups of aPL are anticardiolipin (aCL) antibodies, anti-β₂-glycoprotein I antibodies, and lupus anticoagulants.¹ Primary APS occurs as an isolated entity, whereas secondary APS occurs in the setting of a preexisting autoimmune disease, infection, malignancy, or medication.² The diagnostic criteria for APS requires positive aPL titers at least 12 weeks apart and a clinically confirmed thrombotic event or pregnancy morbidity.³

About one-third to half of patients with APS exhibit cutaneous manifestations.^4,5 Livedo reticularis is most commonly observed and represents the first clinical sign of APS in 17.5% of cases.6 Cutaneous findings of APS also include anetoderma, cutaneous ulceration and necrosis, necrotizing vasculitis, livedoid vasculitis, thrombophlebitis, purpura, ecchymoses, painful skin nodules, and subungual hemorrhages.⁷ The various cutaneous manifestations of APS are associated with a range of histopathologic findings, but noninflammatory thrombosis in small arteries and/or veins in the dermis and subcutaneous fat tissue is the most common histologic feature.⁴ Our patient exhibited cutaneous ulceration and necrosis, and biopsy clearly showed the presence of vasculitis and fibrin thrombi within postcapillary venules. These findings along with the persistently elevated β₂-glycoprotein I IgA solidified the diagnosis of APS.

The most common cutaneous manifestations of RA are nodules (32%), Raynaud phenomenon (10%), and vasculitis (3%).⁸ The mean prevalence of aPL antibodies in patients with RA is 28%, though reports range from 5% to 75%.¹ The presence of aPL or aCL does not predict the development of thrombosis and/or thrombocytopenia in RA patients^9,10; however, aCL antibodies in RA patients are associated with a higher risk for developing rheumatoid nodules. It is hypothesized that the majority of aCL antibodies identified in RA patients have different specificities than those identified in other diseases that are associated with thrombotic events.¹

Anticoagulation has been proven to decrease the risk for recurrent thrombotic events in patients with APS.¹¹ Patients should discontinue the use of estrogen-containing oral contraceptives; avoid smoking cigarettes; and treat hypertension, hyperlipidemia, and diabetes mellitus, if present. The type and duration of anticoagulation therapy, especially for the treatment of the cutaneous manifestations of APS, is less well defined. Antiplatelet therapies such as low-dose aspirin or dipyridamole often are used for less severe cutaneous manifestations such as livedoid vasculopathy. Warfarin with a target international normalized ratio of 2.0 to 3.0 is most commonly used following major thrombotic events, including cutaneous necrosis and digital gangrene. The role of corticosteroids and immunosuppressants is unclear; one study showed that these therapies did not prevent further thrombotic events in patients with systemic lupus erythematosus.⁴

Conclusion

Although aPL antibodies are most prevalent in patients with systemic lupus erythematosus, an estimated 28% of patients with RA have elevated aPL titers. The aPL antibodies recognized in RA patients are thought to have a different specificity than those recognized in other APS-associated diseases because elevated aPL antibody titers are not associated with an increased incidence of thrombotic events in RA patients; however, larger studies are needed to clarify this phenomenon. It remains to be determined if this case of APS and RA represents a coincidence or a true disease association, but the recognition of the cutaneous and histological features of APS is crucial for establishing a diagnosis and initiating anticoagulation therapy to prevent further morbidity and mortality.

Case Report

A 39-year-old woman with a 20-year history of rheumatoid arthritis (RA) presented to a university-affiliated tertiary care hospital with painful ulcerations on the bilateral dorsal feet that started as bullae 16 weeks prior to presentation. Initial skin biopsy performed by an outside dermatologist 8 weeks prior to presentation showed vasculitis and culture was positive for methicillin-sensitive Staphylococcus aureus. She was started on a prednisone taper and cephalexin, which did not improve the lower extremity ulcerations and the pain became progressively worse. At the time of presentation to our dermatology department, the patient was taking prednisone, hydroxychloroquine, hydrocodone-acetaminophen, and gabapentin. Prior therapy with sulfasalazine failed; etanercept and methotrexate were discontinued years prior due to side effects. The patient had no history of deep vein thrombosis, pulmonary embolism, or miscarriage.

At presentation, the patient was afebrile and her vital signs were stable. Physical examination showed multiple ulcers and erosions on the bilateral dorsal feet with a few scattered retiform red-purple patches (Figure). One bulla was present on the right dorsal foot. All lesions were tender to the touch and edema was present on the bilateral feet. No oral ulcerations were present and no focal neuropathies or palpable cords were appreciated in the lower extremities. There were no other cutaneous abnormalities.

Laboratory studies showed a white blood cell count of 9.54×10³/µL (reference range, 4.16-9.95×10³/µL), hemoglobin count of 12.4 g/dL (reference range, 11.6-15.2 g/dL), and a platelet count of 175×10³/µL (reference range, 143-398×10³/µL). A basic metabolic panel was normal except for an elevated glucose level of 185 mg/dL (reference range, 65-100 mg/dL). Urinalysis was normal. Erythrocyte sedimentation rate and C-reactive protein level were not elevated. Antinuclear antibodies and double-stranded DNA antibodies were normal. Prothrombin time was 10.4 seconds (reference range, 9.2-11.5 seconds) and dilute viper's venom time was negative. Rheumatoid factor level was elevated at 76 IU/mL (reference range, <25 IU/mL) and anti-citrullinated peptide antibody was moderately elevated at 42 U/mL (negative, <20 U/mL; weak positive, 20-39 U/mL; moderate positive, 40-59 U/mL; strong positive, >59 U/mL). The cardiolipin antibodies IgG, IgM, and IgA were within reference range. Results of β₂-glycoprotein I IgG and IgM antibody tests were normal, but IgA was elevated at 34 µg/mL (reference range, <20 µg/mL). Wound cultures grew moderate Enterobacter cloacae and Staphylococcus lugdunensis.

Slides from 2 prior punch biopsies obtained by an outside hospital approximately 8 weeks prior from the right and left dorsal foot lesions were reviewed. Both biopsies were histologically similar. Postcapillary venules showed extensive vasculitis with numerous fibrin thrombi in the lumens in both biopsy specimens. The biopsy from the right foot showed prominent ulceration of the epidermis, with a few of the affected vessels showing minimal accompanying nuclear dust; however, the predominant pattern was not that of leukocytoclastic vasculitis. Biopsy from the left foot showed prominent epidermal necrosis with focal reepithelialization and scattered eosinophils. The pathologist felt that a vasculitis secondary to coagulopathy was most likely but that a drug reaction and rheumatoid vasculitis would be other entities to consider in the differential. A review of the laboratory findings from the outside hospital from approximately 12 weeks prior to presentation showed IgM was normal but IgG was elevated at 28 U/mL (reference range, 0-15 U/mL) and IgA was elevated at 8 U/mL (reference range, 0-7 U/mL); β₂-glycoprotein I IgG antibodies were elevated at 37 mg/dL (reference range, 0-25.0 mg/dL) and β₂-glycoprotein I IgA antibodies were elevated at 5 mg/dL (reference range, 0-4.0 mg/dL).

The clinical suspicion of a thrombotic event on the dorsal feet, which was confirmed histologically, and the persistently positive antiphospholipid (aPL) antibody titers helped to establish the diagnosis of antiphospholipid syndrome (APS) in the setting of RA. The dose of prednisone was increased from 10 mg daily on admission to 40 mg daily. The patient was started on enoxaparin 60 mg subcutaneously twice daily at initial presentation and was bridged to oral warfarin 2 mg daily after the diagnosis of APS was established. Oral doxycycline 100 mg twice daily was started for wound infection. The ulcerations gradually improved over the course of her 7-day hospitalization. She was continued on prednisone, hydroxychloroquine, and warfarin as an outpatient and has had no recurrence of lesions after 3 years of follow-up on this regimen.

Comment

Antiphospholipid syndrome is an autoimmune condition defined by a venous and/or arterial thrombotic event and/or pregnancy morbidity in the presence of persistently elevated aPL antibody titers. The most frequently detected subgroups of aPL are anticardiolipin (aCL) antibodies, anti-β₂-glycoprotein I antibodies, and lupus anticoagulants.¹ Primary APS occurs as an isolated entity, whereas secondary APS occurs in the setting of a preexisting autoimmune disease, infection, malignancy, or medication.² The diagnostic criteria for APS requires positive aPL titers at least 12 weeks apart and a clinically confirmed thrombotic event or pregnancy morbidity.³

About one-third to half of patients with APS exhibit cutaneous manifestations.^4,5 Livedo reticularis is most commonly observed and represents the first clinical sign of APS in 17.5% of cases.6 Cutaneous findings of APS also include anetoderma, cutaneous ulceration and necrosis, necrotizing vasculitis, livedoid vasculitis, thrombophlebitis, purpura, ecchymoses, painful skin nodules, and subungual hemorrhages.⁷ The various cutaneous manifestations of APS are associated with a range of histopathologic findings, but noninflammatory thrombosis in small arteries and/or veins in the dermis and subcutaneous fat tissue is the most common histologic feature.⁴ Our patient exhibited cutaneous ulceration and necrosis, and biopsy clearly showed the presence of vasculitis and fibrin thrombi within postcapillary venules. These findings along with the persistently elevated β₂-glycoprotein I IgA solidified the diagnosis of APS.

The most common cutaneous manifestations of RA are nodules (32%), Raynaud phenomenon (10%), and vasculitis (3%).⁸ The mean prevalence of aPL antibodies in patients with RA is 28%, though reports range from 5% to 75%.¹ The presence of aPL or aCL does not predict the development of thrombosis and/or thrombocytopenia in RA patients^9,10; however, aCL antibodies in RA patients are associated with a higher risk for developing rheumatoid nodules. It is hypothesized that the majority of aCL antibodies identified in RA patients have different specificities than those identified in other diseases that are associated with thrombotic events.¹

Anticoagulation has been proven to decrease the risk for recurrent thrombotic events in patients with APS.¹¹ Patients should discontinue the use of estrogen-containing oral contraceptives; avoid smoking cigarettes; and treat hypertension, hyperlipidemia, and diabetes mellitus, if present. The type and duration of anticoagulation therapy, especially for the treatment of the cutaneous manifestations of APS, is less well defined. Antiplatelet therapies such as low-dose aspirin or dipyridamole often are used for less severe cutaneous manifestations such as livedoid vasculopathy. Warfarin with a target international normalized ratio of 2.0 to 3.0 is most commonly used following major thrombotic events, including cutaneous necrosis and digital gangrene. The role of corticosteroids and immunosuppressants is unclear; one study showed that these therapies did not prevent further thrombotic events in patients with systemic lupus erythematosus.⁴

Conclusion

Although aPL antibodies are most prevalent in patients with systemic lupus erythematosus, an estimated 28% of patients with RA have elevated aPL titers. The aPL antibodies recognized in RA patients are thought to have a different specificity than those recognized in other APS-associated diseases because elevated aPL antibody titers are not associated with an increased incidence of thrombotic events in RA patients; however, larger studies are needed to clarify this phenomenon. It remains to be determined if this case of APS and RA represents a coincidence or a true disease association, but the recognition of the cutaneous and histological features of APS is crucial for establishing a diagnosis and initiating anticoagulation therapy to prevent further morbidity and mortality.

Two anti–tumor necrosis factor monoclonal antibodies, adalimumab and infliximab, showed evidence of being markedly more effective than the anti-TNF–receptor inhibitor etanercept at reducing the rate of anterior uveitis in patients with ankylosing spondylitis in a retrospective Swedish cohort study.

To compare the efficacy of the three TNF inhibitors, researchers analyzed data in nationwide Swedish population-based registries for 1,365 ankylosing spondylitis (AS) patients who initiated treatment during a 7-year period. Treatment began with adalimumab in 406 patients, infliximab in 605, and etanercept in 354, said Elisabeth Lie, MD, of the department of rheumatology and inflammation research at the University of Gothenburg (Sweden), and her associates.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

Two anti–tumor necrosis factor monoclonal antibodies, adalimumab and infliximab, showed evidence of being markedly more effective than the anti-TNF–receptor inhibitor etanercept at reducing the rate of anterior uveitis in patients with ankylosing spondylitis in a retrospective Swedish cohort study.

To compare the efficacy of the three TNF inhibitors, researchers analyzed data in nationwide Swedish population-based registries for 1,365 ankylosing spondylitis (AS) patients who initiated treatment during a 7-year period. Treatment began with adalimumab in 406 patients, infliximab in 605, and etanercept in 354, said Elisabeth Lie, MD, of the department of rheumatology and inflammation research at the University of Gothenburg (Sweden), and her associates.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

Two anti–tumor necrosis factor monoclonal antibodies, adalimumab and infliximab, showed evidence of being markedly more effective than the anti-TNF–receptor inhibitor etanercept at reducing the rate of anterior uveitis in patients with ankylosing spondylitis in a retrospective Swedish cohort study.

To compare the efficacy of the three TNF inhibitors, researchers analyzed data in nationwide Swedish population-based registries for 1,365 ankylosing spondylitis (AS) patients who initiated treatment during a 7-year period. Treatment began with adalimumab in 406 patients, infliximab in 605, and etanercept in 354, said Elisabeth Lie, MD, of the department of rheumatology and inflammation research at the University of Gothenburg (Sweden), and her associates.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0