January 2012 Clinical Advisor

THE CLINICAL ADVISOR • JANUARY 2012

A F O RU M F O R N U R S E P R AC T I T I O N E R S

NEWSLINE

■ Statin use and cancer ■ Meningococcal vaccination ■ Opioids for stomach pain ADVISOR FORUM

■ Subclinical hypothyroidism ■ Migraine and CAD ■ Squeeze the gag reflex LEGAL ADVISOR

Mishandled medical evidence leads to charges of tampering

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■ Dermatology Clinic

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CE: THE VIEW FROM 2012 FOR

SYSTEMIC LUPUS The “butterfly rash” is a distinctive sign of systemic lupus erythematosus.

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CONTENTS JANUARY 2012

NEWS AND COMMENT 14

77

Newsline ■ Statin use pays off without causing cancer ■ High BP a risk for cognitive problems ■ Updated meningococcal vaccine policy ■ Opioids for stomach pain ■ And more

Derm Dx Read the clinical descriptions, view the images, and then make your diagnosis.

62

Legal Advisor Mishandled medical evidence causes undue emotional harm.

65

CME/CE Dermatologic Look-Alikes

Two linear pink plaques—one on a teenager’s nose and the other on the leg of a young child

No increase in cancer after statin use 14

Commentary

FEATURES 25

61

69

CME/CE Posttest

70

Alternative Meds Update Goldenseal is used as a digestive aid and antibacterial agent.

CME/CE Lupus and the

autoimmune process: the view from 2012 New prevention strategies and safer treatments have improved survival rates.

ADVISOR FORUM 48

34

Making the right choice in hormone therapy Prescribing estrogen replacement therapy remains confusing and controversial.

The future of lupus treatment 25

DEPARTMENTS 51

50

Consultations ■ Subclinical hypothyroidism ■ Halting migraine in someone with coronary artery disease ■ Does gender affect statin efficacy?

■ And more Clinical Pearls ■ Squeeze out the gag reflex ■ Frozen fish-oil capsules

Clinical Challenge ■ A man presents to the ED with pain and swelling that spread from the distal tip of his middle finger to his palm.

50

Your Comments ■ The real motivation for

prescribing antibiotics 55

CME/CE Dermatology Clinic ■ A slow-growing pink, pearly nasal papule on a man’s nose

SPECIAL FEATURE!

■ Pigmented macular lesions on the lip of man with abdominal cramps

MAKING CONTACT

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EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com/web-only Web Exclusives ClinicalAdvisor.com/WebExclusives Rare amoeba infection kills second neti-pot user Health officials are warning people about the potential dangers of using tap water for sinus irrigation after two neti pot users in Louisiana died from infection with Naegleria fowleri, a “brain-eating” amoeba.

Blink inhibition from visual stimuli delayed in autistic children Toddlers slow their blinking for visual stimuli, but the response is delayed in children with autism spectrum disorders, new research indicates.

SABCS: Carb intake linked to breast cancer recurrence Women with low-grade cancer tumors who increased their starch intake by 5 g/day upped their recurrence risk 3%.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments.

ClinicalAdvisor.com/DermDx Café au lait macules and baglike protrusions A pregnant woman presents with scattered café au lait macules; soft skin-colored polyps; and several fleshy protrusions.

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Slideshows ClinicalAdvisor.com/Slideshows Identifying hepatitis infection The severity of hepatitis depends on many factors, including the cause of the liver damage. Hepatitis A does not lead to chronic liver problems. Many patients with hepatitis B and C may develop liver failure later. Learn more with this slideshow.

HIV/AIDS-related skin conditions More than 33.3 million people live with HIV/AIDS worldwide, as of 2009, with 2.6 million people newly infected in that year alone. Learn more about skin-conditions that may occur in later stages of the disease, after the virus has weakened the immune system, with this slideshow.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Leigh Montejo, MSN, FNP-BC Incorporating the peer-review process in primary-care settings The peer review process fosters collaboration between physician assistants, nurse practitioners and physicians, enabling us to exchange our knowledge and experience, and grow as health-care providers.

Robyn Carlisle, MSN, CNM, WHNP Are hospital limitations on midwife scope of practice discriminatory?

It is time to examine the trickle-down affect hospital restrictions that do not coincide with certified nurse midwife state regulations can have on providing collaborative health care.

William B. Mosher, PA-C Redefining the physician assistant profession will take more than a name change A name change to “physician associate” will require collaboration to redefine the training, responsibilities, and privileges of the profession to clarify the health-care community’s perceptions of PAs.

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While there are many diabetes complications,

PAINFUL DPN IS ONE THEY CAN’T IGNORE Help manage your patients’ painful Diabetic Peripheral Neuropathy with LYRICA

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1

“If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved.

For full guideline, visit www.aan.com/guidelines.

Level A=Established as effective, based on at least 2 Class I studies.

Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria.

AAN=American Academy of Neurology.

LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia.

PBP01859A/291945-01

© 2011 Pfizer Inc.

Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.

There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of lifethreatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.

Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebotreated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA All rights reserved.

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention).

Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function.

Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema.

For Full Prescribing Information and Medication Guide, please visit www.LyricaHCP.com.

Please see the Brief Summary of Prescribing Information on adjacent pages.

Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.

September 2011

LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert.

INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week.

Neuropathic pain associated with diabetic peripheral neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)* ≥60 150 300 450 600 30–60

75

15–30 <15

Dose Regimen BID or TID

150

225

300

BID or TID

25–50

75

100–150

150

QD or BID

25

25–50

50–75

75

QD

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose.

CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy.

WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment.

Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing.

Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients

without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 31% of LYRICAtreated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treated patients compared to 7% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICAtreated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICAassociated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision).

Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICAtreated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events.

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.

Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).

Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.

Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 1 0 1 3 2 0 Thinking abnormal† Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses 3 1 3 6 4 2 Blurry vision‡ Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia.

Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section.

Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation.

Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis.

Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men.

There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache.

Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement.

DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs.

Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.

When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for

rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. aedpregnancyregistry.org/. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.

LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment.

DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], suggestive of physical dependence.

OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalintreated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.

Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.

LAB-0294-21.0 June 2011

PBP01873/291898-01

© 2011 Pfizer Inc.

All rights reserved.

CME CE

PROGRAM OUTLINE JANUARY 2012

0.5 CREDITS

Page 25 FEATURE Lupus and the autoimmune process: the view from 2012 Joan McTigue, MS, PA-C, and Byron Croker, PHD, MD ■ LEARNING OBJECTIVES: • Identify lifestyle changes that a person who has high titers of antinuclear antibodies but no lupus-specific symptoms should make.

• Describe the classification criteria for systemic lupus erythematosus (SLE).

• Learn which medications are most often responsible for true drug-induced lupus.

• Identify the most common cause of death in early active SLE.

0.5 CREDITS

Page 55 DERMATOLOGY CLINIC Case #1: Slow-growing pink, pearly nasal papule Esther Stern, NP-C

Case #2: Pigmented macular lip lesion Norman D. Zellers, MSPAS, PA-C, and Ceasar A. Valle, MD, MBA ■ LEARNING OBJECTIVES: • To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment.

Page 65 DERMATOLOGIC LOOK-ALIKES Linear pink plaques Kerri Robbins, MD ■ LEARNING OBJECTIVE: • To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations.

Page 69 POSTTEST

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of January 2012. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

10 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Newsline J A N U A R Y 2 0 12

Adolescent meningococcal vaccination page 16

More opioids prescribed for stomach pain page 23

Let Medicare help patients lose weight page 23

© SCIENCE SOURCE / PHOTO RESEARCHERS, INC,

Statin use pays off without causing cancer

A LARGE, LONG-TERM project by the Heart Protection Study Collaborative Group showed that statin therapy increasingly reduced heart attack, stroke, and other vascular disease as treatment continued, and that these benefits persisted for several years after treatment had stopped. In addition, no increases in cancer incidence or other nonvascular morbidity or mortality were seen over 11 years of follow-up.

Trials have shown that lowering LDL with statins quickly reduces vascular morbidity and mortality, but evidence of long-term efficacy and safety has been limited. In addition, in observational epidemiologic studies, prolonged follow-up has shown lower blood cholesterol concentrations to be associated with higher rates of particular types of cancer as well as other nonvascular morbidity and mortality.

Cholesterol (orange) restricts bloodflow to the heart.

The Heart Protection Study group evaluated these issues and reported their fi ndings online ahead of print in The Lancet. A total of 20,536 patients at high risk of vascular and nonvascular outcomes received either 40 mg simvastatin (Zocor) daily or placebo.

During the in-trial period, allocation to simvastatin resulted in an average reduction in LDL of 1.0 mmol/L and a proportional decrease in major vascular events of 23%. The absolute benefits increased as treatment continued during the five-year trial period.

Post-trial, when statin use and lipid concentrations were similar in both groups, no further significant reductions were noted in either major vascular events or vascular mortality.

During the combined intrial and post-trial periods, no

signif icant differences were recorded in cancer incidence at all sites or at any particular site, or in mortality attributed to cancer.

The results “provide considerable assurance—both to prescribers and to patients—about the long-term safety of lowering LDL cholesterol substantially for about five years.”

In another study featuring statin use, the SATURN trial recently demonstrated that maximum doses of rosuvastatin (Crestor) or atorvastatin (Lipitor) are similarly very effective in reversing atherosclerosis after 24 months of treatment, with few adverse events occurring among the 1,039 participants.

Rosuvastatin was associated with a 1.22% decrease in plaque burden and atorvastatin with a 0.99% decrease (N Engl J Med. 2011;365:2078-2087).

Number of NPs and PAs practicing primary care In 2010, approximately 56,000 NPs and 30,000 PAs were practicing primary care in the United States.

Source: Agency for Health Care Policy and Research, AHRQ Publication No. 12-P001-3-EF.

Nurse practitioners by specialty

48%

52%

Primary Care Subspecialty Care

14 THE CLINICAL ADVISOR • JANUARY 2012• www.ClinicalAdvisor.com

Physician assistants by specialty

57%

43%

Primary Care Subspecialty Care

© ISTOCKPHOTO.COM / RICHARD SEMIK

Picture this

Everyone needs a break during the day. So relax with this photo essay, and pretend you’re someplace else.

12 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Winter brings snow to the red sandstone mesas that populate Bryce Canyon National Park in southern Utah.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 13

Available at myCME.com/UMDNJ NEW for 2011-2012 To listen on the go, download audio files to your MP3 player or burn them to a CD

PANCE/PANRE “I’ll have the egg-yellow omelette.”

ONLINE REVIEW COURSE Q All topics on the NCCPA examination blueprint are covered Q Lectures presented by UMDNJ faculty—more than 27 hours of instruction for 2011-2012 Q Study at your own pace while earning AAPA Category 1 CME credit Q Practice examination questions to achieve peak performance on the PANCE/PANRE Q All presentation materials can be downloaded and printed for off-line review Q Fee is $79 per module or $289 for the full five-module program

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Module 1

Cardiology/EKG Review

Module 2

Pulmonology, Pediatrics, Ophthalmology, Otorhinolaryngology

Module 3

Orthopedics, Neurology, Psychiatry

Module 4

Infectious Disease, Gastroenterology, Dermatology

Module 5

Reproductive System, Endocrinology, Genitourinary System, Hematology

ACCREDITATION INFORMATION This program has been reviewed and is approved for a maximum of 27.25 hours of AAPA Category 1 CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of October 17, 2011. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with the AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. This program has been planned without commercial support.

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Newsline ELEVATED BP, as well as the presence of left ventricular hypertrophy (LVH) and total Framingham Stroke Risk Profile score, predict the development of clinically significant cognitive dysfunction, according to a study that examined vascular risk factors as they related to incident cognitive impairment in a national sample of adults aged 45 years and older.

The 23,752 subjects had no history of stroke or cognitive impairment at baseline and no evidence of stroke during the study. During a mean follow-up of 4.1 years, 1,907 participants met the criteria for incident cognitive impairment, which was significantly associated with their baseline Framingham score. Among these subjects, age and LVH were the only score components that independently predicted cognitive decline: Each

10-year increment in age doubled the risk of cognitive impairment, and LVH, when adjusted for other factors, increased the risk by about 30%. When people with LVH were excluded from the model, elevated systolic BP was related to incident cognitive impairment, with each 10 mm Hg increase in systolic BP raising the risk of cognitive decline by 4%.

The authors concluded that prevention and treatment of high BP may help preserve a person’s cognitive health (Neurology. 2011;77:17291736). A separate study takes that finding a step further, suggesting that people who want to stay physically and cognitively active talk to their clinicians about tracking ambulatory BP levels (Circulation.

2011;124:2312-2319).

This study involved a prospective cohort of persons aged 75 to

Ventricular hypertrophy may be associated with cognitive dysfunction.

89 years. Data for the 72 patients who made it to the 24-month follow-up showed that increased ambulatory systolic BP—but not clinic systolic BP—was associated with increased white matter hyperintensity volume, which is a sign of small-vessel brain damage that has been linked with cognitive decline.

Updated meningococcal vaccine policy THE AMERICAN Academy of Pediatrics and the CDC’s Advisory Committee on Immunization Practices have approved new recommendations for the use of quadrivalent meningococcal conjugate vaccines in adolescents and in people who are at persistent high risk of meningococcal disease (Pediatrics. 2011;128:1213-1218).

• Adolescents should be routinely immunized at ages 11 through 12 years and given a booster dose at age 16 years.

• Adolescents who received their first dose at ages 13 through 15

Teens with HIV should receive a two-dose primary series.

years should receive a booster dose at ages 16 through 18 years or up to five years after their first dose.

• Adolescents do not need a booster dose if they receive their fi rst dose of meningococcal conjugate vaccine at or after age 16 years.

• Persons at increased risk of invasive meningococcal disease because of persistent complement component deficiency (aged 9 months through 54 years) or functional or anatomic asplenia (aged 2 to 54 years),

16 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

and adolescents with HIV infection, should receive a twodose primary series administered two months apart.

• Persons should receive a booster dose three years after the primary series if the primary twodose series was given from ages 2 through 6, or a booster dose every five years if the two-dose series or booster dose was given at age 7 or older or if they are at risk of meningococcal disease because of persistent complement component deficiency or functional or anatomic asplenia.

TOP PHOTO: © SPL / PHOTO RESEARCHERS, INC.; BOTTOM PHOTO: COURTESY OF CDC / DR. BRODSKY

High BP a risk for cognitive problems

Newsline H. pylori Opioids for stomach pain elimination improves dyspepsia Painkiller overdoses have reached epidemic levels.

prescription painkiller overdoses have reached epidemic levels, and are responsible for more deaths among Americans than heroin and cocaine combined.

The agency reports that deaths from overdoses of hydrocodone, methadone, oxycodone, oxymorphone, and other narcotic pain relievers have more than tripled in the past decade (available at www.cdc.gov/vitalsigns/ PainkillerOverdoses/index.html, accessed December 15, 2011).

Other findings may eventually help curb opioid use, however: One recent study has demonstrated that the antidepressant escitalopram—a selective serotonin reuptake inhibitor—improved general pain in opioid-dependent patients (Pain.

2011;152:2640-2644). Another investigation indicated that primary-care patients addicted to prescription painkillers could be effectively treated using Suboxone, which combines buprenorphine plus naloxone (Arch Gen Psychiatry.

2011;68:1238-1246).

Medicare now covers obesity screening, counseling Older primary-care patients may find it easier to stick to their New Year’s resolution to stay in shape now that the Centers for Medicare & Medicaid Services (CMS) has added coverage for preventive services to reduce obesity.

The new benefit applies to obesity screening and counseling performed by primary-care providers for eligible beneficiaries.

Medicare patients who screen positive for obesity with a BMI of >30 can now receive one face-to-face counseling visit each week

for one month and one such visit every other week for an additional five months.

Those who lose at least 6.6 lb during those first six months can then participate in one face-to-face counseling visit per month for an additional six months, for a total of 12 months of counseling.

In announcing the obesity-prevention benefit, CMS noted that more than 30% of both men and women in the Medicare population are estimated to be obese. ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 23

© ISTOCKPHOTO.COM / ADAM GREGOR

PATIENTS with functional dyspepsia reaped significant benefits from Helicobacter pylori eradication, noted a recent study (Arch Intern Med. 2011;171:1929-1936).

Primary-care patients with functional dyspepsia and H. pylori may have symptoms that are less resistant to treatment than do other patient populations. To examine this, investigators randomized 404 H. pylori–positive adults with functional dyspepsia to treatment with the proton pump inhibitor omeprazole (Prilosec) plus the antibiotics amoxicillin trihydrate and clarithromycin (antibiotics group), or to treatment with omeprazole plus placebo (control group), for 10 days.

Of the 389 participants who completed the study, 49% in the antibiotics group and 36.5% in the control group achieved the primary outcome of at least 50% symptomatic improvement at 12 months. In the patient global assessment of symptoms, 78.1% of the antibiotics users reported that they were better symptomatically, compared with 67.5% of the control group members. The antibiotics users also had a significantly larger increase in their mean Medical Outcomes Study 36-Item Short Form Health Survey physical component summary scores than did the control group.

ALTHOUGH THE number of outpatient visits for chronic abdominal pain declined from 14.8 million visits in 1997 through 1999 to 12.2 million visits in 2006 through 2008, the adjusted prevalence of visits for which an opioid was prescribed increased from 5.9% to 12.2% during those periods.

Chronic abdominal pain is a common symptom and a frequent reason for seeing a health-care provider, but is often incurable and can be difficult to manage over time. However, investigators caution that using opioids to treat noncancer chronic pain is supported by very limited evidence, and that when used over long periods of time, these agents can trigger such other GI symptoms as constipation, nausea, and vomiting, and may ultimately worsen abdominal pain. In addition, opioids are frequently misused and sometimes abused (Clin Gastroenterol Hepatol.

2011;9:1078-1085).

These results come at a time when the CDC is warning that

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QUESTIONS 1. Approximately how many U.S. nurse practitioners and physician assistants combined were practicing primary care in 2010? (p. 14) 2. From 2006 to 2008, how many outpatient visits for chronic abdominal pain were recorded? (p. 23) 3. What is the approximate five-year survival rate for people with systemic lupus erythematosus (SLE) in the United States, Canada, and Europe? (p. 25) 4. What patient population is most commonly affected with SLE? (p. 29) 5. What are the three basic forms of estrogen found in women? (p. 37) 6. What is the most-prescribed formulation of estrogen replacement used clinically to treat hypogonadal girls? (p. 43) 7. What tip can clinicians use to prevent the unpleasant aftertaste associated with omaga-3 fish-oil capsules? (p. 50) 8. What is the mean age range of individuals affected with labial melanotic macule? (p. 57) 9. What was lichen striatus originally called? (p. 67) 10. From what area of the U.S. is most goldenseal produced? (p. 70) 24 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

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CME CE FEATURE

■ LEARNING OBJECTIVES : • Identify lifestyle changes that a person who has high titers of antinuclear antibodies but no lupus-specific symptoms should make.

• Describe the classification criteria for systemic lupus erythematosus (SLE).

• Learn which medications are most often responsible for true drug-induced lupus.

• Identify the most common cause of death in early active SLE. ■ COMPLETE THE POSTTEST: Page 69 ■ ADDITIONAL CME/CE: Pages 55, 65

JOAN MCTIGUE, MS, PA-C, AND BYRON CROKER, PHD, MD

Lupus and the autoimmune process: the view from 2012 Thanks to new prevention strategies and safer treatments, patients are surviving almost as long as their counterparts without lupus.

A photosensitive rash (shown) is a hallmark symptom of systemic lupus erythematosus.

C

are for the patient with lupus and other autoimmune diseases has changed dramatically over the past few decades. Advancements in our understanding of the molecular mechanisms of autoimmunity and cell injury have led to useful prevention strategies and safer treatments.

In the early 1960s, the five-year mortality for systemic lupus erythematosus (SLE) was 50%, and treatment-related morbidity was high. The picture is very different today. Survival for people with SLE in the United States, Canada, and Europe has risen to approximately 95% at five years, 90% at 10 years, and 78% at 20 years, and now approaches that of matched controls without lupus.

© BSIP / PHOTOTAKE

Background immunology

The response of certain cells (typically lymphocytes) of the immune system to components of the organism that produced them is called “autoimmunity.”

Inborn mechanisms of self-tolerance normally protect an individual from potentially self-reactive lymphocytes. Early on, as the field of immunology was www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 25

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emerging, scientists thought that all self-reactive lymphocytes were eliminated during the maturation process. By the late 1970s, however, it became known that not all self-reactive lymphocytes are deleted. Some survive with the potential to cause disease. Interestingly, the presence of self-reactive lymphocytes does not inevitably result in disease. Immunologists now know that the activity of these cells is highly regulated in normal individuals by some sort of effective suppression.

A failure of this suppression leads to persistent self-reactive clones of T- and B-cells that can target self-antigens. In certain environments, this deregulation amplifies and persists, resulting in significant damage to target cells or organs and creating autoimmune diseases, some of which can be fatal.

Most immunologists divide autoimmune diseases in humans into organ-specific and systemic autoimmune processes.

Organ-specific autoimmune diseases. In some autoimmune diseases, antibodies act as agonists, binding to receptors and taking the place of normal ligands. This results in the stimulation of inappropriate activity. For example, Graves disease, with its attendant thyroid storm, develops when the thyroid-stimulating hormone receptor is the target.

In other autoimmune conditions, antibodies act as antagonists and block receptor function. Myasthenia gravis results when muscle activation is inhibited by antibodies that have targeted the receptor on the motor end plates.

In some autoimmune processes, direct cellular damage is infl icted when lymphocytes or antibodies bind to cell membrane antigens and cause cell lysis and/or inflammation.

Hashimoto’s thyroiditis and autoimmune hemolytic anemia are classic examples of this process.

Systemic autoimmune diseases. In systemic autoimmune diseases, the response is directed toward a broad range of target antigens and involves a number of organs and tissues. Tissue damage may be widespread. Damage is inflicted by several mechanisms. Cell-mediated responses and direct cellular damage from autoantibodies or immune complex deposition are seen.

Connective tissue diseases. Autoimmune diseases that target the connective tissues are the most common type of systemic autoimmune disease. The older, long out-of-date term for this group of systemic rheumatic diseases is “collagen vascular diseases.”

Connective tissue is one of the four traditional classes of tissue (the others being epithelial, muscle, and nervous tissues. Connective tissue is widespread, and it has three main components: cells, fibers, and extracellular matrix.

Connective tissue makes up a wide variety of physical structures including, tendons, blood, cartilage, bone, adipose tissue, and lymphatic tissue.

TABLE 1. Autoimmune diseases in humans Disease

Organ/cells/system affected

Addison’s disease

Adrenal glands

Graves disease

Thyroid-stimulating hormone receptor

Idiopathic thrombocytopenic purpura

Platelet membranes

Type 1 diabetes

Pancreatic cells

Ankylosing spondylitis

Connective tissue

Rheumatoid arthritis

Connective tissue

Multiple sclerosis

Brain or white matter

All of the connective-tissue autoimmune diseases (CTDs) share similar clinical and pathologic features. Widespread inflammation and autoantibody production are the hallmarks, but then the diseases diverge and clinical distinctions become apparent. Although there are overlaps in target organs (Table 1), each of the CTDs has primary organs most typically affected and produces unique autoantibodies.

Systemic lupus erythematosus

The prototypical autoimmune CTD, SLE is a chronic disease of complex etiology. In both humans and mouse models, SLE is characterized by widespread immunologic abnormalities with the potential for multiorgan damage. Affected individuals may produce autoantibodies to a vast array of tissue antigens, from DNA to clotting factors. When immune complexes form from union of autoantibody with antigen, a dramatic cascade of complement and its membrane-attack complexes is generated.

These products damage blood vessel walls, which can lead to vasculitis and nephritis. This potentially wide array of damage can make the clinical picture of SLE seem baffling. The disease can begin subtly or dramatically and have great impact on patients, particularly women in the reproductive years.

Why one group of lupus patients has low-grade, limited disease and another group develops life-threatening organ failure is a function of the interplay among susceptibility genes and environmental triggers. Lupus autoantibodies are now known to be present in the serum of lupus patients as long as five years prior to the development of clinical disease. Thus, when the genetic load is sufficient and immune triggers present themselves, it seems that chance and timing trigger immune system activation and the disease process turns on.

Persons with high titers of antinuclear antibodies (ANAs) but no lupus-specific symptoms need no therapy. Instead,

26 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

they should be followed with watchful waiting. The percentage of these patients who will develop clinical disease is unknown. The most relevant behavioral changes that patients can make to help themselves are stopping smoking and using sun protection.

A new era in genetic studies. SLE is a complex genetic disease. Multiple interactive susceptibility genes appear to have a role. The manifestations of the disease that emerge depend on which of the various genes are expressed. In the past few years, enormous progress has been made in our understanding of the genetics of SLE. The large numbers of DNA samples collected from lupus patients through the support of government agencies, foundations, industry, and academic centers have made studies of genetic variants more affordable. Genome-wide association studies (GWAS) in humans as well as the identification of susceptibility genes in mouse models of lupus has led to far better understanding of the mechanism of this disease.

Data from these studies have confirmed several candidate genes previously associated with lupus, identified some new lupus-associated genes and gene loci, and identified variants in a novel gene (ITGAM) whose protein product had been studied in SLE but was not previously known to have a genetic association with lupus.

The mouse model. Several strains of inbred mice spontaneously develop a lupuslike syndrome. These strains allow researchers to tease out a simplified version of human lupus from which to work. In order to put the mouse strains in clinical perspective, it has been said that one lupus mouse strain represents one patient. However, it is one patient that can be bred in 100 copies, thus providing a base for detailed, sensitive, and finely-tuned studies. Toward this end, about a half-dozen inbred strains have been studied by linkage analysis to produce significant statistical associations for more than 100 genomic regions with lupus-related characteristics (ANA subsets, skin, nephritis, and so forth). A number of defective cell-signaling pathways have been successfully described based on studies in the mouse. (See “How UV light triggers lupus: recent lessons from the mouse model,” bottom right.)

Magnitude of SLE in clinical practice and investigational settings

SLE is uncommon. One of the challenges for both clinical practice and laboratory investigation is the small size of the patient population.

Estimates of SLE prevalence vary widely, from a high of 1.5 million1 to approximately 250,000.2 That same group

estimated a 2005 prevalence of 161,000 persons with definite SLE and 322,000 persons with definite or probable SLE.2 Currently, the prevalence rate in the United States is probably 40 to 50 persons per 100,000.3 The frequency of SLE varies significantly by race and ethnicity, with higher rates reported among blacks and Hispanics.4 In 2002, the prevalence rate of SLE was approximately 40 per 100,000 whites in Rochester, Minn., versus 100 per 100,000 Hispanic persons in Nogales, Ariz., in 2008.2 Incidence refers to the number of new cases per population in a given time period. National incidence data for lupus are a challenge to pinpoint because the onset of a definitive diagnosis is difficult to determine. Lupus often presents with nonspecific signs and symptoms. Resource-intense studies are frequently done in small geographic areas, largely by regional academic centers and foundations.

New-incident cases per 100,000 patients viewed from one large clinical practice illustrate how uncommon lupus is.5 An interesting review of a year’s worth of musculoskeletal or rheumatologic disorders seen in this large primary-care setting noted that 2,500 patients had osteoarthritis; 600 had gout; and 50 had some type of inflammatory arthritis, half of which was rheumatoid arthritis. SLE accounts for five patients in this per-100,000 new-patient analysis. Thus, the clinical challenge is to identify the actual case of SLE while being careful not to overcall the disease and, at the same

How UV light triggers lupus: recent lessons from the mouse model The skin has a wide complement of immunocytes, including B-cells, a spectrum of T-cells of classic types (particularly effector memory cells [Tem], regulatory cells [Treg]), and helper cells [TH17]); dendritic cells; and monocytes/macrophages.

These cells participate in local immune responses.

In the MRL mouse model of SLE, a loop mechanism for this process has recently been established. UV radiation (UVR) produces DNA damage, which is linked to local immunosuppression in the skin via Tregs but also stimulates autoimmunity.

UVR damage to keratinocytes in the skin stimulates colonystimulating factor-1, leading to recruitment and activation of macrophages that then release other cytokine activators, which cause keratinocyte death. This process leads to continued and enhanced amplification of inflammation. It is described in animals with the lupus-prone genetic background and is not seen in animals with normal genetic background.

Adapted from Menke J, Hsu MY, Byrne KT, et al. Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice. J Immunol.

Immunol. 2008;181:7367-7379.

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time, not letting this potentially life-threatening disease smolder undiagnosed. The clinical research challenge is to find enough patients to study in meaningful ways.

Triggers. All sources agree that the incidence of SLE is rising. Many basic science and epidemiologic researchers focus their work on exploring several environmental triggers that appear to influence SLE. For example, exposure to UV radiation causes disease flares in approximately 70% of patients.

One of the early and still compelling clinical observations is the female predominance of SLE in a ratio of 9:1.

This is augmented by increased risk associated with both postmenopausal hormone replacement therapy and estrogen oral contraceptive (OC) therapy. Lupus mouse studies have formalized the relationship of lupus with sex hormones.

In vitro studies show how various immunocytes (B-cells, T-cells, and natural-killer cells) as well as interferon (the signature cytokine of SLE) are stimulated by estrogen. The advent of extremely low-dose combination OCs has led to a reappraisal of the role of OCs in SLE. Men who have SLE exhibit abnormalities in the toll-like receptor gene on the Y chromosome. Toll-like receptors are a family of innate immune signaling molecules on cell surfaces.

A variety of environmental contaminants can have estrogenic effects. Lupus mice that were exposed to organochlorine pesticide experienced acceleration in their autoimmune disease, lending support to the hypothesis that the increase in SLE incidence may be partially attributable to environmental contaminants.6 AT A GLANCE ●

Serologic presence of antinuclear antibody (ANA) is widely considered the first and most appropriate confirmatory test for systemic lupus erythematosus (SLE) and other connective-tissue autoimmune diseases.

●

The high prevalence of positive ANA titers in the normal population makes this a poor screening test.

●

Lupus autoantibodies are known to be present in the serum of lupus patients as long as five years prior to the development of clinical disease.

●

Although there is a strong familial aggregation, most cases of SLE are sporadic.

●

Hydroxychloroquine modifies cell signaling and, as a result, reduces the activation of dendritic cells that mitigate the inflammatory process. It is used for maintenance therapy as well as treatment.

●

Patients can help themselves by using sun protection and not smoking.

Infections with certain viruses, such as Epstein-Barr, induce a normal immune reaction that can progress to involve some immunocytes (T- and B-cells) that uniquely recognize selfantigens. When these cells are not tightly regulated, autoantibody production can begin. The search for a consistent role for active infection or exposure to various infectious agents in the development of lupus remains inconclusive.

Of late, a converse hypothesis has emerged, proposing that a reduction in exposure to infectious disease burden may predispose to autoimmunity. This is a hypothesis that has been around for decades, but the supporting evidence is growing.

Animals raised in specific pathogen-free environments have earlier onset and higher rates of autoimmunity in genetically susceptible strains. The immunologic mechanisms of this hypothesis indicate that chronic and repeated exposure to infection involves a shift in precursor cells away from the potential dysregulated autoimmune response back to an efficient response to the infection challenge.

An increase in both allergic and autoimmune diseases seen over the past three decades in developed countries is not unique to SLE. A dramatic rise in other autoimmune diseases (e.g., type 1 diabetes, multiple sclerosis, inflammatory bowel disease) and such allergic conditions as asthma and atopic dermatitis is impressive. Decreases in chronic infection come from improved hygiene, vaccination use, and antibiotic use.7 Since the immune system is no longer as vigorously engaged in fighting infection, it is more or less “released” to produce autoimmunity. Although the prevalence of SLE is high in black persons in the United States and the United Kingdom, the disease is rarely reported among blacks who live in Africa, implying that more hygienic environs may permit the previously described shifts in cell population.

The antinuclear antibody test

Serologic presence of ANA is widely considered the fi rst and most appropriate confirmatory test for SLE and other CTDs. ANA determinations are never used to monitor disease activity. To do so is a waste of time and money.

If a reported ANA titer of 1:40 is considered positive, 20% (or 20,000 persons per 100,000 persons) or more of the normal population will be positive. If a low-positive titer is defined as 1:160, the normal population will have a prevalence of rate of 5% (or 5,000 persons per 100,000).

Titers of 1:640 or higher are generally considered indicative of some kind of CTD. An ANA report has three parts: (1) a positive or negative result; (2) if positive, what the titer is; and (3) the pattern of fluorescence.

28 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

ANA patterns. Titers and patterns can vary between laboratory testing sites, most likely because of variation in the methodology used. The commonly recognized patterns are: • Homogeneous—indicates uniform nuclear fluorescence due to antibody directed against nucleoprotein.

• Peripheral—fluorescence at the edges of the nucleus in a shaggy appearance. Anti-DNA antibodies cause this pattern.

• Speckled—results from antibody directed against different nuclear antigens.

• Nucleolar —results from antibody directed against a specific RNA configuration of the nucleolus or antibody specific for proteins necessary for maturation of nucleolar RNA. Nucleolar ANA is seen in patients with systemic sclerosis.

The homogeneous pattern is commonly observed in the general population, and low-positive titers are rarely meaningful. Be aware that a number of significant conditions cause a positive ANA result, such as drug-induced lupus; irritable bowel disease; malignancy; advancing age; viral infections, especially hepatitis C; and other rheumatologic autoimmune diseases. The clinician should have a high index of suspicion before ordering ANA testing, or he or she will be left to worry about a laboratory result. Too often, the busy clinician who is presented with an array of vague symptoms—from fatigue to low-grade fever to various arthralgias—orders laboratory studies that include an ANA determination. When the result is positive, an unfortunate chain of events may be set off. Many patients are told that they might have lupus and they are referred to rheumatology. Patients pass their time reading about SLE on the Internet, so that by the time they are seen in rheumatology, the cart is far ahead of the horse, and their anxiety level is high. Requesting a consult with a specialist for a laboratory test is not an appropriate referral, and yet it happens every day. This practice wastes time and money and leads to patient anxiety. Only 1% of ANA results will be true positives for SLE, and the patient’s clinical picture must fit the diagnosis as well. A rheumatologist is usually needed to make a firm diagnosis of SLE, but many referrals to rule out lupus could be avoided.

The need for such diagnostic procedures as skin, nerve, or kidney biopsy will often require other subspecialists. A rheumatologist is best qualified to manage cases of authentic lupus. There are many regional autoimmune centers in academic medical centers with large lupus cohorts and multispecialty expertise.

TABLE 2. Classification criteria for SLE Malar rash Discoid rash Photosensitivity Oral ulcers Nonerosive arthritis involving two or more peripheral joints Pleuritis or pericarditis Renal disorder (persistent proteinuria or the presence of cellular casts in the urine) Neurologic disorder (seizures or psychosis) Hematologic disorder (hemolytic anemia, leukopenia, lymphocytopenia, thrombocytopenia) Immunologic disorder (presence of anti-DNA, anti-Sm, or antiphospholipid antibodies) Positive antinuclear antibody determination Adapted from: American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus.

Available at www.rheumatology.org/practice/clinical/classification/SLE/1997_update_of_ the_1982_acr_revised_criteria_for_classification_of_sle.pdf. Accessed December 15, 2011.

Clinical features and types of lupus

While there are classification criteria for SLE (Table 2), the essential features when considering the diagnosis are: • Age: onset after puberty • Population affected: most common in black and Hispanic women in their 20s and 30s • Core features: photosensitive rashes, polyarthritis (not mere arthralgias) of the hands, and nephritis often noticed first • Core labs: persistent or large amount of protein in the urine • Autoantibody formation quantified by a significantly positive ANA determination (generally felt to be >1:640).

The populations in which the preponderance of this disease burden will be found are young black and Hispanic women. Native American women are a third group in which the disease expresses uniquely. Men also develop lupus; it is especially severe in black and Hispanic men.

Caucasians are also affected. Older persons can develop SLE as well, but they are outliers on the general epidemiologic curve.

Although there is a strong familial aggregation, most cases are sporadic. SLE may occur with such other autoimmune conditions as thyroiditis, hemolytic anemia, and idiopathic thrombocytopenia purpura.

Continues on page 30

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Special-case lupus

Discoid lupus (Figure 1) is a chronic rash typically found on the face and scalp that has characteristic skin findings and is generally ANA-negative. Fewer than 5% of cases progress to SLE. Subacute cutaneous lupus erythematosus (SCLE) (Figure 2) is often mistaken for a severe fungal rash because it is scaly.

Fifty percent of SCLE patients will test positive for ANA, and 50% of patients with SCLE will have SLE. Drug-induced lupus is a reactive form of the diseease that develops in response to specific drugs. The presentation consists primarily of arthritis and serositis, such as pleuritis or pericarditis. Patients test positive for ANAs. The condition resolves with cessation of the culprit drug (See “Drugs associated with lupus,” below).

Neonatal lupus erythematosus (NLE) is a rare disorder caused by the transplacental passage of maternal autoantibodies.

Most mothers are healthy when they give birth to their baby, but some mothers have defined or undifferentiated autoimmune disorders. Overall, only 1% of infants with positive maternal autoantibodies develop NLE. The most common clinical manifestations of NLE are cardiac, dermatologic, and hepatic in nature.

While the features designated above may be considered essential to guide the clinician toward thinking about who gets lupus and how it commonly presents, eight organ systems may be involved in SLE. A number of validated measures have been developed for clinicians to use in scoring the degree of disease activity a patient with lupus has across these various domains.

Drugs associated with lupus Dozens of medications have been reported to “trigger” systemic lupus erythematosus (SLE). However, more than 90% of cases of true “drug-induced lupus” occur in individuals taking: • Hydralazine (Apresoline) • Isoniazid (Tubizid) • Phenytoin (Di-Phen, Dilantin, Phenytek) • Procainamide (Procanbid) • Quinidine There are reports on the development of drug-induced lupus in persons taking such anti-tumor necrosis factor medications, as infliximab (Remicade) and etanercept (Enbrel).

Fortunately, drug-induced SLE is infrequent (accounting for less than 5% of all people with lupus) and mild and usually resolves within weeks to months after the culprit medication is discontinued.

The earliest signs and symptoms of lupus are often fatigue, hair loss (especially around the face), a sun-sensitive facial rash, and arthralgias. It is not unusual, however, to have a patient present with one very dramatic feature, such as nephritis or a pleural/pericardial effusion, in the setting of a significantly positive ANA titer. When the manifestations of disease are so dramatic, diagnosis should not wait for criteria. Such patients require prompt and well-coordinated subspecialty care. Therapies for many of these complications are usually immunosuppressive and managed by the clinicians who prescribe them. However, follow-up is often left in the hands of primary-care providers.

Role of primary care in persons with SLE

Primary-care providers monitoring lupus patients often find it challenging to identify which new events or complications are lupus-related. Not only do lupus symptoms vary widely, they come and go. Worsening symptoms signify a flare, while symptoms that are under control signify a remission.

Many lupus patients require lifelong community-based symptom and laboratory monitoring for their therapies. Such care requires coordination. Communication among the patient, the primary-care provider, and the subspecialist is crucial.

Patients and clinicians can be encouraged by the fact that the 10-year survival of persons with SLE has vastly improved in recent decades. Safer and more successful treatment with immunosuppression—especially for severe disease, such as nephritis—along with the development of such renal-protective drugs as ACE inhibitors has made a critical difference.

Many SLE patients with low disease activity are treated with sun protection, long-term hydroxychloroquine (Plaquenil), and such simple arthritis therapies as nonsteroidal anti-infl ammatory drugs or acetaminophen.

Hydroxychloroquine is an antimalarial drug used in many patients with lupus. It modifies cell signaling and, as a result, reduces the activation of dendritic cells that mitigate the inflammatory process. Yearly ophthalmologic exams for those on hydroxychloroquine are necessary to screen for toxicity related to that drug. Two distinct areas of the eye—the cornea and the macula—may be affected. Many patients are on this medication indefi nitely, as hydroxychloroquine is used for maintenance therapy as well as treatment. Encouraging patients to remain on the medication and get the requisite eye exams is important.

Persons who have concomitant lupus and cardiovascular disease will experience acceleration of their cardiovascular disease, especially if they have been treated with

30 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

© SCOTT CAMAZINE / PHOTO RESEARCHERS, INC.

glucocorticosteroids. Aggressive modification of cardiovascular risk factors usually falls to the primary-care provider and should be started early. Many patients will require a statin.

Some persons with SLE have the antiphospholipid syndrome and a prothrombotic state and may be on anticoagulation. In some communities, monitoring the antiphospholipid syndrome falls to the primary-care provider. The needed specific form of anticoagulation and duration of treatment is highly individualized to the patient and requires good clinician coordination to avoid overtreatment or undertreatment.

Fetal loss related to several factors may be higher in lupus patients. Women with SLE should try to plan their pregnancies for times of low disease activity and should be followed by clinicians specializing in high-risk pregnancy.

Because lupus is seen primarily in women of childbearing age, birth-control issues are very important. Effective contraception and proper understanding of contraceptive options are important, as unwanted pregnancy can result in health risks to the mother and fetus. Overall, OCs have a number of positive health effects. However, estrogencontaining OCs increase the risk of clotting events and need to be used carefully in patients with an underlying clotting disorder, such as those who have antiphospholipid antibodies. The well-known association between lupus and estrogen has added to the hesitancy to prescribe OCs to patients with lupus. Older confi rmatory studies reported disease flares when women with lupus received a combination birth-control pill containing both estrogen and a progestin. However, recent studies have shown that OC use does not increase the risk of lupus flare, time to fi rst flare, or global disease activity in women with mild lupus.

Low-dose OCs are probably safe in women with mild lupus but should be avoided in women at increased risk of clotting or in those with moderate to severe disease. This includes women with antiphospholipid antibodies, the antiphospholipid syndrome, or the nephrotic syndrome (i.e., renal lupus, which is characterized by marked protein in the urine). Progestin-only OCs are better choices if tolerated.

The kidney is the visceral organ most commonly involved in SLE. Although only an estimated 50% of patients with SLE develop clinically evident renal disease, biopsy studies demonstrate some degree of renal involvement in almost all patients with moderate to severe disease. Kidney failure is a leading cause of death. Sometimes the renal status of a lupus patient with treated renal disease deteriorates slowly, but it can also deteriorate precipitously. BP control and renalprotective therapy are lifelong and require monitoring. At

FIGURE 1. Discoid lupus (pink) is a chronic rash that typically occurs on such sun-exposed areas as the face and scalp.

all office visits, analysis for proteinuria should be performed and often quantified.

Screening for the complications of corticosteroid use often falls to the primary-care provider as well. Dual-energy x-ray absorptiometry scanning, calcium supplementation, monitoring of vitamin D levels, screening for cataracts, and recommending the use of polarized sunglasses are essential.

Fatigue, depression, and fibromyalgia are quite common in the lupus patient. These symptoms do not improve with immunosuppression or when severe disease goes into remission. Approximately 10% of SLE patients will develop hypothyroidism. Dry mouth and eyes are common. All these health problems will come under the purview of the primary-care provider.

Self-care. One of the more important steps SLE patients can take is to protect themselves from the sun. Photosensitivity occurs in approximately 75% of SLE patients, and sun protection is the cornerstone of the management of cutaneous lupus.

A number of good strategies are available, from sunblocks to protective clothing to timed exposure. Patients who practice good sun protection will usually require vitamin

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© ISM / PHOTOTAKE

CME CE

FIGURE 2. Subacute cutaneous lupus erythematosus (pink) is treated with sunscreen, topical corticosteroids, and antimalarials.

D supplementation. Smoking not only drives hypertension, it also interferes with the benefit of hydroxychloroquine and seems to worsen skin disease in and of itself. Regular exercise helps prevent fatigue and joint stiffness.

Biologic therapies

The age of biologics has arrived. Biologics are injected or infused agents rarely used by primary-care providers. While that is best practice, primary-care providers must be aware of these medications and their potential adverse events.

Most currently used therapies for lupus are borrowed from other diseases and conditions and are often used off label.

Belimumab (Benlysta), approved by the FDA in early 2011, is the first drug to have been developed specifically to treat lupus. Belimumab is a novel biologic agent that targets B-cell maturation and survival. A human monoclonal antibody, belimumab is infused monthly and binds to B-cell surface molecules called “BLyS” (bliss). These cell-surface molecules are drivers of intercellular signaling. By binding to BLyS, the

inhibitor blunts the survival of B-cells, including autoreactive B-cells, and reduces the differentiation of B-cells into antibody-producing plasma cells.

Patients with mild lupus may not ever need immunosuppressive or biologic treatment. They may be able to keep their symptoms under control with the relatively safe antimalaria drugs, such as hydroxychloroquine. Patients with the most severe disease, including lupus affecting the kidneys or brain, benefit from more aggressive treatments. In some ways, patients in the middle category are more challenging to treat. Most of the benefit of belimumab seems to come from improvement of skin rash and ulcers in the nose and mouth as well as diminished corticosteroid use. Skin symptoms can be prominent drivers of patient disability and prominent factors in ongoing corticosteroid use.

Primary-care providers need to be aware that live vaccines should not be given for 30 days before use of belimumab or any other biologic concurrently, because the biologic may blunt the response to immunizations. Persons being considered for belimumab are also typically prescreened for TB and hepatitis B and C. As with many biologic agents, serious infections are the greatest risk. These agents are not stopped for routine low-grade infections, such as colds, or for other minor infections or minor surgeries, such as dental work or skin biopsies. Do not decide whether to hold therapy without consulting the prescriber. Infectious complications related to active SLE and immunosuppressive treatment are still the most common cause of death in early active SLE. Based on experience with such other biologic agents as the anti-tumor necrosis factor inhibitors, persons on biologics may be less likely to develop life-threatening infections than are patients on aggressive immunosuppression with corticosteroids or cytotoxic agents, such as those used to treat nephritis or vasculitis.

The future is here

These so-called targeted therapies have long been in development. Derived from basic science elucidation of cellsignaling mechanisms, some are cell-surface-based, like the biologic abatacept (Orencia), which affects T-cell receptors; B-cell-based, like belimumab and rituximab (Rituxan); or in-development agents, like Janus tyrosine kinase modifiers, which approach the cell signaling pathways from within the cell rather than on the cell surface.

More easily tolerated pulse immunosuppressive approaches now include the use of rituximab and mycophenolate (Cellcept) for severe manifestations. These are far better-tolerated

32 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

approaches. Such newer, less-difficult-to-manage anticoagulants as dabigatran (Pradaxa) for long-term anticoagulation may also help SLE patients feel that the treatments are not worse than the disease. Finally, broad-spectrum sunblock and effective sun-protective clothing are available and affordable.

Both the basic science and clinical-care pipelines for SLE are exciting. Hopefully, they will shift the risk/benefit ratio of treatment and improve the lives of patients over the entire clinical spectrum of SLE. ■ Ms. McTigue is a physician assistant in the Division of Rheumatology and Dr. Croker is a professor in the Department of Pathology, Immunology, and Laboratory Medicine at the University of Florida College of Medicine and the VA Medical Center, both in Gainesville. The authors have no relationships to disclose relating to the content of this article.

“You said it—everybody heard you.”

References 1. Lupus Foundation of America. Statistics on lupus. Available at www.lupus .org/webmodules/webarticlesnet/templates/new_newsroomreporters .aspx?articleid=247&zoneid=60.

2. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum. 2008;58:15-25. Available at onlinelibrary.wiley.com/ doi/10.1002/art.23177/pdf.

3. Tassiulas IO, Boumpas DT. In: Firestein GS, Budd RC, Harris ED Jr, et al, eds. Kelley’s Textbook of Rheumatology. 8th ed. Philadelphia, Pa.; 2008:1263.

4. Uramoto KM, Michet CJ Jr, Thumboo J, et al. Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992. Arthritis Rheum.

1999;42:46-50.

Louis, Mo.: Mosby; 2003:1291-1296.

“I installed Skype, so it’ll be just like you never went away to college.” © The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

5. Hochberg MC, Silman AJ, Smolen JS, et al. Rheumatology. 3rd ed. St. 6. Sobel ES, Gianini J, Butfiloski EJ, et al. Acceleration of autoimmunity by organochlorine pesticides (NZB × NZW)F1 mice. Environ Health Perspect.

2005;113:323-328. Available at: www.ncbi.nlm.nih.gov/pmc/articles/ PMC1253759/.

7. Okada H, Kuhn C, Feillet H, Bach JF. The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160:1-9.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2841828/.

All electronic documents accessed December 15, 2011.

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

“Is it so important that it be a rescue ship?” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 33

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www.tradjenta.com Copyright © 2011, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

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Please see brief summary of full Prescribing Information on the following page.

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50K 25K

Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com

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USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

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ADVERSE REACTIONS Adverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (eg, rifampin).

Therefore, use of alternative treatments is strongly recommended.

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WARNINGS AND PRECAUTIONS Use With Medications Known To Cause Hypoglycemia Insulin secretagogues (eg, sulfonylurea) are known to cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

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Important Safety Information CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus zero in 433 person-years for comparator).

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Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA has not been studied in combination with insulin.

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−0.6% A1C placebo-adjusted in combination with metformin

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Alone or in combination with metformin, TRADJENTA provided statistically significant improvements in A1C at 24 weeks

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No dose adjustment is recommended for patients with hepatic or renal impairment

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The only DPP-4 inhibitor approved at 1 dose for adult patients with type 2 diabetes

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FOR ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS

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Tradjenta™ (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

INDICATIONS AND USAGE TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

TRADJENTA has not been studied in combination with insulin.

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

OVERDOSAGE During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis.

Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Monotherapy* n (%)

Nasopharyngitis Hyperlipidemia Cough Hypertriglyceridemia† Weight increased

Combination with SU n (%)

TRADJENTA Placebo n = 765 n = 458

Combination with Metformin# n (%) TRADJENTA Placebo n = 590 n = 248

– – – – –

– – – – –

7 (4.3) – – 4 (2.4) –

– – – – –

– – – – –

TRADJENTA Placebo n = 161 n = 84 1 (1.2) – – 0 (0.0) –

Combination with Metformin + SU n (%) TRADJENTA Placebo n = 791 n = 263

Combination with Pioglitazone n (%) TRADJENTA Placebo n = 259 n = 130

– – 19 (2.4)

– 7 (2.7) – – 6 (2.3)

–

– – 3 (1.1) – –

– 1 (0.8) – – 1 (0.8)

SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)

Copyright © 2011 Boehringer Ingelheim Pharmaceuticals, Inc. Revised: July 2011

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USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

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Table 1

DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp or CYP3A4 inducer.

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ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with pioglitazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in ≥5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyngitis (5.8% vs 5.5%). Adverse reactions reported in ≥2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥ 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).

Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.

FEATURE: EILEEN DURHAM, C-PNP, CNS, MSN

Making the right choice in hormone therapy A young cancer survivor prompts consideration of best practice in prescribing estrogen replacement therapy for her and for others.

E

strogen is one of the most prescribed drugs worldwide. It is used to treat menopausal symptoms and ovarian failure.1 Although estrogen replacement therapy (ERT) was approved by the FDA more than 60 years ago, the best practice in prescribing ERT remains a confusing and controversial subject.

In the fall of 2007, a 14-year-old patient with ovarian failure challenged our beliefs and our ERT prescribing practices. What we learned can be of great value to clinicians who treat both pediatric and adult patients.

© CAROLYN A. MCKEONE / PHOTO RESEARCHERS, INC.

Case study

Transdermal estrogen offers a number of advantages over oral formulations.

34 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Patient history. At age 6 years, Ashley was diagnosed by pediatric oncology with acute myelocytic leukemia. She was treated with multiple rounds of chemotherapy, but these failed to cure the disease. The only intervention that could save her life was a bone marrow transplant. In preparation for this procedure, Ashley received high-dose chemotherapy and total body irradiation. Two years after treatment, she celebrated being cancer-free, but the treatment that saved her life had also adversely affected her endocrine system.

Post-transplant side effects. When she was age 8 years, Ashley was referred to the pediatric endocrinology service for evaluation of her short stature; her growth for age was less than the third percentile. A physical examination and laboratory results revealed growth hormone deficiency, as well as central hypothyroidism. Treatment with growth hormone and

HORMONE THERAPY

POLL POSITION

More than 80% of readers who responded to our poll have had their prescribing habits influenced by reports about risks associated with hormone replacement therapy.

Yes

82%

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16%

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2% 0

n=71

20%

40%

60%

80%

100%

Three forms of estrogen

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levothyroxine produced an excellent response. She remained euthyroid, and within 18 months, her growth for age was at the 25th percentile.

Ashley returned to the pediatric endocrinology clinic yearly for laboratory studies and physical examinations. Although she was progressing well, she remained prepubertal. Results of her evaluation at age 13 indicated that she had made no progress. Her Tanner staging was completely prepubertal.

Her luteinizing hormone (0.1 mIU/mL), follicle-stimulating hormone (2 mIU/mL), and estradiol (2.5 ng/dL) levels were low and confirmed the diagnosis of hypogonadotropic hypogonadism. Initiating feminization in girls with this diagnosis requires the use of estrogen. Ashley and her parents were given information on ERT and encouraged to call and/or make a list of any questions they would like to have answered before beginning therapy.

Starting ERT. At age 14 years, Ashley came for her annual visit and to begin ERT. Standing beside her mother, Ashley proclaimed, “I know I need to start estrogen, and I want to go over my options. You know I am a vegetarian. I love animals, and I will not take the estrogen they get from horses. It is totally cruel. I have been on the Internet, and I want the estrogen that comes from plants.”

PEER PERSPECTIVES

Over the past 10 years, there has been a rise in vegetarianism2 in the United States, especially among adolescent girls.

Many patients or their parents request information on the source of their medications based on religious, moral, or ethical concerns. Additionally, widespread use of the Internet allows providers and the lay public access to information that, in the past, was only debated in scientific communities.3-5 Ashley was correct; the prescription awaiting her was for Premarin, a formulation of conjugated estrogens that is derived from the urine of pregnant mares. To address Ashley’s moral concerns and provide the best estrogen formulation for her required a greater understanding of this complex and evolving drug field.

Although estrogen sounds as if it is one hormone, it is, in fact, the name of a group of hormones. There are three basic forms of estrogen in the human female body: estrone (E1), estradiol (E2), and estriol (E3).6 Estrone is a weak form of estrogen that is most abundant in a woman’s body after menopause.

Estradiol is the primary and most potent form of estrogen produced in the body before menopause. Estriol is the primary estrogen of pregnancy. From menarche to menopause, the primary source of estrogen in normally cycling women is the ovarian follicle, which secretes estradiol daily. Estradiol induces puberty and maintains feminization.7 In most girls, puberty starts at approximately age 10 years, when the pituitary begins to secrete luteinizing hormone, which stimulates the ovaries to develop and secrete estrogen.

Estrogen is responsible for enlarging the uterus and the fallopian tubes, development of the breasts, and accruing and maintaining optimal bone mineral density.

Estrogen deficiency

Estrogen deficiency can be a primary or secondary disorder.

Primary estrogen deficiency results from failure of the ovary, while secondary estrogen deficiency results from failure of the pituitary to regulate the ovaries. Ovarian failure can occur in patients with genetic disorders, such as Turner syndrome; after surgical removal; or following exposure to some forms of chemotherapy or radiation to the pelvis.

“In our busy endocrinology division, we see a number of young women who need hormone replacement, and our preference is definitely bioidentical hormones.”

Caroline K. Buckway, MD, Stanford, Calif. (via ClinicalAdvisor.com)

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 37

HORMONE THERAPY

TABLE 2. Estrogen equivalencies

TABLE 1. FDA-approved estrogens Form of estrogen Conjugated estrogens

Brand name

Source

Active ingredients

Premarin

Horse urine

Sodium estrone sulfate, sodium equilin sulfate, sodium sulfate conjugates, 17α 17 α-dihydroequilin, 17α 17 α-estradiol, 17β 17 β-dihydroequilin

Esterified estrogens

Estratab, Menest

Yams

Sodium estrone sulfate, sodium equilin sulfate

Estradiol

Estrace, Climara, Estraderm, Vivelle

Soy/yams

17β 17 β-estradiol

Adapted from Dong B. Hormonal drugs: Female sex hormones. In: Anderson PO, Knoben JE, Troutman WG, eds. Handbook of Clinical Drug Data. 10th ed. New York, N.Y.: McGrawHill; 2002:679-698.

Pituitary failure can be caused by tumors of the central nervous system (CNS), trauma, malformations, pituitary adenomas, or CNS irradiation.8 Treatment advances have increased the survival rates for children with cancer. Today, 80% are alive five years after therapy. However, significant survival benefits are also associated with short- and long-term morbidity later in life.

Among the many consequences of these advanced lifesaving cancer therapies is damage to the endocrine system, resulting in short- or long-term hormone deficiencies, including ovarian failure.9 Prescribing plant-derived derivatives

Before prescribing an FDA-approved plant-derived alternative to estrogen, it is essential to review the history of estrogens, current research, the pharmacology of available ERT regimens, and coverage by insurance carriers.

History of ERT. In 1942, Wyeth was the first pharmaceutical manufacturer to obtain FDA approval for ERT. Premarin, an equine-derived estrogen formulation, was marketed and approved for the treatment of menopause.10 That approval was based on clinical studies that were conducted by Wyeth

CLINICAL SLIDESHOW For more information on the symptoms and potential complications of menopause, view the slideshow at ClinicalAdvisor.com/MenopauseSlideshow.

Agent

Equipotent dose

Dosage forms

Conjugated estrogens (Premarin)

0.625 mg

Tablet: 0.3, 0.625, 0.9,1.25, 2.5 mg Vaginal cream 0.625 mg/g

Esterified estrogens (Estratab, Menest)

0.625 mg

Tablet: 0.3, 0.625, 1.25, 2.5 mg

Estradiol-17β Estradiol-17β (Estrace)

1 mg

Tablet: 0.5, 1, 1.5, 2 mg

Estradiol-17β patch Estradiol-17β (Vivelle, Climara, Estraderm)

50 µg/d

Sustained-release patch: 25, 37.5, 50, 75, 100 µg/d

Adapted from Dong B. Hormonal drugs: Female sex hormones. In: Anderson PO, Knoben JE, Troutman WG, eds. Handbook of Clinical Drug Data. 10th ed. New York, N.Y.: McGrawHill; 2002:679-698.

and certified the safety of the product for its intended use.

In 1962, Congress passed the Kefauver-Harris Amendment, also known as the “Drug Efficacy Amendment,” which required pharmaceutical manufacturers not only to prove safety but also to provide substantial evidence of effectiveness for the product’s intended use. The evidence had to consist of adequate and well-controlled studies. This was a revolutionary FDA requirement. FDA approval of estrogen provided American women with a medication that could prevent the symptoms of menopause, but few physicians were comfortable with prescribing it.

The estrogen revolution. In 1966, Robert A. Wilson, MD, published a best-selling book, Feminine Forever. Dr. Wilson, a recognized authority in the field of hormone therapy and menopause prevention, was credited with one of medicine’s most revolutionary breakthroughs—the discovery that menopause was a hormone deficiency that was curable. Estrogen replacement could restore women mentally, physically, and sexually to a premenopausal state, the only difference being that they could not bear children.

Postmenopausal women were encouraged to take estrogen therapy for the rest of their life, and millions of American women did just that. In 2001, approximately 67 million women were fi lling prescriptions for Premarin or Prempro (conjugated estrogens and medroxyprogesterone).

In 2002, the belief in ERT as the solution to women’s declining estrogen levels changed dramatically. The Women’s Health Initiative (WHI), the largest federally funded study of long-term estrogen replacement, revealed that rather than having their health protected, patients on ERT were experiencing stunning adverse side effects. Women who were

38 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

HORMONE THERAPY

TABLE 3. Comparing oral vs. transdermal estrogen administration All oral estrogens result in:

Transdermal 17β-estradiol 17 -estradiol results in:

First pass through the GI tract and liver—higher dose required

Does not pass through liver— lower effective dose possible

Serum estrogen peaks and troughs

Serum estrogen levels relatively constant

Increased hepatic enzymes, inflammatory markers

No change in inflammatory markers

Increased triglycerides

No change or decrease in triglycerides

Increase in BP

Decrease in BP

Reduced IGF-1

No effect on growth hormone/ IGF-1

Decreased LDL and increased HDL

Decreased LDL but no change in HDL

Key: HDL=high-density lipoprotein cholesterol; IGF-1=insulinlike growth factor-1; LDL= low-density lipoprotein cholesterol.

Adapted from Kopper NW, Gudeman J, Thompson DJ. Transdermal hormone therapy in postmenopausal women: a review of metabolic effects and drug delivery technologies.

Drug Des Devel Ther. 2009;2:193-202. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC2761184/. Accessed December 15, 2011.

TABLE 4. Sample of patient costs for estrogen therapy Managed-care member co-pays: • Premarin: $21-$40 • Esterified estrogen: $21-$40 • Estrace: <$10 • Estradiol patch: $21-$40 In northern California, the out-of-pocket expense for a 30-day supply through local pharmacies was approximately: • Premarin: $63.99 • Esterified estrogen (Estratab): $28 • Estrace: $4 • Estradiol patch (Vivelle dot): $66

receiving estrogen had more heart disease, breast cancer, strokes, and blood clots, compared with those taking a placebo. At first, in 2002, only the estrogen-and-progesterone arm of the study was closed, but then in 2004, subjects in the estrogen-only arm were found to have an increased risk of stroke.11

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What the general public and many health-care professionals did not know then—and may not know today—is that the only form of estrogen used in the WHI was equine-derived estrogen in the form of Premarin or Prempro.12 FDA-approved estrogens. Researchers and medical professionals questioned whether these same adverse events would have been observed with the newer estrogen formulations. The agents currently approved by the FDA include: • Premarin—the most-prescribed formulation of estrogen replacement used clinically to treat hypogonadal girls. It contains more than 100 individual estrogenic compounds of different biologic potency and cannot be measured in conventional assays. Premarin is derived from the urine of pregnant mares.

• Esterified estrogens—a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, derived from yams.

• Estradiol—identical to the E2 produced by the human ovary. A white, crystalline solid, chemically described as “bioidentical” 17β-estradiol, it is derived from soy or yams.13 Defi ning bioidentical. Some of the estrogens listed were defined as “bioidentical.” There is much confusion surrounding the meaning of this term and we needed a clear understanding of what it meant before choosing the formulation we would prescribe.

The Endocrine Society defines bioidentical hormones as “compounds that have exactly the same chemical and molecular structure as hormones that are produced in the human body.”14 Shortly after The Endocrine Society published its position statement on bioidentical compounds, the American Medical Association also adopted the society’s official definition. Information found in The Handbook of Clinical Drug Data allowed us to create charts comparing the estrogens15 (Table 1).

We shared the charts with Ashley and her parents and explained the different formulations. Together, they chose bioidentical estradiol-17β. However, converting Premarin to the equivalent estradiol dose was challenging (Table 2).

Choosing the route of administration. The next decision was to determine the best route of administration. Ashley was on growth hormone (GH) therapy. Studies show that oral estrogen in any form interferes with GH serum levels

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HORMONE THERAPY

●

Treatment advances have increased the survival rates for children with cancer.

●

Advanced lifesaving cancer therapies may damage the endocrine system.

of therapy adherence but also provided education about the potential side effects. At her return visit three months later, Ashley reported almost 100% adherence and no side effects. Moreover, she preferred the patch versus having to remember to take another oral medication.

●

Therapeutic effects are achieved at lower peak doses of transdermal estrogen compared with oral formulations.

Best practice for ERT?

●

Rapid cessation of drug administration is possible with removal of the transdermal system.

AT A GLANCE

and decreases the levels of insulinlike growth factor-1 by up to 30%, potentially counteracting the benefits of GH.16 Additionally, females with hypogonadism, like Ashley, are at increased risk of cardiovascular disease. Numerous studies link oral estrogen therapy to increased cardiovascular risk. This is thought to be due to the first-pass effect, which theorizes that after oral consumption, the bolus of estrogen travels through and is metabolized by the liver. There, it stimulates biochemical factors that result in an increase in C-reactive protein (CRP). Elevated CRP levels have been observed in patients on long-term oral ERT; women with cardiovascular disease; and healthy women as well.17 Studies using transdermal estradiol-17β have not duplicated these findings, possibly because it is not first metabolized through the liver. Transdermal estrogen offers other advantages over oral formulations: (1) Therapeutic effects are achieved at lower peak doses because first-pass hepatic metabolism and enzymatic degradation in the GI tract are avoided. (2) Serum hormone levels remain constant. (3) Rapid cessation of drug administration is possible with removal of the transdermal system.18 We reviewed the pros and cons of oral versus transdermal estradiol (Table 3) with Ashley and her family. Given the information at hand, it was clear to every member of the team that transdermal estradiol was the best choice.

Cost. One last question remained: Was the newer drug covered by Ashley’s family’s insurance plan? And, if not, what was the out-of-pocket cost? Each insurance carrier and individual policy is different, but to get an idea of how ERT is covered in my state, I checked with one of the largest carriers in California (Table 4).

Before leaving that day, Ashley asked, “Did you check out the Internet? Did you read about the horses?” I did know about the horses, and I understood why she, as an animal-loving vegetarian, had insisted on nonequine estrogen. Anyone wishing to know about the fate of the horses and their foals should search “pregnant mare’s urine” on the Internet.

There is ample precedent for a movement away from animal sources for hormone replacement. Recombinant human technology has been used to make thyroxine and insulin rather than relying on older hormones extracted from beef and pork. After reviewing the scientific and ethical issues, we decided that in most cases, it was best practice to prescribe estrogens identical to that found in the human body rather than those derived from animals.

Our experience with Ashley changed our prescribing practice. Today we wonder why anyone, in pediatric or adult practice, would prescribe animal-derived hormones when those identical to that produced by the human female body are available.19 ■ Ms. Durham is a pediatric nurse practitioner in the Division of Pediatric Endocrinology & Diabetes at Lucile Packard Children’s Hospital at Stanford, in Palo Alto, Calif.

References 1. Kiess W, Conway G, Ritzen M, et al. Induction of puberty in the hypogonadal girl—practices and attitudes of pediatric endocrinologists in Europe. Horm Res. 2002;57:66-71.

2. Sanders TA, Reddy S. Vegetarian diets and children. Am J Clin Nutr.

1994;59:1176S -1181S. Available at: www.ajcn.org/content/59/5/1176S.long.

3. Kenyon PM, Barker ME. Attitudes towards meat-eating in vegetarian and non-vegetarian teenage girls in England—an ethnographic approach.

Appetite. 1998;30:185-198.

4. Fox N, Ward K. Health, ethics and environment: a qualitative study of vegetarian motivations. Appetite. 2008;50:422-429.

5. Di Genova T, Guyda H. Infants and children consuming atypical diets:

Empowering patients and families

vegetarianism and macrobiotics. Paediatr Child Health. 2007;12:185-188.

Researching and sharing all the information we could gather with our patient and her family validated their concerns and empowered them as team members. Our work together served not only to increase the likelihood

Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC2528709/.

6. Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In: Sperling, MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, Pa.: Saunders Elsevier; 2008:530-609.

44 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

7. Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009;121:73-85.

8. Lantinga GM, Simons AH, Kamps WA, Postma A. Imminent ovarian failure in childhood cancer survivors. Eur J Cancer. 2006;42:1415-1420.

9. Hershlag A, Rausch ME, Cohen M. Part 2: Ovarian failure in adolescent cancer survivors should be treated. J Pediatr Adolesc Gynecol. 2011;24:101-103.

10. Stefanick ML. Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. Am J Med. 2005;118 Suppl 12B:64-73.

11. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333. Available at: jama.ama-assn.org/content/288/3/321.long.

12. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.

Available at: jama.ama-assn.org/content/291/14/1701.long.

13. Taboada M, Santen R, Lima J, et al. Pharmacokinetics and pharmacodynamics of oral and transdermal 17β estradiol in girls with Turner syndrome. J Clin Endocrinol Metab. 2011;96:3502-3510.

14. The Endocrine Society. Position statement: bioidentical hormones.

October 2006. Available at www.menopause.org/bioidenticalHT_ Endosoc.pdf.

15. Dong B. Hormonal drugs: Female sex hormones. In: Anderson PO, Knoben JE, Troutman WG, eds. Handbook of Clinical Drug Data. 10th ed.

New York, N.Y.: McGraw-Hill; 2002:679-698.

16. Janssen YJ, Helmerhorst F, Frölich M, Roelfsema F. A switch from oral (2 mg/day) to transdermal (50 microg/day) 17beta-estradiol therapy increases serum insulin-like growth factor-1 levels in recombinant human Endocrinol Metab. 2000;85:464-467. Available at: jcem.endojournals.org/ content/85/1/464.long.

“We have a couple of items that are trending this evening.”

17. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, et al. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial.

Atheroscler Thromb Vasc Biol. 1997;17:3071-3078. Available at: atvb.ahajournals.org/content/17/11/3071.long.

18. Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study.

Circulation, 2003;108:2317- 2322. Available at: circ.ahajournals.org/content/108/19/2317.long.

19. Bondy CA, Ceniceros I, Lange E, Bakalov VK. Declining estrogen use in young women with Turner syndrome. Arch Intern Med. 2006;166:1322-1345.

All electronic documents accessed December 15, 2011.

“My people will get back to your people.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 45

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

growth hormone (GH)-substituted women with GH deficiency. J Clin

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum JANUARY 2012

Consultations Subclinical hypothyroidism. . . . . . . . .46 Halting migraine in someone with coronary artery disease . . . . . . . . . . .47 Does gender affect statin efficacy? . . . .47 What to test before ordering a radiologic study with contrast . . . . . .47 Osteoporosis medications in patients with kidney disease . . . . . . . . . . . . .50

Clinical Pearls Squeeze out the gag reflex . . . . . . . . .50 Frozen fish-oil capsules . . . . . . . . . . .50

Your Comments

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com.

If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter.

No anonymous contributions will be accepted.

The real motivation for prescribing antibiotics . . . . . . . . . . .50

CONSULTATIONS SUBCLINICAL HYPOTHYROIDISM What is the preferred thyroid management for a woman aged 34 years who presents with an enlarged thyroid, no nodules, and irregular menstrual periods for the past six months? Her thyroid-stimulating hormone (TSH) was slightly elevated, thyroxine (T4) was within normal limits, thyroid ultrasound was normal, and prolactin level was normal. Complete blood count revealed slight iron-deficiency anemia, and an occult stool test was negative. I plan to start her on a low-dose birth-control pill and iron sulfate to control the bleeding and alleviate the anemia, but I am not sure what to do about her thyroid.—MARGARET DEMARCO, RNC, WHNP, Odessa, Tex. It looks like this patient has subclinical hypothyroidism (as evidenced by slightly elevated TSH and normal free T4). Checking thyroid antibodies might help determine whether she has any further predisposition to thyroid disease (e.g., family history of thyroid disorders or personal history of autoimmune problems). Hashimoto’s thyroiditis is something else to consider. Subclinical hypothyroidism would not cause the change in her menstrual pattern.

Individuals with subclinical hypothyroidism have a 3%-20% increased risk of going on to develop overt hypothyroidism, especially if goiter and thyroid antibodies are present. There is some debate over whether to treat patients with subclinical hypothyroidism with thyroid

OUR CONSULTANTS

Bruce D. Askey, MSN, CRNP, is

Rebecca H. Bryan, APRN, CNP, is a

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD, is clinical

a clinician in the Department of Hepatology/ Gastroenterology at the Guthrie Clinic in Sayre, Pa.

lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia..

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANPBC, is associate

program director, gerontology NP program, University of Pennsylvania School of Nursing, Philadelphia.

48 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

JoAnn Deasy, PA-C, MPH,

Virginia H. Joslin, PA-C, MPH, is

a primary-care clinician, teaches in the PA program at Pace UniversityLenox Hill Hospital, New York City.

assistant professor and PA Program division director at Emory University School of Medicine in Atlanta.

Maria Kidner, DNP, FNP-C, is

a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

© ISTOCKPHOTO.COM / DAVID KILPATRICK

Picture this

Everyone needs a break during the day. So relax with this photo essay, and pretend you’re someplace else.

46 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Frost-covered trees line the banks of the River Tweed in Kelso, a small city found in the Borders region of Scotland.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 47

hormone. The American Association of Clinical Endocrinologists recommends treatment with a low dose of levothyroxine (25-50 µg) for those with TSH levels between 5 and 10 µIU/mL who also have a goiter and positive thyroid antibodies; the goal is to get TSH to 0.3 to 3.0 µIU/mL (Endocr Pract. 2002;8:457-469). If TSH <5 µIU/mL, recheck thyroid labs in six months to look at trends.

Does your patient have a history of oligomenorrhea, or is this a new change in menstrual pattern? Does she have any signs of hyperandrogenism, such as hirsutism or persistent acne? Chronic oligomenorrhea (sometimes accompanied by dysfunctional uterine bleeding) paired with hyperandrogenism would suggest polycystic ovary syndrome. This would not change your approach but would prompt patient education about the ramifications of this diagnosis, along with higher suspicion for diabetes risk.—Kathy Pereira, MSN, FNP-BC, assistant professor, co-coordinator, Family Nurse Practitioner program, Duke University School of Nursing, Durham, N.C. (159-1)

HALTING MIGRAINE IN SOMEONE WITH CORONARY ARTERY DISEASE What treatment would you recommend for aborting a migraine in a patient with known coronary artery disease (CAD)?—LORI MEADORS, PA-C, Houston

with multivessel disease. Educate patients to treat migraines early and aggressively with the prescribed dose regimen. If patients wait too long to treat, GI uptake is delayed, and abortion of migraine is limited.—Maria Kidner, DNP, FNP-C (159-2)

DOES GENDER AFFECT STATIN EFFICACY? Is there evidence showing that women taking statins saw little improvement in their lipid levels?—BEVERLY ABLETT, MSN, COHN-S, APRN-BC, Somerville, N.J. A meta-analysis of randomized clinical trials (BMJ. 2009;338:b2376, available at www.bmj.com/content/338/bmj.b2376, accessed December 15, 2011) showed beneficial effects of statins on survival across a wide range of patients with varying degrees of cardiovascular risks. There was no significant difference in treatment benefit among men, women, the elderly, and those with diabetes. A study of the impact of gender on statin efficacy (Curr Med Res Opin.

2007;23:565-574) concluded that statins decreased the risk of cardiovascular events in both men and women. However, it was noted that women who are on statins may not have the same reductions in stroke and mortality as men.—Eileen F. Campbell, MSN, CRNP (159-3)

First, try nonsteroidal anti-inflammatory drug (NSAID) therapy with ibuprofen 400-1,200 mg or naproxen 750-1,250 mg. Next, add acetaminophen and caffeine concurrently with NSAID therapy (you may want to protect the stomach). If this does not abort migraine, consider triptans. Triptans inhibit transmission in the trigeminal nucleus caudalis while promoting vasoconstriction. In the setting of CAD, vasoconstriction can precipitate angina. If CAD is mild, triptans can be used as long as the first dose is monitored in a medical setting. However, triptan therapy would be highly risky

WHAT TO TEST BEFORE ORDERING A RADIOLOGIC STUDY WITH CONTRAST How much of a workup do you recommend before ordering diagnostics with contrast (assuming kidney function tests are normal)? Is a basic metabolic panel enough?—SHARON OWENS, NP, Salisbury, Md.

Debra August King, PhD, PA,

Samuel J. Mann, MD is associate

Daniel R. Mishell Jr, MD, is chairman

Christopher Ruser, MD, is

Sherril Sego, FNP-C, DNP, is a

Daniel G.Tobin, MD, is assistant

Jeffrey Weinberg, MD, is director of

is senior physician assistant, New York-Presbyterian Hospital, New York City.

professor of clinical medicine, Weill Medical College of Cornell University, New York City.

of the Department of Obstetrics and Gynecology, University of Southern California, Los Angeles.

assistant professor of medicine, Yale University School of Medicine, New Haven, Conn.

primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

professor of medicine, Yale University School of Medicine, New Haven, Conn.

clinical research, Department of Dermatology, St. Luke’s-Roosevelt Hospital Center, New York City.

Claire Babcock O’Connell, MPH, PA-C, is an

associate professor, University of Medicine and Dentistry of New Jersey, PA program, Piscataway.

Specifically, kidney function tests need to be evaluated prior to ordering a radiologic study with contrast. While a basic metabolic

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 49

Advisor Forum smaller study evaluating alendronate in dialysis patients resulted in stabilization of hip density in subjects taking alendronate, while subjects on placebo showed worsening of BMD. However, current FDA recommendations have not been revised. For a detailed summary of the latest evidence regarding this unsettled topic, see Am J Kidney Dis. 2010;55:941-956.—Claire Babcock O’Connell, MPH, PA-C (159-5)

OSTEOPOROSIS MEDICATIONS IN PATIENTS WITH KIDNEY DISEASE To minimize the risk of chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD), such osteoporosis medications as alendronate (Fosamax) and ibandronate (Boniva) are contraindicated in individuals whose glomerular fi ltration rate (GFR) is <30%. But is it safe to restart these medications once stage 5 CKD (or dialysis) has been reached?—JASON TIEDE, PA, Edmond, Okla.

CLINICAL PEARLS

The FDA currently warns against using bisphosphonates in patients with GFR <30 mL/min/1.73 m2, which includes patients with stage 3, 4, or 5 CKD. This warning is based on studies with rats that were given rapid high doses of the drug, which resulted in histologic changes and acute kidney injury. Several subsequent large trials suggest that in the absence of secondary causes of low bone mineral density (BMD), use of recommended doses of bisphosphonates in patients with age-related stage 2, 3, or 4 CKD may not be as nephrotoxic as believed. Additionally, a large trial using ibandronate in dialysis patients (stage 5) showed a significant improvement in BMD. A

FROZEN FISH-OIL CAPSULES To help mitigate the unpleasant aftertaste of omega-3 fish-oil capsules, tell patients to freeze the pills. The capsules will thaw in the upper intestine and provide all the effectiveness without the fishy taste.—ERYN K. SMITH, PA-C, Ann Arbor, Mich. (159-7)

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

panel is an acceptable option, the results of creatinine and blood urea nitrogen levels are what are needed (electrolytes are not necessary).

Contrast is metabolized through—and can be toxic to—the kidneys.

This is especially important to consider in the elderly, as age-related decline in kidney function can be asymptomatic. Radiologic contrast is useful when cancer is one of the differential disgnoses.—Rebecca H. Bryan, APRN, CNP (159-4)

“There is one more thing we could try.”

SQUEEZE OUT THE GAG REFLEX To dampen the gag reflex while conducting a throat exam, have the patient make a fist with the left hand, tucking the thumb underneath the fingers. I have no idea why, but it works. Try it on yourself.—EMILY W. ROGERS, PA-C, Talent, Ore. (159-6)

YOUR COMMENTS THE REAL MOTIVATION FOR PRESCRIBING ANTIBIOTICS Anyone who paid attention in Pharmacology 101 is familiar with the information presented in the article “Antibiotic stewardship to preserve benefits” (November 2011). What no one will say out loud is that we don’t prescribe antibiotics because we think the patient needs them. We prescribe antibiotics because that is what the patient wants and expects.

In 15 years of practice, I have never been called into an administrator’s office for overprescribing antibiotics, but I have been called into the office because a patient who I talked out of antibiotics for the sniffles wrote a negative comment on some survey. Now that the government has decided to base part of our reimbursement on patient satisfaction scores, this “give them what they want” mentality will only make the situation worse. So please stop publishing articles on right and wrongs of prescribing and focus on what really matters to the powers that be—keeping the patient happy.—JOEL STOIA, PA-C, Dayton, Md. (159-8) ■

50 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Clinical Challenge What looks like a simple case of cellulitis on the third finger is a lot more JENNIFER SNYDER, CNP

A patient presents to the emergency department complaining of pain that originated over the distal tip of the digit.

Mr. K, a 58-year-old, righthand-dominant man, arrived at the emergency department (ED) with a five-day history of increased redness, pain, and swelling in his left middle finger. He reported that the pain originated over the distal tip of the finger and rapidly spread proximally and volarly into his palm.

Mr. K reported no fever, chills, or recent illnesses, nor any trauma or penetration to the finger, but complained of unrelated pain in his right knee.

CASE

1. HISTORY Mr. K was diagnosed with systemic lupus erythematosus (SLE) 25 years ago. He denied ever having any problems with joint pain or swelling,and noted that he takes his daily medications diligently. Mr. K maintains on several drugs for hypertension, including furosemide (Lasix). He is 6 foot 5 inches tall and is obese.

Mr. K’s surgical history includes bilateral orthopedic knee surgery.

2. EXAMINATION

FIGURE 1. Kanavel signs: fixed flexion with fusiform swelling

Examination of the left middle finger revealed all four of Kanavel signs, indicative of septic flexor tenosynovitis (fusiform swelling, pain with passive extension, pain with palpation along the flexor tendon, and fixed flexion).1 The finger also appeared cellulitic along both the volar and dorsal aspects and was erythematous (Figure 1). Results of the tests were negative for lymphangitis or lymphedema, and there was no evidence of injury.The ED tests revealed a slightly elevated WBC count of 11.94 K/μl (4.5-11 normal range), an elevated ESR of 89 mm/hr, and an elevated CRP at 128.4 mg/L.

3. DIAGNOSIS

FIGURE 2. A small amount of soft tissue was excised from the patient’s finger to encourage drainage from the tendon sheath.

Infectious flexor tenosynovitis is an emergency and when left unattended, it can lead to skin loss, tendon necrosis or rupture, and, eventually, osteomyelitis and finger contracture.1,2 Due to Mr. K’s rapid onset of symptoms, as well as the appearance of Kanavel’s four signs, immediate incision and drainage of the

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 51

Clinical Challenge flexor tendon was performed. Initial incisions over the volar PIP joint and proximal tendon sheath expelled murky secretions.

Subsequently, a knee aspiration was performed on the affected knee. Both the finger and knee synovial analyses were positive for urates—conclusive for gout. A secondary blood draw also revealed an elevated uric acid level of 8.9 mg/dL (3.4-7.0 mg/dL is normal for males). After 48 hours, cultures of the left middle finger revealed coagulase-negative staphylococcus; however, no growth was noted from the knee cultures.

Gouty flexor tenosynovitis, as an initial presentation of gout, is quite rare. Gout is a form of arthritis that is caused by an inflammatory reaction to urate crystals that build up in joints, bones, and subcutaneous structures.The surrounding skin can become so inflamed that it can often be mistaken for cellulitis.6,7 Mr. K presented with a number of risk factors for gout; his alcohol use, acute renal insufficiency from his SLE medications, and use of diuretics for hypertension were all considered contributing factors.7

4. TREATMENT AND OUTCOME

6. SUMMARY

The flexor tendon sheath was copiously irrigated with sterile saline, and a small amount of soft tissue was excised around the incisions to delay closure and encourage continued drainage from the tendon sheath (Figure 2). The wounds were covered with Vaseline gauze and dry, sterile dressings. Mr. K was admitted to the hospital and IV antibiotic (vancomycin [Vanocin]) was administered. He underwent hand soaks and dressing changes four times a day. Mr. K was also started on indomethacin (Indocin) 50 mg q.i.d. for acute gout and his furosemide was discontinued, pending resolution of the gout.Within 48 hours, Mr. K showed significant decreases in pain, erythema, and swelling.

Recognizing flexor tenosynovitis is critical, as it is a potential orthopedic emergency. Patients with autoimmune diseases or diabetes may present with inflammatory tenosynovitis. Infectious causes must be ruled out when there is obvious trauma or penetration into the palmar aspect of the finger or hand.A detailed history and physical examination are key to determining proper care. Flexor tenosynovitis is not suited for outpatient treatment.

Providers need to refer patients to the nearest hand or orthopedic surgeon or emergency department for immediate evaluation and treatment. ■

5. DISCUSSION Flexor tenosynovitis is a disorder of the sheath, or lining, of each of the flexor tendons of the fingers.The sheath contains synovial fluid, which protects and lubricates the fingers, allowing for ease of flexion.1 When the sheath becomes inflamed, a patient will typically present with one or more of the Kanavel signs.1 Flexor tenosynovitis can be inflammatory (secondary to diabetes, rheumatoid arthritis, or overuse of the digit), but infectious flexor tenosynovitis is more common and often requires immediate intervention.3 If diagnosed within 24 hours of initial symptoms, it can be treated conservatively with antibiotics. However, lack of significant improvement after 12 hours demands surgical incision and drainage of the tendon sheath.

Several underlying facts pointed toward inflammatory causes in Mr. K’s case: SLE is a chronic, autoimmune disease that causes systemic inflammation and tissue damage.There do exist cases of reported flexor tenosynovitis as a manifestation of SLE.4,5 Mr. K’s associated knee erythema and pain would also be consistent with a systemic inflammatory issue.

Although the workup of Mr. K’s hand showed no signs of penetration into the tendon and no report of injury, bacterial infection cannot be overlooked.The elevated WBC and ESR counts indicate infection.

Ms. Snyder is a nurse practitioner at Riverside Methodist Hospital in Columbus, Ohio. She specializes in hand orthopedics.

References 1. The Wheeless Text of Orthopaedics Infectious Flexor Tenosynovitis information page. Duke Orthopaedics Wheeless Text of Orthopaedics website. Available at www.wheelessonline.com/ortho/ infectious_flexor_tenosynovitis.

2. Moore JR, Weiland AJ. Gouty tenosynovitis in the hand. J Hand Surg Am. 1985;10:291-295.

3. Aslam N, Lo S, McNab I. Gouty flexor tenosynovitis mimicking infection: a case report emphasizing the value of ultrasound in diagnosis.

Acta Orthopaedica Belgica. 2004;70:368-370.

4. Centers for Disease Control and Prevention Systemic Lupus Erythematosus information page. Centers for Disease Control and Prevention website. Available at www.cdc.gov/arthritis/basics/lupus.htm.

5. Tada Y, Sadakata M, Koarada S, et al. Flexor tenosynovitis of the hands as an initial manifestation of systemic lupus erythematosus. Mod Rheum.

2000;10:173-175.

6. Mayo Clinic Gout information page. Mayo Clinic website. Available at www.mayoclinic.com/health/gout/DS00090.

7. Rothschild BM. Griffith’s 5-Minute Clinical Consultant. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2006:454-455.

All electronic documents accessed on December 15, 2011.

52 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Test your clinical acumen with our monthly quiz

CME Dermatology Clinic CE

■ LEARNING OBJECTIVES: To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment.

■ COMPLETE THE POSTTEST: Page 69

■ ADDITIONAL CME/CE: Pages 25, 65

CASE #1

Slow-growing pink, pearly nasal papule ESTHER STERN, NP-C

A man aged 73 years presented with a “pimple” on his nose that just would not go away. He reported that he first noticed the lesion four months earlier, and since then, it has been slowly increasing in size, occasionally bleeding when scratched. The man had no history of skin cancer, although he described frequent sunbathing as a child during the summer. Clinical exam revealed a 5 ⫻ 6 mm pink, pearly papule on the nasal dorsum. On dermoscopy, the lesion was found to have arborising blood vessels, flecks of pigment, and structureless areas.

What is your diagnosis? Turn to page 56

CASE #2

Pigmented macular lip lesion NORMAN D. ZELLERS, MSPAS, PA-C, AND CEASAR A. VALLE, MD, MBA

An active-duty airman aged 30 years presented for an assessment of intermittent abdominal cramps. Physical examination revealed five macular, brown, hyperpigmented lesions on his lower lip. The first lesion appeared two years earlier and remained asymptomatic except for a slight increase in size. The four similar lesions developed at different stages during this time period. The man is a nonsmoker with a fair amount of sun exposure. No known heavy-metal exposure was reported. Family history was negative for skin or GI cancer.

The patient took daily doxycycline for malaria prophylaxis during his recent deployment.

What is your diagnosis? Turn to page 57 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 55

CME CE

CASE #1

Dermatology Clinic

Basal cell carcinoma

Occurring with an estimated frequency of 0.3%-1% in the general population, basal cell carcinoma (BCC)—a nonmelanoma skin cancer—is the most common malignancy in the United States and in countries with a fair-skinned population. Incidence increases greatly with advancing age, particularly after the fifth decade of life.

Although it is most commonly found on sun-exposed areas—including the scalp, face, ears, upper chest, back, and legs—BCC may appear anywhere on the body. Both sexes are equally affected, but incidence on the anterior shins is greater in women, and incidence on the bald scalp is greater in men.

The greatest risk factor for BCC appears to be intermittent intense sun exposure in childhood, particularly with a history of blistering sunburns. In addition, lighter-skin complexion, radiation therapy, a family history of BCC,1 and immunosuppresion are all known contributing conditions. The role of smoking2 and trauma with subsequent scar formation is debated.

Because BCCs are generally slow-growing, they are usually detected when still localized and amenable to surgical removal. Left untreated, however, they tend to grow locally, and at times aggressively, leading to considerable disfigurement. Very rarely, BCC may metastasize to regional lymph nodes or elsewhere; once this occurs, the prognosis is poor.

Although several variants exist, the classic presentation is that of the nodular BCC that presents as a shiny, waxed, semi-translucent nodule with spreading telangiectases and a characteristic rolled border. Crusting, bleeding and ulceration may occur. The pigmented variant is frequently mistaken for a melanocytic lesion, but the shiny pearliness and absence of pigment network can differentiate it.

The morpheaform BCC, often mistaken for a scar, appears as a white sclerotic plaque. Superfi cial BCC, appearing mostly on the trunk and extremities, may resemble an eczematous or psoriasiform pink, scaly plaque. Infiltrative BCCs are poorly circumscribed, have an irregular spiky appearance at the edges, and tend to penetrate deeper.

The term “rodent ulcer” refers to an ulcerating BCC that is likely the result of longstanding neglect. Finally,

fibroepithelioma of Pinkus is a variant of BCC that appears as a flesh-colored sessile papule on the lower trunk and resembles a neuroma.

BCCs originate from the basal cells, which reside in the lower level of the epidermis. Ultraviolet radiation is believed to induce mutation in the cells’ DNA, promoting the growth of carcinogens. Genetic inheritance may also be a factor.

Shave biopsy is usually sufficient to correctly diagnose a BCC. Further imaging is reserved for select cases in which deep invasion is suspected.

Histologically, BCC presents distinctively based on subtype, although most growths exhibit cohesive nests or islands of basaloid tumor cells and palisading of nuclei at the periphery of cell nests. There may be variable inflammatory infi ltrate and ulceration. Immunohistochemical stains may be used to highlight the tumor cells.

Several acceptable treatment modalities exist, and the ultimate goal is complete cure with maximal function and cosmetic outcome. Factors that must be considered to determine the most appropriate treatment include patient age, location and size of the tumor, and clinical and histopathologic subtype.

Standard treatment options include Mohs micrographic surgery, excisional surgery, and electrodesiccation and curettage (ED&C). The most recent National Comprehensive Cancer Network guidelines recommend ED&C for BCC in a non-hair-bearing area in a young, low-risk patient or excision with confirmation of negative margins.3 Higherrisk patients should undergo Mohs micrographic surgery, a staged removal of the tumor, which has the lowest recurrence rate. Micronodular, infi ltrative, and morpheaform BCCs have the highest incidence of positive tumor margins

Treatment options for BCC include Mohs micrographic surgery, excisional surgery, and electrodesiccation and curettage. after excision—as well as the highest recurrence rates—and these should be treated with Mohs surgery.

Alternate treatment options include topical chemotherapeutic and immune-modulating agents, radiation, and photodynamic therapy, among others.

Topical therapy is generally reserved for superficial BCC only. Although imiquimod 5% cream (Aldara) is

56 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

FDA-approved for use five times a week for six to eight weeks, many studies conclude that more frequent use may be more effective.4 Similarly, 5-fluorouracil (Efudex) interferes with DNA synthesis and cell proliferation.

Radiation therapy is generally reserved for individuals who cannot undergo surgical procedures, or for use in cases of recurrence. Photodynamic therapy appears to be somewhat effective for areas of extensive and diffuse BCC,5 but its use for this purpose is not FDA-approved.

Interferon-alfa and topical tazarotene (Tazorac) are considered experimental treatments.

All patients should be warned regarding the dangers of sun and artificial ultraviolet radiation exposure. In addition, 30% -50% of patients with a history of BCC will develop another nonmelanoma skin cancer within the subsequent five years.3 Clinical yearly skin examinations and monthly self-examinations will aid in the early detection of any new or recurrent tumors.

This patient was treated with Mohs micrographic surgery, and the tumor was completely excised in two stages. The defect was closed with a full-thickness skin graft, providing excellent cosmetic results. ■ Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. The author has no relationships to disclose relating to the content of this article.

References 1. Corona R, Dogliotti E, D’Errico M, et al. Risk factors for basal cell carcinoma in a Mediterranean population: role of recreational sun exposure early in life. Arch Dermatol. 2001;137:1162-1168. Available at archderm. ama-assn.org/cgi/content/full/137/9/1162.

2. Boyd AS, Shyr Y, King LE Jr. Basal cell carcinoma in young women: an evaluation of the association of tanning bed use and smoking. J Am Acad Dermatol 2002;46:706-709.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Basal cell and squamous cell carcinoma. Available at www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf.

4. Geisse JK, Rich P, Pandya A, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: A double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol. 2002;47:390-398.

5. Oseroff AR, Shieh S, Frawley NP, et al. Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy.

Arch Dermatol. 2005;141:60-67. Available at archderm.ama-assn.org/cgi/ content/full/141/1/60.

All electronic documents accessed December 15, 2011.

CASE #2

Labial melanotic macule

A deep 4-mm complete excisional punch biopsy of the largest macule confirmed the suspected diagnosis of labial melanotic macule (LMM).

LMMs are chiefly noted on the vermilion border of the lower lip. They are usually welldefined, solitary, uniformly tan-to-brown macules that, once developed, remain unchanged in size and color, rarely exceeding 5 mm in diameter. Young women are most frequently affected, with a mean age range between 27.5 and 34.9 years, and patients appear to be almost exclusively white.1,2 Mucosal melanotic macule is a broader term encompassing lesions of the mouth as well as the lip. Oral melanotic macules may have more of a predilection toward malignant melanoma than LMM. These macules, noted on gingival, buccal, or palatal mucosa, usually present in patients older than age 40 and may be larger, reaching up to 1 cm in diameter. A lingual macule is a specific type of oral lesion noted on the tongue at birth and proportionally grows to between 2 and 5 mm.1 Specific terminology for LMM can be variable and confusing. Such terms as ephelis and lentigo are typically used to describe these lip lesions, both of which are synonymous with the term freckle. The phrase labial melanotic macule was first suggested by Weathers et al in oral pathology literature, and although LMMs histologically resemble ephelides, they do not usually darken with sun exposure or fade in the winter months, nor are they found on mucous membranes.3,4 Microscopic examination of lentigines will reveal elongated rete ridges not seen with LMM.2 LMM histopathology reveals increased melanin pigment in the basal cell layer (and possibly the lamina propria) along with occasional pigment incontinence. When coupled with elongation of the rete ridge, nuclear atypia or an increased number of melanocytes would suggest malignant melanoma or lentigo, respectively.1,4 While LMMs are considered benign, and diagnoses can most often be made clinically, a punch biopsy is a simple enough procedure to reassure the patient and provide the definitive diagnosis.

The differential diagnoses to consider for mucosal melanotic macules fall into two categories: (1) melanocytic lesions, and (2) nonmelanocytic lesions.

Of the melanocytic lesions, mucosal melanoma is the most important to recognize, as it is invasive at discovery 85% of

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 57

CME CE

Dermatology Clinic

the time due to delay in diagnosis. Lesions usually present on the palate and gingival surfaces and have a racial predilection for adult Asians and blacks.5 Any lesions with pigmentation patterns that have changed over time suggest melanoma. The ABCDs should be noted: Asymmetry, Borders (irregular), Color (variable), Diameter (enlarging), and satellite lesions.

Fortunately, primary oral melanoma is rare, accounting for approximately 0.2% to 8% of all melanomas.1 Physiologic or ethnic/racial pigmentation is symmetric and diffuse and usually presents at birth but can appear in persons of any age with no gender predilection. This pigmentation is most commonly found on the gingival mucosa. A related type, known as postinflammatory pigmentation, is usually seen after mucosal reaction to injury and usually fades with time.

Abnormal melanin pigmentation has also been related to cigarette smoking, resulting in smoking-associated melanosis (smoker’s melanosis). A component in tobacco smoke stimulates melanocytes. Gingival pigmentation in children has been linked to passive smoking from parents and other adults who smoke.6 Cessation of smoking improves this condition, with resolution ranging from months to years.

Systemic conditions associated with mucosal melanotic macules include Addison’s disease, Laugier-Hunziker syndrome, and Peutz-Jeghers syndrome. These conditions must be considered in patients with numerous oral pigmentations. Addison’s disease (primary adrenal insufficiency) results in reduced cortisol production by the adrenal gland, resulting in increased pituitary adrenocorticotropic hormone and melanocytic-stimulating hormone as part of a negative feedback mechanism. This leads to diffuse pigmentation of the skin, including irregular and patchy darkening of the oral mucosa (gums). Other presenting symptoms indicative of systemic involvement include weakness, weight loss, nausea, vomiting and hypotension. LaugierHunziker syndrome is a rare acquired benign disorder that involves pigmentation of the oral mucosa to include the lips, as well as finger macules and subungual melanocytic streaks.

Although there is virtually no systemic involvement, the syndrome is usually listed under systemic pigmentation disorders.1,6 Peutz-Jeghers syndrome is an inherited autosomal-dominant condition that presents with more speckled extensive pigmentation and is associated with GI polyposis later in life. The polyps

have limited neoplastic potential and are usually found in the small intestine, resulting in potential systemic signs and symptoms of abdominal pain, rectal bleeding, and diarrhea.

The nonmelanocytic lesion differential is smaller. Amalgam tattoo is iatrogenic and the most common pigmentation of the oral mucous membrane.6 It is mainly found in adult patients in the soft tissue next to teeth restored with amalgam alloy from chronic low-grade frictional contact or traumatic implantation. Amalgam tattoo is typically seen on mandibular gingival mucosa but may also be seen on the buccal mucosa, palate, and tongue.5 Observation is all that is needed, but elective removal for cosmoses may be performed.

Drug-induced oral pigmentation usually occurs after months of chronic use and usually resolves once the medication is discontinued. Some of the more common causative agents are tetracyclines and antimalarial drugs.6 All of these pigment changes can also be seen on sun-exposed areas. Systemic exposure to such heavy metals as silver, gold, bismuth, and mercury may also be responsible for mucocutaneous discoloration.

The patient in this case had concerning multiple lesions with systemic GI symptoms and a history of prolonged doxycycline malaria prophylaxis during deployment. His screening bloodwork was negative. A colonoscopy was normal, and the excisional punch biopsy of the lesion was not only diagnostic but curative as well. The patient was given the option of cryotherapy or observation for his remaining lesions. ■ Mr. Zellers is a physician assistant and Dr. Valle is a flight surgeon and pediatrician at the Los Angeles Air Force Base in El Segundo, Calif. The authors have no relationships to disclose relating to the content of this article.

References 1. Dohil MA, Billman G, Pransky S, Eichenfield LF. The congenital lingual melanotic macule. Arch Dermatol. 2003;139:767-770. Available at archderm.ama-assn.org/cgi/content/full/139/6/767.

2. Spann CR, Owen LG, Hodge SJ. The labial melanotic macule. Arch Dermatol. 1987;123:1029-1031.

3. Weathers DR, Corio RL, Crawford BE, et al. The labial melanotic macule. Oral Surg Oral Med Oral Pathol. 1976;42:196-205.

4. Pais S, Hegde SK, Bhat SS. Oral melanotic macule—a case report. J Indian Soc Pedod Prev Dent. 2004;22:73-75.

5. Flint PW, Haughey BH, Lund VJ, et al. Cummings Otolaryngology: Head &

MORE DERMATOLOGY ON THE WEB

Neck Surgery. 5th ed. Philadelphia, Pa.: Mosby; 2010:1241-1244.

Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

6. Regezi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathology Correlations. 5th ed. St Louis, Mo.: Saunders; 2008:127-139.

All electronic documents accessed December 15, 2011.

58 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Pruritic papules in a healthy 42-year-old woman A woman with no prior medical problems presents with multiple pruritic papules and hyperpigmented spots on her arms, trunk, and legs. The pruritis is often worse at night, but at other times she is asymptomatic.

WHAT IS YOUR DIAGNOSIS?

• • • • •

Kyrle’s disease Prurigo nodularis Sarcoidosis Lichen amyloidosis Dermatofibromas

● See the full case at ClinicalAdvisor.com/DermDx0112A

Café au lait macules and baglike protrusions A 37-year-old pregnant woman with lifelong skin problems presents for an obstetric exam with scattered, tan café au lait macules; soft skin-colored polyps; and several fleshy, baglike protrusions.

WHAT IS YOUR DIAGNOSIS?

• • • •

Tuberous sclerosis Neurofibromatosis type 1 Cowden disease McCune-Albright syndrome

● See the full case at ClinicalAdvisor.com/DermDx0112B

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Brown patch present at birth

Fever and rash for eight days

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 61

LEGAL ADVISOR CASE

Navigating a negligence lawsuit

BY ANN W. LATNER, JD

Clinical work in the emergency department (ED), with its fast pace and constant challenge, did not deter Ms. J from wanting a full-time career as an ED nurse. Ms. J found ED work demanding but immensely rewarding in contrast to what she saw as the monotony of life in general practice. The day-in, day-out routine of seeing patients in an office setting was not for her.

And after just three years on staff in the ED of a large, suburban hospital, Ms. J had experienced the gamut: She had witnessed death firsthand and had played a part in saving many lives. Certain trauma cases were especially disturbing to her—particularly those involving children. But for the most part, Ms. J was always able to leave her work behind when she went home—at least until the day Ms.Y, aged 19 years, arrived in the ED. Ms. Y had been brought in by police officers after she reported being raped. When Ms. J entered the exam room, Ms. Y was pale and trembling. Ms. J spoke to her soothingly and looked at the chart, where intake personnel had written a description of the events that had transpired that night. According to the chart,

© SHUTTERSTOCK / TYLER OLSON

Mishandling of medical evidence jeopardizes a criminal case and causes undue emotional harm.

Ms. J was able to leave her work behind when she went home—at least until the day Ms.Y arrived in the emergency department.

62 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Ms. Y, a freshman at the local university, had been walking home from an evening lecture when she was dragged into an alley and sexually assaulted by an unknown male.

Ms. J flashed back to her own student years. She too had been sexually assaulted while in college, and although it wasn’t rape, the aftereffects of fear, anxiety, depression, and mistrust had lasted long after the physical healing process.

Ms. J suddenly snapped back to reality and noticed Ms. Y looking at her questioningly. The nurse realized that she must have been gazing off into space lost in her thoughts. To steady herself, Ms. J went to get a rape-evidence kit. She was more shaken than she would have expected. That had happened so long ago and Ms. J thought that she was mentally at a point where she was past feeling this kind of emotion.

Continues on page 64

Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

LEGAL ADVISOR Health-care practitioners, like all human beings, are not immune to being affected by patients or situations. It’s natural for a particular case or person to trigger unpleasant or difficult memories that could compromise one’s professional demeanor. What is important, however, is being aware of this, and not letting it impact treatment of the patient.

When Ms. J returned to the exam room, she had regained her composure and set about collecting the physical specimens and skin scrapings for the rape-evidence kit. When the swabs

Trial attorneys will attack any breach of protocol in evidence-handling in the hopes that the evidence will be inadmissible. were collected, she placed them carefully in evidence and sealed the kit per procedure. She then explained to Ms.Y that a crisis counselor would be coming in shortly to speak with her.

But as Ms. J was carrying the evidence kit to waiting police officers, she couldn’t remember whether or not she had included the required documentation within the kit, because she had been so distracted by her memories. Unsure of what to do, Ms. J decided to break the seal to check whether the paperwork was inside. The paperwork was there, so Ms. J resealed the evidence pack with extra tape and gave the kit to the police for laboratory analysis.

Subsequently, an arrest was made: A man was detained on suspicion of raping Ms. Y in addition to several other young women.

The hospital administrator called Ms. J to let her know that the district attorney’s office had called to inquire about procedure the night Ms. Y was seen in the ED. The tamper-evident seal on the rape-evidence kit had been broken, and the DA’s office wanted to question Ms. J about this. Embarrassed, Ms. J admitted to her supervisor that she thought she had neglected to include the documentation when she first sealed the kit, so she opened it up just to check.

“But everything was there, and I didn’t touch the samples.

I simply resealed the kit,” Ms. J explained.

The DA who was prosecuting the case informed Ms. J that she might be called to testify if the defense alleged that evidence-tampering might have occurred.

And that’s precisely what happened. At trial, all evidence pointed to the defendant’s guilt—including DNA evidence from the rape-evidence kits of several victims. But the defense argued that since the tamper-evident seal on this kit was damaged, the

evidence might be compromised: Ms. J told the jury exactly what she had told her supervisor, that she simply opened the seal to verify that she had included proper documentation.

After a moderately lengthy trial, the defendant was convicted— despite the evidence irregularities. Ms. J breathed deeply, feeling a great sense of relief. The emotional pressure had been intense when there was a chance that this man would walk because she had breached protocol.

Ms. J relief was short-lived, however. The defense appealed the conviction, arguing that the rape-evidence kit should not have been admissible at trial because of “chain of custody” violations. “Chain of custody” is a legal term referring to the movement and location of evidence from the moment it is obtained until the time it is presented in court. The appeals court was convened to answer two crucial questions: (1) Did reopening the rape kit—a clear breach of protocol—suggest evidence tampering, and (2) was Ms. J negligent?

Ultimately, the verdict stood, as the appeals court found the sum evidence against the defendant damning and accepted the credibility of Ms. J and her story regarding why the evidence kit was opened and resealed.

Legal background

After examination, the court upheld the defendant’s conviction for rape. The court ruled that a claim of tampering was not supported in this case because Ms. J did not disturb the actual sample containers. In addition, the defense could not show that the integrity of the specimens had been violated.

Typically, trial attorneys will attack any breach of protocol in evidence-handling in the hopes that either the evidence will be ruled inadmissible or the jury will question the credibility of the evidence.

Protecting yourself

Criminal cases can stand or fall based on whether evidence was properly collected, labeled, and stored. In this case, a seemingly harmless error might have resulted in the defendant’s conviction being overturned.

Clinicians who work in the ED will probably, at some point in their career, handle and catalogue evidence.When collecting medical evidence, it is crucial to follow set protocol. Had Ms. J been completely focused, she might not have made an error here. Lastly, if she felt that she couldn’t retain her objectivity, Ms. J could have gone to a supervisor and asked to be excused from handling this case. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations.

■ COMPLETE THE POSTTEST: Page 69

■ ADDITIONAL CME/CE: Pages 25, 55

Linear pink plaques KERRI ROBBINS, MD

CASE #1

CASE #2

A woman aged 17 years was concerned about a rash on her nose. She stated that she had always had a little hyperpigmentation and roughness of the skin in that area. Within the past two years, however, the area had thickened, and she became very concerned about the cosmetic appearance.

No previous treatments had been tried, and none of the woman’s family members had similar lesions. On physical examination, pink verrucous papules with minimal scale were located in a linear streak that extended along the right nasal sidewall to the right nasal tip.

A 3-year-old girl presented with a rash on her right lateral leg. The girl’s mother stated that she first noticed the rash two months ago and suspected it was dry skin. She had been applying an emollient to the area daily and noted that the lesion became larger over time. However, the mother stated that there had been no significant increase in size over the past two weeks. There was no pain or pruritus, and no previous treatments had been attempted. On physical examination, pink papules with minimal scale were noted in a linear pattern on the right lateral thigh.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 65

CME CE

CASE #1

Dermatologic Look-Alikes

Epidermal nevus

Epider mal nevus is also known as nevus verrucosus, nevus unius lateris, and ichthyosis hystrix. The word nevus is derived from Latin and has three different meanings. The fi rst of these meanings is a harmartoma, which means a focal benign growth resembling a neoplasm that develops with an excess or deficiency of structural elements that are normally found in the affected area. The second meaning is a benign tumor of melanocytes. The fi nal meaning is a congenital lesion or a lesion that arises early in life— essentially a birthmark.1 An epidermal nevus is considered a hamartoma of the epidermis and papillary dermis. The two forms of epidermal nevus are the nonorganoid and the organoid versions. The latter consists of nevus sebaceus and follicular nevi. The former consists of keratinocytic nevi.

Approximately one of every 1,000 infants will develop an epidermal nevus. The disease affects all racial backgrounds and genders equally. Prevalence studies have determined that epidermal nevus develops sporadically, although there have been familial cases.2,3 The age of onset ranges from birth to approximately age 14 years; however, roughly 80% of cases occur before the fi rst year of life.4 Epidermal nevi arise from the embryonic epidermis, particularly from pluripotential germinative cells in the basal layer. Mosaicism was thought to be the cause of most epidermal nevi, and until recently, only nevi histologically associated with acantholytic dyskeratosis and epidermolytic hyperkeratosis had been proven to be due to genetic mosaicism.5 More recently, fibroblast growth factor receptor 3 was found to have mosaicism for activating mutations in those with “common” epidermal nevi.5 There is a risk of various malignancies developing within an epidermal nevus, with most of them occurring after puberty. These include such neoplasms as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and keratoacanthoma.

Epidermal nevi usually present as a single linear lesion; however, they may be seen as multiple linear plaques or have a bilateral distribution. The nevi often follow Blaschko’s lines (lines that trace the migration of embryonic cells) and are most commonly seen on the trunk, neck, and extremities.

Blaschko’s lines will appear in a wavy or V-shaped pattern on the trunk and in a linear pattern on the extremities. The lesions are generally hyperpigmented, well-circumscribed papillomatous papules and plaques that are asymptomatic.

Once the growth of the plaque stabilizes, it may become thicker over time, especially in such flexural regions as the neck and joints.

Nevus verrucosus is a localized form of epidermal nevus.

The plaques of this nevi tend to be very warty in appearance.

When lesions appear extensive, unilateral, and often involve the trunk, it is termed nevus unius lateris. Systematized epidermal nevus, also known as ichthyosis hystrix, is a variant with extensive bilateral involvement.6 Epidermal nevus with a combination of such developmental abnormalities as mental retardation, central nervous system abnormalities, and/or musculoskeletal abnormalities could be a good indicator of epidermal nevus syndrome.5,7 A study that evaluated 119 patients with epidermal nevi found that approximately 33% of participants had one organ-system abnormality, approximately 6% had two organ systems with abnormalities, 5% had three organsystem abnormalities, and 5% with five or more organ system abnormalities.5 A thorough history and physical examination should be performed at the time of presentation to rule out any systemic involvement.

A biopsy and histologic examination of an epidermal nevus will reveal hyperkeratosis, papillomatosis, and acanthosis with rete ridge elongation in a psoriasiform pattern.8 Such other findings as epidermolytic hyperkeratosis and acantholytic dyskeratosis may also be seen. Evaluation for the presence of neoplasms such as BCC, SCC, and keratoacanthoma should ensue.

There are many nevoid conditions that are distributed along Blaschko’s lines that must be differentiated from an epidermal nevus. These include such disorders as porokeratotic eccrine ostial and dermal duct nevus, linear lichen planus, and X-linked dominant chondrodysplasia punctata.5 Lichen striatus is a common entity that may be confused with an epidermal nevus. However, lichen striatus is not present at birth and is associated with spontaneous resolution over time. On histology, there is less hyperkeratosis

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66 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

and acanthosis with more dyskeratosis, spongiosis, and lichenoid inflammation.9 Nevus sebaceus usually occur on the head (instead of the trunk); however, it can also have a verrucous appearance and is considered a subtype of an epidermal nevus with sebaceous and apocrine gland hamartomatous components. If the epidermal nevus is small in size, it must be differentiated from a seborrheic keratosis, verruca vulgaris, or psoriasis.

Multiple or extensive epidermal nevi in an infant or child may be a sign of systemic abnormalities. A strong working relationship between the patient, parent, dermatologist, and pediatrician is necessary to diagnose and treat the disorder properly. The clinician should perform a thorough history and physical examination to screen for any signs that may be a prelude to the diagnosis of epidermal nevus syndrome. Surgical removal of the lesion by curettage or shave excision is common.10 However, these surgical modalities generally remove only the epidermis, so recurrence is not unexpected, and the patient usually needs repeated procedures to minimize the appearance of the epidermal nevus. Full-thickness surgical excision is another option for localized and small epidermal nevi and often leads to resolution. However, hypertrophic and keloidal scars are common. Chronic retinoid therapy has been found to be effective in reducing the thickness of ichthyosis hystrix but does not result in complete resolution.5 The risks and benefits of treatment must be discussed prior to the initiation of therapy. Laser ablation as been attempted but frequently results in scars that may not be cosmetically acceptable to the patient. Other topical treatments that have been used with some benefit include corticosteroids, tars, anthralin, 5-fluorouracil, and podophyllin.5 Most patients who are diagnosed with an epidermal nevus will have no complications. Depending on the location, cosmesis may be an issue. If it is, any of the above modalities may be attempted. With more extensive epidermal nevi, the clinician must worry about the diagnosis of epidermal nevus syndrome, which may lead to systemic complications.

These nevi are also more difficult to treat and can cause great distress cosmetically.

This patient was treated with a shave excision in an attempt to improve the cosmetic appearance and minimize the risk of scarring. She was informed that this was not being done to remove the epidermal nevus but would likely improve the cosmetic appearance. She was advised of the likely need for further treatment in the future, as recurrence of the nevus is common. She was also given a trial of tazarotene (Tazorac) 0.05% cream to be used at bedtime as tolerated.

CASE #2

Lichen striatus

Lichen striatus was f irst described as a peculiar linear papular eruption and named lichenoid trophoneurosis by Balzer and Mercier in 1898. It would not be until 1938 that Senear and Caro implemented the current name, lichen striatus.5 Lichen striatus is an uncommon, asymptomatic, self-limited linear and lichenoid dermatosis. Skin is the only organ affected, and the lesions primarily occur on the extremities.11,12 On occasion, the face, trunk, and buttocks may also be affected.

In most cases, the age of onset is anywhere from 4 months to approximately 15 years. The vast majority of cases occur in preschool-aged children, and the median age of onset is 2 to 3 years. There have been occasional case reports of the disorder occurring in adults. The female-to-male ratio is approximately 2:1.13 The eruption is usually asymptomatic and takes a few weeks to months to reach the full clinical appearance.

Lichen striatus is classified as a mosaic condition because it tends to follow Blaschko’s lines, which are thought to trace the embryologic development of skin. However, the genes involved are unknown, as are the triggers for the disorder.

Seasonal prevalence in the spring and summer months has led to examination of environmental factors, viruses, and toxic agents.1 The prevailing theory holds that during early fetal development, abnormal clone epidermal cells produced by somatic mutations will migrate out along the lines of Blaschko.

During this time, any exposure to such infectious agents as a virus could break previous tolerance to the clone by bringing to mind a novel membrane antigen. Clustered or scattered CD8+ T-cells found around necrotic keratinocytes support a cell-mediated immunologic reaction by which cytotoxic T-cells would attack and eliminate the mutated or virally modified keratinocytic clones.8 This causes the characteristic lesions of lichen striatus. It is also though that the disorder may represent a manifestation of an atopic diathesis or be the cause of an infectious agent in genetically predisposed individuals.

The lesions range from 2 to 4 mm in diameter and may be flat-topped, smooth, or scaly. The lesions are often clustered in a discrete band that may be continuous or interrupted and often measures 1 to 2 cm in width. Lesions may be seen as skin-colored, pink, or tan papules. The lesions are usually in a unilateral streak along Blaschko’s lines and are located mainly on the extremities. Occasionally, they may be seen in a bilateral

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 67

CME CE

Dermatologic Look-Alikes

distribution pattern or in parallel bands. Uncommonly, lichen striatus may involve the trunk, head, or neck. There are reports of the disorder spreading proximally from an extremity to the trunk or distally from the trunk to an extremity.5 Although lichen striatus is usually asymptomatic, the condition can be associated with severe pruritus. The lesions take weeks to months to fully develop and often resolve spontaneously within months to years after onset. Once the lesion resolves, a postinflammatory hypopigmentation can occur. This is more common in darker-skinned individuals. Total nail loss can result if the lesion spreads to the nail apparatus. Onycholysis, splitting, and fraying may also occur.5 While lichen striatus does not usually recur, if a relapse is seen, it may strike at the same site or on the same side of the body.8 The histopathologic examination of lichen striatus is variable and depends on the age of the lesion at the time of the biopsy. Spongiosis, exocytosis, parakeratosis, dyskeratosis, and focal or diffuse lysis of the basal layer are all alterations that may be seen within the epidermis.8 In the dermis, there is a superficial perivascular or lichenoid (bandlike) inflammation with a variable number of histiocytes and lymphocytes.14 This infiltrate may extend into the epidermis in areas where there are necrotic keratinocytes and vacuolar alteration of the basal layer.15 If the inflammatory infi ltrate is seen in the reticular dermis around hair follicles and eccrine glands, this may help to make the diagnosis of lichen striatus.8 Plasma cells and eosinophils are rarely seen. Older lesions may appear similar to lichen nitidus or lichen planus.

The main differential diagnoses for lichen striatus are those inflammatory diseases that are linear in nature, including linear lichen planus, blaschkitis, and linear graft-versus-host disease.5 Linear lichen planus and lichen striatus are two disorders that may be hard to distinguish histologically, thus careful clinical observation is needed to differentiate the two.1,8 The primary lesions often differ in size and color; hypopigmentation is often the by-product of lichen striatus, whereas hyperpigmentation occurs during the course of linear lichen planus. Lichen striatus also resolves spontaneously and often does not need treatment. Blaschkitis is usually seen on the trunk of adults as multiple streaks that have features of dermatitis. Other differential diagnoses to consider are linear Darier disease, linear inflammatory verrucous epidermal nevus, linear psoriasis, and linear porokeratosis.5 When the diagnosis is in question, a histopathologic examination of a cutaneous biopsy will help differentiate lichen striatus from most other linear eruptions.

Lichen striatus will usually resolve spontaneously within three to 12 months, and patients and parents should be reassured.9 Topical corticosteroids and oral antihistamines may be used

to treat symptoms of intense pruritus. Topical corticosteroids (under occlusion) or calcineurin inhibitors have been shown to be effective at accelerating the resolution of the lesions in sporadic case reports.5 Resolution of lichen striatus usually goes without incident. However, the area may be hypopigmented once the lesion is resolved, but even this will disappear over time.

This patient was given reassurance that the lesion would resolve within months to years with no complications. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. The author has no relationships to disclose relating to the content of this article.

References 1. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed.

Philadelphia, Pa.: Elsevier Saunders; 2006:216-217, 71-72.

2. Alsaleh QA, Nanda A, Hassab-el-Naby HM, Sakr MF. Familial inflammatory linear verrucous epidermal nevus (ILVEN). Int J Dermatol. 1994;33:52-54.

3. Goldman K, Don PC. Adult onset of inflammatory linear verrucous epidermal nevus in a mother and her daughter. Dermatology. 1994:189:170-172.

4. Rogers M, McCrossin I, Commens C. Epidermal nevi and the epidermal nevus syndrome. A review of 131 cases. J Am Acad Dermatol. 1989;20:476-488.

5. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:1671-1672, 170-172.

6. Loff HJ, Bardenstein DS, Levine MR. Systematized epidermal nevi: case report and review of clinical manifestations. Ophthal Plast Reconstr Surg.

1994;10:262-266.

7. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, N.Y.: McGraw-Hill; 2005:214-215.

8. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin. 10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:88, 103-106, 690, 110-111, 193-194.

9. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:233-234.

10. Dellon AL, Luethke R, Wong L, Barnett N. Epidermal nevus: surgical treatment by partial-thickness skin excision. Ann Plast Surg. 1992;28:292-296.

11. Kennedy D, Rogers M. Lichen striatus. Pediatr Dermatol. 1996;13:95-99.

12. Taieb A, el Youbi A, Grosshans E, Maleville J. Lichen striatus: a Blaschko linear acquired inflammatory skin eruption. J Am Acad Dermatol.

1991;25:637-642.

13. Patrizi A, Nevi I, Fiorentini C, et al. Lichen striatus: clincal and laboratory features of 115 children. Pediatr Dermatol. 2004;21:197-204.

14. Reed RJ, Meek T, Ichinose H. Lichen striatus: a model for the histological spectrum of lichenoid reactions. J Cutan Pathol. 1975; 2:1-18.

15. Gianotti R, Restano L, Grimalt R, et al. Lichen straitus—a chameleon: a histopathological and immunohistological study of 41 cases. J Cutan Pathol.

1995;22:18-22.

68 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

Evolving anticoagulation in patients with NVAF, including those at increased stroke risk...

HELP INTERCEPT STROKE RISK

...combining proven protection, a demonstrated safety profile, and convenient once-daily dosing XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

IMPORTANT SAFETY INFORMATION WARNING A. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO® discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort).

Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban.

NSAIDs/Aspirin: In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. In a singledose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.

Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions].

Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)]. XARELTO should be used in patients with CrCL 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Use in Specific Populations].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions].

Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.

Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.

Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information].

Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.

Table 2: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study Renal Impairment Class [CrCl (mL/min)] Parameter Mild Moderate Severe [50 to 79] [30 to 49] [15 to 29] N=8 N=8 N=8 Exposure AUC 44 52 64 28 12 26 (% increase relative to normal) Cmax FXa Inhibition AUC 50 86 100 9 10 12 (% increase relative to normal) Emax PT Prolongation AUC 33 116 144 4 17 20 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1) in full Prescribing Information].

Hepatic Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed.

Table 3: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study Hepatic Impairment Class (Child-Pugh Class) Parameter Mild Moderate (Child-Pugh A) (Child-Pugh B) N=8 N=8 Exposure AUC 15 127 0 27 (% increase relative to normal) Cmax FXa Inhibition AUC 8 159 0 24 (% increase relative to normal) Emax PT Prolongation AUC 6 114 2 41 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions].

OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

© Janssen Pharmaceuticals, Inc. 2011 10185201 02X11309BBA

Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

CE

POSTTEST Expiration date: January 2013

The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC).

The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

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Lupus and the autoimmune process: the view from 2012

Case #1: Basal cell carcinoma

Case #1: Epidermal nevus

1. In what location is the incidence of basal cell carcinoma (BCC) greater in women? a. Shins b. Scalp c. Trunk d. Nasal tip

5. Where are epidermal nevi most commonly found? a. Face b. Chest c. Buttocks d. Extremities

1. What is one of the most relevant behavioral changes a person who has high titers of antinuclear antibodies but no lupus-specific symptoms can make? a. Lose weight b. Stop smoking c. Limit alcohol consumption d. Reduce stress 2. What is a classification criterion for systemic lupus erythematosus (SLE)? a. Discoid rash b. Pericarditis c. Oral ulcers d. All of the above 3. More than 90% of cases of true druginduced lupus occur in individuals taking a. Procainamide (Procanbid) b. Hydroxychloroquine (Plaquenil, Quineprox) c. Digoxin (Cardoxin, Digitek, Lanoxin) d. Metoclopramide (Maxolon, Metozolv, Reglan) 4. What is the most common cause of death in early active SLE? a. Renal failure b. Myocardial infarction c. Lymphoma d. Infectious complications TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureJan2012

6. Which treatment for epidermal nevi 2. How does BCC classically present? frequently results in scarring? a. Plaques with scales and associa. Chronic retinoid therapy ated edema and crust b. Laser ablation b. Solid, firm, thick plaques with c. Podophyllin little or no scaling d. Topical corticosteroids c. Violaceous papules with fine Case #2: Lichen striatus white lines on the surface d. Shiny, semi-translucent nodules 7. What is the typical appearance of with a characteristic rolled border lichen striatus lesions? a. Papules and plaques on flexural Case #2: Labial melanotic macule surfaces 3. Mucosal melanotic macule has a b. Skin-colored, pink, or tan papules racial predilection for adult clustered in a discrete band a. Hispanics c. Plaques and scaling with b. Asians lichenification c. American Indians d. Grouped vessels coalescing to d. Ashkenazi Jews coin-shaped plaques 4. Which condition associated with mucosal melanotic macules is associated with GI polyposis later in life? a. Peutz-Jeghers syndrome b. Laugier-Hunziker syndrome c. Addison’s disease d. Neurofibromatosis

8. What is the preferred treatment for lichen striatus? a. Patient reassurance b. Topical podophyllin c. Shave excision d. Cryotherapy

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermJan2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 69

CME

POSTTEST Expiration date: January 2013

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of January 2012. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Posttests must be completed and submitted online. PAs may register at no charge at myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 25

page 55

page 65

Lupus and the autoimmune process: the view from 2012

Case #1: Basal cell carcinoma

Case #1: Epidermal nevus

1. In what location is the incidence of basal cell carcinoma (BCC) greater in women? a. Shins b. Scalp c. Trunk d. Nasal tip

5. Where are epidermal nevi most commonly found? a. Face b. Chest c. Buttocks d. Extremities

1. What is one of the most relevant behavioral changes a person who has high titers of antinuclear antibodies but no lupus-specific symptoms can make? a. Lose weight b. Stop smoking c. Limit alcohol consumption d. Reduce stress 2. What is a classification criterion for systemic lupus erythematosus (SLE)? a. Discoid rash b. Pericarditis c. Oral ulcers d. All of the above 3. More than 90% of cases of true druginduced lupus occur in individuals taking a. Procainamide (Procanbid) b. Hydroxychloroquine (Plaquenil, Quineprox) c. Digoxin (Cardoxin, Digitek, Lanoxin) d. Metoclopramide (Maxolon, Metozolv, Reglan) 4. What is the most common cause of death in early active SLE? a. Renal failure b. Myocardial infarction c. Lymphoma d. Infectious complications TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureJan2012

6. Which treatment for epidermal nevi 2. How does BCC classically present? frequently results in scarring? a. Plaques with scales and associa. Chronic retinoid therapy ated edema and crust b. Laser ablation b. Solid, firm, thick plaques with c. Podophyllin little or no scaling d. Topical corticosteroids c. Violaceous papules with fine Case #2: Lichen striatus white lines on the surface d. Shiny, semi-translucent nodules 7. What is the typical appearance of with a characteristic rolled border lichen striatus lesions? a. Papules and plaques on flexural Case #2: Labial melanotic macule surfaces 3. Mucosal melanotic macule has a b. Skin-colored, pink, or tan papules racial predilection for adult clustered in a discrete band a. Hispanics c. Plaques and scaling with b. Asians lichenification c. American Indians d. Grouped vessels coalescing to d. Ashkenazi Jews coin-shaped plaques 4. Which condition associated with mucosal melanotic macules is associated with GI polyposis later in life? a. Peutz-Jeghers syndrome b. Laugier-Hunziker syndrome c. Addison’s disease d. Neurofibromatosis

8. What is the preferred treatment for lichen striatus? a. Patient reassurance b. Topical podophyllin c. Shave excision d. Cryotherapy

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermJan2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 69

ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Goldenseal

© GAIL JANKUS / PHOTO RESEARCHERS, INC.

Goldenseal, one of the most popular herbs in the United States today, is used as a base in many herbal preparations. Also known as yellow root, ground raspberry, or Indian turmeric, goldenroot is credited with a number of different medicinal properties. It is typically associated with supposed anti-inflammatory and antimicrobial properties.1 The plant grows in the wilds of southeastern Canada and the northeastern United States, and is also known as. Goldenseal is a perennial with a thick, yellow root characterized by knoblike sections and hairlike root fibers.1

Background Native goldenseal has actually been overharvested in the United States to the point that it is listed as an endangered species by the Convention on International Trade in Endangered Species of Wild Fauna and Flora, an organization dedicated to ensuring that international trade in specimens of wild animals and plants does not threaten their survival.2 Today, commercial growers supply the bulk of the plant products for use in supplements, with most production originating from the area of the Blue Ridge Mountains.2 Goldenseal is a member of the buttercup family and appears as a purple-stemmed, fuzzy plant with pointed, saw-toothedged leaves.3 These dark-green, hairy leaves bear a single white flower that yields a late summer fruit resembling a raspberry.3 In spite of its widespread use as a medicinal herb, goldenseal is frequently used as an additive to other herbal mixtures because of its synergistic effects.3 The primary

active ingredients in goldenseal are the alkaloids hydrastine and berberine, which function primarily as anticholinergics and antioxidants.1

Science Goldenseal is most commonly used as an antibacterial agent and an aid to digestion.3 One interesting bench trial examined the antimicrobial effect of goldenseal on cell cultures of Helicobacter pylori, the bacterium known to induce duodenal ulcers. The extract of goldenseal rhizomes showed a robust in vitro mean inhibitory concentration of 12.5 μg/mL in all of the 15 strains of the bacterium cell lines.4 One hypothesis regarding goldenseal’s efficacy against bacterial infection is that it blocks the release of pro-inflammatory cytokines from the macrophages in the system, thereby reducing the symptoms and longevity of the infection. In a study of goldenseal extract with lipopolysaccharide-stimulated macrophages, the production of tumor necrosis factor-alpha,

70 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

ALTERNATIVE MEDS UPDATE interleukin (IL)-6, IL-10, and IL-12 was inhibited in a dose-dependent curve.5 Goldenseal extract was measured against cultured cell lines of Staphylococcus aureus, Streptococcus sanguis, Escherichia coli, and Pseudomonas aeruginosa.6 Each bacterium was subjected to direct exposure to the goldenseal extract.The measured “killing time” and mean inhibitory concentration values supported goldenseal’s antibacterial claims.6 Another study explored goldenseal’s antioxidant activity as it applied to cholesterol. In an in vivo study with rats, all rats were given a high-cholesterol diet and then randomized to either placebo treatment or goldenseal treatment. At the end of the 24-day treatment period, serum lipid levels in both groups of rats were examined.The goldenseal cohort showed a total cholesterol reduction of more than 31%, a 25% drop in LDL, and nearly a 33% decrease in triglycerides.7 Goldenseal is being evaluated for its potential use in the treatment of Alzheimer disease (AD).

Chinese researchers recently explored goldenseal’s potential to slow the progressive degeneration associated with AD.8 Berberine, an active ingredient in goldenseal, is a natural isoquinolone alkaloid with a wide range of pharmacologic effects. In this new study, berberine was reviewed for its antioxidant properties as well as for its activities as an acetylcholinesterase and butyrylcholinesterase inhibitor, a monoamine oxidase inhibitor, a beta-amyloidal peptide blocker, and a cholesterol-lowering agent.8 All of this suggests that berberine may act as a promising multipotent agent to combat AD.8

times daily for the dried rhizome powder-filled capsules for short periods of time.The powderfilled capsules—used to treat such minor illnesses as respiratory infections—are not recommended for use longer than a period of 14 days.1 The total cost varies depending on the dose concentration, but a typical month’s supply of goldenseal ranges from $20-$30.

Summary

In laboratory tests, goldenseal has proven effective in fighting such bacteria as P. aeruginosa (brown).

Goldenseal is now being evaluated for its potential use in slowing the degeneration associated with Alzheimer disease.

The use of goldenseal as an adjunctive therapy is safe in appropriate patient groups. As long as proper dosing guidelines and safety issues are addressed, health-care providers may find the short-term use of goldenseal a reasonable recommendation. ■ References 1. Fetrow C, Avila J. Professional’s Handbook of Complementary & Alternative Medicines. 2nd ed.

Philadelphia, Pa.: Lippincott, Williams & Wilkins; 2001.

2. National Center for Complementary and Alternative Medicine. Goldenseal. Available at nccam.nih.gov/health/ goldenseal/.

3. University of Maryland Medical Center. Goldenseal.

Available at www.umm.edu/altmed/articles/goldenseal-000252.htm.

4. Mahady GB, Pendland SL, Stoia A, Chadwick LR. In vitro susceptibility of Helicobacter pylori to isoquinoline alkaloids from Sanguinaria canadensis and Hydrastis canadensis.

Phytother Res. 2003;17:217-221.

5. Clement-Kruzel S, Hwang SA, Kruzel MC, et al.

Immune modulation of macrophage pro-inflammatory response by goldenseal and Astragalus extracts.

Safety, interactions

J Med Food. 2008;11:493-498.

6. Scazzocchil F, Cometa M, Tomassini L, Palmery M. Antibacterial activity of Hydrastis canadensis extract and its major isolated alkaloids. Planta Med. 2001;67:561-564.

7. Abidi P, Chen W, Kraemer FB, et al. The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms. J Lipid Res. 2006;47:2134-2147.

8. Ji HF, Shen L. Berberine: a potential multipotent

Dosage and cost

natural product to combat Alzheimer’s disease. Molecules.

2011;16:6732-6764.

Recommended doses of the extract are 250 mg by mouth three times daily, or 0.5 to 1.0 g three 72 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

All electronic documents accessed on December 15, 2011.

© CDC / JANICE HANEY CARR

Toxicity from goldenseal has been reported.The lethal dose of the berberine isolate is thought to be 27.5 mg/kg.1 Goldenseal is not recommended for use in pregnant or nursing women or in children.2 Patients using warfarin or cardiac glycosides should also avoid using goldenseal.1

Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept.

We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit.

CLINICAL FEATURES update our readers with the latest information about conditions seen in everyday practice. Running no more than 2,500 words, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view.

If at all possible, articles should be accompanied by clinical photos, for which we pay extra. Charts, tables, and algorithms are also encouraged. References are optional; if you opt not to use any, please provide a recommended reading list of books, articles, and Web sites. In addition, include your curriculum vitae, which should list all current titles and affi liations.

CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general.

We pay extra for any photographs or images that we use. The length should be about 1,500 words. Please include your title, affi liations, and curriculum vitae.

DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a brief description of the patient and/or his presentation, without giving away the diagnosis.

This is followed by a 750- to 1,000-word summary that includes a fuller description of the ailment, how the correct diagnosis was achieved, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome.

Topics must be approved by the editor prior to submission.

COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. Support your views with as many facts, statistics, studies, and personal anecdotes as possible. A typical Commentary runs about 700 words in length.

To discuss your editorial ideas, contact us by phone at 646.638.6077; by e-mail to editor@clinicaladvisor.com; or by mail to: The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

76 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

COMMENTARY Rachael Buitrago, CPNP, is an ANCC-board-certified pediatric nurse practitioner in a private office in South Florida, and has taught as adjunct nursing faculty at local universities.

What to remember when job-hunting Employment opportunities are limited today for many people seeking work, yet health-care needs are on the rise and the demand for nurse practitioners (NPs) and physician assistants (PAs) to care for the country’s baby-boomers is increasing. Considering the vast numbers within this population, this is a great marketplace for clinicians in search of employment.

When looking for a job, NPs and PAs must be aware of the given state’s requirements and scopeof-practice protocols. Understanding the scope of ability attached to the position for which you are being interviewed will alleviate any misconceptions about the role to be fulfi lled. Ask exactly

Health insurance should be offered or at least negotiated into the package regardless of hours worked.

what it is the employer is looking for. Get specific details pertaining to the job role, hours, benefits, and performance appraisal/incentives.

What does the employer have to offer? Make sure to ask all questions up-front. This way, if something is not offered, you might be able to negotiate it in with the terms of agreement.

A contract written to include all employment details is great to have. Some contracts may expire after one year or after two years.

Just remember that if the contract protects the employee, it will also protect the employer.

The idea is to have terms listed to your benefit, meaning you should be careful before accepting any noncompete clauses and resignation-notice requirements. Although in general, an employee leaving a job is required to give the employer two weeks’ notice, NPs and PAs might be required to give the employer as much as 60 days’ notice when leaving a job. However, this also means that the NP/PA gets 60 days’ notice if the position is terminated.

Benefits packages may vary depending on amount of hours worked. NPs and PAs should always consider negotiating partial benefits, even if the position is part-time. Health insurance should be offered or at least negotiated into the package regardless of hours worked. Annual salary increases are also a must. In addition, it would be wise to negotiate profit-sharing or possible partnership. NPs and PAs are as

important as physicians to the livelihood of any health-care practice or institution. Insurance reimbursements are higher today than in previous years for NPs and PAs; surely the future will show these reimbursement rates to be equivalent to those of physicians. Reaching for a piece of the pie is definitely possible for NPs and PAs and should be a part of the decision-making process when choosing among employment opportunities.

Make sure all terms are negotiated and none are left out. Confirm major details, such as salary, and even minor ones, such as how breaks and lunches will work. If the employer reveals the salary before asking the NP or PA what salary he or she is seeking, the NP or PA has the advantage of knowing where the dollar amount starts, and he or she can then try to negotiate up from that amount.

Whether one desires to work in primary care or specialized practice, strong interviewing skills are a must. Demonstrating confidence, strength, and intelligence during the interview will make any employer take notice. Be prepared and be knowledgeable about the position for which you are interviewing.

Once you land the job, be sure to iron out any and all details before signing a contract.

And most important, be satisfied with the terms of the employment agreement that have been reached. ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 77

CLASSIFIEDS PA WANTED

For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

PA WANTED Neuro-Oncology NP Job University of Southern California Department of Neurology, Los Angeles, CA Please respond with CV and cover letter: Contact - Cindy Naveira, NP; phone: 323-442-7537; naveira@usc.edu

Physician Assistant Program Director

DeSales University seeks a Director for its nationally recognized Physician Assistant Program. Nine of the 11 DeSales graduating PA classes have ranked first in the nation on the PACKRAT examination. DeSales PA students’ National Board Scores have exceeded the 99th percentile for eight consecutive years. Since 2002, DeSales PA graduates have had a 100% first-time pass rate on the National Certification Examination for Physician Assistants. Students serve at the DeSales Free Clinic for homeless men at the Allentown Rescue Mission. The University has broken ground for the magnificent Gambet Center for Business and Health Care Education, which will house the Physician Assistant Program. The $27,000,000 building will include state-of-theart simulation laboratories, a standardized patient suite, examination rooms, a gross anatomy lab, and related amenities and technological advances. Candidates must be knowledgeable about and supportive of Catholic moral issues with respect to health care, and must hold a master’s degree in physician assistant studies or related field or an M.D. or D.O. degree. Both PA and physician candidates must be licensed. They must also have successful administrative and teaching experience on the college or university level. This 12-month, tenure-track appointment begins June 1, 2012. Salary and rank are commensurate with the candidate’s qualifications.

Patient care in academic setting with multidisciplinary team. NP works and collaborates with two MD Neuro-Oncologists. Get involved at beginning of new Brain Tumor Center!

MEDICAL EDUCATION

VACATION CME AAFP PRESCRIBED CREDIT Live Seminars - 15 Prescribed Credits New Drug Update DVD 10 Prescribed Credits - Anytime - Anywhere!

www.universitylearning.com 1-800-940-5860

Please contact us to place your classifi ed advertisement in The Clinical Advisor.

(877) 394-1388 • Fax: (727) 445-9380 ca@russelljohns.com

Clinical Coordinator

DeSales University seeks a Clinical Coordinator for its Physician Assistant Program. This 12-month, full-time, nontenure-track position is responsible for obtaining and maintaining clinical training sites for students and visiting and evaluating students and their preceptors during their clinical rotations within the greater Lehigh Valley. Clinical experience as a certified physician assistant required; master’s degree and successful teaching experience preferred. This appointment begins July 1, 2012. Salary and rank are commensurate with the candidate’s qualifications.

For each position, please send letter of application, curriculum vitae, three letters of recommendation, and photocopies of transcripts to: Fr. Peter Leonard, OSFS, Dean of Graduate Education, DeSales University, 2755 Station Ave., Center Valley, PA 18034-9568 or to peter.leonard@desales.edu.

Review of applications begins immediately and continues until the positions are filled.

DeSales University is a Catholic liberal arts institution on a beautiful 480-acre campus in the Lehigh Valley of eastern Pennsylvania, approximately one hour from Philadelphia and two hours from New York City. Traditional-age students (1,700), evening-degree students (800), and graduate students (800) comprise the student body of 3,300.

As a member of the Lehigh Valley Association of Independent Colleges, DeSales University participates in cooperative programs with Lehigh University and with Cedar Crest, Lafayette, Moravian, and Muhlenberg Colleges. EOE

78 THE CLINICAL ADVISOR • JANUARY 2012 • www.ClinicalAdvisor.com

For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

CLASSIFIEDS

PA WANTED

MEDICAL EDUCATION

MEDICAL EDUCATION

MEDICAL EDUCATION

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2012 79