June 2012 Clinical Advisor.com by The Clinical Advisor

THE CLINICAL ADVISOR • JUNE 2012

A F O R U M F O R P H Y S I C I A N A S S I S TA N T S

NEWSLINE

■ Colonoscopy compliance ■ Steroids for sciatica relief ■ Vitamin C helps lower BP ADVISOR FORUM

■ Help with eating disorders ■ Vitamin B12 deficiency ■ Best tests for hepatitis C LEGAL ADVISOR

Elementary-school clinician sued for invasion of privacy

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■ Dermatology Clinic

AN INFANT WITH AN ITCHY TORSO PAGE 45

VOLUME 15, NUMBER 6

■ Dermatologic Look-Alikes

PAPULOSQUAMOUS BACK PLAQUE PAGE 57 Expanded job listings! www.ClinicalAdvisor.com/Jobs

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CME: DISEASE CLUES IN THE

ORAL CAVITY Kaposi sarcoma (purple) is the most common tumor seen in HIV-positive patients.

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ClinicalAdvisor.com! Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Production director Leslie Carsman Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley@haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy@haymarketmedia.com Editorial director Tanya Gregory Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco

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“The road I tried to cross was the freeway.”

6 THE CLINICAL ADVISOR • JUNE 2012 • www.ClinicalAdvisor.com

The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 15, Number 6, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send all address changes to:The Clinical Advisor, c/o DMDData Inc., 2340 River Road, Des Plaines, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2012.

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. Brief Summary Retin-A Micro® (tretinoin gel) microsphere, 0.1% and 0.04% is a formulation containing 0.1% or 0.04%, by weight, tretinoin for topical treatment of acne vulgaris. This formulation uses patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. IMPORTANT NOTE: This information is a BRIEF SUMMARY of the complete prescribing information provided with the product and therefore should not be used as the basis for prescribing the product. This summary has been prepared by deleting information from the complete prescribing information such as certain text, tables, and references. The physician should be thoroughly familiar with the complete prescribing information before prescribing the product. INDICATIONS AND USAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the use of this product in the treatment of other disorders have not been established. CONTRAINDICATIONS: This drug is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted. PRECAUTIONS: General: • The skin of certain individuals may become excessively dry, red, swollen, or blistered. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established. If a reaction suggesting sensitivity occurs, use of the medication should be discontinued. Excessive skin dryness may also be experienced; if so, use of an appropriate emollient during the day may be helpful. • Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products (SPF 15) and protective clothing over treated areas are recommended when exposure cannot be avoided. • Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. • Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. • Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Information for Patients: A Patient Information Leaflet has been prepared and is included with each package of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is begun. Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of these clinical formulations (0.04% and 0.1%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose applied topically, when normalized for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, normalized for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose applied topically is defined as 1 gram of Retin-A Micro (tretinoin gel) microsphere, 0.1% applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). Dermal carcinogenicity testing has not been performed with Retin-A Micro (tretinoin gel) microsphere, 0.04% or 0.1%. Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. The components of the microspheres have shown potential for genetic toxicity and teratogenesis. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, the HGPRT forward mutation assay, and the mouse micronucleus assay. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose applied topically, and normalized for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose applied topically and normalized for total body surface area) and above were observed. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (17 times the human topical dose normalized for total body surface area). Dermal fertility and perinatal development studies with Retin-A Micro (tretinoin gel) microsphere, 0.1% or 0.04%, have not been performed in any species. Pregnancy: Teratogenic Effects: Pregnancy Category C. In a study of pregnant rats treated with topical application of Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.5 to 1 mg/kg/day on gestation days 6-15 (4 to 8 times the maximum human systemic dose of tretinoin normalized for total body surface area after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%) some alterations were seen in vertebrae and ribs of offspring. In another study, pregnant

New Zealand white rabbits were treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.2, 0.5, and 1.0 mg/kg/day, administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. There appeared to be increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 3 times the maximum human systemic dose of tretinoin after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area. In a repeat study of the highest topical dose (1.0 mg/kg/day) in pregnant rabbits, these effects were not seen, but a few alterations that may be associated with tretinoin exposure were seen. Other pregnant rabbits exposed topically for six hours to 0.5 or 0.1 mg/ kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any teratogenic effects at doses up to 17 times (1.0 mg/kg/day) the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, adjusted for total body surface area, but fetal resorptions were increased at 0.5 mg/kg. In addition, topical tretinoin in non Retin-A Micro (tretinoin gel) microsphere formulations was not teratogenic in rats and rabbits when given in doses of 42 and 27 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively, (assuming a 50 kg adult applied a daily dose of 1.0 g of 0.1% gel topically). At these topical doses, however, delayed ossification of several bones occurred in rabbits. In rats, a dose-dependent increase of supernumerary ribs was observed. Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. Tretinoin was teratogenic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is more similar to humans than other species in its handling of tretinoin, fetal malformations were reported for doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose normalized for total body surface area), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids. There are no adequate and well-controlled studies in pregnant women. Retin-A Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of Retin-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Non-Teratogenic Effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose applied topically and normalized for total body surface area), resulting in fetal resorptions and variations in ossification. Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (21 times the maximum human systemic dose applied topically and normalized for total body surface area). There are, however no adequate and well-controlled studies in pregnant women. Animal Toxicity Studies: In male mice treated topically with Retin-A Micro (tretinoin gel) microsphere 0.1%, at 0.5, 2.0, or 5.0 mg/kg/day tretinoin (2, 8, or 21 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area) for 90 days, a reduction in testicular weight, but with no pathological changes were observed at the two highest doses. Similarly, in female mice there was a reduction in ovarian weights, but without any underlying pathological changes, at 5.0 mg/kg/day (21 times the maximum human dose). In this study there was a dose-related increase in the plasma concentration of tretinoin 4 hours after the first dose. A separate toxicokinetic study in mice indicates that systemic exposure is greater after topical application to unrestrained animals than to restrained animals, suggesting that the systemic toxicity observed is probably related to ingestion. Male and female dogs treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at 0.2, 0.5, or 1.0 mg/kg/day tretinoin (5, 12, or 25 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively) for 90 days showed no evidence of reduced testicular or ovarian weights or pathological changes. Nursing Mothers: 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 Retin-A Micro (tretinoin gel) microsphere, 0.1% or 0.04%, is administered to a nursing woman. Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established. Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of Retin-A Micro did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ADVERSE REACTIONS: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. However, efficacy has not been established for lower dosing frequencies. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin. OVERDOSAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is intended for topical use only. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Rx only.

Distributed by: Ortho Dermatologics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Los Angeles, CA 90045 11DD0126 07/11 © OMP 2011 RETIN-A MICRO ® is a registered trademark of Ortho-McNeil Pharmaceutical, Inc. ® MICROSPONGE is a registered trademark of AMCOL International Corporation.

CONTENTS JUNE 2012

NEWS AND COMMENT 16

Newsline ■ Hemoglobin A1c featured in diabetes diagnosis ■ Drugs don’t help urinary incontinence much ■ Disparities in colonoscopy compliance explored ■ A sibling’s stroke hikes risk ■ Shingles vaccine safe for older adults ■ Steroids given edge in sciatica relief ■ Vitamin C helps lower blood pressure ■ ACR endorses measures of RA disease activity

DEPARTMENTS 45

■ A woman’s oval-shaped scaly plaques spread from her trunk and arms to her chest, abdomen, and back.

Commentary

CME/CE Oral involvement of systemic diseases Recognizing oral manifestations of systemic disease can point the way to a prompt diagnosis.

CME/CE Dermatology Clinic ■ An infant’s itchy and inflammatory papules and nodules were concentrated in the axillary areas and the palms.

Increases in HbA1c may predict diabetes 16

FEATURES 25

Dismiss a problem patient in 10 safe steps Most clinicians have dealt with a dissatisfied or noncompliant patient. But how do you end the relationship without putting yourself at risk?

Legal Advisor An experienced school clinician comes under fire after performing an external vaginal exam on a student.

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

Alternative Meds Update Niacin is best known for its ability to lower LDL levels.

Oral clues point to systemic illness 25

Continues on page 10

“When it’s an elephant, we’ll talk.”

MAKING CONTACT

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CONTENTS DEPARTMENTS, cont’d

■ Decreasing secretions following

■ Vitamin B12 deficiency in

tracheostomy CME/CE Dermatologic

Look-Alikes Two cases of asymptomatic red lesions—one a slow-growing plaque in a fair-skinned man, the other thought to be “ringworm” and psoriasis. 64 66

older adults

CME/CE Posttest

Evidence-Based Medicine

Rash does not respond to topical meds 45

Clinical Pearls ■ The best tests for hepatitis C ■ Plumbing for atherosclerosis

Your Comments ■ Abstinence is a must for a depressed alcoholic

mortality and need for intubation in elderly patients with acute hypercapnic respiratory failure ■ Briakinumab appears to reduce severity of psoriasis better than methotrexate ■ Addition of pedometer-based physical activity intervention to smoking cessation program may increase quit rates in teenagers

ADVISOR FORUM 38

Consultations ■ Help for a young adult with

anorexia and bulimia

“I’m sorry—this is literally my first rodeo.”

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■ Noninvasive ventilation reduces

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USE UNDER MEDICAL SUPERVISION. * 35% less calories (150 cal vs 240 cal) for PediaSure Sidekicks vs original PediaSure per 237 mL serving. † When used as lower calorie complete feeding. ‡ 3 g fiber per 8 fl oz serving; 12% of 25 g Daily Value (See nutrition information for fat content). § For oral use for children requiring a lower calorie supplement. ¶ For tube feeding for children requiring a lower calorie complete feeding. Abbott Nutrition does not represent NDC format codes to be actual National Drug Codes (NDCs). NDC format codes are product codes adjusted to standard industry practice to meet the format requirements of pharmacy and health insurance computer systems. NDC format codes have been submitted by Abbott Nutrition to data warehouses. While Abbott Nutrition cannot confirm that NDC format codes have been published, the codes listed are based on the formatting established by NDC data warehouses. HCPCS Codes are taken from government publications and are provided from information correct at the time of publication. Health care providers are ultimately responsible for making appropriate product selections per individual patient and verifying that codes used for third-party billing are accurate for the items provided. © 2012 Abbott Laboratories 84017/MAY 2012 www.abbottnutrition.com

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Slideshows

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Benefit of inhaled corticosteroids for sinusitis small A review shows benefits of inhaled corticosteroids may be greater at higher doses and longer duration, but lower-cost OTC remedies may be a better option. Blood clot risk elevated with contraceptive patches, vaginal rings Women who use the contraceptive transdermal patch or vaginal ring are at significantly higher risk for venous thrombosis, results of a Danish study show.

Neuropathic Pain Symptoms & Treatment Nerve damage affects approximately 20 million Americans. There more than 100 different types of nerve damage with a range of different causes. Learn more about the symptoms of and treatments for neuropathic pain with this slideshow.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog

Waist-to-hip ratio linked to sudden cardiac death Carrying more weight around the belly may increase the risk for sudden cardiac death.

Cartoon Archive The Clinical Advisor’s monthly cartoons are now available online as well. ClinicalAdvisor.com/cartoons

Leigh Montejo, MSN, FNP-BC Promoting national nurse practitioner awareness Let’s make sure patients understand that NPs are responsible for much of the quality health care they receive. Robyn Carlisle, MSN, CNM, WHNP Versatility makes nursing a career that spans a lifetime It’s comforting to know that as a nurse, there are plenty of options to change my career path at any given moment to fit my lifestyle and needs. Julee Waldrop, DNP, PNP, FNP Celebrity status raises awareness about breastfeeding benefits Are the new moms you treat on the fence about breastfeeding in public? Tell them Beyoncé does it. Sharon M. O’Brien, MPAS, PA-C Is a child’s snoring the root cause of his ADHD? Unrefreshing sleep can lead to prefrontal cortical dysfunction. In children, this can manifest as behavioral problems.

“I was hoping for eternal rest.”

MAKING CONTACT

Deanna Bridge Najera, MPAS, PA-C Why I’m worried it’s not just croup With decreased immunization rates, whooping cough seems to be making a comeback, particularly on the Pacific coast.

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12 THE CLINICAL ADVISOR • JUNE 2011 • www.ClinicalAdvisor.com

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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

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

15–30 <15

Dose Regimen BID or TID

150

225

300

BID or TID

25–50

100–150

150

QD or BID

25–50

50–75

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

Newsline J U N E 2 0 12

Consider FOBT as an alternative to colonoscopy page 18

Herpes zoster vaccine is safe for older adults page 19

Six measures to distinguish levels of RA activity page 20

HbA1c featured in diabetes diagnosis

MARKED INCREASES in hemoglobin (Hb) A1c were shown to predict the development of diabetes, and individualizing HbA1c targets is a goal of new guidelines for managing blood glucose levels in persons with type 2 diabetes. Hirohito Sone, MD, PhD, and colleagues measured HbA1c and fasting plasma glucose (FPG) annually for a mean of 9.5 years in 1,722 Japanese individuals without diabetes. As reported in Diabetes Care, among the 193 participants who developed the disease, mean HbA1c levels were higher than 5.6% each year before diagnosis. From three years to one year prediagnosis, HbA1c increased 0.09% per year, reaching 5.9% one year prediagnosis. In the entire group, marked increases in HbA1c of 0.3% per year and FPG of 11.34 mg/dL per year predicted diabetes. New guidelines emphasize the importance of individualizing

Hemoglobin A (shown) is composed of four subunits.

HbA1c treatment targets. In addition to the clinical elements that may guide the practitioner in choosing an HbA1c target for a specific patient, the desires and values of the patient should also be considered, “since the achievement of any degree of glucose control requires active participation and commitment,” wrote investigators (Diabetologia. 2012;55:1577-1596). The position statement holds that glucose-lowering therapies also must be tailored to the specific patient, with diet, exercise, and education remaining as the foundation of any treatment program for type 2 diabetes. Metformin is named as the optimal first-line drug. “After metformin, there are limited data to guide us,” the research team explained. “Combination therapy with an additional 1–2

oral or injectable agents is reasonable, aiming to minimize side effects where possible.” Many patients will ultimately require insulin therapy alone or in combination with other agents to maintain glucose control, according to the group. Regardless of the glucoselower ing methods chosen, comprehensive cardiovascular risk reduction must be a major focus of therapy, cautioned the authors. An unrelated report in The American Journal of Cardiology illustrates this point: G. Sofia Tomova and associates found that higher HbA1c levels were linked with improved outcomes in persons with advanced heart failure and diabetes. For every unit HbA1c increase, there was a 15% decreased hazard ratio of death or urgent heart transplantation and all-cause mortality.

Skeletal status of persons age 50 years and older According to the CDC, 9% of persons aged 50 years and older had osteoporosis at either the femur neck or the lumbar spine in 2005–2008. Source: CDC/NCHS, National Health and Nutrition Examination Survey, 2005–2008

Normal at femur neck and lumbar spine

Osteoporosis at femur neck or lumbar spine

9% 48% 49%

Note: Percentages will not add up to 100% due to double counting among those with osteoporosis or low bone mass at either skeletal site.

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

Low bone mass at femur neck or lumbar spine

Newsline TH E COM MON pract ice of universally recommending colonoscopy may reduce adherence to screening for colorectal cancer (CRC). Clinicians might increase a patient’s compliance with CRC screening recommendations if fecal occult blood testing (FOBT) is recommended as an alternative. This finding came from a study of 997 persons at average risk for CRC in a racially and ethnically diverse urban setting. The participants were randomized to receive recommendation for screening by FOBT, by colonoscopy, or by their choice of one method or the other. One year after randomization, 58% of the group had completed the CRC screening strategy assigned to or chosen by them.

Persons randomized to a recommendation of colonoscopy completed screening at a significantly lower rate (38%) than those who received a recommendation of FOBT (67%) or who were given a choice between colonoscopy and FOBT (69%). Latinos and Asians (primarily Chinese) completed screening more often than did blacks. Nonwhite participants adhered more often to FOBT, whereas white participants adhered more often to colonoscopy. “[Our] results suggest that patient preferences should be considered when making CRC screening recommendations,” wrote the investigators (Arch Intern Med. 2012;172:575-582). The results of an additional new study showed that differences

Disparities in colonoscopy compliance

Consider the patient’s preferences in CRC screening.

in screening may be responsible for more than 40% of the disparity in CRC incidence and nearly 20% of CRC mortality between blacks and whites (Cancer Epidemiol Biomarkers Prev. 2012;21:728-736).

ALTHOUGH drug therapy proved more effective than placebo in achieving continence and improving urinary incontinence (UI) in women, the improvements were small, and treatment discontinuation due to bothersome adverse effects was frequent. A research team led by Tatyana Shamliyan, MD, MS, concluded in Annals of Internal Medicine that overall, agents for urgency UI (the sudden, compelling urge to urinate, as opposed to stress incontinence, which is the involuntarily loss of urine during such acts as coughing or sneezing) showed

Caffeine intake had no effect on UI in women.

similar small benefit. The group based this information on their analysis of 94 randomized controlled trials centering on drugs used for urgency UI in women. For every 1,000 women treated with drugs for urgency UI, continence was achieved in: 130 with fesoterodine (Toviaz); 114 with oxybutynin (Ditropan); 114 with trospium (Sanctura); 107 with solifenacin (Vesicare); and 85 with tolterodine (Detrol). Adverse effects led to treatment discontinuation in 63 per 1,000 treated with oxybutynin, 31 per 1,000 treated with fesoterodine,

18 THE CLINICAL ADVISOR • JUNE 2012 • www.ClinicalAdvisor.com

18 per 1,000 treated with trospium, and 13 per 1,000 treated with solifenacin. Inconsistent def initions of improvement in UI and quality of life among studies hampered synthesis of evidence. Women who do suffer from UI are often advised to avoid caffeine, but in a recent study, long-term caffeine intake over the course of one year was not associated with risk of progression of either urge UI or stress UI over two years of follow-up in women with moderate incontinence (Obstet Gynecol. 2012;119:950-957).

Drugs do not help urinary incontinence much

A sibling’s stroke hikes risk A PATIENT whose brother or sister has had a stroke could be up to 94% more likely to suffer the same fate than a person with strokefree siblings, caution researchers in Sweden (Circ Cardiovasc Genet. 2012;5:226-233). The study identified 30,735 stroke-free siblings of persons with incident ischemic stroke recorded between 1987 and 2007. (The stroke-free siblings were referred to as “exposed” participants in the study.) An additional 152,391 stroke-free persons with stroke-free siblings were also included in the analysis; these individuals were known as “unexposed” participants. Compared with unexposed siblings, exposed siblings were: 94% more likely to have an ischemic stroke at age 55 years or younger if their sibling’s stroke occurred at age 55 years or younger; 64% more likely to have an ischemic stroke if they shared two parents

The gender of either sibling did not influence stroke risk.

with the affected sibling (the sibling who had a stroke); 61% more likely to have an ischemic stroke whether they shared one or two parents with their affected sibling; and 41% more likely to have an ischemic stroke if they shared only one parent with the affected sibling. Stroke risk was not influenced by the gender of either sibling. Genetics might not be the only factor at play: Similar—and modifi able—lifestyle habits within families can also affect a person’s stroke risk, the researchers said.

Shingles vaccine safe for older adults The herpes zoster vaccine has been found to be generally safe and well-tolerated in an analysis of 193,083 adults aged 50 years and older conducted as part of the Vaccine Safety Datalink (VSD) project, a joint effort between the CDC and integrated-care organizations. Investigators from eight managed-care organizations participating in the VSD project analyzed data from patients who received a zoster vaccine from January 2007 through December 2008. The risk of allergic reaction was significantly increased

within one to seven days of vaccination, but no increased risk was found for cerebrovascular events, cardiovascular events, meningitis, encephalitis, encephalopathy, Ramsay-Hunt syndrome, or Bell’s palsy. “The results of this study support the findings from the prelicensure clinical trials, providing reassurance that the zoster vaccine is generally safe and well-tolerated with a small increased risk of allergic reactions in [one to seven] days after vaccination,” the researchers concluded ( J Intern Med. 2012;271:510-520).

Steroids given edge in sciatica relief EPIDURAL STEROID injections appear to be more effective than etanercept (Enbrel) injections or saline in providing relief to people suffering from moderate sciatica, but not to a statistically significant degree. In a study of 84 adults with lumbosacral radiculopathy of less than six months’ duration, the participants were randomized to two epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by two weeks. One month after the second injection, the group that received epidural steroids had greater reductions in the primary outcome measure of leg pain than did those who received saline or etanercept. For back pain, smaller differences favoring steroids compared with saline and etanercept were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments (Ann Intern Med. 2012;156:551-559). While acknowledging the study’s short follow-up period and small sample size as well as the possibility that a subtherapeutic dose of etanercept was administered, the investigators concluded that epidural steroid injections may provide modest short-term pain relief for some individuals with lumbosacral radiculopathy.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 19

Newsline A WORKING group convened by the American College of Rheumatology (ACR) has recommended six measures that primary-care providers can use in everyday clinical practice to help distinguish the various levels of disease activity for rheumatoid arthritis (RA). Up until this time, no such recommendations had existed. The ACR recommendations were narrowed down from the larger pool of 63 currently available RA disease activity measurement tools by means of a systematic review of the literature conducted to identify such measures and a survey of rheumatologists. The working group’s final selections include: • Clinical Disease Activity Index (CDAI);

• Disease Activity Score with 28-joint counts (erythrocyte sedimentation rate or C-reactive protein) (DAS-28); • Patient Activity Scale (PAS); • PAS-II; • Routine Assessment of Patient Index Data with three measures (RAPID 3); and • Simplified Disease Activity Index (SDAI). The ACR recommended these measures because they are accurate reflections of disease activity; are sensitive to change; discriminate well between low, moderate, and high disease-activity states; have remission criteria; and are feasible to perform in clinical settings (Arthritis Care Res [Hoboken]. 2012;64:640-647). The same journal issue also includes an update of the ACR’s

ACR endorses measures of RA activity

The six measures can be performed in a clinical setting.

previous recommendations from 2008 with regard to the use of disease-modifying antirheumatic drugs (DMARDs) and biologic agents in the treatment of RA (Arthritis Care Res [Hoboken]. 2012;625-639).

SHORT-TERM units of vitamin C supplementation can reduce systolic and diastolic BP, indicated a systematic review and metaanalysis of clinical trials. Increased vitamin C intake, vitamin C supplementation, and higher blood concentrations of vitamin C have been associated with lower BP. Despite this, evidence from clinical trials regarding the BP–lowering effects of vitamin C is inconsistent. Now, an analysis of 29 clinical trials examining the effects of short-term vitamin C supplementation on BP has demonstrated some benefit.

Vitamin C did not protect against colon cancer.

The median dose of vitamin C supplementation was 500 mg per day over a median duration of eight weeks. The trials included 10 to 120 participants. The pooled changes in systolic BP (SBP) and diastolic BP (DBP) were -3.84 mm Hg and -1.48 mm Hg, respectively. In trials involving persons with hypertension, SBP fell by 4.85 and DBP decreased by 1.67. Long-term trials on the effects of vitamin C supplementation are needed, contend the investigators (Am J Clin Nutr. 2012;95:10791088). According to a different study, neither short-term nor

20 THE CLINICAL ADVISOR • JUNE 2012 • www.ClinicalAdvisor.com

long-term use of another substance related to BP will protect people from colorectal cancer (CRC). Beta blockers might reduce the risk of CRC due to the weakening of norepinephrine signaling. After studying 1,762 persons with CRC and 1,708 control individuals in Germany, Lina Jansen, MSc, and colleagues reported in the journal Cancer that they found no association between beta blocker use and CRC risk reduction. In fact, the team noted a connection between long-term use of the drug (six years or longer) and risk of stage IV CRC. ■

Vitamin C helps lower blood pressure

CME CE

PROGRAM OUTLINE JUNE 2012

0.5 CREDITS

Page 21 FEATURE Oral involvement of systemic diseases Stephanie Weiss, MD, DDS, and Adam Weiss, DDS Dr. Stephanie Weiss and Dr. Adam Weiss have no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • Describe the oral manifestations of acute sarcoidosis. • Identify the extraintestinal characteristics of Gardner syndrome. • Describe the most common oral manifestations of amyloidosis. • Explain the clinical triad of symptoms seen in individuals with pernicious anemia. 0.5 CREDITS

Page 45 DERMATOLOGY CLINIC Itchy papules on an infant’s torso and palms Audrey Vass and Julia R. Nunley, MD Dr. Vass and Dr. Nunley have no relationships to disclose relating to the content of this article.

Pink, scaly rash on the trunk and arms Esther Stern, NP-C Ms. Stern has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 57 DERMATOLOGIC LOOK-ALIKES Asymptomatic red lesions Joe Monroe, PA-C Mr. Monroe has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVE: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 64 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 June 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. Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. 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.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 21

■ LEARNING OBJECTIVES :

CME CE FEATURE

• Describe the oral manifestations of acute sarcoidosis. • Identify the extraintestinal characteristics of Gardner syndrome. • Describe the most common oral manifestations of amyloidosis. • Explain the clinical triad of symptoms seen in individuals with pernicious anemia. ■ COMPLETE THE POSTTEST: Page 64 ■ ADDITIONAL CME/CE: Pages 45, 57 Turn to page 21 for additional information on this month’s CME/CE courses.

STEPHANIE WEISS, MD, DDS, AND ADAM WEISS, DDS

Oral involvement of systemic diseases Oral manifestations are often an early signal of systemic disease, so recognizing them can point the way to a prompt diagnosis.

any systemic diseases have unique oral manifestations that can aid a primary-care clinician in making a diagnosis. Careful oral examination may reveal findings suggestive of a systemic disorder. Specifically, many granulomatous, immunologic, hematologic, and microbial diseases can have manifestations in the oral mucosa. In addition, multiple digestive, endocrine, metabolic, genetic, and nutritional diseases present with unique signs and symptoms in the oral environment, and looking for those characteristics can aid in early diagnosis. Digestive disorders

Ulcerated plaques caused by Kaposi sarcoma may form on the roof of the mouth in an individual with AIDS.

Gastroesophageal reflux disease. One GI disorder with oral manifestations is gastroesophageal disease (GERD), which affects 15% -40% of the population. A chronic disorder, GERD results from continual passage of acid from the stomach up into the esophagus, which damages the mucosal lining. Common symptoms include heartburn, dysphagia, and regurgitation, especially while the patient is www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 25

CME CE

ORAL INVOLVEMENT OF SYSTEMIC DISEASES

In the majority of reported cases of sarcoidosis with intraoral involvement, the oral lesion was the first sign of the disease. lying flat. Reflux esophagitis, esophageal hemorrhage, stricture, Barrett esophagus, and adenocarcinoma have all been linked to untreated GERD.1 Potential oral manifestations of GERD include a burning or itching sensation affecting the oral mucosa, mouth ulcers, erosion of tooth structure, halitosis, altered salivary flow, and a bad taste in the mouth. Additionally, the teeth may be affected, becoming sensitive to thermal insult and prone to fracture as the underlying dentin becomes exposed. Eventually, the acid erosion can lead to exposure of the tooth pulp and impaired chewing. Erosion is most often observed on the palatal surfaces of the maxillary dentition and the occlusal surfaces of the mandibular posterior teeth. Regular dental care and medical control of acid production help decrease the prevalence of erosion. However, once the erosion occurs, it is irreversible and can be treated only with dental restorative procedures. Therefore, early recognition and patient education are the most effective treatment approach. Sarcoidosis. This multisystem granulomatous disorder of unknown cause affects young adults and is more common in women and blacks. Some of the systemic manifestations most often seen include bilateral hilar lymphadenopathy, pulmonary fibrosis, erythema nodosum on the skin, ocular inflammation, hepatic involvement, parotid gland swelling, and fever. Acute sarcoidosis manifests with abrupt onset of erythema nodosum, which is characterized by nontender, elevated purple areas on the skin, whereas chronic sarcoidosis demonstrates a slow onset with progressive pulmonary fibrosis and multisystem involvement. Acute sarcoidosis often undergoes spontaneous resolution. In addition to the skin lesions, sarcoidosis patients may demonstrate oral manifestations as well. The clinician may notice painless, nonulcerating, maculopapular, dark-red to brown lesions, occurring most often on the buccal mucosa and hard palate. One-fourth of all intraoral sarcoidosis cases are located in bone and identified on x-ray by an ill-defined radiolucency with no expansion. In the majority of reported cases of sarcoidosis with intraoral involvement, the oral lesion was the first sign of the disease. Recognizing the oral manifestations of sarcoidosis is important because they may lead to a definitive diagnosis of systemic disease. Crohn disease and ulcerative colitis. Two other systemic diseases that can present with distinct oral manifestations are Crohn disease and ulcerative colitis (UC). A chronic granulomatous inflammatory disease of the intestines, Crohn disease

is characterized by frequent exacerbations. Although Crohn disease primarily affects the distal portion of the small intestine, manifestations can be seen at any point along the GI tract from the mouth to the anus. Crohn disease is frequently seen in patients aged 10 to 30 years and has a high incidence in patients of Jewish ancestry. Patients often present with abdominal pain, nonbloody diarrhea, low-grade fever, and malabsorption. Oral manifestations can be found in 6%-20% of patients. The clinician conducting an examination of the patientâ&#x20AC;&#x2122;s mouth can see aphthous ulcers that exacerbate prior to the intestinal attack. The lips and cheeks will demonstrate inflammatory hyperplasia with surface fissuring. Polypoid, taglike lesions in the vestibular and retromolar mucosa and linear ulcers with hyperplastic margins can also be observed in some patients. When intestinal symptoms are under control, oral ulcerations resolve. UC is an inflammatory disease of the colon. Patients present with abdominal pain, bloody diarrhea, fever, and weight loss. Unlike Crohn disease, which can demonstrate lesion-free areas of the small intestine, lesions of UC extend in a continuous fashion proximally from the rectum with no skip lesions. UC has a bimodal age distribution, with the first peak occurring at ages 15-20 years and the second occurring at ages 55-60 years. Oral manifestations can include aphthous ulcers whose recurrence correlates with the appearance of diarrhea and other intestinal symptoms. The clinician may see pyostomatitis vegetans, which is characterized by purulent but sterile pustules of the lips, buccal mucosa, and gingiva. Submandibular lymphadenopathy and edematous and inflamed lips with deep fissures and ulceration may be noted as well. Gardner syndrome. An autosomal dominant disorder, Gardner syndrome (GS) is a well-recognized variant of familial adenomatous polyposis. GS is characterized by the presence of colonic polyposis; osteomas; and numerous soft-tissue tumors, such as epidermal cysts, desmoid tumors, and lipomas.2 In addition to the polyposis, patients with GS may have various extraintestinal manifestations, including multiple jaw osteomas, odontomas, impacted teeth, and supernumerary teeth.3 Unless the osteomas interfere with normal function or are deemed cosmetically unacceptable, they typically require no treatment. Development of the osteomas precedes that of the premalignant polyps, which usually start to appear during puberty. Patients become symptomatic in their early 20s. If not treated, intestinal polyps will become malignant. Therefore, diagnosis of GS early in life is imperative so the

26 THE CLINICAL ADVISOR â&#x20AC;˘ JUNE 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

patient can have a prophylactic colectomy and siblings can be evaluated for the disease. Peutz-Jeghers syndrome. Another autosomal dominant disorder, Peutz-Jeghers syndrome (PJS) is characterized by oral and perioral ephelides, oral melanotic macules, and intestinal polyposis. The polyps are typically found in the small intestine and are thought to be hamartomas, benign polyps with an extraordinarily low potential for malignancy. The pigmentations present as dark blue to brown macules, ranging in size from 1 to 5 mm, predominately found on the vermilion border of the lip, buccal mucosa, and hands. The oral pigmentations appear first and thus play an important part in early diagnosis. Ideally, early recognition of the characteristic mucocutaneous melanosis would lead to a thorough medical workup and the diagnosis of PJS. In reality, most cases of PJS are diagnosed subsequent to the onset of GI complaints, such as abdominal pain, obstruction, and bloody stools, typically between the ages of 10 and 30 years. Amyloidosis. Deposition of an extracellular proteinaceous material called amyloid is the underlying cause of a heterogenous group of conditions referred to as amyloidosis. Amyloid deposited in organs and tissues can cause significant harm, including tissue damage. The prognosis of amyloidosis depends on which organs are involved and the extent of the deposition. For example, protein accumulation in the heart and kidney can result in organ failure. When the GI tract is affected, the patient may experience vomiting, hemorrhaging, and diarrhea. The most common oral manifestation of amyloidosis is macroglossia, which occurs in approximately 20% of amyloidosis patients. Macroglossia may appear as a diffuse or nodular enlargement of the tongue, which may demonstrate lateral ridging due to indentation by the teeth. The tongue may have yellowish peripheral nodules as well.4 Rarely, amyloid deposition may also occur in gingival tissues (gingival hyperplasia).5 Deposition of amyloid is confirmed by biopsy.

Case report of a patient with Kaposi sarcoma A 24-year-old HIV-positive male who suffered depression following the death of his father had not taken his highly active antiretroviral therapy for the past three months. The patient reported new onset of purple lesions on both legs, the right periorbital region, trunk, and oral mucosa (Figures 1 and 2) for the past month and was given a diagnosis of Kaposi sarcoma (KS). The oral lesions, in particular, were extremely painful. They were treated with three injections of vinblastine sulfate over a period of four weeks, and the patient was encouraged to resume his highly active antiretroviral therapy. The combination of the chemotherapeutic injections plus the patient’s increased compliance led to a gradual fading and ultimate elimination of the lesions associated with the KS.

Figure 1

Hematologic diseases

Pernicious anemia. In patients with pernicious anemia (PA), autoimmune destruction of parietal cells in the stomach leads to atrophy of the gastric mucosa. Such atrophy results in a failure to secrete intrinsic factor, which is needed for the absorption of vitamin B12 across the intestinal mucosa. PA results in a megaloblastic, macrocytic anemia that affects both males and females. The key triad of clinical symptoms seen with PA includes generalized weakness, painful tongue, and numbness or tingling of the extremities. The oral manifestations include an inflamed and burning tongue,

Figure 2 FIGURES 1 and 2. An HIV-positive patient who had stopped his highly active antiretroviral therapy presented with lesions on the legs, in the periorbital region, on the trunk, and on the oral mucosa.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 27

CME CE

ORAL INVOLVEMENT OF SYSTEMIC DISEASES

The overall prevalence of oral manifestations of HIV disease has decreased since the advent of potent antiretroviral therapy. mild to severe atrophy of the lingual papillae resulting in bald appearance of the tongue, and shallow aphthous ulcers. Although there is no permanent cure for pernicious anemia, repletion of vitamin B12 should be followed by cessation of anemia-related symptoms. PA can be treated with monthly intramuscular injections of cyanocobalamin. HIV-related conditions. Oral manifestations have also been observed in a large proportion of patients with HIV, although the overall prevalence of oral manifestations of HIV disease has decreased since the advent of potent antiretroviral therapy. Common oral manifestations include xerostomia, candidiasis, oral hairy leukoplakia, periodontal disease, and ulcerative lesions. Kaposi sarcoma (KS) is the most common tumor seen in HIV-infected patients and is considered an AIDS-defining illness by the guidelines of the CDC.6 KS may present with cutaneous and oral involvement. Being a predominantly vascular tumor, KS usually appears red to purple, but in some people, it may be almost skin-colored, pale lilac, often bruiselike, or deeply pigmented.7 Lesions in the mouth are common and highly characteristic, occurring particularly on the palate, tongue, and buccal mucosa. The progression of oral lesions requires management because they may result in a mass or swelling that can be extremely painful and can interfere with oral function. This mass or swelling may then ulcerate and cause discomfort and esthetic issues. The treatment of oral lesions ranges from localized injections of chemotherapeutic agents, such as vinblastine sulfate, to surgical removal. Systemic chemotherapy may be the treatment of choice for patients with extraoral and intraoral KS. (See, “Case report of a patient with Kaposi sarcoma,” on the preceding page.) AT A GLANCE ●

Diagnosis of Gardner syndrome early in life is imperative so the patient can have a prophylactic colectomy and siblings can be evaluated for the disease.

●

The prognosis of amyloidosis depends on which organs are involved and the extent of the deposition.

●

Although there is no permanent cure for pernicious anemia, repletion of vitamin B12 should be followed by cessation of anemia-related symptoms.

●

Progression of oral lesions in Kaposi sarcoma requires management because they may result in a mass or swelling that can be extremely painful and can interfere with oral function.

Behçet syndrome. A chronic, relapsing-remitting, occlusive vasculitis, Behçet syndrome (BS) affects multiple organ systems in the body. The disease most often involves recurrent oral aphthous ulcerations, ocular inflammation (uveitis), and ulceration of the genital mucosa. BS typically occurs only in young people and is more commonly seen in men. The remissions and exacerbations “burn out” after approximately 10 years of activity. The first symptoms of BS are numerous painful oral aphthous ulcers. These can be followed by acnelike skin lesions and inflammatory eye problems. Without treatment, the disease may progress to include arthritic and neurologic manifestations. Occurring in groups or as isolated lesions, the oral ulcers vary in size. They are typically round, well-defined, and painful, and they last seven to 10 days. These ulcers, which can be induced by trauma, present primarily on the gingiva, lips, buccal mucosa, and tongue, but they also occur on the palate, tonsils, and pharynx. In most cases, the oral lesions can be managed with anesthetic topical treatments, topical or systemic steroids, or antibiotics. Recently, there has been evidence of possible benefit from treatment of aphthous lesions with carbon dioxide lasers.8 Leukemia. Patients with leukemia can also show oral symptoms. The clinical signs and symptoms of leukemia are related to the crowding out of normal hematopoietic stem cells by the abnormal increase of immature WBCs in the bone marrow. This results in a decrease in the number of functional WBCs, RBCs, and platelets. As a result, a patient with leukemia is more susceptible to fatigue, bleeding, bruising, fevers, and infections. Acute myelomonocytic leukemia is the most likely type of leukemia to exhibit oral involvement. The oral manifestations of leukemia may include mucosal bleeding, ulceration, petechiae, recurrent herpetic lesions, and diffuse or localized gingival enlargement.9 On examination, the gingiva may feel boggy and appear hemorrhagic with or without concurrent ulceration. Additionally, impaired immune function can lead to various secondary oral complications, such as candidiasis, herpes simplex virus infection, and periodontal bone loss. Patients receiving treatment for leukemia may develop opportunistic infection and chemotherapy-related oral mucositis. Various preventive protocols that include such agents as acyclovir (Zovirax), nystatin, and a chlorhexidine oral rinse (Peridex, Periogard) may be used to decrease these complications.10 In addition, leukemia, like lymphoma, can cause bone destruction and the radiographic appearance of “teeth floating in air.”

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

Erythematous candidiasis occurring as central papillary atrophy of the dorsal tongue is seen in patients with poorly controlled diabetes. Endocrinologic disorders

Diabetes mellitus. Because of the growing number of patients with diabetes, primary-care clinicians must be familiar with the oral manifestations that can occur with this disorder and how to treat them. The disruption in carbohydrate metabolism seen in diabetes mellitus may be the result of either decreased production leading to eventual absence of insulin (type 1) or tissue resistance to the effects of insulin (type 2). Oral findings are usually limited to type 1 diabetes. Problems include periodontal disease, delayed wound healing, and an increased risk of infection. Enlargement of the parotid glands may also be seen. Erythematous and enlarged attached gingiva surrounding the teeth has also been described in uncontrolled diabetes. Erythematous candidiasis occurring as central papillary atrophy of the dorsal tongue is also seen in patients with longstanding poorly controlled diabetes. The fungal infection mucormycosis may also occur in diabetes patients and is potentially fatal. Additionally, dry mouth has been reported in people with diabetes mellitus.11 Evidence suggests that periodontal changes are the fi rst clinical manifestation of diabetes.12 Moreover, there is emerging evidence of a two-way relationship: Diabetes can lead to poor periodontal health, and poor periodontal health can make diabetes difficult to control.13 Severe uncontrolled periodontal disease may be a strong predictor of various complications of diabetes, including nephropathy, stroke, transient ischemic attack, angina, MI, and heart failure.14 Acromegaly. This disorder, characterized by excess production of growth hormone by the anterior pituitary gland after closure of the epiphyseal plates, can also have oral manifestations. Acromegaly usually occurs in middle-aged adults. There is renewed growth of the small bones of the hands and feet as well as the membranous bones of the skull and jaws. Intraorally, patients with acromegaly can demonstrate mandibular prognathism (protruding lower jaw), macroglossia, and diastema formation (space between upper front teeth). Addison disease. Another important disorder that can demonstrate oral involvement is Addison disease (AD). It results from insufficient production of corticosteroid hormones due to destruction of the adrenal cortex. Clinical features are not usually observed until at least 90% of the gland is destroyed. Symptoms include diffuse hyperpigmentation of the skin (bronzing), fatigue, irritability, depression, hypotension, and

weakness. The oral mucosa may show diffuse pigmentation or patchy pigmented macules. Brown patches on the gingiva, vermilion border of the lips, buccal mucosa, palate, and tongue may represent the first signs of AD.15 Vitamin deficiency

Vitamin C. Vitamin C is found in many vegetables and fruits, but it is most abundant in citrus fruits. This vitamin is needed for the proper synthesis of collagen. Scurvy, a deficiency of vitamin C, can demonstrate spontaneous hemorrhage in the form of purpura and ecchymoses of the skin and gingival mucosa as well as subperiosteal hematomas, weak capillary support, ulceration, and severe periodontal disease. The gingiva may appear swollen around the teeth, which may become loose from bone loss. The gingival lesions are called scorbutic gingivitis. Wound healing and localization of focal infections are affected because of impaired collagen synthesis. Vitamin B3. Deficiency of vitamin B3, or pellagra, is classically associated with diarrhea, dermatitis, dementia, and eventual death. Oral symptoms typically include stomatitis and glossitis. The tongue appears fiery red, smooth, and raw. Although the tongue first appears swollen, it later becomes darker red and atrophic. Patients may complain of a generalized burning sensation in the mouth or just a burning tongue. Erosions and painful aphthouslike ulcers may appear on the tongue and gingiva. Patients with early pellagra may exhibit increased salivary flow, resulting in drooling and angular cheilitis, which is inflammation manifesting as cracks, splits, and shallow ulcers at the corner of the mouth. Conclusion

A wide variety of systemic diseases encountered by nurse practitioners and physician assistants will have oral manifestations. The oral cavity is frequently involved in conditions that affect the skin or other multiorgan diseases. Most of these manifestations are nonspecific but should alert the clinician to the possibility of a concurrent systemic disease

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.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 29

CME CE

ORAL INVOLVEMENT OF SYSTEMIC DISEASES

or a latent systemic disease that may develop. Some disease manifestations identified in the oral cavity may be specific enough to make a defi nitive diagnosis. Oral involvement often precedes the occurrence of other symptoms or development of lesions at other locations. A thorough oral examination is critical for proper patient care and early diagnosis. ■

6. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet. 1990;335:123-128. 7. Schwartz RA. Kaposi’s sarcoma: an update. J Surg Oncol. 2004;87:146-151. 8. Demetriades N, Hanford H, Laskarides C. General manifestations of Behçet’s syndrome and the success of CO2-laser as treatment for oral lesions: a review of the literature and case presentation. J Mass Dent Soc. 2009;58:24-27. 9. Dreizen S, McCredie KB, Keating MJ, Luna MA. Malignant gingival and skin

Dr. Stephanie Weiss is a senior oral and maxillofacial surgery resident at Kings County Hospital Center in Brooklyn, N.Y. Dr. Adam Weiss is a senior oral and maxillofacial surgery resident at The Brooklyn Hospital Center in New York.

“infiltrates” in adult leukemia. Oral Surg Oral Med Oral Pathol. 1983;55:572-579. 10. Stokman MA, Spijkervet FK, Boezen HM, et al. Preventive intervention possibilities in radiotherapy- and chemotherapy-induced oral mucositis: results of meta-analyses. J Dent Res. 2006;85:690-700. 11. Moore PA, Guggenheimer J, Etzel KR, et al. Type 1 diabetes mellitus,

References

xerostomia, and salivary flow rates. Oral Surg Oral Med Oral Pathol Oral

1. Lipan MJ, Reidenberg JS, Laitman JT. Anatomy of reflux: a growing

Radiol Endod. 2001;92:281-291.

health problem affecting structures of the head and neck. Anat Rec B New

12. Lamster IB, Lalla E, Borgnakke WS, Taylor GW. The relationship

Anat. 2006;289:261-270. Available at onlinelibrary.wiley.com/doi/10.1002/

between oral health and diabetes mellitus. J Am Dent Assoc. 2008;139

ar.b.20120/pdf.

Suppl;19S-24S. Available at jada.ada.org/content/139/suppl_5/19S.long.

2. Fotiadis C, Tsekouras DK, Antonakis P, et al. Gardner’s syndrome: a case

13. Mealey BL. Periodontal disease and diabetes. A two-way street. J Am

report and review of the literature. World J Gastroenterol. 2005;11:5408-

Dent Assoc. 2006;137 Suppl:26S-31S. Available at jada.ada.org/content/137/

5411. Available at www.wjgnet.com/1007-9327/11/5408.pdf.

suppl_2/26S.long.

3. Payne M, Anderson JA, Cook J. Gardner’s syndrome—a case report. Br

14. Thorstensson H, Kuylenstierna J, Hugoson A. Medical status and com-

Dent J. 2002;193:383-384. Available at www.nature.com/bdj/journal/v193/

plications in relation to periodontal disease experience in insulin-dependent

n7/full/4801571a.html.

diabetics. J Clin Periodontol. 1996;23(3 Pt 1):194-202.

4. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J

15. Nieman LK, Chanco Turner ML. Addison’s disease. Clin Dermatol.

Med. 1997;337:898-909.

2006;24:276-280.

5. Keith DA. Oral features of primary amyloidosis. Br J Oral Surg. All electronic documents accessed May 15, 2012.

“We’re from Student Loans—we came to repo your B.A.” 30 THE CLINICAL ADVISOR • JUNE 2012 • www.ClinicalAdvisor.com

1972;10:107-115.

FEATURE: ROSLYN WALDEN, MSN, FNP-BC

Dismiss a problem patient in 10 safe steps Most clinicians have dealt with a dissatisfied or noncompliant patient. But how do you end the relationship without putting yourself at risk?

‘‘F

iring a patient” has become common in the modern health-care environment. The phrase can be seen in print or heard uttered by exasperated providers in reference to individuals who have become “problem patients.”1,2 These are patients who fail to complete indicated tests, refuse necessary treatments, miss appointments, do not pay bills, or are rude, unreasonably demanding, dissatisfied, dishonest, threatening, violent, or litigious.3 When the relationship is unable to continue towards a therapeutic goal, termination may become an attractive option for both parties.2,4 A provider may become concerned about being blamed for a poor outcome when a patient is continually noncompliant with prescribed interventions.5 A conflict of interest may arise between the provider and the patient (involving, for example, a financial investment or a familial relation) that makes termination of the relationship an ethical or legal necessity. Termination may even be necessary for such benign reasons as the patient changing insurance carriers or the relocation or retirement of the clinician.6 This discussion will focus on the nurse practitioner or physician assistant as a primary provider of outpatient services and the patient as an established recipient of the provider’s care.

Speak with the patient before making the final decision to terminate the relationship.

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

Protecting yourself

Although there are no formal laws against a provider terminating a patient relationship for nondiscriminatory reasons,1,7 certainly ethical concerns exist, but these are beyond the scope

of this article. However, such valuable resources as time, money, and manpower can be diverted away from one’s profession when terminating a patient becomes a legal issue in defense against litigation arising from accusations of abandonment.8 Practitioners may feel compelled to continue a relationship that they would prefer to terminate, out of fear of legal reprisal or simply not being aware of alternatives.9 Knowing how to protect oneself, one’s business, and one’s profession from nontherapeutic relationships can result in a safe and productive practice environment. The American Medical Association (AMA) has formally addressed this issue by outlining legitimate reasons for dismissing a patient and offering a protocol for dismissal that advocates safety in patient care as well as legal protection for the provider.6 The American Academy of Physician Assistants (AAPA) offers general guidance but no specific protocol. The AAPA guide states, “A PA…may discontinue their professional relationship with an established patient as long as proper procedures are followed. The PA…should provide the patient with adequate notice, offer to transfer records, and arrange for continuity of care if the patient has an ongoing medical condition. Discontinuation of the professional relationship should be undertaken only after a serious attempt has been made to clarify and understand the expectations and concerns of all involved parties.”10 Having studied in Texas, I am familiar with the state’s regulations. The Texas Administrative Code, which defines the scope of practice and rules of NPs, is silent on the issue of terminating the clinician-patient relationship.11 The Texas Board of Nursing addresses patient abandonment from employment and licensure perspectives but with verbiage more suited to bedside or inpatient nursing care. The board does not speak to dismissing a patient as a primary provider in the advanced practice role.12 If a relationship has never been established, abandonment cannot be construed.13 The AMA defines abandonment of an established patient as, “the termination of a professional relationship between physician and patient at an unreasonable time and without giving the patient the chance to find an equally qualified replacement.”6 To prove abandonment, three items must be demonstrated: (1) termination must not have been mutual; (2) termination transpired without reasonable notice; and (3) the need for care remained.8 The AMA suggests that 30 days’ time is a “reasonable notice.”6 Thirty days’ notice was also cited as good risk management by a malpractice insurer.14 In the absence of an official guideline for the termination of the NP/PA–patient relationship, I propose the following 10-point plan:

POLL POSITION

Have you had a relationship with a patient deteriorate to the point where dismissal was required?

n=388

11% Yes No 89%

For more polls, visit www.ClinicalAdvisor/polls

1. Develop a policy for provider-patient termination that is made available to patients at the initiation of service.14 2. Keep accurate and detailed documentation.6,7 3. Speak with the patient prior to making a final decision regarding the relationship termination, and consider sending a “pre-withdrawal letter” that gently expresses your concern over his or her noncompliance.5 4. Discuss the situation with a colleague, risk-management professional, or legal advisor.9 5. Explain to the patient that he or she is being terminated from care, and provide an explicit reason. Do not delegate this task; speak directly with the patient.4,15,16 6. Inform clinic staff of the termination.14 7. Send a certified letter with return receipt17 to the patient and to the insurance carrier16 stating that the patient is being terminated and that care will be discontinued in 30 days’ time, noting the specific date.18 8. Offer the patient interim care.6 9. Provide names and contact information for suggested potential alternate providers.19 10. Offer to transfer records when given written permission.6 Establishing national guidelines for NPs and PAs

The American Nurses Association’s (ANA) Code of Ethics and Scope and Standards of Practice can certainly provide ethical guidance to the NP concerning the patient relationship.20,21 The National Commission on Certification of Physician Assistants’ Code of Conduct for Certified and Certifying PAs22 and the AAPA’s Guidelines for Ethical Conduct for the Physician Assistant Profession10 can inform PAs regarding ethical conduct within the provider-patient relationship. Of course since there is no official legal guidance to NPs

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 33

DISMISSING A PATIENT

6. American Medical Association. Ending the patient-physician

CLINICAL SLIDESHOW

relationship. Available at www.ama-assn.org/ama/pub/physician -resources/legal-topics/patient-physician-relationship-topics/ending -patient-physician-relationship.page.

This 10-point patient termination plan outlines the best way to dismiss a difficult or noncompliant patient. Visit ClinicalAdvisor.com/PatientDismissalSlideshow.

7. Smith JA. Terminating the provider-patient relationship. Nurse Pract. 2005;30:58-60. 8. Fishbain DA, Lewis JE, Gao J, et al. Alleged medical abandonment in chronic opioid analgesic therapy: case report. Pain Med. 2009;10:722-729. 9. Mossman D, Farrell HM, Gilday E: ‘Firing’ a patient: May a psychiatrist

or PAs regarding termination of relationships, observing guidelines already established by the AMA is appropriate.7 Developing and incorporating guidelines similar to the AMA protocol into a national template for NPs and PAs would involve input from the ANA and AAPA similar to the processes used in past revisions of their guidelines. Input would be needed from individual clinicians, specialty organizations, major stakeholders, and focus groups. The newly created standard would need to be reviewed and approved by the ANA Congress on Nursing Practice and the AAPA Board of Directors. Having a guided pathway available to protect oneself and one’s staff from unfortunate patient situations will result in better patient outcomes, better delivery of care, and better business overall. Embracing established steps to terminate a patient relationship can help prevent vulnerability to claims of abandonment. Finally, being aware of an existing alternative to staying in a negative patient-provider relationship will offer the NP and PA increased autonomy in practice. ■

unilaterally terminate care? Curr Psychiatry. 2010;9:18-29. 10. Nelson RL; AAPA. Guidelines for ethical conduct for the PA profession. JAAPA. 2001;14:10-2, 15-6, 19-20. 11. Texas Administrative Code, 22 TX Sec of State § 11. Available at info. sos.state.tx.us/pls/pub/readtac$ext.ViewTAC?tac_view=3&ti=22&pt=11. 12. Texas Board of Nursing Board Rules Associated with Alleged Patient “Abandonment.” Available at www.bon.texas.gov/about/January10/7-4-2.pdf. 13. Buppert C. Nurse Practitioner’s Business Practice and Legal Guide, 3rd ed. Sudbury, Mass.: Jones and Bartlett; 2007:479. 14. Greenwald L. Terminating the physician-patient relationship. Available at www.metrowestins.com/DISNE/PracticeInfo/terminating_patient _relationship.pdf. 15. NSIDE MD. Firing a patient: Recognizing the signs and symptoms and prescribing an effective treatment. Available at www.getnside.com/sa/ magazine/medical/022008/articles/1178-FIRING_A_PATIENT/. 16. Willis DR, Zerr A. Terminating a patient: is it time to part ways? Fam Pract Manag. 2005;12:34-38. Available at www.aafp.org/fpm/2005/0900/ p34.html. 17. O’Brien, L. When a patient refuses your dismissal letter. Med Econ. 2008;85:58.

Ms. Walden is a family nurse practitioner in Las Cruces, N.M.

18. Borglum K, Martin V, Kern SI. Liability issues after dismissing a patient. Med Econ. 2008;85:46.

References

19. O’Brien, L. Defense against abandonment charges. Med Econ. 2005;82:116.

1. Kern SI. Discharging the problem patient. Med Econ. 2008;85:32.

20. American Nurses Association. Code of ethics for nurses with

2. Parikh RK. Showing the patient the door, permanently. The New York Times. June

interpretive statements. Available at www.nursingworld.org/codeofethics.

10, 2008. Available at www.nytimes.com/2008/06/10/health/views/10case.html.

21. American Nurses Association. Nursing: Scope and standards of prac-

3. American Medical News. Take care when firing a patient. Available at

tice. Available at www.nursingworld.org/scopeandstandardsofpractice.

www.ama-assn.org/amednews/2008/02/04/bica0204.htm.

22. National Commission on Certification of Physician Assistants. Code

4. Gianola FJ. Terminating your professional relationship with a patient.

of conduct for certified and certifying PAs. Available at www.nccpa.net/

JAMA. 2009;22:57-58.

CodeOfConductLEP.aspx.

5. Chiropractic Economics. How to fire a bad patient. Available at www. chiroeco.com/news/chiropractic-news.php?id=2234.

PEER PERSPECTIVES

All electronic documents accessed May 15, 2012.

“Usually, these patients do not pay their bills or are rude and demanding. It is frustrating when you send a certified letter, explain the reasons for the discharge, and provide 30 days’ notice only to have the patient suddenly call and beg to come back in.This has happened to me several times.” Eileen Ginsburg, ARNP, Boynton Beach, Fla. (via ClinicalAdvisor.com)

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

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 JUNE 2012

Consultations Help for a young adult with anorexia and bulimia . . . . . . . . . . . .38 Decreasing secretions following tracheostomy . . . . . . . . . . . . . . . . . .39 Vitamin B12 deficiency in older adults . . . . . . . . . . . . . . . . . . .39

Clinical Pearls The best tests for hepatitis C. . . . . . . .39 Plumbing for atherosclerosis . . . . . . . . . 44

Your Comments Abstinence is a must for a depressed alcoholic . . . . . . . . . . . . .44

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.

CONSULTATIONS HELP FOR A YOUNG ADULT WITH ANOREXIA AND BULIMIA Is there any new information available on eating disorders? My 21-year-old granddaughter has been anorexic and bulimic since age 15, if not earlier. Everything we have tried has failed, including therapy, acupuncture, nutritionists, in-patient stays at numerous eating-disorder clinics, and visits to the emergency department for low potassium and/or seizures. My granddaughter’s knowledge about her disease is limited, and she refuses to participate in any support groups. She has been prescribed escitalopram (Lexapro) daily plus potassium supplements. I am very concerned for her safety.—DOROTHY BINCKLEY, CRNP (RETIRED), Columbia, Md. I am sure this is very distressing for you. Therapies can be limited by the individual’s willingness to participate and desire to become well. However, I recently participated in a wonderful update on eating disorders through TeenScreen – National Center for Mental Health Checkups at Columbia University (www.teenscreen.org/ resources/events-webinars/jan-2012-eating-disorders/, accessed April 15, 2012). There is some good evidence out there now on the effectiveness of the Maudsley Approach, a family-based treatment approach for teenagers. There is also a manual for this treatment (Lock J, Le Grange D, Agras WS, Dare C. Treatment Manual

OUR CONSULTANTS

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

is a 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.

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

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

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Maria Kidner, DNP, FNP-C,

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

for Anorexia Nervosa: A Family-Based Approach. New York, N.Y.: The Guilford Press; 2002). Although the patient you describe is 21 years old, she may still be functioning at the older teen/young adult level, and the Maudsley Approach may be worth a try. For adults with anorexia nervosa, the best bet appears to be cognitive behavior therapy, which has also been shown to be effective for bulimia.—Julee B. Waldrop, DNP (164-1)

DECREASING SECRETIONS FOLLOWING TRACHEOSTOMY Nine months ago, a woman aged 77 years had a tracheostomy for severe obstructive sleep apnea. She has done well since then except for the copious amounts of secretions from the plastic tracheostomy tube, which requires suctioning several times at night. She has been placed on montelukast (Singulair), tiotropium (Spiriva), ipratropium (Atrovent), acetylcysteine (Mucomyst), and guaifenesin (Mucinex), none of which has decreased the secretions. Do you have any suggestions?—SHARON OGLESBEE, FNP, San Augustine, Tex. Is there other underlying pulmonary disease to explain the sputum production? The case description implies simply sleep apnea. I have seen a similar reaction to the plastic tracheostomy tube. The secretions abated after switching to a metal tracheostomy tube. Short of this, you could try a scopolamine patch (Transderm Sc p). As for the medications, singulair is an anti-inflammatory and should not affect mucus production. Tiotropium and ipratropium are drying bronchodilators and may compete for receptors since they are in the same class. Acetylcysteine and guaifenesin simply thin the secretions, making them easier to raise. I would approach this in steps: (1) rule out any other pulmonary disease that could explain the mucus; (2) try scopolamine; and (3) if unsuccessful, switch to a metal tracheostomy

tube.—MARIANNE FERRIN, MSN, CRNP, Pulmonary Specialist, Presbyterian Hospital, Philadelphia (164-2)

VITAMIN B12 DEFICIENCY IN OLDER ADULTS Should testing for vitamin B12 deficiency be part of a standard geriatric workup? Should methylmalonic acid (MMA) and folic acid tests be included in that lab work?—ANNA RUFO, MSN, McMinnville, Ore. The evaluation of any patient should be focused and evidence-based. If you are concerned an older adult is experiencing signs of dementia, there are several diagnostic tests that will help identify some treatable causes that should not be missed. This would include a complete blood count (to rule out anemia or possible infection), serum chemistries, and thyroid and liver functions tests to rule out a metabolic disorder. Vitamin B12 and folic acid may be deficient in an older adult and can be treated easily with appropriate supplementation. MMA and homocysteine should be considered if the vitamin B12 level is at the lower end of normal. These are just a few of the diagnostic considerations. Further information and resources are available at the website of the Hartford Institute for Geriatric Nursing (hartfordign.org).—Deborah L. Cross, MPH, CRNP, ANP-BC (164-3)

CLINICAL PEARLS THE BEST TESTS FOR HEPATITIS C Since the hepatitis C virus (HCV) antibody remains active even in an individual who has been treated and has achieved viral response as well as in someone who clears the virus spontaneously, it is not sufficient for diagnosing chronic active hepatitis. It can be traumatic for a patient to be told he or she

Debra August King, PHD, PA,

Mary Newberry, CNM, MSN

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

is senior physician assistant of the Department of Cardiothoracic Surgery, Lenox Hill Hospital, New York City.

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

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

teaches at the University of North Carolina School of Nursing in Chapel Hill and practices pediatrics at UNC Hospitals.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 39

New Online Course for Civilian Health Care Providers Identifying and Treating Concussion/Mild Traumatic Brain Injury in Service Members and Veterans t 5XP IPVS TFMG QBDFE NVMUJNFEJB POMJOF DPVSTF GFBUVSJOH QBUJFOU JOUFSWJFXT SFMBUFE MJOLT BOE DPNQMFY QSFTFOUBUJPOT t (P UP #SBJO-JOF.JMJUBSZ PSH UP MFBSO NPSF BCPVU UIF EFUFDUJPO BOE USFBUNFOU PG 5#* BO JOWJTJCMF XPVOE PG XBS

â&#x20AC;&#x153;Knowing if your patient has been to war can help \RX RÎ?HU EHWWHU FDUH &RQFXVVLRQV DUH WUHDWDEOH WKH SURJQRVLV LV JRRG DQG WKLV FRXUVH ZLOO JHW \RX VWDUWHG Č&#x2039; &$37 - / +DQFRFN 3K\VLFLDQ DQG 1DYDO 2É?FHU

Transforming the Lives of Service Members with TBI TBI. Clinical Care. Education. Research. Thatâ&#x20AC;&#x2122;s DVBIC. DVBIC.ORG

BRAINLINEMILITARY.ORG

has HCV and then be referred to hepatology/gastroenterology, only to discover that all the worry was for naught when no evidence of the virus is detected. Before making a diagnosis of HCV, either order the test that will reflex to quantitative, or follow up with the HCV-RNA polymerase chain reaction assay: The qualitative type provides a positive or negative result, and the quantitative type gives a viral load.â&#x20AC;&#x201D;JUNE BARNHOUSE, CRNP, Frederick, Md. (164-4)

PLUMBING FOR ATHEROSCLEROSIS When explaining atherosclerosis to my patients, I compare plumbing in a new house versus the plumbing in an older house. The concept of â&#x20AC;&#x153;build upâ&#x20AC;? in pipes brings clarity and, ultimately, buy-in for improved adherence to cholesterollowering agents.â&#x20AC;&#x201D;MARICELA LARA-NEVAREZ, PharmD, RPh, Coppell, Tex. (164-5)

YOUR COMMENTS ABSTINENCE IS A MUST FOR A DEPRESSED ALCOHOLIC I was surprised that alcohol abstinence was not encouraged for the anxious and depressed patient described in Item 162-2.

INFO@DVBIC.ORG

Most alcoholics will have comorbid mood disorders. Alcohol use can also cause mood disorders. If someone is drinking enough, no psychotropic medication will effectively treat the depression. This patient should be strongly motivated to enter into a treatment facility for alcohol addiction and monitored by a trained clinician for safe withdrawal and comprehensive multi-axis psychiatric disorders. When I start treatment for mood disorders, I screen for drug and alcohol use and explain that routine alcohol consumption will negate any mood weâ&#x20AC;&#x2122;re trying to improve. If Iâ&#x20AC;&#x2122;ve tried multiple classes of drugs with no success, I refer to an addiction specialist.â&#x20AC;&#x201D;KRISTIN RHODES, RN, MSN, FNP-C, Newport Beach, Calif. I mistakenly thought the patient had a history of alcoholism but was no longer drinking. I agree with Ms. Rhodes. Often, people use alcohol and other substances as a form of self-medication in the setting of mood disorders and other psychiatric illnesses. Screening for such use and abuse is absolutely part of the evaluation for all patients who present with depression and/or anxiety. Alcohol is a depressant and can disturb sleep, which can interfere with the treatment plans for depression and anxiety. Abstinence is the goal for those with a history of substance abuse, and referral to an addiction specialist is very appropriate as part of a comprehensive treatment plan.â&#x20AC;&#x201D;Eileen F. Campbell, MSN, CRNP (164-6) â&#x2013;

44 THE CLINICAL ADVISOR â&#x20AC;˘ JUNE 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

CME CE

Dermatology Clinic ■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment. ■ COMPLETE THE POSTTEST: Page 64

■ ADDITIONAL CME/CE: Pages 25, 57

Turn to page 21 for additional information on this month’s CME/CE courses.

CASE #1

Itchy papules on an infant’s torso and palms AUDREY VASS AND JULIA R. NUNLEY, MD

A previously healthy 9-month-old infant was seen for a rash of three weeks duration. The infant had become increasingly irritable and was feeding poorly. She remained afebrile and had no other associated symptoms. A presumptive diagnosis of impetigo was made, but the eruption failed to respond to topical mupirocin (Bactroban, Centany). Further questioning revealed that both parents began itching about a month ago after a family trip. Examination revealed inflammatory papules and nodules scattered over the infant’s torso, with a concentration of the lesions in the axillary areas and on the palms. What is your diagnosis? Turn to page 46

CASE #2

Pink, scaly rash on the trunk and arms ESTHER STERN, NP-C

A woman, age 35 years, presented to the dermatology clinic with a two-week history of a scaly rash on her trunk and arms. According to the patient, the rash first started with one spot on the arm. Within a few days, it had spread to the chest, abdomen, and back. The rash was mildly pruritic at times. The woman denied any other symptoms of systemic illness and reported no prior medical or medication history. Physical examination revealed multiple discrete salmon and pink-colored oval-shaped scaly plaques scattered over the trunk and proximal arms.

What is your diagnosis? Turn to page 47 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 45

CME CE

CASE #1

Dermatology Clinic

Scabies

The diagnosis of scabies was readily made in the office. Material scraped from one of the inflammatory papules was placed on a glass slide, covered with oil and a cover slip, and examined under a microscope; examination revealed several scabitic mites and scybala (feces). Scabies is a highly pruritic and infectious condition caused by the parasitic mite Sarcoptes scabiei var hominis. The life cycle of a mite is approximately 30 days. Whereas the male mite dies shortly after copulation, the female mite lives on its human (or other animal) host, burrowing into the stratum corneum of the epidermis where she deposits her 60 to 90 eggs. Larvae require only 10 days to mature to adulthood, and the cycle continues. Scabies is usually transmitted by direct skin-to-skin contact between family members, guests in the home, or play in school-aged children. Indirect transmission via such infected fomites as towels, bedsheets, or clothing worn by the infested person, although reported, is rare due to the short 24- to 36-hour lifespan of a mite when separated from an animal host.1 The prevalence of scabies in the general population of industrialized countries is low; however, scabies is associated with poverty and overcrowding, primarily among such subgroups as the homeless or displaced children. Outbreaks are more common in winter months in temperate zones due to crowded habitats and the ability of the mite to live longer at lower temperatures when separated from its host.2 The pruritus and rash associated with scabies become clinically apparent approximately three to six weeks after the initial infestation; however, pruritus may develop within 24 to 48 hours with reinfestation. The delay in symptoms is attributed to the time required to develop a type IV hypersensitivity reaction to the mite’s eggs, feces, and saliva.1 Adults typically complain of an itch that intensifies at night; family members or sexual partners often have similar symptoms. Areas most commonly affected in an adult include finger webs, flexor surfaces of wrists and elbows, axillae, and external genitalia. The head and neck are spared in immunocompetent adults, although the eruption may be generalized in those with AIDS or individuals residing in nursing homes. Clinically, one most commonly

sees linear or serpiginous scaly burrows in body creases of the affected sites. Scabies is a great imitator in adults and children, and the diagnosis is often overlooked in neonates and infants because of the atypical presentation in this population. Infestations in newborns will not become clinically evident until age 4 to 8 weeks, when a sufficient immune response has developed.3 As opposed to adults, eruptions in infants are often generalized with heavy involvement of the palms, soles, axillae, fingers, face, scalp, and even nailbeds.4 The lesions are most commonly pustules, vesicles, and occasionally inflammatory nodules. The characteristic short, wavy, linear burrow is typically absent or obscured by an eczematization process.5 The differential diagnosis for scabies in an infant includes eczema, infantile acropustulosis, infantile or neonatal acne, or insect bites.1,3,6–8 Atopic eczema is very common in infants and typically presents as a pruritic, relapsing, and remitting rash on the face, posterior scalp, and extensor surfaces of the extremities. Patients often have asthma or a family history of allergies and/or asthma.1,6,9 Secondary eczematization from pruritus-driven scratching can lead to the misdiagnosis of infantile eczema.1 Infantile acropustulosis, a self-limited, acrally distributed, vesiculopustular eruption, can be difficult to distinguish from scabies. In fact, this condition frequently follows a suspected case of scabies and is believed by some to be an “id” reaction to the scabitic mite, although the pathogenesis remains speculative.7,8 Neonatal acne presents within the first few months of life, whereas infantile acne presents after age 3 months; both conditions present as pustules and papules on the infant’s face.3 These are typically minimally pruritic, selflimited eruptions of uncertain etiology, although maternal hormones and genetic predisposition may play pivotal roles. These dermatoses are frequently treated with topical steroids. Infants with scabies who have been treated with topical steroids often have reduced itching, inflammation, and morphologically altered lesions that can further delay the proper diagnosis and treatment.10,11 Scabies incognito is a term used to describe this phenomenon. The proper diagnosis usually requires a high index of suspicion.5 A highly specific and sensitive means of diagnosis is not available, leaving examination of scrapings from lesional skin that identify mites, scybala, or larvae as the most definitive approach. If a biopsy is done, the histologic findings may show a female mite burrowed in the epidermis in association with spongiotic edema, vesiculation, hyperkeratosis, and acanthosis.12

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For children, the first line of treatment recommended by the CDC is topical 5% permethrin cream applied over the entire body, covering the face, scalp and neck in infants over age 2 months. The cream should be rinsed off after eight to 14 hours, followed by a repeat application one week after the initial treatment. Because of potential neurotoxicity, lindane (Kwell) is no longer recommended for infants. Other treatment options include topical crotamiton (Eurax), benzyl benzoate, and sulfur ointment; these are not considered first-line modalities due to side effects and/or decreased effectiveness when compared with permethrin. Treat all close contacts—including all the members of the household—from the neck down with 5% permethrin to eradicate scabies from the environment and prevent reinfestation. Such oral therapies as ivermectin (Mectizan , Stromectol) should not be used in children younger than age 5 years.1,2 Towels, linens, clothing, and stuffed toys should be washed in hot water or placed in sealed plastic bags for 72 hours.13 Secondary bacterial infections should be treated if present.2 Parents should be advised that pruritus might persist for two to four weeks despite successful treatment. The patient and family in this case were treated with 5% permethrin cream weekly for two applications. To prevent excessive excoriations, socks were placed over the infant’s hands at night. Symptomatic relief was confirmed two weeks later. ■ Ms. Vass is a fourth-year medical student at Virginia Commonwealth University School of Medicine in Richmond. Dr. Nunley is professor of dermatology at Medical College of Virginia Hospitals, also in Richmond. References 1. Chosidow O. Clinical practices. Scabies. N Engl J Med. 2006;354:17181727. Available at www.nejm.org/doi/full/10.1056/NEJMcp052784. 2. Heukelbach J, Feldmeier H. Scabies. Lancet. 2006;367:1767-1774. 3. Mengesha YM, Bennett ML. Pustular skin disorders: diagnosis and treatment. Am J Clin Dermatol. 2002;3:389-400. 4. Paller AS. Scabies in infants and small children. Semin Dermatol. 1993;12:3-8. 5. Hurwitz S. Scabies in babies. Am J Dis Child. 1973;126:226-228. 6. Fleischer AB Jr. Diagnosis and management of common dermatoses in children: atopic, seborrheic, and contact dermatitis. Clin Pediatr (Phila). 2008;47:332-3346. 7. Mancini AJ, Frieden IJ, Paller AS. Infantile acropustulosis revisited: history of scabies and response to topical corticosteroids. Pediatr Dermatol. 1998;15:337-341. 8. Humeau S, Bureau B, Litoux P, Stalder JF. Infantile acropustulosis in six immigrant children. Pediatr Dermatol. 1995;12:211-214.

9. Krol A, Krafchik B. The differential diagnosis of atopic dermatitis in childhood. Dermatol Ther. 2006;19:73-82. 10. Kim KJ, Roh KH, Choi JH, et al. Scabies incognito presenting as urticaria pigmentosa in an infant. Pediatr Dermatol. 2002;19:409-411. 11. Hengge UR, Currie BJ, Jäger G, et al. Scabies: a ubiquitous neglected skin disease. Lancet Infect Dis. 2006;6:769-779. 12. Falk ES, Eide TJ. Histologic and clinical findings in human scabies. Int J Dermatol. 1981;20:600-605. 13. Centers for Disease Control and Prevention. Parasites – Scabies: Treatment. Available at www.cdc.gov/parasites/scabies/treatment.html. All electronic documents accessed May 15, 2012.

CASE #2

Pityriasis rosea

Pityriasis rosea (PR) is a common inflammatory exanthem that is generally self-limiting. Although there are no known causes, many studies report a temporal clustering of cases,1 suggesting an infectious etiology, with human herpesvirus (HHV)-6 and HHV-7 most frequently suspected.2 Some patients provide a recent history of such mild constitutional symptoms as malaise and fatigue, compatible with a viral illness. Despite this theory, the rash does not appear to be contagious. The rash appears most often in teenagers and young adults, with a greater female incidence. Interestingly, pregnant women appear to be affected at a greater rate. PR is rare in infants and the elderly. Incidence is highest during the spring and autumn months. Given its unique characteristic appearance, PR is usually diagnosed based on physical examination alone. The rash usually starts with a single 1- to 10-cm scaly plaque, termed the herald or mother patch, which can persist for a week or more before subsequent lesions appear. Although the diagnosis can be challenging at this early stage of the disease, it becomes clearer as the rash progresses. New lesions multiply rapidly, are usually smaller than the herald patch, and average 5 mm to 10 mm in diameter. Careful examination of the fully developed eruption reveals oval-shaped salmon-colored plaques with an overlying fine scale that often desquamates and leaves a characteristic

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

CME CE

Dermatology Clinic

collarette of scale. In addition, the lesions are usually arranged along the lines of cleavage. This characteristic pattern is commonly referred to as a “Christmas tree” or “fir tree” distribution. The rash most often appears on the trunk and upper extremities and usually spares the sun-exposed areas. Rarely are the palms, soles, scalp, or penis involved. Typically, no other skin pathology is noted, although oral aphthous ulcerlike lesions have been associated with the rash.3 Atypical cases of PR present a diagnostic challenge. The rash may primarily involve the extremities and spare the trunk. Localized forms may occur and involve one

Secondary syphilis should always be considered and tested for in sexually active young adults with a scaly annular rash. area only, such as the neck, thighs, groin, or axillae.4 An inverse distribution that spares the covered areas is very rare. Some patients present with a herald patch only, and no subsequent lesions appear. The differential diagnoses for classic PR are most commonly tinea, secondary syphilis, erythema annulare centrifugum (EAC), nummular eczema, and guttate-type psoriasis. Tinea versicolor is primarily seen on the trunk and proximal upper extremities; when this condition presents with hyperpigmented pink patches it can be hard to differentiate from PR. A fungal scraping can rule out tinea versicolor. Secondary syphilis should always be considered and tested for in sexually active adolescents and young adults with a scaly annular rash. PR is often confused with EAC, as both rashes consist of oval scaly plaques with a peripheral collarette of scale. If the diagnosis is uncertain, a skin biopsy can be performed. Histopathology of PR lesions shows features of a subacute or chronic eczematous dermatitis. The finding of a decreased or absent granular cell layer, erythrocytes in the papillary dermis, homogenization of the papillary dermal collagen, and the presence of dyskeratotic cells within the epidermis are all features suggestive of PR.5 No treatment is needed for the rash of PR, as the natural history is that of complete resolution. Average duration of the exanthem appears to be between four and seven weeks. At times, the rash may resolve with remaining postinflammatory hyperpigmentation or hypopigmentation. Patients should be reassured that with appropriate sun protection, this too will fade and resolve in time.

Simple emollients are beneficial to relieve the dryness and irritation. If itching is present, a mild topical corticosteroid or an oral antihistamine may be prescribed. Triamcinolone acetonide 0.1% is often the topical treatment of choice and can be applied once or twice a day as needed for itching. Such oral antihistamines as cetirizine (Zyrtec), fexofenadine (Allegra), and diphenhydramine (Benadryl) can also provide relief of pruritus. Some clinical studies have suggested that oral erythromycin6 administered for two weeks or oral acyclovir7 started at the onset of the eruption may expedite resolution of the rash. In addition, narrow-band UVB phototherapy has been suggested for persisting or highly bothersome cases of PR. Relatively few patients experience relapses or recurrences. The patient in this case was educated regarding the benign nature of the rash and the natural course of spontaneous resolution within a few weeks. She was given a prescription for a medium-potency topical steroid to be used once or twice a day as needed for itching. The patient reported that the rash resolved approximately seven weeks after it started without any evidence of scarring. ■ Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Chuh AA, Lee A, Molinari N. Case clustering in pityriasis rosea: a multicenter epidemiologic study in primary care settings in Hong Kong. Arch Dermatol. 2003;139:489-493. Available at archderm.ama-assn.org/ cgi/content/full/139/4/489. 2. Kosuge H, Tanaka-Taya K, Miyoshi H, et al. Epidemiological study of human herpesvirus-6 and human herpesvirus-7 in pityriasis rosea. Br J Dermatol. 2000;143:795-798. 3. Kay MH, Rapini RP, Fritz KA. Oral lesions in pityriasis rosea. Arch Dermatol. 1985;121:1449-1451. 4. Ahmed I, Charles-Holmes R. Localized pityriasis rosea. Clin Exp Dermatol. 2000;25:624-626. 5. Panizzon R, Bloch PH. Histopathology of pityriasis rosea Gibert. Qualitative and quantitative light-microscopic study of 62 biopsies of 40 patients. Dermatologica. 1982;165:551-558. 6. Sharma PK, Yadav TP, Gautam RK, et al. Erythromycin in pityriasis rosea: A double-blind, placebo-controlled clinical trial. J Am Acad Dermatol. 2000;42(2 Pt 1):241-244. 7. Drago F, Vecchio F, Rebora A. Use of high-dose acyclovir in pityriasis rosea. J Am Acad Dermatol. 2006;54:82-85. All electronic documents accessed May 15, 2012.

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

LEGAL ADVISOR CASE

How do you handle the parents?

BY ANN W. LATNER, JD

Ms. E, age 43 years, was employed as a school nurse in a large public-school system. Prior to taking on this position, she had worked for a family practitioner for more than a decade. She left family practice a year earlier because she wanted a job that would allow her to spend more time with her own children. The school job was fairly low-pressure. Most visits to the school nurse’s office involved straightforward care: minor cuts or bruises, sore throats, fevers, stomach aches, head lice, and the like. In treating each child, Ms. E basically had to decide whether the child’s condition warranted sending the child home or whether the child could return to the classroom after treatment. In rare instances, such as a severe asthma attack or a serious playground accident, emergency services would be needed and an ambulance would transport a child to the hospital. But such incidents were few and far between, and visits to the school nurse were usually for a narrow range of issues. One morning, Ms. E received a visit from the first-grade teacher and her 7-year-old student,

A steadfast clinician gets into trouble when she examines a minor without express verbal consent.

A gloved-hand external vaginal exam of the student was conducted in a private and curtained cubicle.

Miss J. The teacher explained to Ms. E that the child had raised her hand in class and then audibly complained that her “private part was hurting.” The teacher also noted that Miss J looked very uncomfortable and was cupping her groin area in class. The child did look uneasy, and Ms. E spoke to her gently to try to ascertain the problem. In the meantime, she asked an assistant to pull Miss J’s file and look up the emergency-contact numbers. The chart noted that Miss J was the daughter of a single working mother. As the assistant tried to contact Miss J’s mother, Ms. E obtained a urine sample from the girl. The dipstick test pointed to a urinary tract infection (UTI). With no success reaching the little girl’s mother directly, Ms. E left voicemail messages indicating that Miss J was in the school infi rmary. Ms. E then checked Miss J’s school 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.

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

LEGAL ADVISOR child’s fi le. The consent form gave general permission for the school to use its discretion to treat the child medically as necessary. This extended to a physical examination when warranted, which, in this case, it was. The court held that no malpractice had taken place, and that Ms. E had handled the situation properly. Protecting yourself

This case shows that you can’t always protect yourself. Ms. E handled the situation appropriately and professionally. She made every attempt to contact the child’s mother when it appeared that the child was suffering from a UTI. Ms. E also ensured that a signed consent form was in the child’s medical fi le. And once every attempt to contact Miss J’s guardian had failed, Ms. E properly and professionally handled the examination, after explaining to the child what was going to happen. Yet, despite Ms. E’s proper handling of the situation, she was still a party to a lawsuit. And as a party to a lawsuit, she had to arrange her schedule to make time for attorney appointments, depositions, and court appearances. She also had to live with the stress of dealing with an ongoing lawsuit. While you can’t always avoid a lawsuit, this case is a good example of how you can position yourself so that you are best able to defend yourself if you are sued. Ms. E handled the situation adeptly. She had all her facts documented and in order regarding all attempts to contact the child’s mother to obtain verbal consent. It is important to have parental consent—or at least a signed medical-consent form—to avoid any issues that might arise. ■

Legal background

A motion to dismiss asks the court to decide whether a case has any merit under the law. When a court is asked to decide whether to dismiss a case, it will look at the facts as stated by the plaintiff as though they are true. If, as a matter of law, there is no valid claim, then the court will dismiss the case. In some circumstances a case can be dismissed for technical reasons: if it was filed after the statute of limitations expired or if it wasn’t properly fi led in some other way. In this case, the court held that Ms. E had done nothing legally wrong, and there was no issue of law here. A medical-consent form, signed by the mother, was in the

“I cooked us a lovely dinner for two—you could at least do the dishes!”

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

fi le to make sure that a signed consent form for treatment was included—and it was. Ms. E proceeded to conduct a gloved-hand external vaginal exam of the student in a private and curtained cubicle. The examination indicated a UTI and ruled out certain injuries that could have been causing the child’s pain. Ms. E was very careful before the exam to explain to Miss J what she was going to do, and she took the time to make sure the little girl understood what was about to happen. When Miss J’s mother arrived, Ms. E explained the situation and the physical examination she had performed, and the subsequent UTI diagnosis. Miss J’s mother was furious when she was told about the exam, and stormed out with her child after berating Ms. E for “going beyond what was acceptable.” Miss J did have a UTI, which was treated with antibiotics, but the child’s mother was extremely upset about the exam. She did not feel satisfied with the explanation given by Ms. E and the school administration for this perceived violation of her child’s privacy. She hired a plaintiff ’s attorney and sued the school district and Ms. E for invasion of privacy and malpractice. Ms. E was livid. “I did nothing wrong,” she told the attorney who was assigned to her by her insurance company. “I did everything by the book. We tried to contact the mother and she wasn’t available. Plus, we had a signed consent form.” The attorney requested a copy of the child’s file, including the consent form, and reassured Ms. E that he didn’t believe the case would stand up in court. He summarily fi led a motion to dismiss the lawsuit. The attorney was correct, but it took several months before the court dismissed the case. The examination of the child’s genitalia was warranted by the symptoms and by the urine dipstick test, and was conducted properly from a medical standpoint, the court stated.

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.

Linear, streaky vesicles at birth An infant presented with a linear and streaky distribution of vesicles on her trunk and extremities that progressed to verrucous plaques at age 2 months and hyperpigmented streaks at age 5 months. WHAT IS YOUR DIAGNOSIS?

• • • • •

Incontinentia pigmenti Neonatal herpes simplex Pigmentary mosaicism Goltz syndrome Gorlin syndrome

● See the full case at ClinicalAdvisor.com/DermDx0612A

Large hemangioma with abnormal brain MRI A small pink patch present at birth developed into a large red plaque covering the infant’s frontal scalp, the forehead and the superior aspects of the face at age 3 weeks. WHAT IS YOUR DIAGNOSIS?

• • • •

PHACE syndrome Sturge-Weber syndrome Klippel-Trenaunay syndrome Parkes Weber syndrome

● See the full case at ClinicalAdvisor.com/DermDx0612B

Have you missed any recent Derm Dx cases? Go to ClinicalAdvisor.com/DermDx for a complete archive of past quizzes as well as additional images of last month’s cases. Symmetrical rash after a cold

Asymptomatic eruption on the back

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2012 53

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.

Niacin

Niacin is not a new member of the pharmacology landscape. Known as vitamin B3, it is one of the eight water-soluble vitamins in the vitamin B complex. The term niacin refers to both nicotinic acid and its amide derivative, nicotinamide (niacinamide). Niacin is used as an antioxidant and in the treatment of nutritional deficiencies.1 While niacin is well known for preventing the disease pellagra, it is only in the past 15 to 20 years that other medicinal uses for this common vitamin have emerged.

Background Niacin has primarily been used to increase HDL cholesterol. HDL helps manage LDL cholesterol in the bloodstream, and this has significant long-term effects on the risk of cardiovascular disease (CVD). Studies show that a 2%-3% increase in HDL corresponds to a 2% -4% reduction in CVD occurrence.2

Science Niacin is found in many foods, including yeast, meat, fish, milk, eggs, green vegetables, beans, and cereal grains.3 Niacin is essential for the body to metabolize fats and sugars. The amino acid tryptophan, found in many proteins, is also partially converted into niacin in the body.3 While clinicians are probably most aware of niacin and its impact on serum lipid levels, the vitamin is also essential in generating energy. Niacin is converted into nicotinamide

adenine dinucleotide, and is ultimately used in adenosine triphosphate and adenosine diphosphoribose transfer reactions.1 Niacin is also a mild anticoagulant. Researchers have found that niacin enhances fibrinolysis, especially in hyperlipidemic men.1 In addition to lowering total LDL numbers, niacin studies including the Familial Atherosclerosis Treatment Study (FATS) verified that the vitamin also changes the molecular size and density of LDL particles.4 Chemically, niacin increases the concentration of lighter, smaller LDL particles and decreases the production of the heavier, denser particles.4 Long-term studies examining the risk factors for CVD show that the atherogenicity of LDL particles is directly proportionate to the density of the dominant particles. In addition, niacin has been linked to the prevention of bothcataracts and Alzheimer disease (AD). In the Blue Mountains Eye Study, researchers monitored nearly 3,000 pros pective food-and-supplement diaries in adults aged 49 to 97 years.5 Various nutrients were tracked, as was the use of

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ALTERNATIVE MEDS UPDATE OTC multivitamins. Patients were examined at baseline and two years later for cataract development. Niacin—in both food and supplement forms—was associated with a reduced occurrence of cataracts. The reduction was more significant when niacin was taken in conjunction with other vitamins and antioxidants, including vitamin A, thiamin, and riboflavin.5 In another long-term dietary study, researchers examined more than 8,000 people older than age 65 years for the development of AD and related cognitive decline.6 In the first three years, niacin intake showed a linear correlation with a decrease in cognitive decline in the geriatric set.6 A subset of study participants who had undergone a cardiovascular event during the trial were placed on niacin and also assessed for cognitive decline. Findings showed a significant 44% reduction in cognitive impairment in patients reporting a median daily niacin intake of 22 mg in either food or supplement form.6

Safety, interactions Niacin is generally considered safe when taken in regular amounts. Common dermatologic side effects of flushing and itching are usually self-limited. However, due to the vasodilatory effect, niacin may produce an excessive drop in BP when taken in conjunction with certain BP medications. Caution is urged when giving niacin to an individual with liver damage, since the vitamin competes for various hepatic metabolic pathways.

The cost of niacin fluctuates depending on the type of formulation and dose, but it generally costs approximately $30 for a one-month supply. Niacin is available as a tablet with varying rates of absorption; the range of a therapeutic daily dose is 1,000 mg-3,000 mg. Depending on the type of tablet used, this may be dispensed in single or in multiple doses.2

Summary

In patients with or at risk for Alzheimer disease, niacin aided cognition.

Niacin—in both food and supplement forms—was associated with a reduced occurrence of cataracts.

With the increasing emphasis placed on the burden of CVD, something as common as niacin should be a top-seller. Cheap, effective, and affordable, niacin should be at the top of our lists when deciding on therapy for patients with hyperlipidemia and other cardiovascular risk factors. ■ References 1.Niacin and niacinamide (vitamin B3) page. Natural Medicines Comprehensive Database website. 2. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592. 3. Niacin and niacinamide (vitamin B3) page. Medline Plus website. Available at www.nlm.nih.gov/medlineplus/ druginfo/natural/924.html. 4. Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a new pathophysiological mechanism for coronary disease regression: hepatic lipase-mediated changes in LDL density. Circulation. 1999;99:1959-1964. 5. Kuzniarz M, Mitchell P, Cumming RG, Flood VM. Use of vitamin supplements and cataract: the Blue Mountains Eye Study. Am J Ophthalmol. 2001;132:19-26.

Dosage and cost

6. Morris MC, Evans DA, Bienias JL, et al. Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive

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decline. J Neurol Neurosurg Psychiatry. 2004;75:1093-1099. 7. McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med. 2004;164:697-705. 8. Mills E, Prousky J, Raskin G, et al. The safety of over-the-counter niacin: A randomized placebo-controlled trial [ISRCTN18054903]. BMC Clin Pharmacol. 2003;13:3-4. All electronic documents accessed on May 15, 2012.

As with all nutrients, the best way to get niacin is through food intake. Obviously, when using niacin as a therapeutic agent, larger doses are needed. Immediate, time-released, and extendedrelease niacin are available OTC.7 The FDA has approved two name-brand formulations of niacin for lowering LDL levels.2 The main consideration with the OTC brands—especially the immediate-release formulations—is the increased intensity of side effects.8

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations. ■ COMPLETE THE POSTTEST: Page 64

■ ADDITIONAL CME/CE: Pages 25, 45

Turn to page 21 for additional information on this month’s CME/CE courses.

Asymptomatic red lesions JOE MONROE, PA-C

CASE #1

CASE #2

A fair-skinned man, age 60 years, presented after his wife noted blood spots on the inside of his undershirt. An asymptomatic lesion was discovered on his right upper back. This lesion was a 6 × 3.5 cm superficial papulosquamous plaque with an annular well-defined border, within which were scattered tiny focal areas of erosion. Dark red focal areas were found within the borders of the lesion. The lesion had been present for at least five years before it began to bleed. At no point had it been painful or itchy, and it had grown quite slowly.

A 27-year-old man was referred to the dermatology clinic for evaluation of an asymptomatic leg lesion. The lesion first appeared two years ago and doubled in size during that period. The patient’s primary-care clinician had diagnosed the lesion as “ringworm” and psoriasis. Various creams, including a combination product containing betamethasone and clotrimazole, had had no effect. Additional history included newly diagnosed diabetes mellitus. No fever, cough, shortness of breath, or unexplained weight loss were reported.

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CME CE

CASE #1

Dermatologic Look-Alikes

Superficial basal cell carcinoma

An antifungal cream/steroid combination prescribed earlier by the patient’s primary-care clinician provided no beneficial effect. The man’s skin was quite fair. An abundance of sun damage was noted, primarily on the patient’s face and arms. He had a history of a number of sun-caused skin cancers, including basal cell carcinomas (BCCs). Shave biopsy confirmed the expected diagnosis of superficial BCC. The most common treatment for superficial BCC is electrodessication and curettage, but this is not practical for such a large lesion. This procedure would result in a large raw area that would be painful and slow to heal. Pyogenic granuloma formation is a frequent complication associated with this treatment as well. Moreover, a large scar would certainly result, and the chance of recurrence with curettement of such a large lesion is all too high.1 Surgical excision of this lesion, with margins, would result in a scar roughly 3.5 times longer than the maximum dimension of the cancer; in this case, almost 1 ft long.2 Radiation therapy has long been used to good effect in individuals with BCCs. In actual practice, however, this treatment is usually reserved for recurrent or other aggressive tumors not amenable to surgical resolution.3 For many patients, radiation treatment is also impractical because it requires multiple visits over the course of several weeks (i.e., five sessions a week for four weeks). Two of the most common topical medicines indicated in the treatment of superficial BCC are 5-fluorouracil (Carac, Efudex, Fluoroplex) cream or solution and imiquimod (Aldara) cream.4 The former is a pyrimidine analog that blocks DNA replication5 while the latter boosts the immune response to the cancer. Neither medication has been studied in cancers as big as this patient’s. Superficial BCC bears no resemblance to any of the other types of BCC. In fact, superficial BCC is often misdiagnosed as fungal infection, psoriasis, or eczema.6 The most obvious clue to its identity is the fact that superficial BCC will almost always occur on sun-exposed skin of fair, sundamaged individuals, typically on the back and shoulders and often in multiples. Unlike psoriasis or eczema, superficial BCCs are fi xed to the same location and grow slowly but steadily over several years’ time. The annular, sharply

defined palpable border—sometimes called “field fire” for its resemblance to the advancing border of a grass fire—is essentially pathognomonic. While UV exposure is the most common cause of BCC, other triggers include arsenic exposure (mostly through groundwater contamination), coal, tar, ionizing radiation exposure, local trauma, vaccination, and even tattooing.7-9 Geographic location, heredity, and skin type are often involved as well.6 BCCs primarily appear on older patients (average age 67.5 years) because it typically takes 20 to 50 years from UV exposure to tumor genesis. However, BCCs are beginning to be seen on younger and younger patients—even in teenagers. Men are more than twice as likely as women to

Radiation therapy is usually reserved for recurrent or other aggressive tumors not amenable to surgical resolution. develop BCC. Patients aged 55 to 70 years are 100 times more likely to be diagnosed with BCC than an individual aged 20 years. Immunosuppression (as seen in HIV and transplant patients, for example) also increases risk.6 As for distribution, 70% of BCCs occur somewhere on the head (usually the face);10 25% on the trunk;11 and most of the rest on the hands, arms, and legs. BCCs have been reported in non-sun-exposed areas, including axillae, and on genitials.12,13 At most, only about 0.1% metastasize,6 first to local nodes, then to the lungs, and fi nally to bones. The predominant theory is that most BCCs develop from pluripotential cells in the basal layer of the epidermis or from certain parts of the follicular structure. In susceptible individuals, the hedgehog gene encodes an extracellular protein that binds to a cell membrane receptor complex, triggering a cascade of cellular events leading to cellular proliferation. Overexposure to UV radiation suppresses immunologic responsiveness to cutaneous tumors. As mentioned, superficial BCCs do not resemble such far more common types as nodular or noduloulcerative tumors. These BCCs are familiar to most providers as a pearly papule or nodule. Other types of BCCs include sclerosing (scarlike) and pigmented types, which can be quite dark, especially in dark-skinned patients. Some BCCs are more aggressive than others, as indicated by their clinical behavior and such histologic features as

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perineural involvement. Location—especially on the perinasilar and canthal areas of the face—can be associated with aggressive behavior and increased rates of recurrence. The superficial BCC in this case was so indolent as to be on the opposite end of the spectrum, requiring many years of neglect before becoming invasive. Given the dearth of suitable treatment choices, the decision was made to begin the application of imiquimod 5% cream five days a week. The treatment is still in progress at this time. Such therapy will certainly cause irritation and weeping during the expected two-month treatment period but has a good chance of eradicating this lesion by promoting the production of cytokine precursors.

CASE #2

Necrobiosis lipoidica

In 1932, Urbach coined the term necrobiosis lipoidica diabeticorum to name the particular kind of plaques seen on the legs of diabetics. In 1935, Goldsmith was the first to note the appearance of the condition in individuals without diabetes.14 Twenty-five years later, Rollins and Winkleman analyzed a number of cases of this disease and again noted its presence in nondiabetics, leading them to suggest changing the name of the condition to necrobiosis lipoidica (NL), a term encompassing all cases of this clinical condition regardless of the presence or absence of diabetes.15 NL represents a disorder of collagen degeneration with a granulomatous response, eventuating clinically in the formation of shiny brown plaques that tend to enlarge slowly, becoming increasingly yellow in color with atrophic surfaces marked by telangiectasias on the periphery.14 Occurring mostly on the leg, the plaques average approximately 1 cm but can grow to many times that size. Multiple lesions are common, and relatively minor trauma to these lesions can result in erosions and ulcers that are difficult to treat. As noted above, NL can occur in people without diabetes, but up to 60% of NL patients have been diagnosed with diabetes prior to the development of the plaques.14 Both diagnoses are made at the same time in 25% of cases, but the presence or progression of NL does not correlate with the severity of diabetes.14

The average age of development of NL is 30 years, but the range of ages varies a great deal. Women with NL outnumber men by at least 3:1.14 The clinical picture displayed by NL is clear enough to be essentially pathognomic, although biopsy is sometimes required to differentiate NL from such conditions as morphea, sarcoidosis, granuloma annulare, and xanthomata.14,16 Microscopically, NL demonstrates interstitial and palisaded granulomas in subcutaneous tissue as well as the dermis.14 In addition, blood vessel walls are thickened, and endothelial cells are swollen in the middle to deep dermis. In some cases, clinical correlation with microscopic fi ndings is invaluable, especially with regard to possible granuloma annulare, NL’s closest look-alike. Fortunately, this patient’s lesion and its clinical context were quite typical, permitting an empirical diagnosis and the initiation of treatment with topical steroid cream (fluocinonide 0.05%) b.i.d. Steroid creams can be useful in treating active, enlarging lesions but can be counterproductive in older, “burnt-out” lesions. Because the cause of the condition is unknown, treatment of NL can be problematic. Arguably, the formation of traumatic ulcers in these lesions is the source of much difficulty.14 The prevention of trauma, with pressure stockings, and an assessment of the patient’s living environment (for potential trauma from wheelchair parts or furniture, for example) are in order. Many different treatment modalities have been used to treat NL with varying degrees of success. These include pentoxifylline (Pentopak, Pentoxil, Trental),17 photodynamic therapy,18 aspirin/dipyridamole (Permole, Persantine) combination,19 calcineurin inhibitors (e.g., tacrolimus [Hecoria, Prograf ]),14 perilesional heparin injections,20 oral vitamin B, and tretinoin (Vesanoid),21 to name just a few. ■ Mr. Monroe is a physician assistant specializing in dermatology at Dawkins Dermatology in Oklahoma City. References 1. James WD, Berger TG, Elston DM. Dermatologic surgery. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Saunders-Elsevier; 2006:876. 2. Brownell I. Nodular basal cell carcinoma. J Drugs Dermatol. 2007;6:1245-1246. 3. Mendenhall WM, Amdur RJ, Hinerman RW, et al. Radiotherapy for cutaneous squamous and basal cell carcinomas of the head and neck. Laryngoscope. 2009;119:1994-1999. 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.

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CME CE

Dermatologic Look-Alikes

5. Efudex (fluorouracil) [package insert]. Valeant Pharmaceuticals; 2005. 6. Medscape Reference. Basal cell carcinoma. Available at emedicine .medscape.com/article/276624-overview. 7. Cabrera HN, Gómez ML. Skin cancer induced by arsenic in the water. J Cutan Med Surg. 2003;7:106-111. 8. Romão-Corrêa RF, Maria DA, Soma M, et al. Nucleolar organizer region staining patterns in paraffin-embedded tissue cells from human skin cancers. J Cutan Pathol. 2005;32:323-328. 9. Keyhani K, Ashenhurst M, Oryschak A. Periocular basal cell carcinoma arising in a site of previous trauma. Can J Ophthalmol. 2007;42:467-468. 10. Erba P, Farhadi J, Wettstein R, et al. Morphoeic basal cell carcinoma of the face. Scand J Plast Reconstr Surg Hand Surg. 2007;41:184-188. 11. Fresini A, Rossiello L, Severino BU, et al. Giant basal cell carcinoma. Skinmed. 2007;6:204-205. 12. Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol. 2007;

“Quick! I need some more charitable donations!”

178:1980-1985. 13. Mulvany NJ, Allen DG. Differentiated intraepithelial neoplasia of the vulva. Int J Gynecol Pathol. 2008;27:125-135. 14. Medscape Reference. Necrobiosis lipoidica. Available at emedicine. medscape.com/article/1103467-overview. 15. Rollins TG, Winkelmann RK. Necrobiosis lipoidica granulomatosis. Necrobiosis lipoidica diabeticorum in the nondiabetic. Arch Dermatol. 1960;82:537-543. 16. Mistry N, Chih-Ho Hong H, Crawford RI. Pretibial angioplasia: a novel entity encompassing the clinical features of necrobiosis lipoidica and the histopathology of venous insufficiency. J Cutan Med Surg. 2011; 15:15-20. 17. Littler CM, Tschen EH. Pentoxifylline for necrobiosis lipoidica diabeticorum. J Am Acad Dermatol. 1987;17(2 Pt 1):314-316. 18. Heidenheim M, Jemec GB. Successful treatment of necrobiosis

“Well, damn, Camembert, you called to tell me you’re runny?”

2006;142:1548-1550. 19. Eldor A, Diaz EG, Naparstek E. Treatment of diabetic necrobiosis with aspirin and dipyridamole. N Engl J Med. 1978;298:1033. 20. Jetton RL, Lazarus GS. Minidose heparin therapy for vasculitis of atrophie blanche. J Am Acad Dermatol. 1983;8:23-26. 21. Heymann WR. Necrobiosis lipoidica treated with topical tretinoin. Cutis. 1996;58:53-54. All electronic documents accessed May 15, 2012.

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

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“If you find anything else wrong, just go ahead and fi x it.”

lipoidica diabeticorum with photodynamic therapy. Arch Dermatol.

POSTTEST Expiration date: June 2013

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Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 25

page 45

page 57

Oral involvement of systemic diseases

Scabies

Superficial basal cell carcinoma

1. Orally, acute sarcoidosis manifests with abrupt onset of a. Blue to brown macules on the lip’s vermilion border b. Burning or itching sensation affecting the oral mucosa c. Painless dark-red to brown lesions on the buccal mucosa and hard palate d. Inflammatory hyperplasia with surface fissuring on the lips

1. What is the most common presentation of scabies? a. Erythematous patches with central clearing b. Serpiginous scaly burrows in body creases c. Scattered excoriations with severe pruritus d. Small vesicles in clusters

1. What is the most common treatment for superficial basal cell carcinoma (BCC)? a. Electrodessication and curettage b. Irradiation c. Cryotherapy d. Surgical excision

3. What is the usual initial appearance of pityriasis rosea (PR)? a. Thick plaques with no scaling b. A single 1- to 10-cm scaly plaque c. Dome-shaped, umbilicated papules d. Violaceous papules with fine white surface lines

plaques, up to 60% of necrobiosis lipoidica (NL) patients have been diagnosed with a. Tuberculosis b. Diabetes c. Hypothyroidism d. Lyme disease

2. Gardner syndrome may be characterized by the presence of a. Impacted teeth b. Supernumerary teeth c. Odontomas d. All of the above 3. What is the most common oral manifestation of amyloidosis? a. Ulcerative lesions b. Macroglossia c. Gingival enlargement d. Patchy, pigmented macules 4. Generalized weakness, painful tongue, and numbness or tingling of the extremities is seen in patients with a. Pernicious anemia b. Behçet syndrome c. Addison disease d. Vitamin C deficiency

2. What feature of BCC is essentially pathognomonic? 2. Which topical therapy for scabies is a. Papules with distinct margins no longer recommended for infants? b. Plaques with a velvety, warty surface a. Crotamiton (Eurax) c. Lesions with an annular, sharply b. Benzyl benzoate defined palpable border c. Sulfur ointment d. Macules of hypopigmentation d. Lindane (Kwell) Necrobiosis lipoidica Pityriasis rosea 3. Prior to the development of the

4. The rash of PR most often appears on the a. Scalp b. Groin c. Palms d. Trunk and upper extremities

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4. What treatment is useful for active, enlarging NL lesions? a. Steroid cream b. Perilesional heparin injection c. Oral vitamin B d. Aspirin/dipyridamole (Permole, Persantine) combination

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

NONINVASIVE VENTILATION REDUCES MORTALITY AND NEED FOR INTUBATION IN ELDERLY PATIENTS WITH ACUTE HYPERCAPNIC RESPIRATORY FAILURE Level 1: Likely reliable evidence Noninvasive ventilation reduces the need for intubation compared to standard medical care in adults with acute exacerbation of chronic obstructive pulmonary disease (COPD) (Lancet. 2000;355:1931-1935; Chin Med J [Engl]. 2005;118:2034-2040). There is also evidence that noninvasive ventilation may reduce mortality in these patients (Crit Care Med. 2002;30: 555-562). Alternatives to intubation are especially important in older patients who may have “do not intubate” (DNI) orders. A new randomized trial evaluated the effects of noninvasive ventilation on mortality and need for intubation in elderly patients with hypercapnic respiratory failure (80% with COPD) (Age Ageing. 2011;40:444450). Eighty-two patients (mean age 81 years) were randomized to non invasive ventilation vs. standard medical therapy. Inclusion criteria included pH <7.35, respiratory rate >20 breaths/ minute, and severe dyspnea. Need for intubation was defined as the presence of one major factor or two minor factors after one hour postrandomization. Major factors included no improvement or worsening of pH, deteriorating neurological status, loss of consciousness, and hemodynamic instability with loss of alertness. Minor factors included continued dyspnea, respiratory rate >35 breaths/minute, and weak cough reflex with accumulation of secretions. Noninvasive ventilation significantly reduced the need for intubation (7.3% vs. 63.4%, p <0.001, NNT 2), in-hospital mortality (2.4% vs. 14.6%,

Trials for a new drug indicated for moderateto-severe psoriasis show a significant response rate in patients at 12 weeks.

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p = 0.04, NNT 9), and total mortality at 12 months (39% vs. 61%, p = 0.014, NNT 5). The mean improvement in dyspnea score at one hour was 1.0 point in the ventilation group vs. 0.4 points in the standard-care group (on 0-10 scale, p = 0.05). Additional analysis of these data suggests that noninvasive ventilation may reduce mortality compared to intubation in patients meeting intubation criteria. Only six patients who met the criteria (two from the ventilation group and four from the standard-care group) actually received intubation. Due to DNI orders, a total of 22 patients (21 from the standard-care group) who met intubation criteria had noninvasive ventilation only as rescue therapy. In observational analysis based on treatment received, the highest mortality at 12 months was in the intubation group (83%). Mortality was 56% in patients who received only standard medical care and 43% in patients receiving ventilation (p <0.05 comparing ventilation vs. intubation).

BRIAKINUMAB APPEARS TO REDUCE SEVERITY OF PSORIASIS BETTER THAN METHOTREXATE IN PATIENTS WITH MODERATE OR SEVERE DISEASE Level 2: Mid-level evidence The American Academy of Dermatology recommends oral methotrexate for severe psoriasis in patients with poor response to other therapies ( J Am Acad Dermatol. 2009;60:643-659), but its efficacy is limited, it can be poorly tolerated, The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

and it has a long list of contraindications. A recent trial compared the efficacy of briakinumab, an experimental human monoclonal antibody, and methotrexate in 317 patients with moderate or severe psoriasis (N Engl J Med. 2011;365:15861596). Patients were randomized to monthly subcutaneous injections of briakinumab vs. oral methotrexate plus folate for 52 weeks. Each group received placebos for the other intervention. The primary outcome was clinically meaningful response (defined as ≥ 75% improvement in score on Psoriasis Area-and-Severity Index [PASI-75]). A total of 151 patients (48%) completed the trial. Most of the dropouts in both groups were for lack of efficacy (22 of 48 for briakinumab and 95 of 118 for methotrexate). Missing data were classified as “no response” in an intention-to-treat analysis. At 52 weeks, significantly more patients achieved PASI-75 in the briakinumab group (66.2% vs. 23.9%, p <0.001, NNT 3). Briakinumab was also associated with a greater rate of patients achieving a physician’s global assessment of either “no apparent disease” or “minimal disease” (63% vs. 20.2%, p <0.001, NNT 3) and with a greater rate of clinically meaningful improvement in quality of life (56.5% vs. 18.4%, p <0.001, NNT 3). Rates of serious adverse events (including infections and cancer) were higher in the briakinumab group, but the differences were not statistically significant. The pattern of results was similar at an interim analysis at 24 weeks. In another recent trial, response rates at 12 weeks were significantly higher with briakinumab than with etanercept or placebo (Br J Dermatol. 2011;165:652660). Briakinumab is not yet available for use.

ADDITION OF PEDOMETER-BASED PHYSICAL ACTIVITY INTERVENTION TO SMOKING CESSATION PROGRAM MAY INCREASE QUIT RATES IN TEENAGERS, PARTICULARLY IN BOYS Level 2: Mid-level evidence Some counseling interventions have been shown to have moderate success in reducing smoking rates in teenagers (Cochrane Database Syst Rev. 2010;1:CD003289). A recent cluster randomized trial evaluated the efficacy of adding physical activity to counseling for teenagers trying to quit smoking (Pediatrics. 2011;128:e801-e811). High schools in West Virginia were randomized to provide one of three smoking cessation programs to students aged 14 to 19 years

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For teens trying to quit smoking, physical activity seems to help.

who smoked on at least one day in the last 30 days: a brief intervention with a single 10-15 minute group meeting conducted by a trained facilitator; Not on Tobacco (N-O-T, www.notontobacco.com), a program from the American Lung Association that includes group counseling and advice on healthy behaviors, stress management, and life skills, once weekly for 10 weeks; or a combination of N-O-T plus a pedometer-based physical activity intervention. Students in the combined group were given pedometers and logs to record steps and daily minutes of other physical activity, and they had additional time in group sessions devoted to encouragement and instruction. A total of 233 teenagers from 19 schools participated in the trial (54% girls, 96% daily smokers, mean smoking rates 10.1-14.5 cigarettes/day). Follow-up rates were 75% at three months and 63% at six months, but all participants were included in intention-to-treat analyses. At six-month follow-up, the combination group had the highest quit rate (31.3%), followed by the N-O-T group (21.1%, p = 0.066 vs. combination) and the brief intervention group (15.9%, p = 0.013 vs. combination). In subgroup analyses by gender, the combination group had significantly increased quit rates compared to the N-O-T program alone in boys (36.8% vs. 18.4%, p = 0.033, NNT 6), but not in girls (26.2% vs. 21.1%). The pattern of results was similar at three months. ■

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