October 2016 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • OCTOBER 2016

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NEWSLINE

■■Tuberculosis screening ■■Intensified diabetes therapy ■■MRI safety in pregnancy EVIDENCE-BASED MEDICINE

■■Asymptomatic bacteriuria ■■ADT and dementia risk ■■Gastrointestinal bleeding

OCTOBER 2016

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THE TOXIC EFFECTS OF

LEAD POISONING Lead poisoning can have serious and sometimes fatal consequences.

LEGAL ADVISOR

A case of cellulitis results from a lack of follow-up.

n Dermatologic Look-Alikes

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Editor Colby Stong, editor@ClinicalAdvisor.com Senior editor Sandhya George Associate editor Lauren Grygotis Assistant editor Madeline Morr Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau

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CONTENTS OCTOBER 2016

NEWS AND COMMENT

DEPARTMENTS

12 Newsline ■■Screening for latent tuberculosis infection: USPSTF issues a final recommendation statement. ■■Early intensification of diabetes therapy after metformin failure is beneficial. ■■The American Academy of Pediatrics provides guidance for clinicians to address parental vaccine concerns. ■■A study cites the leading factors behind the high cost of prescription drugs in the United States. ■■MRI is safe in early pregnancy, but gadolinium-enhanced MRI is linked to adverse outcomes in childhood. ■■Oxycodone/naloxone may be an effective analgesic in patients who have had total knee replacement.

How safe is MRI use in early pregnancy? 14

60 Evidence-Based Medicine n Screening and treating pregnant women with asymptomatic bacteriuria may not be helpful. n Risk of Alzheimer dementia after androgen deprivation therapy n Resumption of antithrombotic therapy after gastrointestinal bleeding in patients with atrial fibrillation Multiple, comedo-like openings 51

30 CME A 42-year old woman with T2DM and comorbidities The ideal use of monotherapy, combination therapy, and triple therapy for patients with type 2 diabetes is reviewed in this case study. 37 CME Feature posttest

MAKING CONTACT

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51 Dermatology Clinic n A pink papule that grew from 1 mm to 10 mm in a week n Multiple, comedo-like openings filled with keratin plugs 55 Dermatologic Look-Alikes Widespread lesions, scarring

FEATURES 16 Lead poisoning: Current practice guidelines An aging national infrastructure and paint in old homes increase the risk for lead poisoning and significant healthrelated problems in children and adults.

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com

64 Legal Advisor Undiagnosed cellulitis. A patient is asked to follow up for care but does not, and severe cellulitis develops. Continues on page 6

Lack of follow-up leads to a case of cellulitis 64

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CONTENTS DEPARTMENTS cont’d Alternative Meds Update Spider web silk. Although it may be some time before we see spider silk–treated bandages available for widespread use, these products could be an option in our future. © The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

ADVISOR FORUM 44

Your Comments ■ Sexual orientation, gender identity, and LGBT health care

Clinical Pearls ■ Yeast infections in skinfolds ■ Successful addiction recovery

Case Files ■ Genetic vascular anomaly

“I’d like to buy a fowl.”

HOW TO CONTACT US THE CLINIC BER 2016

EVIDENCEMEDICINE BASED

■ Asymptoma ■ ADT and tic bacteriuria dem ■ Gastrointes entia risk tinal bleeding LEGAL AD VIS

A case of cellu OR litis results from a lack of follow-u p.

• Send it by e-mail to editor@ClinicalAdvisor.com

OCTOBE R 2016

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THE TOXI

C EFFECT

LEAD POIS ONING S OF

Lead pois oning can have serio us and sometim es fata consequence l s.

■ Dermatolo gic Look-Alik es

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EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

The Waiting Room

ClinicalAdvisor.com/News

Official Blog of The Clinical Advisor

Menopausal transition linked to rapid increase in metabolic syndrome severity The American Heart Association found that during menopausal transition, women have a rapid increase in metabolic syndrome severity. Folic acid-fortified foods linked to lower risk of congenital heart defects Foods fortified with folic acid are associated with a decrease in infants being born with congenital heart defects.

ClinicalAdvisor.com/WaitingRoom Jillian Knowles, MMS, PA-C Alternative treatments for patients with lidocaine allergies Data from the Journal of Clinical and Aesthetic Dermatology address alternative treatment methods for patients who have a lidocaine allergy. Jillian Knowles, MMS, PA-C How long is long enough? Taking time off after an illness Some illnesses require that patients stay home from school or work for different lengths of time. Jim Anderson, MPAS, PA-C, DFAAPA Avoiding hospital care after sustaining an injury Some patients, especially those with a medical background, may be reluctant to seek care after sustaining an injury.

Food allergies in children linked to high risk of asthma, rhinitis Researchers measured rates of childhood allergic conditions with data from healthcare provider-based diagnoses.

Multimedia ClinicalAdvisor.com/Multimedia AAP: What parents should know about alternative vaccine schedules Wendy Sue Swanson, MD, MBE, FAAP, of the American Academy of Pediatrics Council on Communications and Media, discusses alternative vaccine schedules and the risks of delayed vaccination. Watch it here: ClinicalAdvisor.com/AAPVaccineVideo Effects of MRI exposure in early pregnancy on childhood outcomes Joel G. Ray, MD, MSc, FRCPC, from the Department of Medicine at St Michael’s Hospital in Ontario, Canada,

MAKING CONTACT

discusses the effect of MRI use during the first trimester of pregnancy on childhood outcomes. Watch it here: ClinicalAdvisor.com/MRIEffectsVideo What factors contribute to the increasing cost of prescription drugs in the United States? A recent study that was published in JAMA cited multiple factors that are behind the elevated prices of prescription drugs in the United States. Aaron S. Kesselheim, MD, JD, MPH, outlines cost-effective alternatives for reform. Watch it here: ClinicalAdvisor.com/USPrescriptionDrugsVideo

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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/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

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The kind of fracture that you can’t miss An 18-year-old male presents with left foot pain 2 days after twisting his ankle during a basketball game. He was unable to continue playing and has had trouble putting weight on the foot ever since. He has tenderness to palpation over the proximal fifth metatarsal. WHAT IS THE BEST TREATMENT OPTION?

• Weight bearing as tolerated in a boot for 6 weeks • Non-weight bearing in a boot for 6 weeks • Intramedullary screw fixation • Open reduction and internal fixation with bone grafting ● See the full case at ClinicalAdvisor.com/OrthoDx_Oct16

Derm Dx Linear dermatosis that follows the lines of Blaschko A 3-year-old Hispanic male is brought in by his mother for evaluation of scattered papules on his abdomen, which had previously been diagnosed clinically as insect bites. His mother also points out a rash on the child’s right leg that has been present for approximately 4 weeks. CAN YOU DIAGNOSE THIS CONDITION?

• Lichen nitidus • Lichen striatus • Lichen simplex chronicus • Lichen planus ● See the full case at ClinicalAdvisor.com/DermDx_Oct16

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2016 9

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Newsline O C TO B E R 2 016

Multiple factors keep prescription drug costs high page 13

How safe is MRI in early stage of pregnancy? page 14

Managing pain after total knee replacement page 14

Screening for latent tuberculosis infection: USPSTF recommendation adults older than 18 years of age in primary care settings. It identified 67 good or fair-quality studies that examined the accuracy and reliability of screening tests of LTBI. The authors of the recommendation noted the results of the International Union Against Tuberculosis trial, which studied the effectiveness of early tuberculosis treatment. The trial was conducted in 7 European countries and included individuals with fibrotic pulmonary lesions, but not active tuberculosis. After 5 years, the results showed that the relative risk of progression to active tuberculosis was 0.35 for treatment with isoniazid compared with placebo.

Digitally colorized SEM of a group of rod-shaped Mycobacterium tuberculosis bacteria, which usually attack the lungs.

The researchers found no studies that directly reported on the harms of LTBI screening, although some studies noted the stigma associated with screening and a diagnostic workup and treatment of false-positive results as potential harms. “Overall, the USPSTF found adequate evidence that accurate screening tests for LTBI are available, treatment of LTBI provides a moderate health benefit in preventing progression to active disease, and the harms of screening and treatment are small,” the authors stated.

Early intensification of diabetes therapy after metformin failure is beneficial Many patients with newly diagnosed type 2 diabetes do not intensify therapy within 6 months of metformin monotherapy failure, according to data published in Diabetes Care. Kevin M. Pantalone, DO, from the Cleveland Clinic in Ohio, and colleagues used electronic health records from the clinic to identify patients recently diagnosed with type 2 diabetes between 2005 and 2013. Patients failed to reach their A1c goal after 3 months of metformin therapy, and the patients had A1c goals of 7% (n=1168), 7.5% (n=679), or 8% (n=429). The researchers conducted a time-dependent survival analysis to measure the time until A1c attainment among patients who received early intensified therapy within 6 months of

metformin failure compared with the time of A1c goal attainment among patients who received late intensified therapy after 6 months of metformin therapy. Treatment was intensified within 6 months of metformin therapy in 62% of patients when poor glycemic control was defined as A1c >7%, in 69% of patients with poor glycemic control >7.5% A1c, and in 72% of patients with poor glycemic control >8% A1c. Patients were more likely to undergo an early intensification of therapy if they were in a higher A1c category. In addition, patients who underwent early intensification therapy attained their A1c more rapidly than did those who underwent later intensification therapy.

THE US Preventive Services Task Force (USPSTF) recommends screening for latent tuberculosis infection (LTBI) in all persons with an increased risk of infection, according to its recommendation statement published in JAMA. The task force gave a B grade recommendation for asymptomatic adults at increased risk for tuberculosis infection. Populations who are at increased risk include individuals who are former residents of countries with increased tuberculosis presence and those who have lived in homeless shelters or correctional facilities. The task force’s systematic review included evidence about screening for LTBI in asymptomatic

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A REPORT in Pediatrics outlines information on addressing parental concerns of vaccination. The study from the American Academy of Pediatrics noted that vaccines are tested in 3 phases of trials, and monitoring systems are in place, such as the Vaccine Adverse Events Reporting System (VAERS), that detect adverse events associated with vaccines. In addition, the Vaccine Safety Datalink monitors vaccine safety in millions of individuals through a network of health provider databases. The percentage of immunized individuals required to achieve herd immunity can range between 30% and 95%. Therefore, children who have not received immunization can put vaccinated children and children who are medically exempt from

Strategies to reduce pain during vaccination can reassure parents.

vaccination who live in the same area at risk. Re su lt s f rom t he 2 0 0 9 HealthStyles survey found that 44% of parents had concerns over pain associated with multiple injections in a single visit, 34% had concerns about receiving multiple vaccines in one visit, 26% were concerned about

the development of autism after receiving vaccines, 13.5% were concerned about vaccines being associated with chronic illness, and 13.2% believed that vaccines are not tested enough to be considered safe to administer. Clinicians can help reassure parents with concerns by directly providing information and using strategies to reduce pain while administering vaccines, such as holding the child upright or by providing tactile stimulation. The most important factor in convincing parents to accept vaccinations is individual contact with an informed clinician, noted the authors. Pediatricians are advised to clearly articulate to parents that vaccines are safe and effective and emphasize that children can be exposed to serious disease without immunization.

Guidance for addressing parental vaccine concerns

INCREASING DRUG prices in the United States may be a result of the cost and complexity of drug development, government-protected monopolies given to drug manufacturers, and the restriction of price negotiation, according to data published in JAMA. Researchers reported that drug spending in the United States per capita exceeds that in all other countries. The per capita spending was $858 in 2013 compared with the average of $400 for 19 other industrialized nations. Prescription medications in the United States currently comprise

an estimated 17% of personal healthcare services. “The most important factor that allows manufacturers to set high drug prices is market exclusivity, protected by monopoly rights awarded upon Food and Drug Administration approval and by patents,” the study authors wrote. “The availability of generic drugs after this exclusivity period is the main means of reducing prices in the United States, but access to them may be delayed by numerous business and legal strategies.” Negotiating power of the payer could help prevent excessive

Market exclusivity helps drive up drug costs, per JAMA study.

pricing during market exclusively, but this is constrained by several factors, including the requirement that many government drug payment plans cover nearly all products. The researchers also stated that a key contributor to drug spending is a physician’s prescribing choice when comparable medications are available at different costs. There is no evidence to suggest an association between research and development costs and prices, and current prescription prices in the United States are based on the market, noted the study authors.

Factors behind high cost of prescription drugs

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Newsline MRI USE in the first trimester of pregnancy is not harmful to the fetus, although gadoliniumenhanced MRI use at any point during pregnancy is associated with rare adverse outcomes in childhood, according to a study in JAMA. Investigators identified all births of more than 20 weeks between 2003 and 2015 in Ontario. For first-trimester MRI exposure, they evaluated the risk of stillbirth or neonatal death within 28 days of birth and any congenital anomaly, neoplasm, and hearing or vision loss from birth to age 4 years. For gadolinium-enhanced MRI in pregnancy, they identified connective tissue or skin disease resembling nephrogenic systemic fibrosis (NSF-like) and rheumatologic, inflammatory, or infiltrative skin conditions from birth.

Among 1,424,105 deliveries (48% girls; mean gestational age, 39 weeks), the overall rate of MRI use was 3.97 per 1,000 pregnancies. In a comparison of first-trimester MRI use (n=1,737) with no use of MRI (n=1,418,451), 19 stillbirths or deaths occurred vs 9,844 in the unexposed group (adjusted relative risk [RR], 1.68), for an adjusted risk difference of 4.7 per 1,000 person-years. The risk was also not significantly higher for congenital anomalies, neoplasm, or vision or hearing loss. In a comparison of gadolinium MRI (n=397) with no use of MRI (n=1,418,451), the hazard ratio for NSF-like outcomes was not statistically significant. The outcome of any rheumatologic, inflammatory, or infiltrative skin condition was higher after gadolinium MRI (125.8 per 1,000 person-years [123

MRI safe in early pregnancy, gadolinium use may not be

Colored MRI scan of a fetus in the womb during the 36th week of pregnancy.

events]) than for no MRI use (93.7 per 1,000 person-years [384,180 events]), with an adjusted HR of 1.36 and an adjusted risk difference of 45.3. Stillbirths and neonatal deaths occurred in 7 MRI-exposed pregnancies vs 9,844 unexposed pregnancies (adjusted RR, 3.70), for an adjusted risk difference of 47.5 per 1,000 pregnancies.

PROLONGED-release oxycodone/naloxone (OXN) is an effective analgesic and may improve overall function in patients who have had total knee replacement, according to a study published in the Journal of Clinical Anesthesia. Researchers compared the effect of postoperative prolonged-release OXN with other opioids for patients’ early rehabilitation outcome after total knee replacement. Eighty patients were assigned to the OXN group or to a control group in the prospective trial. The investigators evaluated postoperative outcome and pain level at

OXN is an effective analgesic for pain after total knee replacement.

3, 6, 21, and 35 days and at 6 months with use of the Bowel Function Index, Brief Pain Inventory Short Form questionnaire, the Hospital for Special Surgery score, modified Larson score, and ability to attend physiotherapy. All medications were recorded, and a safety analysis was conducted. The researchers found no significant differences between the 2 groups regarding pain levels. Patients in the OXN group reported better bowel function (median value, 0.0 for the OXN group; median value, 20.0 for the control group). No effect of

treatment group and no treatment-by-visit interaction on Hospital for Special Surgery final score were found. However, the Larson function score in the early postoperative phase was “significantly better in the OXN group,” noted Dr Oppermann’s group. The proportion of patients in the OXN group who were able to attend physiotherapy without any restriction was 58.1%. The proportion of patients in the OXN group who experienced mild or moderate adverse drug reactions was 23.3%, compared with a rate of 37.8% in the control group.

Oxycodone/naloxone beneficial for knee replacement pain

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B:8” T:7.75” S:7”

You see recovery. Your patients may see OINV. Opioid-Induced Nausea and Vomiting

References: 1. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372-380. 2. Chang DJ, Desjardins PJ, Bird SR, et al. Comparison of rofecoxib and a multidose oxycodone/acetaminophen regimen for the treatment of acute pain following oral surgery: a randomized controlled trial. Curr Med Res Opin. 2004;20(6):939-949. 3. Daniels S, Casson E, Stegmann JU, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009;25(6):1551-1561. 4. Park YB, Ha CW, Cho SD, et al. A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement. Curr Med Res Opin. 2015;31(1):75-84. 5. Musclow SL, Bowers T, Vo H, Glube M, Nguyen T. Long-acting morphine following hip or knee replacement: a randomized, double-blind, placebo-controlled trial. Pain Res Manag. 2012;17(2):83-88. ©2016 Daiichi Sankyo, Inc. DSNA16102590 06/16

learn more at KnowOINV.com

B:10.75”

S:10”

Is OINV disrupting more recoveries than you realize?

T:10.5”

≈40% of patients receiving opioids experience OINV1-5

FEATURE: SARAH O’BRIEN, BSN, RN

Lead poisoning: Current practice guidelines An aging national infrastructure and paint in old homes increase the risk for lead poisoning and significant health-related problems in children and adults.

Neurodevelopmental problems

Hypertension

Iron deficiency

Kidney dysfunction

Lead is especially harmful to children because their brain and nervous systems are still developing.

he water crisis in Flint, Michigan, that began in April 2014 dominated the news, refocusing America’s attention to the issue of lead poisoning. In an attempt to cut costs, the city of Flint switched its water source from Lake Huron to the Flint River. Because of the corrosive nature of the water in the Flint River, and the lack of any anticorrosive treatment, the protective lining within the aged pipes of the city’s water system was degraded. As a result, high levels of lead were released into the city’s drinking water unbeknownst to residents.1 It is important to note that this incident was not an isolated one. It was legal to use lead pipes and solder in the United States until 1986 (Figure 1).1 Many of the pipes in use today across the country are composed of lead or contain lead solder and/or fixtures.1 Although political and regulatory mismanagement were partly responsible for the devastating levels of lead seen in the blood of the children of Flint, another factor contributing to the problem was an aging infrastructure, which exists not only in Flint but also across the country. In the past 20 years, lead has leached into the water supply of other cities, including Sebring, Ohio; Washington, DC; Greenville, North Carolina; and Jackson, Mississippi.2 It is important that the country’s continuously aging infrastructure be kept in mind as a risk factor when patients are screened for lead exposure. In light of these events and so that primary care providers can deal as effectively as possible with the problem, this article reviews

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the epidemiology and presentation of lead poisoning, how to screen for the condition, and guidelines for its management. In 2012, the Centers for Disease Control and Prevention (CDC) released new guidelines concerning lead. Previously, a blood level of lead at 10 mcg/dL or higher was considered a “level of concern” and resulted in case management. The CDC has now removed the phrase “level of concern,” and a reference level of 5 mcg/dL is currently used to identify children with high levels of lead in their blood.3,4 Any level of lead in the blood can cause negative effects.4-6 Blood levels of lead once thought to be safe are now known to be associated with intelligence deficits and behavioral and learning difficulties in children.6 The level of 5 mcg/ dL is simply a statistical reference value for comparison with levels in the population.5 Since the introduction of this new reference level, more children are being identified with blood levels of lead that are too high. In Philadelphia, Pennsylvania, a study of the prevalence of high blood levels of lead in which this new reference value was used reported a 9-fold increase.7 Chronic lead toxicity is much more prevalent than acute lead toxicity. Lead toxicity in adults is more likely to be acute and related to an occupational exposure.8 Adults exposed at work typically inhale lead dust and fumes.9 Lead can cause problems at any age, but lead toxicity in children is of particular concern because of its long-term effects on the developing brain.6,8 The immature blood–brain barrier of children puts them at particularly high risk.9 Children younger than 3 years of age are at greatest risk for lead toxicity for 2 main reasons: They are at a critical stage in brain development, and they tend to put things in their mouth.8,9 Furthermore, the rate of lead absorption is 4 to 5 times higher in children than in adults, and the presence of an iron deficiency increases the risk for toxicity.4 Unborn fetuses are also vulnerable. Lead exposure during pregnancy can lead to miscarriage, stillbirth, and other complications of birth.6

Epidemiology

FIGURE 1. Lead service line connected with solder to residential plumbing. Lead can enter drinking water when lead pipes corrode.

Low socioeconomic status

High levels of lead are strongly associated with a low socioeconomic status.4,8 Children of low socioeconomic status are disproportionately at risk, partially because their diet tends to lack adequate amounts of calcium or iron.4,10 Therefore, the provider must recognize that a deficiency of calcium and/or iron is not only a problem in itself but also a marker of increased risk for lead toxicity. Because of decreased access to medical care, the families of these children are less likely to receive sufficient education about the primary prevention of lead poisoning.10 Residence in a low-income urban area increases the likelihood of exposure; typically, exposure to lead will occur in groups within neighborhoods.4 Parents exposed to lead in their occupation may bring lead dust or particles home with them on their clothing, thus exposing the household.4 Any person coming from another country, whether as an immigrant, refugee, or adoptee, is at increased risk for lead toxicity.4 Risk factors for chronic lead poisoning are summarized in Table 1.

Diet low in calcium and iron

Sources of lead

TABLE 1. Risk factors for chronic lead poisoning4,6,8-10

Residence in low-income/urban area Immigrant/refugee/adoptee from other country Age younger than 3 years

Familiarity with potential sources of lead enables providers to screen for lead in their patients properly and thoroughly. The disaster in Flint may be an extreme case, but the event has highlighted the aging infrastructure of America and the potential for future cases of poisoning with lead traced to old www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2016 17

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LEAD POISONING: CURRENT PRACTICE GUIDELINES

It is important for primary care providers to ask their patients about their occupations, hobbies, and possible household exposure to lead. pipes, solder, and fixtures composed of lead. Lead piping is especially common in service lines that link street lines to residential homes.1 In general, treatment plants release water that is mostly lead-free, and many of these treatment plants also use anticorrosion chemicals that protect the inside of pipes down the line. However, the service lines that bring water into homes may contain lead or lead solder if the homes were built before 1986, and these service lines are expensive for homeowners to replace.11 The cost of fixing the nation’s service lines would likely be in the billions of dollars, not to mention the millions more it would take to eliminate solder and fixtures composed of lead.1 To complicate matters further, the construction necessary to fix these lines can cause vibrations; as a result, pieces of lead material break off from the piping and enter the water supply.11 Even though lead toxicity due to leaching water pipes has been in the news recently, there are many other sources of lead poisoning that primary care providers should consider when they screen patients for risk factors. Lead-based paint has been banned but continues to be a risk in older homes.8 In fact, most cases of elevated blood levels of lead in recent years have resulted from peeling paint chips in old homes.1 Therefore,

the age of a patient’s residence is relevant information for discerning risk. After 1978, new homes were less likely to use lead-based paint.8 According to the CDC, lead-based paint or lead dust can be found in 24 million homes in the United States, with 4 million children living in these homes. Chipping paint or simple renovations (Figure 2) result in the formation of lead dust, which children can inhale or consume.12 The use of lead-based gasoline and paint for decades has contaminated the soil, creating another source of exposure.4 The paint in old homes is one of the more common sources of exposure to lead, but there are other sources as well. Although leaded gasoline is no longer used in the United States, it continues to be used in some developing countries.4,6 Products imported from other countries may contain lead, including foods and additives.8 Imported toys and toy jewelry may contain lead, and young children who put such toys in their mouth are exposed.4 The glaze on ceramic pottery can contain lead that contaminates food or drink placed within.4 Engaging in hobbies that involve the use of leadbased products or remodeling old homes can result in lead exposure.8 Parents who are exposed to lead through their occupation or hobby can carry lead dust and particles on their clothing, in turn exposing their children.4 Some folk remedies can also have a high lead content.4 Therefore, it is important for primary care providers to ask their patients about occupations, hobbies, and possible household exposure.

Evaluation of the patient presenting with suspected lead toxicity

FIGURE 2. Lead paint scrapings collecting on a floor after flame burning, a method used in exterior renovation.

History. Lead toxicity can be difficult to identify by the history and physical examination alone. Nonspecific symptoms in children are a clue: irritability, behavioral changes, changes in activity levels, developmental delay, and language delay.8 An expert panel formed by the Advisory Committee on Childhood Lead Poisoning Prevention of the CDC reviewed evidence of the effects of lead on academic performance and made recommendations to persons working with children. Deficits in IQ have been seen with blood levels as low as 5 mcg/dL. Attention deficits manifest as distractibility and impulsivity in children. Elevated blood levels of lead increase the likelihood of a diagnosis of attention-deficit/hyperactivity disorder (ADHD). Lead affects dopamine in the brain, leading to deficits in strategic planning and control of impulses. Deficits in visual–spatial skills have been associated with early Continues on page 25

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LEAD POISONING: CURRENT PRACTICE GUIDELINES

POLL POSITION

Which of the following statements about the lead poisoning cases in Flint do you most agree with?? n=442

■ I’m concerned that there are or could be other situations similar to Flint. ■ Lead screening and reporting guidelines are insufficient in my state.

4.75% 86.43%

8.82%

■ Flint is an outlier, and my state’s screening guidelines are sufficient to test for the problem.

For more polls, visit ClinicalAdvisor.com/Polls.

lead exposure. Parents of children with lead poisoning typically report the development of behaviors such as restlessness, impulsivity, and/or aggression. Speech and language deficits have been studied extensively in relation to lead exposure in children. Children with lead toxicity may have difficulties with coordination, balance, and other fine and gross motor skills.10 Like the effects of other environmental toxins, the effects of lead in individual children will vary, so that screening questions aimed at determining the presence of risk factors are especially important. Even if no neurodevelopmental problems are apparent at the time a high blood level of lead is detected, the child is still at risk for future delays.10 Adults may have similar symptoms in addition to weak extensor muscles, delirium, or hallucinations.8 When eliciting a patient’s history, the primary care provider should ask questions about any past developmental delays, behavior problems, pica, or known exposures to lead. The provider should also ask about all places of residence, past and present; information on the age and condition of the homes (ie, chipping paint) and any current or previous renovations should be collected. Adults should be asked about hobbies and occupations, as these can result in exposure. The ingestion of “moonshine” also can affect blood lead levels.8 Physical examination. Typically, children with elevated blood levels of lead are asymptomatic, unless the levels are especially high.4 A mental status examination is an important element; however, it is most likely that only severe lead toxicity will result in notable changes. For example, a decrease in IQ or attention span would be difficult to detect during a physical examination and is more likely to be deduced from information in the history. Lead toxicity frequently is

accompanied by iron deficiency, so the patient may have pale skin or exhibit lethargy.8,9 In adults with occupational lead toxicity, foot drop or wrist drop with decreased reflexes is common. This is because lead tends to affect the peripheral nervous system in adults, whereas in children the central nervous system is more likely to be affected. Every organ system is susceptible to the effects of lead.8 Adults may have lead lines in gingival tissue and may also have sleep disorders.8 Although the neurologic effects are more often considered, lead can also cause hypertension, renal injury, immunotoxicity, and reproductive problems.6 The characteristics of lead toxicity typical in children and in adults are summarized in Table 2. Screening and laboratory tests. Although the CDC recommends screening questionnaires, the questionnaires currently used to identify exposure to lead have not been shown to be valid in recent studies. The sensitivity of the pediatric lead screening questions recommended by the CDC and American Academy of Pediatrics is low, even when the previous lead level guideline of 10 mcg/dL is used.13 The most recent guidelines reported by the US Preventive Services Task Force (USPSTF) are from 2006 and indicate that the specificity of the CDC questionnaires ranges from 32% to 75%.14 In a systematic review of lead screening questionnaires, including those from the CDC as well as state-specific modified questionnaires, the sensitivity and specificity demonstrated a wide range of values, and the questionnaires were not shown to be effective in determining risk for lead poisoning in children.15 Clearly, more research and modification of the existing screening questions are required in order to achieve the goal of preventing lead exposure. The sensitivity of techniques using geographic information system analysis is higher, and these can supplement questionnaires and aid in identifying persons living in high-risk areas.13 The CDC recognizes the geographic variability in lead exposure and therefore recommends that TABLE 2. Characteristics of lead toxicity: Children vs adults4,6,8,9 Child

Adult

Typically chronic

Typically acute

Affects central nervous system: irritability, behavioral changes, decreased IQ or attention span, language delay

Affects peripheral nervous system: decreased reflexes, foot/wrist drop

Often asymptomatic

Lead lines in gingival tissue

Accompanied by iron deficiency

Sleep disorders

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LEAD POISONING: CURRENT PRACTICE GUIDELINES

Any child who is a recent immigrant, refugee, or adoptee

Child aged between 12 and 24 months AND on Medicaid

Child aged 6, 9, 12, 18, 24 months (not on Medicaid) OR 3, 4, 5, 6 years (regardless of insurance status)

Obtain whole blood-lead level

YES

Are there risk factors? (eg, older home) NO

Blood lead level ≥5 mcg/dL: repeat levels at ages 3, 4, 6 years; monitor for cognitive and behavioral manifestations indefinitely

No testing is needed

FIGURE 3. Algorithm for measuring blood lead levels in children.

local and/or state agencies formulate recommendations based on local data. Furthermore, the CDC recommends blood lead level testing for any community with a percentage of pre-1950 houses of 27% or higher or a prevalence of blood lead levels of 10 mcg/dL or higher in children 12 to 36 months of age.5 Early identification through screening is especially important because patients with elevated lead levels are often asymptomatic.4 A whole-blood lead level is the standard diagnostic test and provides an approximation of lead in the body.8,16 Capillary finger-stick methods are appropriate for lead screening. However, because of the possibility of false-positive results with capillary samples, a venous blood draw is needed to confirm a positive result.5,16 A blood lead level higher than 70 mcg/dL is deemed an emergency because of the risk for encephalopathy.8 The American Academy of Pediatrics recommends that children undergo risk assessments for lead exposure at the ages of 6, 9, 12, 18, and 24 months and the ages of 3, 4, 5, and 6 years (Figure 3). Blood lead levels may be measured if the risk assessment is positive. However, many state Medicaid programs require blood lead level tests at the ages of 12 and 24 months because of the higher prevalence of lead toxicity in lower socioeconomic classes. Children who are recent immigrants, refugees, or adoptees are also at increased risk and should be screened no matter what their age. Although blood lead levels can be used to identify acute toxicity, a relatively low level

does not necessarily rule out lead poisoning earlier in life.16 The American Academy of Pediatrics recommends that for children with blood lead levels of 5 mcg/dL or higher before the age of 6 years, levels should be measured again at the ages of 3, 4, and 5 years. Any child with a blood lead level of 5 mcg/ dL or higher must undergo continued monitoring for cognitive or behavioral manifestations of lead toxicity indefinitely.10 An elevated blood lead level should be confirmed within 1 to 3 months.4 The CDC recommends that pregnant and lactating women be screened as well, and subsequently any infant whose mother has a blood lead level of 5 mcg/dL or higher.5 Management. The most important part of the treatment plan is preventing further exposure to lead.4,8 Removing the source of lead is a consistent strategy for any child with a positive blood lead level.8 If removal of lead from the environment is not possible, encapsulation processes by certified lead abatement contractors are another available option.4 The primary care provider may consider consultations with a toxicologist, a nephrologist, the Occupational Safety and Health Administration (OSHA) for occupational exposures, and local health departments.8 Coordinating with local authorities and organizations is necessary to investigate the source of lead.5 The management of an elevated lead level in a child will also include monitoring through adulthood, as the effects of lead toxicity may not manifest initially.4

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Evaluating the patient’s diet is a part of managing elevated lead levels. The CDC recommends assessing iron levels and encouraging an iron-rich diet because of the associations between iron deficiencies and elevated blood lead levels. Calcium supplements should also be included in the treatment plan as calcium impedes lead absorption and bioavailability.4,9 In addition, deficiencies of zinc, vitamin C, protein, and phosphorus can increase the absorption of lead.9 Studies show that a nurturing, supportive home environment has a positive effect on outcomes in children with high lead levels.4,10 This is significant information for parents because a nurturing environment is something that they can provide to mitigate the mostly irreversible consequences of lead exposure. Children with developmental delays respond better to interventions at an earlier age, and this is also true for those with delays resulting from lead exposure. Early and highquality education for patients and their families is imperative in counteracting the negative effects of lead.10 Programs like Head Start aim to provide early education and can further the development of children with elevated lead levels.4 Factors to be considered in formulating a treatment plan include the patient’s age, blood lead level, and symptoms. Environmental interventions should be undertaken for children with levels between 10 and 19 mcg/dL, and they should be followed up in 1 month (Table 3). Those with levels between 15 and 19 mcg/dL for 3 consecutive months or a first level between 20 and 44 mcg/dL may need a more complete workup, including measurement of their hemoglobin and iron levels.9 Oral chelation therapy is indicated for those with a blood lead level below 44 mcg/dL if they have significant symptoms.9 However, although chelation therapy in children with blood lead levels between 20 and 44 mcg/dL may lower the levels, it has not been shown to reverse any neuropsychological effects.16 More simply, chelation therapy may be required for children with blood lead levels of 45 mcg/dL or higher.4 Those with levels between 40 and 79 mcg/dL should be referred to a clinical toxicologist, and those with levels above 80 mcg/dL require urgent medication evaluation and probable chelation therapy. Children with blood lead levels above 100 mcg/dL require hospitalization and parenteral chelation therapy.9 Anticipatory guidance

Primary care providers play an essential role in educating families on how to prevent lead exposure. Primary prevention—for example, removing lead from paint and gasoline—is key to avoiding the irreversible neurological effects of lead toxicity.9 Primary prevention by primary care providers includes prenatal education.4 Providers should educate parents

TABLE 3. Management of lead toxicity based on blood lead levels4,9 Blood lead level

Management

10–19 mcg/dL

Environmental intervention: remove lead; follow up in 1 month

<44 mcg/dL

Likely no chelation therapy unless patient is symptomatic

40–79 mcg/dL

Referral

>80 mcg/dL

Urgent medication evaluation and probable chelation therapy

>100 mcg/dL

Hospitalization and parenteral chelation

about all potential sources of lead exposure. Families with infants should receive guidance on how to use tap water to prepare infant formulas and information on the safety of local water. Parents can request the Environmental Protection Agency to test their water if concerned.16 Parents should also be educated on the topics of home renovation, possible sources of exposure within the home, and occupational hazards that may put them or the children of the household at risk.4 In addition, counseling on proper diet, including sufficient intake of vitamin C, iron, calcium, and zinc, can aid in decreasing risk in children.4 Conclusions

The results of research indicate that any level of lead in the body carries a potential for harm. Primary care providers are essential in preventing, screening for, and managing lead toxicity. They deliver critical education to patients and families that can prevent exposure to lead and the long-term consequences of exposure. Understanding who is at risk and the possible sources of lead exposure will help guide providers in this task. Primary care providers are an integral part of the long-term management of persons with lead toxicity. n Sarah O’Brien, BSN, RN, is a pediatric emergency nurse at Wolfson Children’s Hospital in Jacksonville, Fla. She is currently in graduate school to obtain a doctorate in nursing practice at the University of North Florida. References 1. McWhirter C, Maher K. Flint water crisis shines light on lead pipes across U.S. The Wall Street Journal website. http://www.wsj.com/articles/flintwater-crisis-shines-light-on-lead-pipes-crisscrossing-the-u-s-1453977180. Published January 28, 2016.

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LEAD POISONING: CURRENT PRACTICE GUIDELINES

2. Wines M, Schwartz J. Safety net lacking for clean water; experts say aging infrastructure and lack of regulation pose widespread threats. The Register-Guard (Eugene, OR). February 9, 2016. 3. What do parents need to know to protect their children? Centers for Disease Control and Prevention website. http://www.cdc.gov/nceh/lead/ acclpp/blood_lead_levels.htm. Updated March 15, 2016. 4. Schnur J, John R. Childhood lead poisoning and the new Centers for Disease Control and Prevention guidelines for lead exposure. J Am Assoc Nurse Pract. 2014;26(5):238-247. 5. Advisory Committee on Childhood Lead Poisoning Prevention of the Centers for Disease Control and Prevention. Low-level lead exposure harms children: a renewed call for primary prevention. http://www.cdc.gov/ nceh/lead/acclpp/final_document_030712.pdf. Published January 4, 2012.

“Can you stop that crap? The bison are on the move.”

6. Lead poisoning and health. World Health Organization website. http:// www.who.int/mediacentre/factsheets/fs379/en/ Updated August 2016. 7. Leafe M, Irigoyen M, DeLago C, Hassan A, Braitman L. Change in childhood lead exposure prevalence with new reference level. J Environ Health. 2015:77(10):14-16. 8. Kathuria P. Lead toxicity. Medscape website. http://emedicine.medscape. com/article/1174752-overview. Updated February 8, 2016. 9. Kianoush S, Sadeghi M, Balali-Mood M. Recent advances in the clinical management of lead poisoning. Acta Med Iran. 2015:53(6):327-336. 10. Educational Services for Children Affected by Lead Expert Panel. Educational interventions for children affected by lead. http://www. cdc.gov/nceh/lead/publications/Educational_Interventions_Children_ Affected_by_Lead.pdf. Published April 2015. 11. Young A, Nichols M. Beyond Flint: Excessive lead levels found in almost 2,000 water systems across all 50 states. USA Today. March 11, 2016. http:// www.usatoday.com/longform/news/2016/03/11/nearly-2000-water-systemsfail-lead-tests/81220466/ 12. Infographic: Prevent childhood lead poisoning. Centers for Disease Control and Prevention website. http://www.cdc.gov/nceh/lead/

“I’ll tell you something else I think. I think there are other bowls somewhere out there with intelligent life just like ours.”

13. Nicholson J, Cleeton M. Validation and assessment of pediatric lead screener questions for primary prevention of lead exposure. Clin Pediatr (Phila). 2016;55(2):129-136. 14. Final recommendation statement: Lead levels in childhood and pregnancy, screening. US Preventive Services Task Force website. http://www.uspreventiveservicestaskforce.org/Page/Document/ RecommendationStatementFinal/lead-levels-in-childhood-and-pregnancyscreening. Updated December 2006. 15. Ossiander E. A systematic review of screening questionnaires for childhood lead poisoning. J Public Health Manag Pract. 2013;19(1):E21-E29. 16. Detection of lead poisoning. American Academy of Pediatrics website. https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/ lead-exposure/Pages/Detection-of-Lead-Poisoning.aspx. Published 2016. All electronic documents accessed September 1, 2016.

infographic.htm. Updated December 18, 2013.

28 THE CLINICAL ADVISOR • OCTOBER 2016 • www.ClinicalAdvisor.com

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CME FEATURED COURSE

n EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be better able to: • Describe the complex pathophysiology of T2DM, including the defects that contribute to disease progression • Review the potential glycemic and extraglycemic benefits of novel and emerging combination treatment strategies for appropriate patients with T2DM • Assess the need to initiate or intensify treatment, considering natural disease progression, side effects, glycemic/nonglycemic treatment goals, complications of diabetes, and individual patient needs • Implement strategies for more effective patient education/counseling about ongoing self-management, including treatment goals/expectations, adherence, and managing adverse events and comorbidities n COMPLETE THE POST-TEST: Page 37

Release Date: June 27, 2016 Expiration Date: October 31, 2017 Estimated Time to Complete: 30 minutes Accredited Provider: This educational activity is provided by Haymarket Medical Education. Commercial Supporter: This activity is supported by an educational grant from AstraZeneca. Program Description: An unmet need in type 2 diabetes mellitus (T2DM) management is that few patients achieve established, evidencebased diabetes control targets and treatment goals. Complications from T2DM place a high burden on healthcare resource utilization and costs, rising incrementally with increasing severity of complications. This case study presentation is of a 42-year-old woman with T2DM with multiple comorbidities and increasing beta-cell destruction. It highlights the importance of utilizing a shared decision-making model when adding/ removing an agent. Intended Audience: General internal medicine, internal medicine subspecialties, and other healthcare professionals with an interest in diabetes management Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities.

Accredited Provider Disclosure: Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only those credits commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient's medical condition. Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of AstraZeneca and Haymarket Medical Education. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. If you have any questions relating to the accreditation of this activity, please contact cmequestions@haymarketmedical.com.

Faculty John E. Anderson, MD (Chair) TriStar Centennial Medical Center The Frist Clinic Nashville, TN

Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period June 27, 2016 through October 31, 2017, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete all polling questions; 5) complete the post-test and submit it online.

Ruchit Parikh, PharmD (Reviewer) Associate Medical Director Haymarket Medical Education Paramus, NJ

A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/ Oct16feature.

Faculty Dislosures: Dr. Anderson is a consultant for Eli Lilly, Boehringer Ingelheim, AstraZeneca, Sanofi, Janssen, and Abbott Diabetes. He is also on the speakers’ bureaus for Eli Lilly, Boehringer Ingelheim, AstraZeneca, Sanofi, and Janssen.

Provided by

Dr. Parikh has no relevant financial relationships to disclose.

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CME

FEATURED COURSE:

JOHN E. ANDERSON, MD

A 42-year old woman with T2DM and comorbidities The ideal use of monotherapy, combination therapy, and triple therapy for patients with type 2 diabetes is reviewed in this case study.

The pathogenesis of T2DM involves multiple defects.

ype 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and impaired glucose tolerance due to abnormal metabolism of carbohydrates and fat. T2DM develops when the pancreatic beta cells, responsible for producing insulin, are impaired in the setting of insulin resistance.1,2 Individuals with T2DM exhibit moderate to severe insulin resistance in muscle and the liver, increased insulin secretion, and impaired beta-cell glucose sensitivity.3 In addition, the insulin resistance causes the liver to increase the amount of glucose it releases, regardless of plasma glucose levels. The resulting hyperglycemia can further impair insulin sensitivity and beta-cell function, leading to a cycle of exacerbating metabolic dysfunction.4 The pathogenesis of T2DM involves multiple defects. Its causes include genetic and environmental factors affecting beta-cell function and reducing insulin sensitivity in muscle, liver, adipose, and pancreas tissue.5 Body fat distribution, and intraabdominal fat in particular, seems to be a major determinant of insulin resistance.6 As depicted in Figure 1, when energy input exceeds output, both blood glucose and blood triglycerides will increase, which eventually leads to ectopic fat accumulation in muscle and the liver. The consequence is insulin resistance, thus directing lipids to the adipose tissue. When the adipocytes become dysfunctional, extra ectopic fat accumulation, including fat accumulation in the beta cells, occurs. Whether insulin resistance brings about hyperinsulinemia or vice versa is a highly debated topic. An increase

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in both blood glucose and insulin resistance leads to the induction of beta-cell compensatory mechanisms, including beta-cell hypertrophy and increased insulin secretion, further contributing to hyperinsulinemia. This is a vicious cycle consisting of first physiological events, then pathological events, and finally beta-cell death—leading to a severe blood glucose increase and full-blown diabetes. Meet M.V.

M.V. is a 42-year-old Caucasian woman with T2DM, hypertension, dyslipidemia, and hypothyroidism. She has been taking the commonly prescribed oral glucose-lowering agent metformin to manage her T2DM. She was also prescribed an angiotensin receptor blocker for hypertension, statin therapy for dyslipidemia, and the synthetic thyroid hormone levothyroxine for hypothyroidism. Her hemoglobin A1C level, a measure of average blood glucose level over several months, has been well managed for the past year with metformin monotherapy (see Table 1 for criteria for the diagnosis of prediabetes and diabetes). It is unclear whether the progression of beta-cell destruction in T2DM is inevitable. The progressive loss of beta-cell function causes a decline in glycemic control and consequent complications, and current medications do not completely halt

this.1 However, novel compounds, proliferative agents, and healthy lifestyles maintain beta-cell integrity and function.8 With successful treatment, it is possible for individuals with T2DM to move from stable decompensation of beta-cell mass and function to a state wherein insulin secretion increases enough to maintain normoglycemia despite insulin resistance and/or decreasing beta-cell mass.9 Moreover, a study examining beta-cell function after beta-cell allograft in patients with type 1 diabetes found at least a small population of surviving beta cells, challenging the notion that complete beta-cell destruction is an inevitable consequence of disease progression.10 This finding may offer hope that the mechanisms impairing beta-cell function could be reversed via therapeutic manipulation and immunotherapy to restore immune tolerance to beta cells.11 Evidence from recent clinical trials indicates that early initiation of treatment can prevent or delay the progression of hyperglycemia and the development of related complications in individuals with T2DM. Diabetes-related comorbidities pose an additional burden on individuals with T2DM, and management of cardiovascular risk factors is frequently inadequate.12 Cardiac disease is the leading cause of mortality in T2DM.13 The most common initial manifestations of cardiovascular disease in T2DM are heart failure and peripheral arterial disease.14 Microvascular disease (such as neuropathy, diabetic

Energy intake > Energy output

TG Ectopic fat storage muscle, liver & β-cells

Death β-cells

Insulin resistance muscle, liver & β-cells

Compensation β-cells

Hyperinsulinemia

Dysfunction Adipose tissue

Adapted from: Skovsø S. J Diabetes Invest. 2014;5(4):349-358.

FIGURE 1. Overview of the interactions between multiple tissues in T2DM 32 THE CLINICAL ADVISOR • OCTOBER 2016 • www.ClinicalAdvisor.com

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kidney disease, and diabetic macular edema) in adults with T2DM increases the risk of cardiovascular disease as much as conventional risk factors such as smoking, hypertension, and dyslipidemia do.15 Complications such as peripheral neuropathy with cardiovascular disease often lead to diabetic foot ulcer, which can necessitate amputation.16 Clinical trials show that exercise regimens, such as highintensity intermittent training, should be employed to improve cardiometabolic risk.17 The Look AHEAD study found that increased physical activity and dietary improvements can safely increase weight loss and reduce medication requirements to control cardiovascular disease risk factors without also increasing the risk of cardiovascular events.18 Other lifestyle factors, including diabetes self-management education and support, are also key in improving health outcomes for individuals with T2DM.19 An unmet need in T2DM management is that few patients achieve established, evidence-based diabetes control targets and treatment goals.12,20 Complications from T2DM place a high burden on healthcare resource utilization and costs, rising incrementally with increasing severity of complications.21 Moreover, there are many adverse effects associated with current therapeutic options. Improvements in blood glucose control for many patients with T2DM are limited by the risk of hypoglycemia,22 a complication with serious consequences.23 It is frequently implicated in emergency hospitalizations in older patients with T2DM treated with insulin, especially in those who are also taking an oral hypoglycemic agent.24 An overview of the algorithm for glycemic control in T2DM is presented in Figure 2. No single medication addresses all of the underlying pathophysiologic mechanisms of T2DM. A combination of multiple drugs is eventually required to control glucose homeostasis in most patients with T2DM, even those whose disease is initially well controlled with monotherapy.3 As T2DM inevitably progresses in most cases, increasingly more glucose-lowering medications must be added to maintain glycemic control.25 Regardless of a patient’s initial response to therapy, in most cases blood glucose concentrations will gradually rise over time, requiring the addition of medications.26 Patients with T2DM need vigorous and continual medical intervention because A1C levels continue to increase by 1% every 2 years with most therapies.1 Moreover, regardless of medication regimen, glycemic control can also worsen due to weight gain, a decline in underlying insulin resistance and secretion, or concurrent use of medications for conditions other than diabetes that affect insulin release or glucose production.

Initial evaluation of M.V.

M.V.’s most recent laboratory results indicate that her A1C has risen to above 8.0%. Her hypertension has increased and she has also gained weight, pushing her from overweight into the obese range. Recognizing the importance of good communication with patients, M.V.’s clinician initiates a conversation about M.V.’s life circumstances and learns that she has been experiencing emotional upheaval from a recent divorce and that the stress has been interfering with her sleep. Her clinician recommends a change in treatment strategy, urging M.V. to consider additional medications. Rationale for combination therapy

Because multiple metabolic defects are involved in the pathogenesis of T2DM, combining antidiabetes drugs with different mechanisms of action can prevent compensatory mechanisms and potentially produce a cumulative reduction in A1C.28 The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus guideline for medication therapy to control hyperglycemia in T2DM recommends testing A1C levels every 3 months and adding a second medication if the A1C treatment goal is not achieved within 3 months with metformin plus lifestyle interventions to promote weight loss and increase activity levels.26 Likewise, the ADA recommends that if maximum tolerated noninsulin monotherapy does not achieve or maintain the A1C goal over 3 months, a second oral agent, GLP-1 receptor agonist, or basal insulin should be added.2 Advantages and disadvantages of “triple” oral therapy

When dual therapy is ineffective in controlling blood glucose, a third orally administered medication may be TABLE 1. Criteria for the diagnosis of prediabetes and diabetes Prediabetes

Diabetes

Hemoglobin A1C

5.7–6.4%

≥6.5%

Fasting plasma glucose

100–125 mg/dL (5.6–6.9 mmol/L)

≥126 mg/dL (7.0 mmol/L)

Oral glucose tolerance test

140–199 mg/dL (7.8–11.0 mmol/L)

≥200 mg/dL (11.1 mmol/L)*

Random plasma glucose

–

≥200 mg/dL (11.1 mmol/L)†

*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. † Only diagnostic in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. Adapted from: American Diabetes Association. Clin Diabetes. 2015;33(2):97-111.

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added. Results from the EDICT trial indicate that combination therapy with metformin, pioglitazone, and the GLP-1 agonist exenatide at onset of T2DM is more effective and results in less hypoglycemia than adding sulfonylurea and then basal insulin to metformin sequentially.29 Triple oral therapy offers advantages such as greater A1C reductions, a more sustained treatment response, and sometimes weight loss. In some cases, however, triple therapy can increase hypoglycemia, and in some instances it causes weight gain.30 Synergistic properties of SGLT2 inhibitors combined with DPP-4 inhibitors and metformin

The synergy of particular combinations and other interactions must be considered when medications are combined to combat hyperglycemia.26 Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease blood pressure and weight31 and may play a role as a third-line agent in patients with inadequate glycemic control on 2 oral agents. The glucosuria produced by SGLT2 inhibitors is associated with a compensatory rise in glucagon, which accounts for an increase in the rate of endogenous glucose production, thus

offsetting the glucose-lowering effect by approximately 50%. And because dipeptidyl peptidase-4 (DPP-4) inhibitors impede glucagon secretion and reduce endogenous glucose production, combining the 2 agents—SGLT2 and DPP-4—can prevent the increase in endogenous glucose production and produce an additive, synergistic effect to reduce A1C.28 In other words, because DPP-4 inhibitors reduce plasma glucagon concentrations, combining them with an SGLT2 inhibitor may suppress the latter’s pro-glucagogenic effects.32 New combination therapies and those in development

The fixed dose combination of the SGLT2 inhibitor dapagliflozin and metformin was approved in the US in late 2014; a fixed-dose combination of the SGLT2 inhibitor empagliflozin + the DPP-4 inhibitor linagliptin was approved in 2015. Investigational combination therapies that utilize DPP-4 and/ or SGLT2 agents include the DPP-4 inhibitor saxagliptin + the SGLT2 inhibitor dapagliflozin32,33; a combination of dapagliflozin, saxagliptin and metformin;34 and the SGLT2

GLYCEMIC CONTR OL ALGORITHM LIFESTYLE THERAPY

(Including Medically Assisted Weight Loss)

Entry A1C < 7.5%

Entry A1C ≥ 7.5%

Entry A1C > 9.0%

DUAL THER APY*

YES

DUAL Therapy

INSULIN

Other Agents

MONOTHER APY* Metformin

SYMPTOMS GLP-1 RA

GLP-1 RA SGLT-2i DPP-4i TZD AGi SU/GLN

MET

SGLT-2i

GLP-1 RA

DPP-4i

SGLT-2i

TZD

or other 1st-line agent

Basal Insulin

Colesevelam Bromocriptine QR AGi SU/GLN

If not at goal in 3 months proceed to Dual Therapy

TRIPLE THER APY*

If not at goal in 3 months proceed to Triple Therapy

* Order of medications represents a suggested hierarchy of usage; length of line reflects strength of recommendation

MET

TZD

or other 1st-line agent + 2nd-line agent

Basal insulin

TRIPLE Therapy

DPP-4i

Colesevelam Bromocriptine QR AGi SU/GLN

O F

ADD OR INTENSIFY INSULIN Refer to Insulin Algorithm

LEGEND

If not at goal in 3 months proceed to or intensify insulin therapy

P R O G R E S S I O N

Few adverse events and/or possible benefits Use with caution

D I S E A S E 109

FIGURE 2. Algorithm for glycemic control in type 2 diabetes mellitus 34 THE CLINICAL ADVISOR • OCTOBER 2016 • www.ClinicalAdvisor.com

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inhibitor canagliflozin with various agents. Interim data from the EMPA-REG study showed cardiovascular benefit with the SGLT2 inhibitor empagliflozin,35 suggesting the possibility that the SGLT2 class is cardioprotective. Patients with T2DM and high cardiovascular risk who received empagliflozin had lower mortality rates due to cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke compared with patients receiving placebo.36 In the phase 3 CANVAS study, adding canagliflozin to insulin improved glycemic control and decreased body weight in patients with T2DM.37

customizing treatment for T2DM because they predict the risk of severe hypoglycemia induced by intensification of treatment and could allow for a corresponding modification of therapeutic targets.41 Overall, which particular pharmacologic agents are appropriate should be determined via a patient-centered approach that considers the efficacy, cost, and potential side effects of the medications in the context of the particular patient’s weight, comorbidities, hypoglycemia risk, and individual preferences.2 Summary

Considerations for treatment regimen selection

When making decisions about the specific treatment regimen for a given patient with T2DM, it is important to consider factors such as the natural progression of the disease, glycemic and nonglycemic goals, complications, and adverse effects associated with particular medications. With insulin, the most frequent and significant adverse effects are hypoglycemia and weight gain.38 The thiazolidinediones, sulfonylureas, and meglitinides are associated with weight gain. GLP-1 agonists,39 SGLT2 inhibitors, alpha-glucosidase inhibitors, and DPP-4 inhibitors are associated with weight loss or no change in weight. Sulfonylureas and glinides are associated with higher rates of hypoglycemia.

T2DM is a progressive disease that is caused by genetic and environmental factors affecting beta-cell function and insulin sensitivity. It increases the risk of long-term complications in multiple organs. Because T2DM is a complex disease involving multiple defects, the majority of patients, even those whose disease is initially well managed with monotherapy, will eventually require multiple drugs used in combination. Improving understanding of treatment options for T2DM can help clinicians and patients collaborate to make informed treatment decisions for optimal care. Involving patients in the decision-making process may also improve therapy adherence, health outcomes, and overall quality of life. ■ References

Changes to M.V.’s treatment plan

1. Fonseca VA. Defining and characterizing the progression of type 2 diabetes.

M.V. is initially unwilling to consider taking additional drugs for her diabetes. Her clinician understands the importance of involving patients in treatment decisions and explains why additional medication is needed. After they discuss her treatment options, M.V. realizes that combination therapy is most appropriate for her and agrees to add an SGLT2 inhibitor to her medication regimen. She also decides to begin nightly walks to increase her physical activity level, promote weight loss, lower stress, and improve her sleep. Once M.V. begins to play an active role in her treatment plan, she starts to see results. At a follow-up appointment 3 months later, M.V. learns that she has lost weight and that her A1C level (now at 7.2%) has nearly returned to goal.

Diabetes Care. 2009;32(suppl 2):S151-S156. 2. American Diabetes Association. Standards of medical care in diabetes—2015 abridged for primary care providers. Clin Diabetes. 2015;33:97-111. 3. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288-2296. 4. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states: sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest. 1994;94:1714-1721. 5. Scheen AJ. Pathophysiology of type 2 diabetes. Acta Clin Belg. 2003;58:335-341. 6. Kahn SE.The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3-19. 7. Skovsø S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. J Diabetes Invest. 2014;5:349-358. 8. Cerf ME. Beta cell dysfunction and insulin resistance. Frontiers Endocrinol. 2013;4:37.

Clinical implications

9. Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during

It is important that clinical management of T2DM is individualized.22 Integrated approaches that include electronic health record data, patient information systems, and clinical data are needed to create an environment of shared decisionmaking informed by evidence and individual health data that improve adherence to medication therapy for T2DM.40 On the molecular front, blood biomarkers may prove useful in

progression to diabetes. Diabetes. 2004;53(suppl 3):S16-S21. 10. Liu EH, Digon BJ 3rd, Hirshberg B, et al. Pancreatic beta cell function persists in many patients with chronic type 1 diabetes, but is not dramatically improved by prolonged immunosuppression and euglycaemia from a beta cell allograft. Diabetologia. 2009;52:1369-1380. 11. Zheng S, Mathews CE. Metabolic abnormalities in the pathogenesis of type 1 diabetes. Curr Diab Rep. 2014;14:519.

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CME

FEATURED COURSE

12. Harris MI. Health care and health status and outcomes for patients with type

27. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the

2 diabetes. Diabetes Care. 2000;23:754-758.

American Association of Clinical Endocrinologists and American College of

13. Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: heart dis-

Endocrinology on the comprehensive type 2 diabetes management algorithm -

ease and stroke statistics—2016 update: a report from the American Heart

2016 executive summary. Endocr Pract. 2016;22:84-113.

Association. Circulation. 2016;133:447-454.

28. Abdul-Ghani M. Where does combination therapy with an SGLT2 inhibitor

14. Shah AD, Langenberg C, Rapsomaniki E, et al.Type 2 diabetes and incidence

plus a DPP-4 inhibitor fit in the management of type 2 diabetes? Diabetes Care.

of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes

2015;38:373-375.

Endocrinol. 2015;3:105-113.

29. Abdul-Ghani MA, Puckett C,Triplitt C, et al. Initial combination therapy

15. Brownrigg JR, Hughes CO, Burleigh D, et al. Microvascular disease and risk

with metformin, pioglitazone and exenatide is more effective than sequential

of cardiovascular events among individuals with type 2 diabetes: a population-

add-on therapy in subjects with new-onset diabetes: results from the Efficacy

level cohort study [published online May 20, 2016]. Lancet Diabetes Endocrinol.

and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a

doi:10.1016/S2213-8587:30057-2.

randomized trial. Diabetes Obes Metab. 2015;17:268-275.

16. Rasmussen BS,Yderstraede KB, Carstensen B, et al. Substantial reduction in

30. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with

the number of amputations among patients with diabetes: a cohort study over

sitagliptin for patients with type 2 diabetes who do not have adequate glycemic

16 years. Diabetologia. 2016;59:121-129.

control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes

17. Cassidy S,Thoma C, Hallsworth K, et al. High intensity intermittent exercise

Care. 2013;36:2508-2515.

improves cardiac structure and function and reduces liver fat in patients with

31. Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor

type 2 diabetes: a randomised controlled trial. Diabetologia. 2016;59:56-66.

inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012;2(5).

18. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovas-

doi:10.1136/bmjopen-2012-001007.

cular disease in adults with type 2 diabetes mellitus in light of recent evidence:

32. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes

a scientific statement from the American Heart Association and the American

poorly controlled with metformin monotherapy: a randomized double-blind

Diabetes Association. Circulation. 2015;132:691-718.

trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin

19. Powers MA, Bardsley J, Cypress M, et al. Diabetes self-management educa-

or dapagliflozin to metformin. Diabetes Care. 2015;38:376-383.

tion and support in type 2 diabetes: a joint position statement of the American

33. Williams DM, Stephens JW. Combination therapy with saxagliptin and

Diabetes Association, the American Association of Diabetes Educators, and the

dapagliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother.

Academy of Nutrition and Dietetics. Diabetes Care. 2015;38:1372-1382.

2015;16:2373-2379.

20. Spann SJ, Nutting PA, Galliher JM, et al. Management of type 2 diabetes in

34. Matthaei S, Catrinoiu D, Celiñski A, et al. Randomized, double-blind, phase 3

the primary care setting: a practice-based research network study. Ann Fam

trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in

Med. 2006;4:23-31.

type 2 diabetes. Diabetes Care. 2015;38:2018-224.

21. Hazel-Fernandez L, Li Y, Nero D, et al. Relationship of diabetes complications

35. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empa-

severity to healthcare utilization and costs among Medicare Advantage benefi-

gliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the

ciaries. Am J Manag Care. 2015;21:e62-e70.

EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37:1526-1534.

22. Neupane S, Evans ML. Predicting risk of severe hypoglycaemia in type 2

36. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes,

diabetes. Diabetologia. 2015;58:1143-1145.

and mortality in type 2 diabetes. New Engl J Med. 2015;373:2117-2128.

23. Halimi S. Severe hypoglycaemia the “tip of the iceberg”: an underestimated

37. Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin,

risk in both type 1 and type 2 diabetic patients. Diabetes Metab. 2015;41:105-106.

an inhibitor of sodium-glucose cotransporter 2, when used in conjunc-

24. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hos-

tion with insulin therapy in patients with type 2 diabetes. Diabetes Care.

pitalizations for adverse drug events in older Americans. New Engl J Med.

2015;38:403-411.

2011;365:2002-2012.

38. Rosselli JL, Archer SN, Lindley NK, Butler LM. U300 insulin glargine: a novel

25.Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonyl-

basal insulin for type 1 and type 2 diabetes. J Pharm Technol. 2015;3:234-242.

urea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive

39. Edwards KL, Minze MG. Dulaglutide: an evidence-based review of its poten-

requirement for multiple therapies (UKPDS 49): UK Prospective Diabetes Study

tial in the treatment of type 2 diabetes. Core Evid. 2015;10:11-21.

(UKPDS) Group. JAMA. 1999;281:2005-2012.

40. Dixon BE, Alzeer AH, Phillips EO, Marrero DG. Integration of provider, phar-

26. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyper-

macy, and patient-reported data to improve medication adherence for type 2

glycemia in type 2 diabetes: a consensus algorithm for the initiation and adjust-

diabetes: a controlled before-after pilot study. JMIR Med Inform. 2016;4:e4.

ment of therapy: a consensus statement of the American Diabetes Association

41. Chow LS, Chen H, Miller ME, et al. Biomarkers related to severe hypo-

and the European Association for the Study of Diabetes. Diabetes Care.

glycaemia and lack of good glycaemic control in ACCORD. Diabetologia.

2009;32:193-203.

2015;58:1160-1166.

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CME

POST-TEST Expiration date: October 31, 2017

Credit Designation: Haymarket Medical Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and post-test with a score of 70% or better. All components must be completed and submitted online at ClinicalAdvisor.com/Oct16feature.

CREDITS: 0.50

A 42-year old woman with T2DM and comorbidities

1. Which of the following is not a factor that contributes to type 2 diabetes mellitus (T2DM) progression? a. Beta-cell dysfunction b. Glucose suppression c. Intra-abdominal fat d. Reduced insulin sensitivity 2. Which of the following is a potential benefit of combination treatment strategies for patients with T2DM? a. They improve efficacy by increasing the chance that a patient will adhere to one of the multiple medications in the regimen. b. They prevent the inevitable hypoglycemia induced by long-term monotherapy. c. They circumvent the beta-cell destruction that results from sequential use of single agents. d. They enable more underlying pathophysiologic mechanisms to be addressed therapeutically. 3. A 67-year-old man with type 2 diabetes had been taking metformin alone for 4 years, but his physician added saxagliptin after his A1C rose to 7.5%. Two years later, he has gained weight and his A1C is at 8.0%. Which of the following would you recommend as the best course of treatment? a. Add insulin, because of its low incidence of adverse effects. b. Add a sulfonylurea, because it is not associated with weight gain or hypoglycemia. c. Replace the saxagliptin with a dipeptidyl peptidase-4 (DPP-4) inhibitor, because it has a high degree of efficacy. d. Add a sodium-glucose cotransporter 2 (SGLT2) inhibitor to increase efficacy and induce weight loss.

4. A 41-year-old female patient with T2DM has been taking metformin monotherapy for 2 years. She has maintained a healthy weight and her A1C is consistently at goal. Which of the following statements is true of her case? a. It is unlikely that she will need to take additional medication in the future. b. Insulin would be an advantageous addition to her current regimen at this time. c. It is likely that she will need to add insulin or another therapeutic agent in the future. d. It would be premature to add insulin any sooner than 12 months after failing to maintain A1C goal. 5. Which of the following would you advise a patient with T2DM and cardiovascular comorbidities? a. Engaging in physical activity, making healthy diet and lifestyle choices, and setting goals are especially important given the interconnectedness of T2DM and cardiovascular disease. b. T2DM and cardiovascular disease are unrelated but equally life-threatening, and it is imperative that both diseases be addressed separately. c. Exercise has little impact on T2DM but is crucial to addressing cardiovascular comorbidities. d. The most common initial manifestation of cardiovascular disease in patients with T2DM is peripheral neuropathy, and patients should report any numbness or tingling in the limbs immediately.

TO TAKE THE POST-TEST please go to: ClinicalAdvisor.com/Oct16feature

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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.

YOUR COMMENTS SEXUAL ORIENTATION, GENDER IDENTITY, AND LGBT HEALTH CARE I am happy to see this important topic covered [“Healthcare issues in the LGBT community,” August, p. 22] but concerned that the authors are perpetuating misinformation that will actually do more harm than the good that I’m sure they intended. Transgender is not a sexuality. Sexual orientation includes labels such as lesbian and gay, which describe sexual attraction. This is not directly related to gender identity and may not reflect a person’s sexual behavior. Heterosexual-identified persons may engage in sexual activity with members of the same sex. Therefore, sexual orientation should be defined by the individual, and the healthcare provider should inquire about sexual behaviors. For transgender folks, sexual orientation is described based on the lived gender; a transgender woman attracted to other women would be a lesbian, and a transgender man attracted to other men would be a gay man. Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@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.

Also inaccurate are the cancer risks attributed to crosssex hormone therapy. Long-term, follow-up, case control studies have not identified differences in cancer rates in transgender patients undergoing hormone therapy compared with birth-sex controls. Current recommendations are to conduct routine cancer screening for all transgender patients in accordance with current guidelines. You can find accurate, evidence-based information on primary and gender-affirming care of transgender people at: http://transhealth.ucsf.edu/tr—ANGIE MAGAÑA, NP, Los Angeles (216-1) Labels such as MSM and WSW are behavioral labels only and do not describe underlying romantic or physical attraction. A 2006 study by Pathela et al in the Annals of Internal Medicine found that nearly three-fourths of MSM identified as heterosexual. Transgender is a large umbrella term that includes other terms such as transsexual, cross-dresser, performer, gender non-conforming/expansive/fluid, and intersex identities. Transsexual individuals, otherwise those diagnosed with gender dysphoria, may or may not elect to have any surgical treatment as part of their care. These are important details and nuances in care that can otherwise exclude those with non-binary identities. For those interested in learning more about LGBT health, I recommend the website for GLMA (www.glma.org).— HENRY NG, MD, MPH, FAAP FACP, Cleveland (216-2)

OUR CONSULTANTS

Philip R. Cohen, MD,

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

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

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

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is an assistant professor at Thomas Jefferson University and a dermatology PA at Family Dermatology of Reading, Pa.

44 THE CLINICAL ADVISOR • OCTOBER 2016 • www.ClinicalAdvisor.com

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CLINICAL PEARLS YEAST INFECTIONS IN SKINFOLDS Prevent recurrence of annoying summer yeast infections in skinfolds by having patients apply an alcohol-based hand sanitizer under the breasts or between skinfolds after the initial treatment and acute inflammation is gone (painful if the skin is red). This little trick has dramatically reduced the number of episodes for many patients.—ROSEMARY GRAFFIUS, FNP, Port Alsworth, Alaska (216-3) SUCCESSFUL ADDICTION RECOVERY I had the privilege of creating a Suboxone recovery program and administering it under the direction and supervision of a physician psychiatrist. Our program worked because it was designed and conducted properly. All patients were volunteers, and all had the program and the characteristics of Suboxone explained to them before they began. If patients were on methadone, they had to taper to 40 mg/day before starting Suboxone. Patients started at 16 mg/day for 1 to 2 months, then tapered to 12 mg/day. They were instructed to cut their dose 1 week before the next visit so we could assess the tolerence to the lower dose. Patients had a drug screen for the presence of Suboxone and the absence of other drugs every month. Each person recieved counseling on a monthly basis. At the end of 1 year, 85% of our patients were completely drug-free and living productive lifestyles. The “pearl” is that when properly administered and with appropiate monitoring and planned decreasing doses, Suboxone is a wonder drug! It blocks the mu receptor for 36 hours, which makes taking narcotics a waste of time because you don’t get high if the narcotics can’t reach the receptor. Strict monitoring helped the individuals stay away from temptation, and monthly counseling helped in attitude change.

Debra August King, PhD, PA,

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

Mary Newberry, CNM, MSN,

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

Any medication can and probably will be misused/abused, but don’t blame the medication for the failure of the practitioner to properly run an effective program. Suboxone is the best thing that has ever existed to curb drug addiction if it is used correctly.—GEORGE ROLL, PA, MS, MPA, BA, BS, Seagrove, Fla. (216-4)

CASE FILES GENETIC VASCULAR ANOMALY Contributed by Sherril Sego, FNP-C, DNP (See photo at bottom of this page for more information about Dr. Sego.) A 34-year-old Caucasian woman presented with complaints of years regarding pain in her feet. She said that they ache and turn purple, but no one believes her. She has had multiple surgeries for other likely causes of foot pain, including bilateral bunionectomies, but her pain continues to worsen. Aggravating factors are excessive activity and cold weather. On examination, there were healed scars corresponding with her previous surgeries. Her feet appeared slightly dusky and were cool to the touch. Pedal pulses were faint, even with Doppler. She had poor capillary refill on her toenail beds. Her femoral and popliteal pulses, however, were strong. And MRA showed bilateral absence of the medial and lateral branches of the popliteal artery below the knee, with only the central branch visible. Unfortunately, few options were available to her for symptom relief and none surgically. Without native vessel no surgical intervention would be possible. A localized trial of nitroglycerin ointment to the dorsal aspects of both feet failed to provide pain relief. She was educated on the importance of protecting her feet from injury or infection and consulted with the pain management clinic. (216-5) n

Claire O’Connell, MPH, PA-C,

Katherine Pereira, DNP, FNP,

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

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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Dermatology Clinic CASE #1

A pink papule that grew from 1 mm to 10 mm in a week TIFFANY SHIH, MD

A 28-year-old healthy white woman with no significant past medical history presents with an enlarging papule on her right lateral neck. She describes a 1- to 2-mm pink papule that grew to approximately 10 mm within the past week. With minimal rubbing or trauma, the papule intermittently bleeds. It is otherwise nontender and nonpruritic. She has no history of skin cancer and is taking oral contraceptives. Physical examination shows a pink, friable papule on a stalk on the right lateral neck. There are no other similar lesions seen on examination. What is your diagnosis? Turn to page 52

CASE #2

Multiple, comedolike openings filled with keratin plugs MELINDA LIU, BA, AND MAURA HOLCOMB, MD

A healthy 15-year-old girl presents with a solitary, asymptomatic lesion on her back that has been present since birth but has enlarged in the past 2 years. Examination reveals multiple, comedo-like openings filled with dark lamellate keratinocyte plugs grouped in a linear distribution over a slightly hypotrophic area of 3 cm by 7 cm. Dermoscopy revealed numerous circular and barrel-shaped homogenous areas in dark-brown shades with remarkable keratin plugs. What is your diagnosis? Turn to page 53 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2016 51

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Dermatology Clinic CASE #1

Pyogenic granuloma

Pyogenic granuloma (PG), also known as lobular capillary hemangioma, is a common vascular proliferation of the skin or mucous membranes that typically presents as a solitary red papule or polyp. The most common sites are the gingiva, fingers, lips, face, and tongue.1,2 About one-third of these lesions are thought to develop following trauma.1 The majority of PGs originate from the dermis or mucous membranes, but there are case reports of intravascular or subcutaneous origin.3,4 PGs commonly develop in children and young adults, but they can occur at any age and have a slight male predominance. Gingival lesions, present more commonly in pregnant women.1,2 The term pyogenic granuloma is a misnomer. There is no infectious agent or granulomatous appearance on histology. PGs are better described as a friable reactive neovascularization or exuberant overgrowth of granulation tissue. They often ulcerate and bleed with minimal trauma. There are reported correlations between PGs and medications.1 Due to increased prevalence of PGs in pregnancy, known as granuloma gravidarum or pregnancy tumors, a hormonal influence has been postulated, but there are no studies to support this theory.3,5 The classic histologic appearance of this lesion is an exophytic proliferation of capillaries arranged in a lobular pattern. The capillaries are lined by endothelial cells and rimmed by pericytes. The surrounding stroma is fibromyxoid with scattered fibroblasts. The capillaries are arranged in lobules that are separated by thick, intervening bands of dense fibrous tissue. There is often an epithelial collarette that delineates the margins of this lesion.1 Over time, the epidermis frequently starts to become thin and can erode. Heavy, superimposed staphylococcal colonization is common.2 The differential diagnosis for pyogenic granuloma includes amelanotic melanoma, bacillary angiomatosis or Kaposi sarcoma in immunosuppressed individuals, glomus tumor, hemangiomas, and irritated melanocytic nevi and warts. A thorough history, including immune status, history of malignancy (eg, skin cancers), medications, and hormonal patterns or supplementations, can help with diagnosis of pyogenic granuloma. However, pink papules (especially bleeding lesions) must be biopsied to rule out malignancy, particularly

amelanotic malignant melanoma. From a dermatopathology prospective, the differential diagnosis histologically includes vascular lesions such as bacillary angiomatosis and angiosarcoma.6 There are no special immunohistochemical stains that are helpful, but combining the appropriate clinical presentation and a benign-appearing histology often are sufficient to arrive at the correct diagnosis. Treatment for PG is typically shave excision, followed by electrofulguration or silver nitrate application to the base. If the lesion is not completely removed or destroyed, it may recur and form adjacent satellite lesions.2 For smaller PGs, pulsed dye laser or other lasers with vascular targets can be effective and safe.1 Other previously successful alternatives include sclerotherapy and imiquimod under occlusion.2

Treatment for pyogenic granuloma is typically shave excision, followed by electrofulguration or silver nitrate. In our case, the patient underwent shave excision with electrofulguration under local anesthesia. She tolerated this procedure well, and the specimen was sent for h istologic confirmation to rule out amelanotic melanoma. A pregnancy test was also performed, the result of which was negative, and the patient continued taking her oral contraceptives as prescribed. She has had no recurrence or new lesions develop. Tiffany Shih, MD, is a resident physician at the University of Minnesota in Minneapolis. References 1. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012. 2. James WD, Berger TG, Elston D. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Saunders Elsevier; 2011. 3. Harris MN, Desai R, Chuang TY, et al. Lobular capillary hemangiomas: an epidemiologic report, with emphasis on cutaneous lesions. J Am Acad Dermatol. 2000;42(6):1012-1016. 4. Fortna RR, Junkins-Hopkins JM. A case of lobular capillary hemangioma (pyogenic granuloma) localized to the subcutaneous tissue and a review of the literature. Am J Dermatopathol. 2007;29(4):408-411. 5. Demir Y, Demir S, Aktepe F. Cutaneous lobular capillary hemangioma induced by pregnancy. J Cutaneous Pathol. 2004;31(1):77-80. 6. Brinster NK, Liu V, Diwan H, McKee PH. Dermatopathology: A Volume in the High Yield Pathology Series. 1st ed. Philadelphia, PA: Elsevier Saunders; 2011.

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CASE #2

Nevus comedonicus

Nevus comedonicus is a rare hamartoma of the pilosebaceous unit. Nevus comedonicus is considered an epidermal nevi syndrome and is characterized by dilated comedo-like openings with black-brown keratin plugs following the lines of Blaschko.1-3 Nevus comedonicus occurs at an incidence of 1/45,000 to 1/100,000; it typically appears at birth or early childhood and demonstrates accelerated growth during puberty.1,2,4 Nevus comedonicus does not demonstrate preference for race or sex.4 Complications include inflammation or secondary infections, and bilateral and widespread nevus comedonicus is often associated with the neurocutaneous condition nevus comedonicus syndrome.1,4-6 Patients with nevus comedonicus syndrome have central nervous system abnormalities, including epilepsy, electroencephalographic abnormalities, and transverse myelitis. They have skeletal abnormalities, including scoliosis, pectus excavatum, spina bifida occulta, syndactyly, and hemivertebrae. They may also have cutaneous abnormalities, including ichthyosis, leukoderma, and Sturge-Weber syndrome, and ocular abnormalities, including congenital cataracts, strabismus, and microphthalmus.4,5 These extracutaneous manifestations usually manifest ipsilateral to the nevus comedonicus.6 Although malignant transformation of nevus comedonicus is very rare, it is often reported in association with benign epithelial tumors, including hidradenoma papilliferum, syringocystadenoma papilliferum, and keratoacanthomas.6 Nevus comedonicus manifests as closely arranged, dilated follicular ostia containing keratinous plugs resembling blackhead comedones that are typically grouped in a linear distribution along the lines of Blaschko.6 Although it is typically unilateral, it may be bilateral, and it can also be arranged in dermatomal, interrupted, or segmental patterns.4 Usually, nevus comedonicus is asymptomatic, without inflammatory acne lesions.6 Sebaceous glands are not normally found on the palms and soles, and involvement of these areas is rarely reported.4 Nevus comedonicus is categorized into two forms based on clinical appearance: a form with predominant comedones and a form in which the comedones undergo inflammatory changes with severe cutaneous sequelae.2,4,7 In the comedone-predominant form, the nevus comedonicus merely

represents a cosmetic defect with comedo-like changes.2,4,7 In the other form, patients develop large follicular cysts, which tend to recur and form fistulas, abscesses, and keloids.2,4 Nevus comedonicus is caused by growth deregulation of the mesodermal portion of the pilosebaceous unit, resulting in follicle-based hamartomas, which prevent the affected follicular structures from developing terminal hair and sebaceous glands.6 Instead, the hamartomas produce soft keratin or vellus hair, which occlude the adnexal ostia.6 Improper keratinization of the pilosebaceous unit is thought to occur through a number of different mechanisms including overstimulation of the fibroblast growth factor receptor 2 with high expression of the interleukin-1α, involvement of γ-secretase, and involvement of filaggrin.4 The differential diagnosis for nevus comedonicus includes segmental acne, which typically presents in puberty with polymorphous lesions and distinct histology showing sebaceous hyperplasia; trichofolliculoma, which presents in adults as a single nodule with a central pore draining sebaceous material; familial dyskeratotic comedones, which Take-away points for nevus comedonicus Clinical presentation

• Characterized by closely arranged, dilated follicular ostia containing keratinous plugs, resembling blackhead comedones, arranged along the lines of Blaschko • Palms and soles are rarely involved • Typically asymptomatic without inflammatory acne lesions

Differential diagnosis

• Segmental acne, trichofolliculoma, dilated pore of Winer, folliculocystic and collagen comedo hamartoma, pilar sheath acanthoma, chloracne, and acne conglobata with extensive comedones, familial dyskeratotic comedones, Favre-Racouchot syndrome

Diagnosis

• Diagnosed clinically and can be confirmed through histopathology • Histopathology demonstrates large, grouped, dilated follicular ostia filled with keratin and devoid of hair shafts with singular rudimentary glands at the bases of the follicular invaginations

Management

• Treatment is usually for cosmetic reasons because this is a benign lesion; conservative options include emollients, topical corticosteroids for inflammatory lesions, keratolytic agents, and topical retinoids (alone or in combination with calcipotriol) • Complete surgical resection is the only definitive treatment

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Dermatology Clinic is an autosomal dominant condition presenting in puberty with widespread, symmetrically distributed comedo-like, hyperkeratotic papules; folliculocystic and collagen comedo hamartoma, which is an autosomal dominant condition presenting with large, painless, infiltrated plaques with numerous follicular comedo-like openings and cysts draining keratinous material; and Favre-Racouchot syndrome, which is a condition that typically affects middle-aged to elderly individuals and consists of multiple open and closed comedones in skin with actinic damage.7 Diagnosis of nevus comedonicus is clinical, but it can be confirmed with histopathology.2 Nevus comedonicus also has classic dermoscopy findings, demonstrating numerous

Nevus comedonicus is caused by growth deregulation of the mesodermal portion of the pilosebaceous unit.

have led to improvement include erbium:yttrium-aluminum garnet laser treatment and carbon dioxide ultrapulsed or diode lasers.1,6 Cryosurgery, comedo extraction, and dermabrasion have had unsatisfactory results.6 In our case, the condition and treatment options were discussed with the patient. Because she desired complete resolution, she was treated with surgical removal of the lesion. n Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Bhullar A, Shamsudin N. Images in clinical medicine. Nevus comedonicus. N Engl J Med. 2015;372(26):2541. 2. Kamin´ska-Winciorek G, Spiewak R. Dermoscopy on nevus comedonicus: a case report and review of the literature. Postepy Dermatol Alergol. 2013;30(4):252-254. 3. Dessinioti C, Antoniou C, Katsambas A. Acneiform eruptions. Clin Dermatol. 2014;32(1):24-34. 4. Ganjoo S, Mohanan S, Kumari R, et al. Extensive nevus comedonicus involving the palm: questionable role of the pilosebaceous unit in pathogenesis. Pediatr Dermatol. 2014;31(4):e96-e99. 5. Torchia D, Schachner LA, Izakovic J. Segmental acne versus mosaic conditions with acne lesions. Dermatology. 2012;224(1):10-14. 6. Ferrari B, Taliercio V, Restrepo P, et al. Nevus comedonicus: a case series. Pediatr Dermatol. 2015;32(2):216-219. 7. Tchernev G, Ananiev J, Semkova K, et al. Nevus comedonicus: an updated review. Dermatol Ther (Heidelb). 2013;3(1):33-40.

“You rang?”

circular and barrel-shaped homogenous areas in light- and dark-brown shades with deep keratin plugs.2 In contrast, acne vulgaris demonstrates numerous light or dark brown homogenous areas that are predominantly circular and are situated superficially.2 Characteristic findings of nevus comedonicus on histopathology include large, grouped, dilated follicular ostia filled with keratin and devoid of hair shafts.1 Singular rudimentary glands may be present at the bases of the follicular invaginations.7 Hyperkeratosis and acanthosis of the epidermis may be present, but para- or dyskeratosis are not present.6 Electron microscopy reveals more abundant tonofilaments in the upper part of the stratum spinosum and numerous keratohyalin granules.7 Increased numbers of Langerhans cells may also be present, whereas arrector pili muscles are absent or incompletely differentiated.7 Treatment for nevus comedonicus is usually provided for cosmetic reasons; however, in severe cases, the goal is to alleviate inflammation. In general, the lesions do not spontaneously regress, but, given the benign nature of the condition, patients do not require aggressive therapy.6 Conservative options include emollients, topical corticosteroids for inflammatory lesions, keratolytic agents, and topical retinoids, which have limited efficacy as monotherapy, but can be combined with calcipotriol.6 In contrast, oral isotretinoin is typically ineffective.6 Complete surgical resection is the only definitive treatment, but defining the borders of the nevus comedonicus is difficult.6 Other treatments that

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Dermatologic Look-Alikes Widespread lesions, scarring AARON FONG, BA, AND RANA MAYS, MD

CASE #1

CASE #2

A 55-year-old man presents with skin lesions that have come and gone over the past several years. The lesions cause minor pain and irritation. He has been seen elsewhere several times and received a prescription for an unknown antibiotic that led to improvement; however, the lesions always recurred after the 10- to 14-day course of treatment. The patient is in good health otherwise, with no diabetes or immune suppression. Focal scarring, epidermal thickening, and hyperpigmentation are noted on the surfaces of the lesions, approximately one-third of which are modestly fluctuant. A small amount of pus can be expressed through follicular orifices from a few of the lesions and was sent for culture and sensitivity testing.

A 65-year-old woman presents with a pruritic skin condition that has persisted for more than 20 years. The patient is taking an oral antihypertensive medication and a sleep aid, but her skin condition had begun many years prior to being on any consistent oral medication. Hundreds of almost identical excoriated nodular, scabbed lesions of approximately 1 to 2 cm are uniformly distributed on the patient’s trunk, arms, upper legs, and buttocks, but they are absent from her palms, face, and the middle of her back. Very little erythema is observed around the lesions. Hundreds of scars from healed sites are also seen in the same areas. Her face and skin below the waist are free of notable lesions.

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Dermatologic Look-Alikes CASE #1

MRSA furunculosis

Furuncles, commonly known as boils, is an infection of the hair follicle, with purulent material extending through the dermis into subcutaneous tissue. This can occur anywhere on the skin where there is hair. They are more common in areas with more friction and perspiration, including the back of the neck, face, axilla, and buttocks. Furuncles usually occur after episodes of folliculitis and can coalesce together to form a single inflammatory lesion called a carbuncle. Systemic involvement is uncommon except in larger infections. Infection of the hair follicle by Staphylococcus aureus is the most common cause of furunculosis, and it can be caused by both methicillin-susceptible S aureus and methicillin-resistant S aureus (MRSA). Risk factors include nasal carriage of S aureus. Those carrying MRSA may be at higher risk, though some studies have shown that nasal carriage of S aureus is not correlated with S aureus skin and soft tissue infection of any kind.1 In one pediatric study, rectal colonization by MRSA was strongly associated with increased risk of skin abscesses and furuncles.2 Those in close contact with others with known active infection are also at increased risk. S aureus infection is the most common and accounts for approximately 75% of cases of furuncles.3 Recent studies have shown that strains of MRSA USA300 were virulent and highly prevalent in New York City.3 Colonization with other pathogens, such as Enterobacteriaceae, Enterococci, Corynebacterium, S epidermidis, and S pyogenes, may also put patients at higher risk for recurrence. Exposure to sitting water, such as hot tubs or whirlpools, increases the risk for pseudomonal or mycobacterial furunculosis.4 The most common complications of furunculosis include postinflammatory hyperpigmentation, scarring, and recurrence of lesions. Systemic symptoms and infections are rare. Cases of endocarditis following furunculosis have been reported.5 Those who are colonized with S aureus are at higher risk of recurrent furunculosis and can have 3 or more episodes in a period of 1 year. Differential diagnosis includes folliculitis, hidradenitis suppurativa, sporotrichosis, leishmaniasis, tularemia, myiasis, botryomycosis, nontuberculous mycobacteria, blastomycosis, acne vulgaris, and neurotic excoriations.

Hidradenitis suppurativa presents as tender nodules with extensive scarring and sinus tracks primarily in the axillae, groin, and submammary areas. It can be differentiated from furunculosis by its distribution, more extensive scarring, sinus tracts, and occasional concomitant comedones. Acne vulgaris presents as open and closed comedones with erythematous papules and pustules. It is usually distributed on the upper trunk, neck, and face. It can be differentiated from furunculosis by the history, presence of comedones, and distribution. Sporotrichosis has 3 typical presentations. Lymphocutaneous sporotrichosis presents as painless erythematous nodules on the distal extremities following lymphatic flow. Fixed cutaneous sporotrichosis does not follow the lymphatic distribution and presents as verrucous or gummatous plaques most commonly on the face. Disseminated cutaneous sporotrichosis is diffusely distributed papules and nodules. Sporotrichosis can be differentiated from furunculosis based on distribution and history significant for sporotrichosis risk factors. A skin culture can help differentiate the etiology.

Furuncles usually occur after episodes of folliculitits and can coalesce together to form a carbuncle. Treatment options for furuncles depend on size and severity. For smaller furuncles, warm compresses are usually sufficient to facilitate drainage of purulent material and resolution. Larger lesions may require incision and drainage. Material can be sent for culture and susceptibility testing in more resistant infections. The use of antibiotics depends on a number of factors, including number and size of lesions, amount of cellulitis, associated medical conditions, immunosuppression, systemic symptoms, persistent infection, or whether there is a high risk of transmission (eg, athletes, military personnel). Generally, antibiotics are recommended only in cases in which patients have systemic symptoms and/or fit the criteria for systemic inflammatory response syndrome.6 In those with MRSA, options include vancomycin, linezolid, clindamycin, daptomycin, ceftaroline, doxycycline, minocycline, and trimethoprim/sulfamethoxazole. In our case, the patient’s results showed MRSA that was sensitive to trimethoprim/sulfamethoxazole, clindamycin, and the tetracyclines, among other antibiotics. This

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organism quickly became the focus of treatment, although his clinical picture was confused by the fact that he was also a picker. This patient’s condition was treated successfully with 2 months of double-strength trimethoprim/ sulfamethoxazole twice daily. He was also urged to leave his lesions untouched to allow them to resolve. His longterm prognosis is somewhat guarded.

CASE #2

Neurotic excoriations

Neurotic excoriations can present as polymorphic lesions of varying size and age. There is no consensus on the prevalence of neurotic excoriations. One study reports that 1.6% of a random sample of 2511 adults in the United States have skin picking with visible lesions.7 Another study reports that 5.4% of 354 patients have neurotic excoriations with impairment of daily functioning and psychosocial stress.8 This disease is more common in women, with a ratio of women to men of approximately 8:1; it tends to affect women aged between 20 and 50 years.9 The etiology is unknown. Research now focuses on abnormal brain activity found on magnetic resonance imaging. One study showed abnormally low brain activity in regions important to habit formation, action monitoring, and inhibition.10 Lesions commonly occur on the face, extensor surfaces, scalp, shoulders, and back—anywhere a patient can reach to scratch or cause excoriations.11 More recent lesions appear as angular excoriations that may or may not have a crust. Older lesions present as atrophic scars or hypertrophic nodules. Postinflammatory hypo- and hyperpigmentation is common. The appearance of lesions can also be affected by the tool, such as fingernails, teeth, scissors, or tweezers, used to scratch. The distribution of lesions is among the more important clues, as they only appear where the patient can reach. Some complications include ulceration, infection, scarring, and long-lasting disfigurement. Neurotic excoriations are associated with numerous psychiatric disorders, including affective disorders, anxiety disorders, eating disorders, and substance abuse. It is also commonly seen in patients with Prader-Willi syndrome, a

developmental disorder caused by loss of the paternal 15q1113 gene. Most commonly, it is associated with depression, anxiety, and obsessive-compulsive disorder.12 Patients are typically aware that they have unavoidable urges to pick or scratch their skin where these lesions occur. These urges usually occur episodically and usually last for approximately 5 to 10 minutes; however, some patients may complain of pruritic urges lasting for hours. These urges cause a significant level of psychological distress that is only relieved through picking the skin. Diagnostic criteria, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,13 includes recurrent skin picking and repeated attempts to decrease or stop skin picking. The act of picking causes significant distress or impairment in important areas of functioning. Skin picking cannot be attributed to other medical conditions, medication side effects, or substance abuse, and skin picking is not better explained by symptoms of another mental disorder. The differential diagnosis includes atopic dermatitis, psoriasis, scabies, bullous pemphigoid, furunculosis, and chronic pruritus.

High-potency topical corticosteroid use may reduce symptoms, and intralesional glucocorticoids also can be beneficial. Management options are multifactorial. Psychiatric management is usually needed to help patients with their insight, awareness, and motivation. If a medical cause is suspected (polycythemia vera or uremia), goals should be aimed at focusing on the underlying disorder. High-potency topical corticosteroid use has been found to reduce symptoms. Intralesional glucocorticoids also can be beneficial. Other options include laser treatment for scarring and phototherapy with narrow-band ultraviolet B rays to reduce pruritus.14 Semi-occlusive dressings can help to hinder skin picking, limiting further damage and promoting healing. Antibiotic use is beneficial to treat infected lesions or ulcerations and prevent bacterial colonization. As is the case with many of these patients, the patient in our case was in denial regarding her role in the disorder and refused treatment with psychoactive medications and a referral to psychiatry. She was given a prescription for topical triamcinolone 0.1% cream for application twice daily and a 2-week course of cephalexin, 500 mg 3 times

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Dermatologic Look-Alikes Comparison of MRSA furunculosis and neurotic excoriations MRSA furunculosis

Neurotic excoriations

Dermatologic presentation

Perifollicular erythematous nodule or pustule

Polymorphic lesions of varying size and age; lesions are often angular excoriations with or without crust; older lesions can be atrophic or hypertrophic nodules; lesions are in different stages of healing

Associations

Staphylococcus aureus colonization, most commonly in nares; immunosuppression, diabetes

Underlying mental illness; OCD, anxiety, depression; more common in women aged 20-50 y; substance abuse

Etiology

Infectious S aureus (75%), Enterobacteriaceae, Enterococci, Corynebacterium, S epidermidis, and S pyogenes

Self-inflicted; psychiatric

Characteristic location

Face, neck, arms, hands, buttocks, and anogenital region

Typically on extensor surfaces; also on face, scalp, shoulders, and back; anywhere patient can reach to scratch

Diagnosis

History and physical; skin culture and gram stain; can culture nares for carriage of S aureus

History and physical improvement after occlusion of lesions can help establish diagnosis

Treatment

Incision and drainage; systemic antibiotics for recurrent infections or immunocompromised patients

Treat underlying psychiatric illness/substance abuse; occlusive dressings, topical steroids, antipruritic medication to manage symptoms

MRSA, methicillin-resistant Staphylococcus aureus; OCD, obsessive-compulsive disorder

daily to reduce any bacterial colonization. Her family was counseled regarding the nature of the problem and its likely intractability. n

6. Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-e52.

Aaron Fong, BA, is a medical student and Rana Mays, MD, is a dermatology resident at Baylor College of Medicine in Houston.

7. Keuthen NJ, Koran LM, Aboujaoude E, et al. The prevalence of pathologic skin picking in US adults. Compr Psychiatry. 2010;51(2):183-186. 8. Hayes SL, Storch EA, Berlanga L. Skin picking behaviors: an examination

References

of the prevalence and severity in a community sample. J Anxiety Disord.

1. Pardos de la Gandara M, Raygoza Garay JA, Mwangi M, et al. Molecular

2009;23(3):314-319.

types of methicillin-resistant Staphylococcus aureus and methicillin-sensitive

9. Wong JW, Nguyen TV, Koo JY. Primary psychiatric conditions:

S aureus strains causing skin and soft tissue infections and nasal coloni-

Dermatitis artefacta, trichotillomania and neurotic excoriations. Indian J

zation, identified in community health centers in New York City. J Clin

Dermatol. 2013;58(1):44-48.

Microbiol. 2015;53(8):2648-2658.

10. Odlaug BL, Hampshire A, Chamberlain SR, Grant JE. Abnormal brain

2. Faden H, Lesse AJ, Trask J, et al. Importance of colonization site

activation in excoriation (skin-picking) disorder: evidence from an execu-

in the current epidemic of staphylococcal skin abscesses. Pediatrics.

tive planning fMRI study. Br J Psychiatry. 2016;208(2):168-174.

2010;125(3):e618-e624.

11. Calikusu C, Kucukgoncu S, Tecer Ö, Bestepe E. Skin picking in turkish

3. Uhlemann AC, Dordel J, Knox JR, et al. Molecular tracing of the

students: prevalence, characteristics, and gender differences. Behav Modif.

emergence, diversification, and transmission of S aureus sequence type

2012;36(1):49-66.

8 in a New York community. Proc Natl Acad Sci U S A. 2014;111(18):

12. Miller JL, Angulo M. An open-label pilot study of N-acetylcysteine

6738-6743.

for skin-picking in Prader-willi syndrome. Am J Med Genet A.

4. Macente S, Helbel C, Souza SF, et al. Disseminated folliculitis by

2014;164A(2):421-424.

Mycobacterium fortuitum in an immunocompetent woman. An Bras

13. American Psychiatric Association. Diagnostic and Statistical Manual

Dermatol. 2013;88(1):102-104.

of Mental Disorders. 5th ed. Washington, DC: American Psychiatric

5. Bahrain M, Vasiliades M, Wolff M, Younus F. Five cases of bacterial

Association; 2013.

endocarditis after furunculosis and the ongoing saga of community-

14. Özden MG, Aydin F, Sentürk N, et al. Narrow-band ultraviolet B as a

acquired methicillin-resistant Staphylococcus aureus infections. Scand J

potential alternative treatment for resistant psychogenic excoriation: An

Infect Dis. 2006;38(8):702-707.

open-label study. Photodermatol Photoimmunol Photomed. 2010;26(3):162-164.

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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.

SCREENING AND TREATING PREGNANT WOMEN WITH ASYMPTOMATIC BACTERIURIA MAY NOT BE HELPFUL Level 2 [mid-level] evidence The Infectious Diseases Society of America (IDSA) and the United States Preventive Services Task Force (USPSTF) both strongly recommend screening all pregnant women for asymptomatic bacteriuria with urine culture around 12 to 16 weeks gestation and treating women with positive urine cultures with antibiotics. These recommendations are based on a Cochrane review finding that antibiotic treatment of asymptomatic bacteriuria in pregnant women was associated with a decreased incidence of maternal pyelonephritis as well as a reduced risk of preterm birth and low birthweight (Smaill FM, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev. 2015;[8]:CD000490.). The quality of evidence included in the Cochrane review is poor, however. All included trials were published before 1987, with 9 of the 14 trials published between 1960 and 1969 when methods for determining gestational age were less accurate. In addition, most of the trials treated women with positive urine cultures with antibiotics that are no longer used for pregnant women and for durations far exceeding the current IDSA recommendation of 3 to 7 days, and only 1 trial reported treatment-related adverse events. Due to this low quality of evidence, a recent cohort study with an embedded randomized trial was performed to assess the need for screening and treating pregnant women for asymptomatic bacteriuria (Kazemier BM, Koningstein FN, Schneeberger C, et al. Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria

Screening for asymptomatic bacteriuria may not lead to better outcomes among pregnant women and exposes them to unnecessary antibiotics.

in pregnancy: A prospective cohort study with an embedded randomised controlled trial. Lancet Infect Dis. 2015;15[11]:1324-1333.). A total of 4,283 women (mean age, 31 years) with singleton pregnancies at 16 to 22 weeks gestation were screened for asymptomatic bacteriuria at 13 centers in the Netherlands and 248 women (5.8%) had positive urine cultures from a single dipslide. Eighty-five women with asymptomatic bacteriuria were then randomly assigned to receive either 100 mg of nitrofurantoin or placebo twice daily for 5 days. The remaining 163 women with asymptomatic bacteriuria declined trial participation because they did not want to receive antibiotics for an asymptomatic condition, but all the women were followed until 6 weeks postpartum. Comparing women with asymptomatic bacteriuria treated with nitrofurantoin to women treated with placebo or refusing treatment (Table), there were no significant differences in the rates of pyelonephritis or delivery at < 34 weeks. Comparing untreated or placebo-treated women to women screening negative for bacteriuria, women with asymptomatic bacteriuria had a significantly higher rate of pyelonephritis but no significant difference in the rate of deliveries at < 34 weeks. Furthermore, while the untreated women had significantly higher rates of symptomatic urinary tract infection (20.2%) and recurrent urinary tract infection (8.7%) treated with antibiotics during pregnancy compared to women with negative screenings (7.9% and 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).

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2.6%, respectively), there were no significant differences in other adverse maternal or neonatal outcomes. Although pregnant women with untreated asymptomatic bacteriuria had a slightly higher risk of developing pyelonephritis compared to women without bacteriuria, the absolute risk was small and the subsequent disease course was mild. The increase in pyelonephritis as well as that of uncomplicated urinary tract infections did not influence the development of other adverse maternal or neonatal outcomes. However, this study was not large enough to detect differences in most of these outcomes due to low event rates. These results suggest that screening for asymptomatic bacteriuria may not clearly lead to better pregnancy-related outcomes and exposes a large number of women to unnecessary antibiotics. Overall, these findings call into question recommendations for routine screening of all TABLE. Rates of pyelonephritis and preterm delivery in women Pyelonephritis (n)

Delivery at <34 weeks (n)

Antibiotic-treated asymptomatic bacteriuria (n=40)

0% (0)b

2.5% (1)b

Untreated asymptomatic bacteriuria (n=208)

2.4% (5)a

1% (2)

Bacteriuria negative (n=4,035)

0.6% (24)

1.3% (54)

All pregnant women (n=4,283)

0.68% (29)

1.3% (57)

P > 0.05, compared to women negative for bacteriuria b No significant differences compared to women with untreated asymptomatic bacteriuria a

pregnant women and for treatment of asymptomatic pregnant women, particularly in the climate of growing antimicrobial resistance. Of note, the European Association of Urology has recently updated its guidelines to make no recommendation for screening or treating pregnant women with asymptomatic bacteriuria based on the lack of benefit derived in this study combined with the low quality of the evidence for benefit in previous studies (Pickard R, Bartoletti R, Bjerklund-Johansen TE, et al. 2016 Urological Infections Guidelines. European Association of Urology website. http://uroweb.org/guideline/ urological-infections. Accessed September 7, 2016.).

RISK OF ALZHEIMER DEMENTIA AFTER ANDROGEN DEPRIVATION THERAPY Level 2 [mid-level] evidence Androgen deprivation therapy (ADT) is frequently used for men with metastatic prostate cancer, although it has been associated with an increased risk of adverse events including cognitive decline (NCCN Clinical Practice Guidelines in

Oncology. National Comprehensive Cancer Network web site. https://www.nccn.org/professionals/physician_gls/f_ guidelines.asp. Accessed September 7, 2016; Nelson CJ, Lee JS, Gamboa MC, Roth AJ. Cognitive effects of hormone therapy in men with prostate cancer: a review. Cancer. 2008;113[5]:1097-1106.). The studies to date, however, have been no more than a year in duration and the deficits reported have typically been subtle changes assessed on memory tests, not clinical diagnoses such as Alzheimer disease or mild cognitive impairment (MCI). A recent retrospective cohort study using data from electronic medical records evaluated the risk of developing Alzheimer dementia after ADT in 16,888 men with prostate cancer, 14.2% of whom were treated with ADT. Men receiving chemotherapy as well as men with a history of dementia and those diagnosed with Alzheimer dementia before initiating ADT were excluded. However, a diagnosis of MCI was not part of the exclusion criteria and baseline rates of MCI were not assessed (Nead KT, Gaskin G, Chester C, et al. Androgen deprivation therapy and future Alzheimer’s disease risk. J Clin Oncol. 2016;34[6]:566-571). During the median follow-up of 2.7 years, 0.74% of men were diagnosed with Alzheimer dementia. A propensity scorematched analysis was performed to adjust for factors associated with dementia. The propensity score was determined based on the following for each patient: age at prostate cancer diagnosis; race; smoking status; antiplatelet, anticoagulant, antihypertensive, and statin medication use; and a history of cardiovascular disease, diabetes, or malignancy. All 2,397 men with prostate cancer receiving ADT were matched to 11,985 men with prostate cancer not receiving ADT. Compared to no ADT, ADT was associated with an increased risk of Alzheimer dementia (hazard ratio, 1.88; 95% confidence interval [CI], 1.1-3.2). In analyses assessing ADT duration, ADT for ≥ 12 months was associated with an increased risk of Alzheimer dementia (hazard ratio, 2.12; 95% CI, 1.11-4.03) compared to no ADT, but ADT for < 12 months was not. While the results of this study are important, there are some significant limitations to consider. Although 16,888 patients from two large hospitals were included in the analysis, only 125 patients developed Alzheimer dementia during follow-up. This low incidence rate is reflected in the wide confidence intervals associated with the hazard ratios for Alzheimer dementia and this decreases the ability to clearly assess risk. Also, the median follow-up time was 2.7 years while the median time to a diagnosis of Alzheimer dementia was 4 years. A longer follow-up would likely have increased the rate of incident Alzheimer dementia diagnoses but was not possible given the datasets used. Additionally, the failure to assess MCI at baseline may hide a significant source of bias, since MCI is a significant

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Evidence-Based Medicine risk factor for developing Alzheimer dementia. This risk factor should have been controlled for in the propensity score, especially given the short median follow-up time. Overall, the results of this study suggest that ADT may increase the risk of Alzheimer dementia in men with prostate cancer, but the magnitude of the absolute risk appears small.

RESUMPTION OF ANTITHROMBOTIC THERAPY AFTER GASTROINTESTINAL BLEEDING IN PATIENTS WITH ATRIAL FIBRILLATION Level 2 [mid-level] evidence In patients with atrial fibrillation experiencing a gastrointestinal bleed while on antithrombotic therapy, the decision to resume antithrombotic therapy or not can be difficult. The risk of thromboembolism needs to be weighed against the risk of recurrent bleeding to determine if thromboembolic prophylaxis should be continued and if continued, what antithrombotic therapy to use (oral anticoagulation, antiplatelet agent, dual therapy, or triple therapy). A recent retrospective cohort study evaluated 3,409 patients aged ≥ 30 years (mean age, 78 years) with atrial fibrillation who were hospitalized for a first gastrointestinal bleed while on single or combined antithrombotic therapy. Patients were followed for up to 5 years (median follow-up, 2 years) and follow-up began 90 days after hospital discharge. Patients with thromboembolic events, major bleeding, or recurrent gastrointestinal bleed, or those who died within 90 days of hospital discharge, were excluded from the study. Major bleeding was defined as intracranial bleeding or severe respiratory, gastrointestinal, or urinary tract bleeding. Baseline comorbidities included ischemic heart disease in 38%, heart failure in 30.7%, and stroke or thromboembolism in 22.5% (Staerk L, Lip GY, Olesen JB, et al. Stroke and recurrent TABLE. Outcomes with antithrombotic therapy compared with no antithrombotic therapy All-cause mortality (adjusted hazard ratio)

Thromboembolism (adjusted hazard ratio)

Major bleeding (adjusted hazard ratio)

Single oral anticoagulant

0.39 (95% CI, 0.34–0.46)

0.41 (95% CI, 0.31–0.54)

1.37 (95% CI, 1.06–1.77)

Single antiplatelet agent

0.76 (95% CI, 0.68–0.86)

0.76 (95% CI, 0.61–0.95)

1.25 (95% CI, 0.96–1.62)

Oral anticoagulant plus antiplatelet agent

0.41 (95% CI, 0.32–0.52)

0.54 (95% CI, 0.36–0.82)

1.44 (95% CI, 1–2.08)

CI, confidence interval

haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study. BMJ. 2015;351:h5876.). By day 90 post-discharge, 72.9% of patients had resumed antithrombotic therapy, with single therapy with oral anticoagulation in 21.3% or antiplatelet agent in 38.5% and dual therapy with oral anticoagulation plus antiplatelet agent in 11.3%. At 2 years, the cumulative incidence of all-cause mortality was 39.9%, thromboembolism was 12%, major bleeding was 17.7%, and recurrent gastrointestinal bleeding was 12.1%. Resumption of a single oral anticoagulant, single antiplatelet agent, or dual anticoagulant/antiplatelet therapy were all associated with reduced risk of all-cause mortality and thromboembolism compared to not restarting antithrombotic therapy (Table), but there were no significant differences in either outcome with dual aspirin plus adenosine diphosphate receptor antagonist therapy. Also, while oral anticoagulation therapy was associated with a small increased risk of major bleeding compared to no therapy, there were no significant differences in the risk of major bleeding with single antiplatelet therapy or either dual therapy regimen. There were also no significant differences in recurrent gastrointestinal bleed with any antithrombotic regimen. The results of this study are consistent with a smaller retrospective cohort study finding that patients who restarted warfarin had a reduced risk of thromboembolism or death but no significant differences in recurrent gastrointestinal bleeding compared to patients not restarting therapy (Qureshi W, Mittal C, Patsias I, et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol. 2014;113[4]:662-668.). In the current study, single therapy with antiplatelet agents decreased mortality compared to not restarting therapy, but this regimen was not as effective as therapy with an oral anticoagulant. Dual therapy with oral anticoagulation plus an antiplatelet agent was also no more effective than oral anticoagulation alone, further suggesting that antiplatelet agents may not be effective for reducing mortality or the risk of thromboembolism. These results were consistent across subgroup analyses of patients also taking proton pump inhibitors and in sensitivity analyses using 30 days after hospital discharge as the start of follow-up. However, the effects of novel oral anticoagulants (NOACs) could not be determined due to the low number of patients taking these medications at the time of the study. Overall, this study suggests that resuming antithrombotic therapy with a single oral anticoagulant in patients with atrial fibrillation and a serious gastrointestinal bleed results in better overall mortality outcomes despite potentially increasing the risk of major bleeding. n

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LEGAL ADVISOR CASE

Undiagnosed cellulitis

A patient is asked to follow up for care but does not, and severe cellulitis develops.

ANN W. LATNER, JD

Ms J, aged 45 years, was a nurse practitioner who worked in the emergency department of a small regional hospital. She had been working at the hospital for the last decade and was well regarded among her peers. On the day in question, a Tuesday, Ms J’s shift began at 6 am. She was relieved to see that the emergency department seemed quiet. She had just poured herself a cup of coffee when she got a call from the floor nurse in the intensive care unit (ICU). “We’re sending someone down to the emergency department,” the floor nurse said. “Her name is Mrs B. Her mother is in the ICU, and Mrs B stayed in the mother’s room overnight. She slept on two chairs last night, and this morning she was complaining terribly about pain and swelling in her right ankle. I’ve told her to go down to the emergency department to get looked at.” “Okay,” Ms J said. “Anything else I should know?” “She’s wound up pretty tight,” the floor nurse said. “She’s very concerned about her mother, who isn’t doing well. She’s a little worked up.”

Clinicians can protect themselves from liability by giving clear instructions to patients about what follow-up entails and why it is necessary.

Ms J thanked the nurse for the information and waited for Mrs B to arrive. When she did, Ms J ushered her into an examination room. The patient, aged 60 years, told Ms J that her 85-year-old mother was in the ICU with congestive heart failure and that she had stayed with her overnight. “She gets agitated if she’s alone for too long,” the patient said of her mother. “I thought it would be a good idea to stay last night, and I slept on two chairs that I pushed together. But when I woke up, my right ankle was killing me. I don’t know why.” Ms J examined the ankle, which was swollen and clearly painful. Other than the swelling and pain, there were no signs of anything abnormal—no redness or heat. Ms J concluded that the injury was a sprained ankle, and she placed the patient’s right foot in a splint to help it heal. 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.

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However, when cases do go to trial, studies have shown that they end in the favor of the healthcare practitioner a great deal of the time. According to a 2009 analysis of claims recorded in the National Practitioner Data Bank, between 1991 and 2007, 37% of physicians, 3.1% of physician assistants, and 1.5% of nurse practitioners had to make a malpractice payment ( Journal of Medical Licensure & Discipline. 2009;95:6-16). In the ten-year period between 2003 and 2013, fewer than 3,000 malpractice judgments were returned against nurse practitioners. Protecting yourself

Ms J did several things right in this case, and those things are what helped her to succeed at trial. First, she gave her patient clear and specific instructions: “return to the emergency department or your own doctor within the next 48 hours to have the ankle checked.” Second, and most important, she noted that in the file. This provided evidence that she could use in court. Patients do not always follow directions. All a clinician can do is clearly instruct the patient about what follow-up entails, and why it is necessary. You cannot force a patient to follow instructions. But if a patient fails to heed instructions, and you can prove that you have relayed those instructions, you can protect yourself from liability. n Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

“Try to rest it,” she told the patient, “and either see your own doctor or come back here within the next two days so someone can check the splint.” Ms J noted in her file that the patient had been instructed to follow up with her own physician or the emergency department within 48 hours. She wished the patient well and ushered her out of the examination room. Mrs B did not return to the emergency department or see a doctor within two days; instead she waited four days and then went to her private physician complaining of a fever and severe right leg pain. When the splint was opened, severe cellulitis was found throughout the right leg and foot. Mrs B required hospitalization for surgical debridement and intravenous antibiotic therapy. She was left with extensive scarring on her right leg, constant pain in that leg, and limited range of motion. On the advice of a friend, Mrs B consulted with a plaintiff’s attorney who advised her to sue Ms J for medical malpractice. When Ms J was notified about the lawsuit, she was angry. She met with her defense attorney and explained her side. “I did not do anything wrong,” she told the attorney. “There was nothing to indicate cellulitis when I examined her, and I gave her specific instructions to go get the ankle looked at again within 48 hours. I have notes! I wrote it down! She waited double that amount of time. I don’t think she developed the cellulitis until after she left the emergency department. If she had seen the doctor in the amount of time that I’d told her to, this would not have happened! It’s not my fault!” The attorney warned her that a trial would be stressful and time-consuming, but Ms J was insistent that she had not committed malpractice and wanted to go to trial. The case dragged on for many months but eventually went to a jury trial. Ms J testified about her instructions to Mrs B, and the medical records showing her instructions were introduced into evidence. When Mrs B testified, she had to admit that she had not returned within the 2 days as instructed. “I was caring for my ill mother,” she testified. The jury was sympathetic to Mrs B, but sided with Ms J and returned a verdict for the defense. Legal background

The majority of cases are settled out of court and never make it to a jury. There are many good reasons for this. Trials are costly and extremely time consuming. Litigated claims take an average of over 2 years to resolve. Juries are unpredictable and can sometimes side with a plaintiff due to sympathy. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2016 65

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ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP Ms. Sego is an independent consultant in Kansas City, Mo.

Spider web silk We all have seen the detailed construction of spider webs. Sometimes, when the morning dew is on them, they are beautiful. But, for most people, that is as far as our admiration goes. Spiders, in general, are not one of our favorite creatures. Although these 8-legged, fuzzy creatures can be very menacing in appearance, their ability to produce webs of incredible geometry and strength has been studied for centuries. The web silk itself has been used for everything from fabric to wound care. What was once considered ancient has now been resurrected and is the topic of solid research. Spider web silk, colored scanning electron micrograph.

Background

Science

Human interest in the utility of spider silk is not new. There is documentation that the ancient Greeks used cobwebs to treat wounds.1 The silk served as a matrix for platelet and fibrin deposition to enhance hemostasis. The Greeks also observed that wounds treated by this method did not become infected as readily. Only in the last few decades have scientists discovered that some species of spiders secrete an antimicrobial protein coating on their silk fibers. Despite its delicate appearance, spider silk is extremely strong, elastic, and resilient. Spider silk is 5 times as strong as steel, despite having a fraction of the density of steel, but by weight, and able to stretch and retract to a far greater degree than nylon.2 The strongest of spider silks requires 7 to 10 times more energy to fracture than an equivalent volume of synthetic Kevlar, which is designed to stop bullets,3 so it is no surprise that this super fiber is finding its way into unique and exciting biomedical applications.

Nerve damage has always been considered a catastrophic outcome in medicine. Whether traumatic or disease-related, loss or impairment of nerve function can result in major disability. Promising research is being conducted using sterilized frameworks of spider silk seeded with Schwann cells to regrow damaged nerves. One group conducted this procedure in vitro and showed that 48 hours after seeding Schwann cells into the culture media onto the silk matrix, there was complete coverage of the silk, with multiple wrapping layers of Schwann cells.4 The next step in the research was to devise a method that would direct the growing fibers to bridge gaps between proximal and terminal nerve stumps. This was accomplished using totally acellularized vein as a conduit to bridge the gap of the nerve ends.4 Another study showed successful in-vivo regeneration of a 20-mm sciatic nerve defect in rats.5 At the end of 6 months, the measurement of diminished degeneration of the gastrocnemius was

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significantly superior in the treated group over the control group.5 This same type of seeding has been shown to be successful using fibroblasts6 and chondrocytes.7 Researchers have successfully grown artificial skin by seeding spider silk matrices with fibroblasts. The skin cells grew into multilayered, well-ordered sheets of artificial skin that potentially could become the answer for human skin grafting. When examining the success of chondrocyte growth on spider silk matrices, these same researchers turned to braided spider silk, the suture used to repair structures such as flexor tendons in hand injuries.8 This suture has been shown to provide better long-term mechanical function without the risk for infection or foreign body reactions that occur with traditional suture material.8 Some very small in-vitro experiments examining the potential of spider silk as an antimicrobial agent have been less than robust. Very low-powered activity in the presence of a gram-positive bacteria strain appeared to be sensitive to degradation over time, indicating a possible bacteriostatic action rather than a bactericidal action.9 Activity against a chosen strain of gram-negative bacteria was weak and decreased over time.9

Safety, interactions, side effects Spider silk is surprisingly inert when used with human cell lines. Current research has devised several methods for sterilizing the natural web fibers as well as for removing much of the proteinaceous material that might cause an inflammatory response. As a result of these methods, the safety of the silk itself is proving superior to that of currently used materials.

How supplied, dose, cost

fine wand, delicately winding the fibers onto spools before moving to the next phase of the experiment. Consequently, products that may eventually appear for human use will likely be very costly because of the nature of their production and because of the types of uses for them.

Summary

Will spider silk–treated bandages be available in the near future?

Researchers are able to sterilize the natural web fibers and remove proteinaceous material that may cause an inflammatory response.

It may be some time before we see these products available for widespread use, but the concepts are both intriguing and very promising. Going to the store and buying spider silk–treated bandages could very well be in our future. n References 1. Powers A. Spider silk: stronger than steel? Nature’s super material. Berkely Sci J. 2013;18:46-49. http://escholarship.org/uc/item/2r16q1p5. Accessed September 9, 2016. 2. Griffiths JR, Salanitri VR. The strength of spider silk. J Mater Sci. 1980;15:491-496. 3. Blackledge TA. Spider silk: a brief review and prospectus on research linking biomechanics and ecology in draglines and orb webs. J Arachnology. 2012;40:1-12. http://www. americanarachnology.org/joa_free/joa_v40_n1/arac-40-11.pdf. Accessed September 9, 2016. 4. Allmeling C, Jokuszies A, Reimers K, Kall S, Vogt PM. Use of spider silk fibres as an innovative material in a biocompatible artificial nerve conduit. J Cell Mol Med. 2006;10:770-777. 5. Allmeling C, Jokuszies A, Reimers K, et al. Spider silk fibres in artificial nerve constructs promote peripheral nerve regeneration. Cell Prolif. 2008;41:408-420. 6. Kuhbier JW, Allmeling C, Reimers K, et al. Interactions between spider silk and cells—NIH/3T3 fibroblasts seeded on miniature weaving frames. PLoS ONE. 2010;5:e12032. 7. Gellynck K, Verdonk PC, Van Nimmen E, et al. Silkworm and spider silk scaffolds for chondrocyte support. J Mater Sci Mater Med. 2008;19:3399-3409. 8. Hennecke K, Redeker J, Kuhbier JW, et al. Bundles of spider silk, braided into sutures, resist basic cyclic tests: potential use for flexor tendon repair. PLoS ONE. 2013;8:e61100. 9. Wright S, Goodacre SL. Evidence for antimicrobial activity associated with common house spider silk. BMC Res Notes. 2012;5:326. All electronic documents accessed September 9, 2016.

Unlike most herbs and supplements, medicalgrade spider silk is not readily available to the general public. Of the thousands of species of spiders, several have been singled out because of their superior silk qualities as well as their quantity of production. In laboratory experiments, researchers actually “milk” these spiders by stroking the silk-producing glands with a

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