A PEER-REVIEWED FORUM FOR PHYSICIAN ASSISTANTS
■ Prostate cancer screening ■ Diabetes prevalence ■ Multiple sclerosis guideline LEGAL ADVISOR
Diagnostic test results are ordered but never received
JUNE 2 018
AMYOTROPHIC LATERAL SCLEROSIS
Multidisciplinary care for maximizing function and quality of life A motor neuron from the anterior horn of the spinal cord with an inclusion from ALS
Dry, scaly skin on the lower extremities in a young boy
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Viewpoints in gout and hyperuricemia A history of race and the emerging role of genetics: understanding their influence in primary care PAGE 22
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If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.
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.
It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)
NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s
INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)
YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the
Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.
Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may 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.
These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS
TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecPhysicians Dermatology University of Pennsylvania School blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision It p recurr•ent 44 THE ADVISOR AUGUST 2015 •on www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that infections. for glycemic impede the receptor blocke There are control in ability to cleansenter into this decisio rs are FDA adults with n. Poor hygien should the e and quell -approved child have e may appro diet and exercise, but with type 2 diabetes phimosis, simpl infection potential. appropriate the in ved conjun FDA for use in patien Moreover, AdvisorForum_CA0815.indd urine 44 9/29/15ction 2:38 PM e cathet culture can ts with type has stated that they ketoacidosi steroid cream be a challenge. erization to obtain s, or those are not may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,
is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.
Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous
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VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold
Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.
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Deborah L. Cross, MPH, ANP-B
CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.
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practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.
is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.
CONTENTS JUNE 2018
NEWS AND COMMENT 10 Newsline ■■Screening for prostate cancer: USPSTF recommendation ■■Diabetes prevalence by type in the US ■■New guidelines for multiple sclerosis ■■Some anticholinergic drugs may be linked to a risk for dementia ■■Screening for intimate partner violence 10 Prostate cancer screening
FEATURES 15 Amyotrophic lateral sclerosis: update for the primary care clinician Patients with ALS require multidisciplinary care and rehabilitative interventions.
22 Race and genetics in primary care
22 A history of race and the emerging role of genetics in primary care Race remains prominent in health research and clinical guidelines and is routinely invoked in clinical practice. 34 CME Viewpoints in gout and hyperuricemia: Updated treatment guidance Despite the fact that effective treatments are available, management of the disease is widely recognized as suboptimal. 44 CME/CE Feature posttest
45 Ecchymosis and bullous lesions
Continues on page 6
54 Diagnostic test results never received
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CONTENTS JUNE 2018
DEPARTMENTS , cont’d A PEER-REVIEWED FORUM FOR PHYSICIAN ASSISTANTS
■ Prostate cancer screening ■ Diabetes prevalence ■ Multiple sclerosis guideline LEGAL ADVISOR
Diagnostic test results are ordered but never received
THE CLINICAL ADVISOR • APRIL 2018
THE CLINICAL ADVISOR • MAY 2018
Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com
THE CLINICAL ADVISOR • JUNE 2018
JUNE A 2P018 E E R -|R Ewww.ClinicalAdvisor.com V I E W E D F O RU M F O R N U R S EA PPEER-REVIEWED R AC T I T I O N E R S FORUM | M AY 2FOR 01 8 NURSE | www.ClinicalAdvisor.com PRACTITIONERS | APRIL 2 018
■ Skin cancer prevention
■ Type 2 diabetes guideline ■ Antibiotic-resistant bacteria ■ Adolescent depression Multidisciplinary care Emergence of NOACs ■ Allergic disease risk ■ Varicose veins and DVT ■ IBD and DPP-4 inhibitors for maximizing function expands treatment and quality of life Sudden cardiac death options for patients STAT CONSULT
Advances in reversal agents LEGAL ADVISOR A motor neuron key for preventing bleeding from the anterior A clinician attempts to void horn of the spinal a noncompete clause cord with an LEGAL ADVISOR from ALS A patient dies after inclusion a missed diagnosis
Clinical Pearls ■ X-ray for chronic cough ■ Seasonal allergies ■ Liquid stool softener as an earwax removal agent ■ Postprandial insulin Case Files ■ Arthralgias after cancer
■ Dermatology Clinic
PAINFUL PLAQUES ON THE ELBOWS PAGE 45
A pink rash with fine scale in a 7-year-old boy
FREE CME COURSE
Viewpoints in gout and hyperuricemia A history of race and the emerging role of genetics: understanding their influence in primary care PAGE 22
FREE CME COURSE
Rheumatoid arthritis: a journey toward remission
✶ FREE CE COURSE!
VOLUME 21, NUMBER 4
VOLUME 21, NUMBER 5
Legal Advisor Patient test results never received
Campylobacter jejuni infection can lead to food poisoning and diarrhea.
DVT typically consists of pain and swelling in a lower extremity.
Dry, scaly skin on the lower extremities in a young boy
VOLUME 21, NUMBER 6
Dermatology Clinic ■ Dry, scaly skin in a young boy ■ Ecchymosis and bullous lesions on the back
AMYOTROPHICNEWSLINE LATERAL SCLEROSIS NEWSLINE DEEP VEIN THROMBOSIS A CLINICAL APPROACH FOR
POSTOPERATIVE PAIN MANAGEMENT PAGE 34
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For first-line constipation therapy, stick with the leader
The AGA recommends PEG laxatives (like MiraLAX) as a first-line constipation treatment1
✔ 96% patient satisfaction rate* ✔ #1 GI-recommended laxative for over 10 years Start with MiraLAX for proven relief of occasional constipation. *Survey of 300 consumers, 2017. Use as directed on product labeling or as directed by your doctor. Reference: 1. Clinical decision support tools. American Gastroenterological Association website. http://campaigns.gastro.org/algorithms/constipation/index.html. Accessed May 12, 2017. Bayer, the Bayer Cross, and MiraLAX are trademarks of Bayer. © 2017 Bayer May 2017 68522-PP-MLX-BASE-US-0328
Doctor recommended, patient approved
6/2/17 10:21 AM
EXCLUSIVE TO THE WEB AT
NP, PA Employment Increasing in Primary Care and Specialty Practices Among the top 10 specialties, NPs and PAs are employed in at least a quarter of practices in the following specialties: cardiology, obstetrics-gynecology, dermatology, gastroenterology, and orthopedic surgery.
Dark Chocolate Linked to Enhanced Visual Acuity Contrast sensitivity and visual acuity were significantly higher 2 hours after consumption of a dark chocolate bar compared with a milk chocolate bar.
THE WAITING ROOM
Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Sharon M. O’Brien, MPAS, PA-C Will a New Cooling Device Benefit Patients With Insomnia? Cooling the forehead decreases the brain temperature and reduces frontal cerebral metabolism, which helps promote sleep in insomnia patients.
CASE STUDY ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Mottling and Infection in an Adult
Children With Autism and Their Younger Siblings Are Undervaccinated Children diagnosed with autism spectrum disorder and their younger siblings are less likely to be vaccinated for the recommended vaccines.
Parkinson Drug May Be Linked to Deaths The FDA approval of Nuplazid (pimavanserin) for patients with Parkinson disease psychosis has led to adverse events.
A 44-year-old woman presents to her local emergency department after 5 days of persistent fever, productive cough, and worsening dyspnea on exertion. Read the full case at: ClinicalAdvisor.com/ CaseMottlingInfection Jennifer Freitag, APRN, CNP, and Jennifer Grenell, APRN, CNP Case Study in Diabetes: Fungal Infections A 68-year-old patient with type 2 diabetes presents to a urologist to evaluate funguria, and a CT scan showed right hydroureteronephrosis. Read the full case at: ClinicalAdvisor.com/CaseFungalInfection
MULTIMEDIA ClinicalAdvisor.com/Multimedia Seasonal Allergies: Which Medication Is Right for You? Seasonal allergies are usually caused by plant pollen, which can come from trees, weeds, and grasses in the spring, and by ragweed and other weeds in late summer and early fall. Watch the video here: ClinicalAdvisor.com/ SeasonalAllergyVideo
8 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
Advisor Dx 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. Check out some of our latest cases below!
A large lesion on the thumb A 74-year-old woman presents for treatment of a bothersome lesion on her thumb. She reports a history of arthritis. The lesion is frequently traumatized when doing housecleaning and cooking. A flesh-colored, semitranslucent nodule is noted between the proximal nailfold and the distal interphalangeal joint. No other fingers or toes are similarly affected. CAN YOU DIAGNOSE THIS CONDITION?
• Epidermoid cyst • Ganglion
• Myxoid cyst • Amelanotic melanoma
● See the full case at ClinicalAdvisor.com/DermDx_June18
In partnership with
Journal of Orthopedics for Physician Assistants
Knee pain over the lateral patellofemoral facet joint A 42-year-old woman presents with a few months of right knee pain. The pain is worse when going up and down stairs. She also complains of start-up knee pain after sitting for a long period of time. On examination, she has anterior knee pain over the lateral patellofemoral facet joint. She is noted to have lateral patella tilt on sunrise view radiograph WHICH IS NOT LINKED TO LATERAL TILT OF THE PATELLA?
• Vastus medialis weakness • Tight hamstrings
• Iliotibial band tightness • Genu varum
● See the full case at ClinicalAdvisor.com/OrthoDx_June18
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 9
Newsline THE US PREVENTIVE Services Task Force (USPSTF) has updated its 2012 recommendations on prostate-specific antigen (PSA)–based screening for prostate cancer, according to a study in JAMA. This recommendation applies to adult men in the general US population without symptoms or a previous diagnosis of prostate cancer. It also applies to men with an increased risk of death from prostate cancer because of race/ethnicity or family history of prostate cancer. Screening for prostate cancer in men aged 55 to 69 years offers a small potential benefit of reducing the chance of death. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and
treatment complications, such as incontinence and erectile dysfunction. The USPSTF does not recommend screening for prostate cancer unless men express a preference for screening after being informed of and understanding the benefits and risks.The USPSTF also concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms. In 2012, the USPSTF concluded that although there are potential benefits of screening for prostate cancer, these benefits did not outweigh the expected harms enough to recommend routine screening (D recommendation). The change in recommendation grade is based in part on additional evidence that increased the USPSTF’s certainty about the reductions
© JARUN011 / GETTY IMAGES
Screening for prostate cancer: USPSTF recommendation
in risk of dying of prostate cancer and risk of metastatic disease. In an editorial commentary, H. Ballentine Carter, MD, , stated, “The USPSTF has provided a timely and careful approach to reassessment of the benefits and harms of PSA-based screening for prostate cancer. Patients, together with their physicians, should decide whether prostate cancer screening is right for the patient.”
Diabetes prevalence by type in the US: a CDC report THE PREVALENCE of diagnosed type 2 diabetes in the United States in 2016 was 8.6%, or 21.0 million adults, while the prevalence of diagnosed type 1 diabetes was 0.55%, or 1.3 million adults, according to the Centers for Disease Control and Prevention (CDC). Non-Hispanic white adults had a higher prevalence of diagnosed type 1 diabetes compared with Hispanic adults, and non-Hispanic blacks had the highest prevalence of diagnosed type 2 diabetes, as reported in Morbidity and Mortality Weekly Report.
The findings are based on the 2016 NHIS Sample Adult Core, which consisted of 33,028 adults aged 18 years and older. A total of 3,519 respondents reported having diabetes, including 211 classified as having type 1; 3,210 classified as having type 2 (including 182 who reported having type 1, but not taking insulin; 2,897 who reported having type 2; one who reported an unknown type; and one refusal); and 98 classified as having “other” type. The prevalence of type 1 diabetes, type 2 diabetes, and other diabetes types was 0.55%, 8.58%,
10 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
and 0.31%, respectively. The weighted percentages of all diagnosed diabetes cases that were type 1 and type 2 were 5.8% and 90.9%, respectively; the remaining were other types. Based on the weighted NHIS population, the estimated numbers of adults with type 1, type 2, and other diabetes types were 1.3 million, 21.0 million, and 0.8 million, respectively. The prevalence of type 1 diabetes was higher among men (0.64%) than among women (0.46%) and higher among nonHispanic whites (whites) (0.67%) than among Hispanics (0.22%).
New guidelines for multiple sclerosis STARTING TREATMENT with disease-modifying therapy (DMT) for multiple sclerosis (MS) as early as possible allows for the greatest chance to alter disease course, according to new MS guidelines published by the American Academy of Neurology (AAN). A systematic review was conducted by the AAN’s Guidelines Development, Dissemination, and Implementation Subcommittee and included 20 Cochrane reviews and 73 full-text articles. Overall, the authors found high-quality evidence suggesting that in patients with RRMS, many DMTs are superior to placebo for the reduction of annualized relapse rates and new disease activity as measured by new MRI T2 lesion burden and disease progression. Patients with primary progressive MS may benefit from treatment with ocrelizumab vs placebo for reducing disease progression, and
treatment with glatiramer acetate and interferon beta-1a vs placebo is more likely to reduce the risk for conversion to MS in patients with clinically isolated syndrome. “We now know that treating earlier is better in reducing the number of new relapses and reducing the chance of having more injury to the brain,” stated guideline author Alexander Rae-Grant, MD, FRCP, FAAN. The panel made recommendations in the following areas: patient engagement; individualization of treatment; monitoring of treatment adherence; assessment of disease comorbidities; identifying which patients should begin DMT treatment; switching DMTs after a disease breakthrough event; and counseling on risks associated with DMTs.The recommendations were categorized based on level of obligation: Level A (must), Level B (should), and Level C (may).
Screening for intimate partner violence THE US PREVENTIVE Services Task Force (USPSTF) has found that screening for intimate partner violence (IPV) is beneficial for reproductive-aged women, although there is inadequate evidence to weigh the balance of benefits and harms of screening for abuse in elderly and vulnerable adults, according to a draft recommendation statement. The task force reviewed studies that included women from adolescence to about age 40 years, with most research focusing on women aged 18 years or older. This review identified 15 fairquality studies (n=4,460) that assessed the accuracy of 12 screening tools for IPV. The USPSTF found adequate evidence that available screening instruments can identify IPV in women. The task force found inadequate evidence to assess
the accuracy of screening instruments designed to detect elder abuse or abuse of vulnerable adults. The USPSTF found inadequate direct evidence that screening for IPV can reduce violence, abuse, and physical or mental harms in adults and adolescents. However, the task force found adequate evidence that effective interventions can reduce violence, abuse, and physical or mental harms in women of reproductive age. The USPSTF concluded with moderate certainty that screening for IPV in women of reproductive age and providing or referring women who screen positive to ongoing support services has a moderate net benefit.The task force also concluded that the benefits and harms of screening for elder abuse or abuse of vulnerable adults are uncertain.
Some anticholinergic drugs may be linked to a risk for dementia THE USE OF certain classes of anticholinergic drugs is linked to prospective dementia and cognitive decline, according to a study published in the BMJ. The study included 40,770 participants between the ages of 65 and 99 with dementia and 283,933 participants without dementia (control cohort).The primary outcome was the odds ratio (OR) for dementia.The Anticholinergic Cognitive Burden (ACB) scale was used to define drug doses. Eligible patients in the case group were administered anticholinergic drug(s) 4 to 20 years prior to dementia diagnosis. Of the entire case group, 35% of patients (n=14,453) were prescribed at least one anticholinergic drug with definite anticholinergic activity, recorded with an ACB score of 3; 30% of control participants (n=86,403) scored 3 on the ACB scale for the same criteria (OR, 1.11). An increased ACB score was positively correlated with increased likelihood of dementia. Dementia was also positively correlated with increased exposure to antidepressants and urologic and antiparkinson drugs with anticholinergic activity but not in gastrointestinal drugs. “A robust association between some classes of anticholinergic drugs and future dementia incidence was observed,” reported the authors.“This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure. ■
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 11
FEATURE: TERI CAPRIOTTI, DO, MSN, CRNP; ERIN DONNELLY; SIMONE BRISSENDEN
Amyotrophic lateral sclerosis: update for the primary care clinician Patients with ALS require multidisciplinary care and rehabilitative interventions; maximizing independent function and quality of life are the goals.
© ISM / PR J.J. HAUW / MEDICALIMAGES.COM
Motor neuron from the spinal cord containing an inclusion from ALS.
myotrophic lateral sclerosis (ALS), which is often referred to as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that is characterized by a loss of upper and lower motor neurons. Muscle weakness and atrophy develop gradually over many years. Often, the diagnosis is delayed because of the vague symptomatology, and primary care clinicians may be the first healthcare providers whom patients consult. Primary care clinicians should refer patients with suspected neurodegenerative symptoms to a neurologist, preferably one who specializes in movement disorders. Primary care clinicians may also be involved in palliative care and symptom management as the disease process progresses. Frequently, primary care clinicians are also a source of education and support for the caregivers of patients with ALS. It is diﬃcult to estimate the incidence and prevalence of ALS because it is not a reportable disease. According to the Mehta et al, the estimated incidence of ALS across all ages is approximately 4 to 5 persons per 100,000.1 ALS is diagnosed each year in the United States in an estimated 5000 persons, with an estimated prevalence of 12,000 to 15,000 cases.ALS is more prevalent in men than in women, with a typical age at diagnosis of 55 to 75 years.1,2
The etiology of ALS is unknown, but some risk factors have been proposed, including genetic predisposition, toxic eﬀects of heavy metal, viral infection, environmental and occupational exposures, www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 15
AMYOTROPHIC LATERAL SCLEROSIS
POLL POSITION Which of the following have you most frequently recommended for patients with ALS?
6.74% ■ Medication ■ Physical therapy
■ Speech therapy ■ Nutritional support
personnel who have served in the Middle East.14 Malfunction of RNA transcription and splicing is a common causal factor in both familial and sporadic ALS, in which the accumulation and misassembly of neurofilaments disrupt neuronal axon integrity—another hallmark of ALS pathology.15
■ Breathing support 4.49%
For more polls, visit ClinicalAdvisor.com/Polls.
cigarette smoking, repeated physical trauma, military service, and participation in strenuous physical activity, such as professional athletics.3-5 Investigations into etiology have revealed a pathologic overlap between frontotemporal degeneration (FTD) and ALS; these two diseases have similar features.6,7 Two classifications of ALS have been described: familial (inherited) and sporadic. Approximately 10% of all cases of ALS are thought to be familial and due to genetic mutations.8 Numerous genetic mutations have been associated with ALS. A mutation in the superoxide dismutase gene 1 (SOD1) accounts for approximately 20% of familial cases of ALS. Superoxide dismutase is a critical enzyme involved in protecting mitochondria from oxidative stress.8 In addition, a repeated nucleotide abnormality at the 9p21 genetic locus, termed the C9orf72 mutation, has been detected in 60% of familial cases of ALS and 10% of sporadic cases.9 At the molecular level, the pathology of ALS is highly complex, and dysfunction has been found in numerous cellular components. However, the “trigger” of these cellular changes is unknown.A pathologic process of excessive glutamate excitation of motor neurons, leading to degeneration and dysfunction, is found in ALS.10 Mitochondrial abnormalities in the spinal cord, such as swelling and vacuolization, are a pathologic hallmark of ALS.11 The presence of proteinaceous aggregates in the spinal cord in ALS suggests malfunction of protein degradation and clearance.12 Diminished levels of vascular endothelial growth factor (VEGF) and angiogenin (ANG), which are involved in the maintenance of neural networks and vasculature, have also been implicated in ALS.13 A neurotoxin, β-methylamino-Lalanine, is related to ALS in some populations, including military
ALS progressively destroys the motor neurons that control voluntary muscles. Upper motor neurons, located in the brain, send messages to lower motor neurons in the spinal cord and from there to various voluntary muscle groups. In individuals affected by ALS, both the upper and lower motor neurons become sclerotic and die. Consequently, the neurons can no longer conduct impulses to the muscles, so that muscular weakness and atrophy develop. In a process called astrocytic gliosis, lost motor neurons are replaced by astrocytes, which form a kind of scar tissue that can be seen on magnetic resonance imaging (MRI) within the corticospinal tracts, brain stem, and spinal cord. Motor neuron degeneration is accompanied by a neuroinflammatory process and the proliferation of glial cells (gliosis), which do not conduct impulses.16,17 Eventually, as damage to the motor neurons increases, the brain is unable to start or adequately control voluntary muscle movement. The affected muscles become increasingly weak and atrophic, and the muscles that control speech, swallowing, and breathing slowly become impaired. Ultimately, paralysis develops, and the patient requires artificial ventilation for respiratory failure.18 ALS damages motor neurons, but the sensory neurons usually remain intact—the senses of sight, touch, hearing, taste, and smell are not affected.The eye muscles and sphincter control are spared.8 Cognitive impairment is not a major feature of ALS, and dementia does not occur in all patients. However, a link between ALS and FTD has recently been postulated because the two conditions are characterized by similar neuropathologic changes, clinical features, and genetic mutations. Some investigators refer to this overlap of features as the ALS-FTD spectrum.19-22 Clinical presentation
The initial symptoms of ALS may include cramping and weakness in the upper and lower extremities. Foot drop and clumsiness may cause the patient to fall. Twitching, stiffness, slurred speech, and difficulty walking occur.8 Symptoms of upper motor neuron involvement include muscle spasticity, hyperreflexia, and the presence of a Babinski reflex. Symptoms of lower motor neuron damage include muscle weakness, atrophy, cramping, and fasciculations.22 Emotional lability due to pseudobulbar palsy may also develop.23 Later in the disease process, dysphagia due to esophageal muscle dysfunction, inability to move the arms and legs, dysarthria, dysphonia, and respiratory failure commonly
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occur. In more than half of patients with ALS, hypermetabolism causes weight loss, muscle wasting, and cachexia.24 In the past, ALS was thought to spare cognitive function but is now known to cause a range of cognitive impairments. According to Gillingham et al,25 50% of persons with ALS have mild cognitive impairment with subtle executive deficits, and 10% to 15% have FTD.26,27
Symptom management and palliative care
ALS is usually diagnosed on the basis of clinical symptomatology. Alternative diagnoses can usually be ruled out with neuroimaging studies and laboratory evaluation. Because ALS is a diagnosis of exclusion, a substantial delay in diagnosis, upward of 12 months after the onset of symptoms, is common, and patients may seek health care from multiple providers early in the disease course.28 No laboratory tests can identify the disorder, no biomarkers for the condition are known, and the findings on MRI and computed tomography (CT) are unremarkable. Electromyographic (EMG) studies may be helpful to rule out muscle or neurologic conditions that can mimic ALS.The value of positron emission tomography (PET), functional MRI, and magnetic resonance spectroscopy in ALS is being studied.29 For a diagnosis of ALS, the patient must have signs and symptoms of both upper motor neuron and lower motor neuron damage that cannot be attributed to other causes.Two classification systems have attempted to characterize definite versus probable signs of ALS. The El Escorial criteria, which experts commonly use, rely mainly on the clinical examination findings (Table 1).30 Some investigators find that use of the Awaji criteria allows an earlier diagnosis. The Awaji criteria include EMG results for the identification of lower and upper motor neuron damage and incorporate fasciculation potentials as evidence of ALS (Table 1).31-33
A neurologist and a multidisciplinary team are required for the management of ALS.Whenever possible, primary care clinicians should refer the patient to a specialized ALS clinic.Treatments to manage the various symptoms can improve the quality of life (Table 2). Medications to reduce fatigue, relieve muscle cramps, control spasticity, and reduce excessive oral secretions can be beneficial. Gentle, low-impact aerobic activity and range-ofmotion and stretching exercises can help to prevent painful muscle spasticity and contractures. When respiratory muscles weaken, intermittent positive pressure ventilation may be used to ease the work of breathing during sleep. Most patients remain asymptomatic until the forced vital capacity (FVC) is less than 50% of the predicted level as a result of respiratory muscle weakness.The patient’s preferences regarding life-sustaining treatment and approaches to palliative care should be discussed soon after the diagnosis of ALS, and any decisions should be reconsidered on several occasions before respiratory failure occurs.
No cure is available for ALS. However, riluzole is believed to reduce the damage to motor neurons by decreasing the release of the excitatory neurotransmitter glutamate. Another drug, edaravone, is a free radical scavenger that is thought to decrease oxidative stress on neurons in ALS. Both drugs claim to slow the progression of ALS, and studies reveal modest results.34,35
The primary care clinician may be involved early in the ALS disease process. Often, the diagnosis is delayed because the clinical presentation is unclear at an early stage.The primary care clinician may be involved in managing the symptoms of a patient with ALS and serve as a source of support for
TABLE 1. Criteria used to diagnose amyotrophic lateral sclerosis Criteria
Definite diagnosis of ALS
El Escorial criteria
UMN and LMN signs in 3 regions
UMN and LMN signs in 2 regions with UMN signs rostral to LMN signs
UMN and LMN signs in 1 region, UMN signs alone in 2 or more regions, or LMN signs rostral to UMN signs
Clinical or EMG evidence, demonstrated by the presence of UMN and LMN signs in the bulbar region and at least 2 spinal regions, or the presence of UMN and LMN signs in 3 spinal regions
Clinical or EMG evidence, demonstrated by the presence of UMN and LMN signs in the bulbar region and at least 2 spinal regions, or the presence of UMN and LMN signs in 3 spinal regions with some UMN signs necessarily rostral to the LMN signs
Clinical or electrophysiologic signs of UMN and LMN dysfunction in only 1 region, or UMN signs alone in 2 or more regions, or LMN signs rostral to UMN signs
ALS, amyotrophic lateral sclerosis; EMG, electromyographic; LMN, lower motor neuron; UMN, upper motor neuron. From Hardiman O et al.36
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AMYOTROPHIC LATERAL SCLEROSIS
TABLE 2. Symptoms of amyotrophic lateral sclerosis and suggested treatment Symptom
Modafinil 100-300 mg/d
Baclofen,Tizanidine, Dantrolene, Benzodiazepines, Levetiracetam, Cannabinoidsa
Physical therapy, stretching, ROM exercise; Hydrotherapy, Cryotherapy, Heat, Ultrasound
Pain (muscle cramps)
NSAIDs, Non-opioid analgesics, Muscle relaxants, Levetiracetam, Gabapentin, Botulinum toxin, Tricyclic antidepressants
Physical therapy, Occupational therapy, Pressure-relieving mattress, Foam wedges to facilitate proper positioning, Daily ROM exercise, Orthotics, Walkers, wheelchairs, Quad cane, Hand-held shower, bath bench, grab bars, raised toilet seat, commode, ADL aids (occupational therapy consultation); Removal of throw rugs, Exercise strategies: ROM, stretching, resistance, aerobic
Fiber supplement, Fluid increase, Stool softeners, Lactulose/ polyethylene glycol (osmotic agents), Mild laxatives
Excessive salivation (can cause choking and aspiration pneumonia)
Amitriptyline 10 mg tid, Atropine drops 0.5%-1% SL qid, Glycopyrrolate 1 mg tid, Transdermal scopolamine 1.5 mg every third day
Botulinum toxin injection into salivary glands, Salivary gland radiation
Benzodiazepines, Zolpidem tartrate 10 mg qhs Antidepressant: mirtazapine 15 mg qhs
Electrical hospital bed to enhance positioning, NIPPV
Pseudobulbar affect (uncontrollable laughter, crying, emotional outbursts)
SSRI antidepressants, Tricyclic antidepressants, Dextromethorphan 20 mg/quinidine sulfate, 10 mg (Nuedexta)
Respiratory insufficiency (due to respiratory muscle weakness, lack of full inspiration; most patients asymptomatic until FVC <50% of predicted value)
Puréed food, Fluid thickeners, Enteral feeding
Communication difficulty (dysarthria)
Speech therapy, Computerized communication boards
Flu vaccine annually, Pneumovax (pneumococcal polysaccharide vaccine)
ADL, activities of daily living; FVC, forced vital capacity; NIPPV, noninvasive positive pressure ventilation; NSAIDs, nonsteroidal anti-inflammatory drugs; qhs, each bedtime; qid, 4 times daily; ROM, range of motion; SL, sublingually; SSRI, selective serotonin reuptake inhibitor; tid, 3 times daily. a See Amtmann et al.37 Adapted from Hobson EV and McDermott CJ26 and from Hardiman O et al.38
the caregiver(s). Patients require multidisciplinary care and rehabilitative interventions; maximizing independent function and quality of life are the goals. Family members, particularly spouses, commonly care for patients with ALS.The caregiver role frequently causes strain, which generally increases as the disease process progresses. Continued support and education from the primary care provider are essential for caregivers. Currently, numerous investigations into the genetic basis of ALS and the development of drugs to diminish the progressive degeneration associated with this disease are under way. ■
Teri Capriotti, DO, MSN, CRNP, is a clinical associate professor, Erin Donnelly is an honors student, and Simone Brissenden is an honors student at Villanova University, PA. References 1. Mehta P, Kaye W, Bryan L, et al. Prevalence of amyotrophic lateral sclerosis– United States 2012-2013. MMWR Surveill Summ. 2016;65 (No. SS-8): 1-12. https://www.cdc.gov/mmwr/volumes/65/ss/ss6508a1.htm. Accessed April 24, 2018.
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2. Centers for Disease Control and Prevention. National amyotrophic
20. Liscic RM. Als and Ftd: insights into the disease mechanisms and
lateral sclerosis registry. https://www.cdc.gov/als/Default.html. Updated
therapeutic targets. Eur J Pharmacol. 2017 Oct 12. doi: 10.1016/j.ejphar.2017.
February 8, 2018. Accessed April 24, 2018.
10.012 [Epub ahead of print]
3. Beard JD, Kamel F. Military service, deployments, and exposures in
21. Trojsi F, Siciliano M, Femiano C, et al. Comorbidity of dementia with
relation to amyotrophic lateral sclerosis etiology and survival. Epidemiol Rev.
amyotrophic lateral sclerosis (ALS): insights from a large multicenter Italian
cohort. J Neurol. 2017;264:2224-2231.
4. Peters TL, Kamel F, Lundholm C, et al. Occupational exposures and the risk
22. van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis.
of amyotrophic lateral sclerosis. Occup Environ Med. 2017;74:87-92.
Lancet. 2017 Nov 4;390(10107):2084-2098. doi: 10.1016/S0140-6736
5. Wang MD, Little J, Gomes J, Cashman NR, Krewski D. Identification
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of risk factors associated with onset and progression of amyotrophic
23. Thakore NJ, Pioro EP. Laughter, crying and sadness in ALS. J Neurol
lateral sclerosis using systematic review and meta-analysis. Neurotoxicology.
Neurosurg Psychiatry. 2017;88:825-831.
24. Vucic S. Hypermetabolism appears to be an adverse prognostic biomarker
6. Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of
in ALS. A potential for therapeutic intervention? Eur J Neurol. 2017 Sep 20.
genes, environment and time. Nat Rev Neurol. 2013;9:617-628.
doi: 10.1111/ene.13470 [Epub ahead of print]
7. Strong MJ, Abrahams S, Goldstein LH, et al. Amyotrophic lateral
25. Gillingham SM, Yunusova Y, Ganda A, et al. Assessing cognitive
sclerosis – frontotemporal spectrum disorder (ALS-FTSD): revised
functioning in ALS: a focus on frontal lobe processes. Amyotroph Lateral
diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;
Scler Frontotemporal Degener. 2017;18:182-192.
26. Hobson EV, McDermott CJ. Supportive and symptomatic management
8. Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med.
of amyotrophic lateral sclerosis. Nat Rev Neurol. 2016;12:526-538.
27. Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic
9. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics
lateral sclerosis. Lancet Neurol. 2007;6:994-1003.
of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat
28. Salameh JS, Brown RH Jr, Berry JD. Amyotrophic lateral sclerosis: review.
expansion: a population-based cohort study. Lancet Neurol. 2012;11:232-240.
Semin Neurol. 2015;35:469-476.
10. King AE, Woodhouse A, Kirkcaldie MT, Vickers JC. Excitotoxicity in ALS:
29. Jésus P, Fayemendy P, Nicol M, et al. Hypermetabolism is a deleterious
overstimulation, or overreaction? Exp Neurol. 2016;275 Pt 1:162-171.
prognostic factor in patients with amyotrophic lateral sclerosis. Eur J Neurol.
11. Smith EF, Shaw PJ, De Vos KJ. The role of mitochondria in amyotrophic
lateral sclerosis. Neurosci Lett. 2017 Jun 30. doi: 10.1016/j.neulet.2017.06.052
30. Al-Chalabi A, Hardiman O, Kiernan MC, Chiò A, Rix-Brooks B, van den
[Epub ahead of print]
Berg LH. Amyotrophic lateral sclerosis: moving towards a new classification
12. Webster CP, Smith EF, Shaw PJ, De Vos KJ. Protein homeostasis in
system. Lancet Neurol. 2016;5:1182-1194.
amyotrophic lateral sclerosis: therapeutic opportunities? Front Mol Neurosci.
31. Costa J, Swash M, de Carvalho M. Awaji criteria for the diagnosis of amyo-
2017;10:123. doi: 10.3389/fnmol.2017.00123. eCollection 2017.
trophic lateral sclerosis: a systematic review. Arch Neurol. 2012;69:1410-1416.
13. Keifer OP Jr, O’Connor DM, Boulis NM. Gene and protein therapies
32. Geevasinga N, Menon P, Scherman DB, et al. Diagnostic criteria in
utilizing VEGF for ALS. Pharmacol Ther. 2014;141:261-271.
amyotrophic lateral sclerosis: a multicenter prospective study. Neurology.
14. Cox PA, Richer R, Metcalf JS, Banack SA, Codd GA, Bradley WG.
Cyanobacteria and BMAA exposure from desert dust: a possible link to spo-
33. Li DW, Liu M, Cui B, et al. The Awaji criteria increases the diagnostic
radic ALS among Gulf War veterans. Amyotroph Lateral Scler. 2009;10 Suppl
sensitivity of the revised El Escorial criteria for amyotrophic lateral sclerosis
diagnosis in a Chinese population. PLoS One. 2017;12:e0171522. doi:
15. Xu Z, Henderson RD, David M, McCombe PA. Neurofilaments as bio-
10.1371/journal.pone.0171522. eCollection 2017.
markers for amyotrophic lateral sclerosis: a systematic review and meta-
34. Miller RG, Appel SH. Introduction to supplement: the current status
analysis. PLoS One 2016;11: e0164625. doi: 10.1371/journal.pone.0164625.
of treatment for ALS. Amyotroph Lateral Scler Frontotemporal Degener.
16. Menke RA, Agosta F, Grosskreutz J, Filippi M, Turner MR. Neuroimaging
35. Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic
endpoints in amyotrophic lateral sclerosis. Neurotherapeutics. 2017;14:11-23.
lateral sclerosis. Expert Opin Pharmacother. 2017;18:735-738.
17. Philips T, Rothstein JD. Glial cells in amyotrophic lateral sclerosis. Exp
36. Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and
Neurol. 2014;262 Pt B:111-120.
management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7:639-649.
18. Connolly S, Galvin M, Hardiman O. End-of-life management in patients
37. Amtmann D, Weydt P, Johnson KL, Jensen MP, Carter GT. Survey of
with amyotrophic lateral sclerosis. Lancet Neurol. 2015;14:435-442.
cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat
19. Couratier P, Corcia P, Lautrette G, Nicol M, Marin B. ALS and frontotem-
poral dementia belong to a common disease spectrum. Rev Neurol (Paris).
38. Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat
Rev Dis Primers. 2017;3:17071.
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A history of race and the emerging role of genetics in primary care Race and genetics have a prominent role in health research and clinical guidelines and are routinely invoked in clinical practice. In 2003, the Human Genome Project became the culmination of the history of genetics research, allowing us to understand the role of genetics in human health and disease. As part of The Clinical Advisor’s 20th Anniversary, this article explores the influence of race and genetics in clinical practice.
© SAM OGDEN / SCIENCE SOURCE
A geneticist works on a sequencing machine on the Human Genome Project.
22 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
edical professions, including the field of genetics, have long struggled with defining race. “Race” remains an especially fraught and imprecise term.1 In the first few decades of the 20th century, race was defined by the notion that one member of a race was thought to share the same social and physical traits as other members of that race.2 Historically, race has been mapped into continental populations and described in the context of evolutionary biology. In recent years, however, the concept of race has become a way to understand the frequency of individual genes in diverse human populations.2 Today, new genetic data have enabled researchers to re-examine the relationship between human genetic variation and race.3 Race remains prominent in health research and clinical guidelines and is routinely invoked in clinical practice.4 Recent studies suggest that race is important to consider in clinical care because it provides common assumptions about biologic genetics and cultural characteristics as these factors relate to health.4 The need for a genetically competent workforce that can assure
advanced care practitioners’ ongoing participation in translation of genomic discoveries into everyday health care will be vital for inclusion of race in health research, evidence-based practice (EBP), and clinical guidelines.This article will address genetic disorders in relation to race, analyze trends in contemporary issues, and discuss potential innovations for healthcare practice, as well as evaluate the evidence for appropriateness when applying an intervention or a treatment modality into clinical practice. Literature and studies
The term “race” in scientific literature refers to biologic differences between groups who are assumed to have different biogeographic ancestries or genetic makeup.5 Race is a construct of human variability based on perceived differences in biology, physical appearance, and behavior.5 In the United States, the majority of racial differences in health are explained by socioeconomic status and factors surrounding access to medical care.6 To fully understand the role of race in clinical practice, it is important to consider the contribution of genetic factors. Researchers describe the variation in gene alteration or gene expression by race or ancestry.6 There are various barriers to genomic medicine for racial minorities such as socioeconomic status, rural settings, and lack of participation. Moreover, clinical trial research, including biomarkers and drug development, continues to lack inclusion of and participation by minorities.6 This lack of representation presents a disadvantage for minority groups such as people from African ancestries. Most large-scale, genome-wide association studies have been conducted in populations of European ancestry.6 Although there has been an improvement in research on genetics and race, further studies need to be conducted as precise genetic information on race could affect clinical practice. Background
Some disease processes are more prevalent in specific races versus others and present more frequently in clinical practice. Sickle cell disease (SCD), for example, is prevalent in AfricanAmerican and African populations, as well as in populations from descendants with Mediterranean heritage.7 Tay-sachs disease (TSD) is more likely to occur among people of Ashkenazi (Eastern and Central European) Jewish or FrenchCanadian ancestry. Cystic fibrosis (CF) is common among people of European lineage. Alpha thalassemia mostly affects people of Southeast Asian, Indian, Chinese, or Filipino descent, whereas beta thalassemia most often affects people who are of Mediterranean (Greek, Italian, and Middle Eastern), Asian, or African descent.7,8
In the last few decades since the decoding of the human genome, a growing wealth of data have made it clear that the concept of race and genetics is complex.9 The analysis of genomes around the world confirms that there is a biologic basis for race, despite statements to the contrary from some social science organizations.9 For example, in mixed races such as African-Americans, geneticists can now track a person’s genome and assign each segment to African or European ancestors. This analysis would be impossible if race did not have some basis in genetic and biologic component.9 Prevalence and incidence of conditions
The demographics of race throughout the world population vary:African (11.8%),Asian (47.8%), European (15.4%), Mixed races (4.9%), Native American (0.9%), Middle Eastern (10.9%), Oceanic (3.4%), and other (5%).10 Similarly, in the United States, demographics of race throughout the population vary: whites (61%), blacks (12%), Hispanics (18%), Asian (6%), and American/Alaska Native (1%).11 Globally, approximately 5% of children are born with genetic disorders,12 whereas in the US, approximately 3% of children are born with genetic disorders.13 The most commonly reported genetic conditions are SCD, TSD, CF, and thalassemia. These disorders have an autosomal recessive mode of inheritance and have higher carrier rates in specific races or patient populations.14 In the US, SCD occurs in nearly 1 of every 365 African American births and is estimated to affect about 100,000 Americans.12 Approximately 1 in 13 African Americans is born with sickle cell trait (SCT).12 Sickle cell trait is an inherited sickle cell gene from one or both parents.15 SCT is not a disease and people with SCT do not show symptoms of SCD and are able to live a normal life.15 The incidence of SCT in the US is estimated as 73.1 cases per 1,000 black newborns, 2.2 cases per 1,000 Asian or Pacific Islander newborns, 6.9 cases per 1,000 Hispanic newborns, and 3.0 cases per 1,000 white newborns.12 The frequency of TSD is much higher in the Ashkenazi Jews of Eastern European origin than in others.16 Approximately 1 of every 27 Jewish people in the US is a carrier of the TSD gene.16 Among Jewish people of Sephardic origin, the carrier rate is about 1 in 250.16 French-Canadians and the Cajun community of Louisiana have the same carrier rate as Ashkenazi Jews, 1 in 27. Also, people of Irish ancestry have an increased risk for the TSD gene mutation.16 Current research studies indicate that among Irish Americans, the carrier rate is about 1 in 50.16 The incidence of CF varies across around the world.Although it is underdiagnosed in Asia, existing evidence
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RACE AND GENETICS
Diseases affected by race
indicates that the prevalence of CF is rare among this population. In the European Union, 1 in 2,000 to 3,000 newborns is found to be affected by CF.16 In the US, the incidence of CF is reported to be 1 in every 3,500 births.16 The prevalence of thalassemia varies with geographic locations. It is estimated in India that 0.37 per 1,000 fetuses have a hemoglobin disorder.17 Beta thalassemia, the most severe form of thalassemia, affects at least 1,000 people in the US.18 Impact on person and family
IMAGES: TOP: © BIOLOGY PICS, MIDDLE: © RALPH C. EAGLE, JR., BOTTOM: © JAMES CAVALLINI. ALL IMAGES FROM SCIENCESOURCE.COM
Sickle cell anemia is an inherited blood disease largely affecting black people, in which the red blood cells contain abnormal hemoglobin, the oxygen-carrying pigment.
All patients with Tay-Sachs disease have a “cherry-red” spot, easily observable by a clinician using an ophthalmoscope, in the back of their eyes.
CT scan of the thorax showing respiratory diseases due to cystic fibrosis. Cystic fibrosis is a genetic disease affecting the glandular epithelium of many organs.
The diagnosis of a genetic disorder and test results have wideranging implications for patients and their families.19 Genetic information can have a strong emotional impact, such as feelings of blame, guilt, sadness, alienation, and futility. It is important that patients from every race realize and understand the cause of a genetic disorder and their inability to cause or change genetic risk. The cost of genetic testing, diagnosis, and disorder can be a burden to people from races with high prevalence of genetic disorders. This burden can lead to greater stress potentially affecting both physical and mental well-being of patients as well as their family members.20 The lack of information on genomics and limited financing options are barriers that affect the use of genetic services and resources among patients in both high income and low-to-middle-income populations. Furthermore, due to the nature of genomics, cultural norms play a major role in determining beliefs, attitudes, and behaviors of patients toward the science of genetic testing and its implications.20 Current diagnostic criteria and diagnostic aids
Diagnostic testing, such as genetic testing, identifies changes in chromosomes, genes, or proteins.The results of a genetic test can confirm or rule out a suspected genetic disorder and help determine an individual’s probability of developing or passing on a genetic disorder to his or her offspring.21 Early testing, such as newborn screening, is critical in chromosomal genetic testing, as this may produce improved health outcomes.22 Newborn screening (NBS) is the practice of testing every newborn for certain harmful or potentially fatal conditions that typically are not otherwise apparent at birth.23 Universal NBS has become a well-established, state-based, public health system involving education, screening, diagnostic follow-up, treatment and management, and system monitoring and evaluation.23 It is important to routinely screen for genetic conditions, especially disorders prevalent in certain races. NBS requires a capillary specimen collected between 24 and 48 hours of age, to ensure the results will come back by the time the newborn begins to exhibit symptoms. A second
24 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
sample is then collected between 1 and 2 weeks of age for the newborn, as some disorders are not detectable until this time frame, making an additional test needed.24 Each year, more than 98% of approximately 4 million newborns in the US are screened.25 Through early identification, newborn screening offers an opportunity for treatment and significant reductions in morbidity and mortality.23 Of the 4 million infants screened, approximately 12,500 are diagnosed with 1 of the 29 core conditions of the uniform screening panel.23 The goal of newborn screening is the pre-symptomatic detection of infants with congenital conditions so treatment may be initiated as early as possible to prevent, or ameliorate, the long-term consequences of the condition.26 Most states in the US screen for SCD, TSD, CF, and thalassemia in newborns.26 It is important for clinicians to be aware of the conditions that newborns are screened for in the state in which they practice. Potential innovations for healthcare practice
Discoveries about the role of race in genetics can decrease disease incidence, associated morbidity, and present a distinctive opportunity to impact healthcare costs; however, these discoveries will be limited by the lack of knowledgeable professionals who can educate different races and communities on the risks, benefits, or value of such genetic tests.27 The role of race in genomics has produced an unprecedented number of assets to propel innovation. Initial accessibility of genomicsbased applications in economic medicine validate a substantial potential to address worldwide challenges and is one of the most discernible areas in which genomics innovation is likely to add to a more individualized, predictive, and preventive medical practice. It is reasonable to foresee that genomics applications will lead to a shift in the ability to ease substantial health, economic, and social encumbrances of people of different races.28 The pace at which racial genomic data are being produced poses important technologic challenges for data storage, processing capacity, quality control management, and the interpretation of vast amounts of sequence data.29 In addition, the cost of genomics technologies is still a major constraint inhibiting genomics innovations from more expeditious advancement.29 It is reasonable to predict that novel high-throughput sequencing and analytical technologies will emerge, and given the size of the markets integrating these technologies into their processes, costs will continue to decrease to a level at which global access becomes possible.29 To successfully benefit from genomics innovations regarding race, it is imperative to address numerous hurdles related to generating large quantities of scientific evidence, developing lower-cost sequencing technologies, effective bioinformatics, as well as sensitive ethical,
legal, and social aspects associated with the development and use of genomics innovations.28 Some clinicians debate that taking race into consideration is clinically useful and can provide insight into a patients’ genetic heritage and behavioral habits. Others argue that such practices are not scientifically defensible and may increase disparities by promoting stereotyping, and minority patients may receive “racialized care,” rather than care designed to be specifically and culturally appropriate for them as individuals. Despite this debate, the prevalence of race conveys that racial identity is pertinent to genetic variation and that certain racial groups are to be considered “at-risk” for some diseases or genetic conditions.4 EBP management and treatment of genetic disorders varies based on the genetic condition and an individual’s health needs. Most EBP treatment and management strategies for genetic disorders do not alter the underlying genetic mutation; however, a few conditions have been treated with gene therapy.4 Experimental techniques involving changing a person’s genes to prevent or treat a disease along with other treatment and management approaches for genetic disorders are being studied in clinical trials.4 EBP and guidelines for disease conditions are constantly changing based on research and clinical trials. It is important for clinicians to be current with the guideline in treating and managing genetic conditions. Potential ethical, legal and social (ELSI) conflicts
The swift and constant feed of new evidence from scientific discoveries related to the human genome makes translation and incorporation of information into the clinical setting problematic and generates potential ethical, legal, and social challenges for clinicians.25 Ethical and legal fundamentals provide a framework for comprehending the appropriate integration of genomic information and its translation into healthcare practice.30 Primary care providers have a professional responsibility to ensure fairness and equity to patients, families, and communities amid rapidly emerging technology.25 The necessity for clinician education and competency of racial differences has been established and developed in the US.31 However, even with these accepted and approved competencies, education and resources are still in development and are confronted by an endless stream of new genomic information.29 Familiarity of emerging racial genomic science affects practice as well as information about emerging ethical, legal, and social issues—including but not limited to confidentiality, decision-making capacity, informed consent, genetic testing, and research—are necessary to ensure the delivery of appropriate and equitable health care.25 Continues on page 30
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RACE AND GENETICS
Since the human genome was unraveled a decade ago, research regarding the role of race in genetics has advanced at a rapid speed. When applying ethical principles to the role of race in genomics, autonomy supports both the providing of information to an individual and the individual’s right to remain uninformed.The ethical principal justice argues that individuals should be treated alike without consideration of their gender, age, ethnicity, health, or socioeconomic status. This includes access to care and participation in research.25 From an ethical perspective, the best solutions are those that least impinge on the values of those involved in the ethical discourse.31 Potential cost implications
Since the human genome was unraveled a decade ago, research regarding the role of race in genetics has advanced at a rapid speed.32 During the past decade, two influential scientific movements in the US, population genetics and health disparities research, have re-ignited a debate on the multifaceted relationships between genes, race, and disease.33 Ten years ago, genetic tests were available for about 900 diseases.Today, that number is over 2,500.And what was once considered a costly procedure that could only be administered in a medical setting can now cost as little as $100 for a DNA test that can be taken at home.32 The cost of genetic testing can range from less than $100 to more than $2,000 per test, contingent on the nature and complexity of the test.34 For newborn screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant.34 In many cases, health FIGURE 1: Cost per genome
insurance plans will cover the costs of genetic testing when it is recommended by a healthcare provider.35 Unnecessary medical care is estimated to cost the US between $750 billion and $1 trillion dollars a year, and accounts for nearly a third of the overall spending on health care.36 According to a study from the University of Michigan, unnecessary testing can waste up to half a billion dollars each year.36 Researchers found it important for clinicians to have conversations with patients about the pros and cons of tests and forgo the tests that do not offer any clinical benefit.36 It can be argued that performing a genetic test is not going to change therapy and could lead to anxiety, unclear results, and more testing.36 Additionally, some races that are not privileged and classified as poor or with low-socioeconomic status are affected because they cannot afford the cost for testing and screening, leading to health disparities in such communities. Assessing the health benefits and return on investment of screening has its challenges, given the diversity of conditions and their varying outcomes. Overall, screening and treating disabling genetic conditions can reduce healthcare costs.26 Application of legal/governmental/regulatory issues
As science of the role of race in genomics progresses, genetic testing is becoming more ordinary in the everyday clinic.37 However, most genetic tests are not regulated, meaning there are no independent analyses to authenticate claims of the seller.37 The FDA has the authority to regulate genetic tests, but so far has only regulated a relatively small number of genetic tests sold to laboratories as kits.38 Whereas the Centers for Medicare and Medicaid Services (CMS) does regulate clinical laboratories, it does not examine whether the tests performed are clinically meaningful. Compared to the FDA and CMS, the Federal Trade Commission’s (FTC) regulatory authority is relatively narrow and is limited to how tests are advertised. The FTC has authority to regulate advertising that delivers health-related information to consumers to ensure it is not false or misleading.38 Prior to clinicians ordering, screening, and testing patients, legal and regulatory authorities must approve the tests for validation and clinical use. Implications for clinical practice, race, and genetic competency
Advances in the field of genomics during the past quarter-century have led to substantial reductions in the cost of genome sequencing.
All clinicians, despite location or practice setting, need to be properly trained in genetics and genomics to provide
30 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
The gap concerning genetics in clinical care, and what the primary care community is prepared to provide, grows larger every day. best practices for prevention, recognition, and/or treatment of diseases.27 For at risk populations and specific prevalent races to benefit from widespread genetic discoveries, clinicians must be proficient in obtaining comprehensive family histories, identifying family members at risk for developing a genomic influenced condition and for genomic-influenced drug reactions, helping people make informed decisions about and understand the results of their genetic/genomic tests and therapies, and referring at-risk people to appropriate healthcare professionals and agencies for specialized care.39 The incorporation of the role of race in genetics information into all aspects of health care provides the tools to treat patients as truly unique individuals and implement novel screening, diagnostic, and therapeutic interventions all aimed at improving population health.27 The gap concerning genetics in clinical care, and what the primary care community is prepared to provide, grows larger every day.27 With increasing development of practice guidelines, commercially available tests, insurance coverage, and legislative protection, race in genetic testing are moving into the mainstream healthcare setting.39 Race is a potential indicator for those at risk for or protected from a disease, as well as for different treatment responses.40 As technology continues to improve, the ability to identify and interpret an individual’s combination of genetic variations associated with health outcomes will also improve.40 This will require appropriate use of new scientific knowledge and a continued emphasis on caring for each patient as an individual.31 The interpretation of the role of race in genetics, in a sensitive and appropriate manner, requires precise awareness of all the manipulating factors affecting healthcare outcomes including genetics and the socioeconomic, lifestyle, and environmental influences that affect disease occurrence and treatment decisions.38 The need for a genetically competent workforce that can lead and assure primary care’s ongoing participation in translation of genomic discoveries into everyday health care is not limited to the US.4
primary care providers can help lower the disability-related healthcare costs in the US41 resulting in an improvement noted in disease management and quality of life in those who undergo early testing versus those tested at a later age. ■ Olubanke M. Babalola, MSN, APRN, FNP-C, RRT; Ashley K. Hughes, MSN, APRN, FNP-C; Jessica L. Peck, DNP, RN, CPNP-PC, CNE, CNL, FAANP; and Christina L. Murphey, PhD, RNC-OB, are affiliated with Texas A&M University Corpus Christi. References 1. Rich M. Genetics and the unsettled past: the collision of DNA, race, and history; race and the Genetic Revolution: science, myth, and culture. N Genet Soc. 2015;35:4. 2. Howard J. What scientists mean when they say ‘race’ is not genetic. 2016. Retrieved from http://www.huffingtonpost.com/entry/ race-is-not-biological_us_56b8db83e4b04f9b57da89ed 3. Krimsky S, Sloan K. Race and the genetic revolution: Science, myth, and culture. 2011. doi: 10.7312/columbia/9780231156974.001.0001 4. Hunt L, Truesdell N, Kreiner M. Genes, race and culture in clinical care. Med Anthropol Q. 2013;27:253-271. doi: 10.1111/maq.12026 5. Mersha T, Abebe T. Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities. Hum Genomics. 2015;9:1. doi: 10.1186/s40246-014-0023-x 6. Lynch J, Whatley A, Uchend U, Ibrahim S. Race and genomics in the Veteran Health Administration. Am J Public Health. 2014;4(Suppl 4): S522-S524.. doi: 10.2105/AJPH.2014.302202 7. National Institutes of Health (NIH). 2017a. Why are some genetic conditions more common in particular ethnic groups? Retrieved from https://ghr.nlm.nih.gov/primer/inheritance/ethnicgroup 8. National Institutes of Health (NIH). 2017b. What is a gene mutation and how do mutation occur? Retrieved from https://ghr.nlm.nih.gov/ primer/mutationsanddisorders/genemutation 9. Wade N. What science says about race and genetics? 2014. Retrieved from http://time.com/91081/what-science-says-about-race-and-genetics/ 10. Hoglund J. World population by ethnicity and race. 2016. Retrieved from http://www.aryanwisdom.com/tradition/race/data/world-population-
Implications for future practice
To successfully implement the role of race in genetics, clinicians must be competent in clinical practice implications of race and genetics. Understanding how race plays a vital role in genetics helps clinicians understand the need for early identification for treatment.This significantly reduces morbidity and mortality in at-risk populations and communities.23 By understanding race, genetics, and the importance of early genetic screening,
11. Kaiser Family Foundation. 2017. Population distribution by race/ethnicity. Retrieved from http://kff.org/other/state-indicator/distribution-byraceethnicity/?currentTimeframe=0&sortModel=%7B%22colId%22:%22 Location%22,%22sort%22:%22asc%22%7D 12. Centers for Disease Control and Prevention (CDC). 2016a. Sickle cell disease (SCD) data and statistics. Retrieved from https://www.cdc.gov/ ncbddd/sicklecell/data.html
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RACE AND GENETICS
13. Centers for Disease Control and Prevention (CDC). 2015. Facts
30. Burgess MM. Beyond consent: ethical and social issues in genetic testing.
about birth defects. Retrieved from https://www.cdc.gov/ncbddd/
Nat Rev Genet. 2001;2:147-151. doi:10.1038/35052579
31. Andrews V, Tonkin E, Lancastle D, Kirk M. Using the Diffusion of
14. Hussein N, Weng S, Kai J, Kleijnen J, Qureshi N. Preconception
Innovations theory to understand the uptake of genetics in nursing practice:
risk assessment for thalassemia, sickle cell disease, cystic fibrosis and
identifying the characteristics of genetic nurse adopters. J Adv Nurs.
Tay-Sachs disease. Cochrane Database Syst Rev. 2015;12. doi:
32. Scarantino D. Is genetic testing worth the money? 2013. Retrieved
15. Centers for Disease Control and Prevention (CDC). 2017. Sickle cell
trait. Retrieved from https://www.cdc.gov/ncbddd/sicklecell/traits.html
16. World Health Organization (WHO). 2017b. Genes and human disease.
33. Fine M, Ibrahim S, Thomas S. The role of race and genetics in health
Retrieved from http://www.who.int/genomics/public/geneticdiseases/en/
disparities research. Am J Public Health. 2005;95:2125-2128. doi: http://doi.
17. Mondal S, Mandal S. Prevalence of thalassemia and hemoglobinopathy
34. National Institutes of Health (NIH). 2017d. What are the benefits of
in eastern India: A 10-year high-performance liquid chromatography
genetic testing? Retrieved from https://ghr.nlm.nih.gov/primer/testing/benefits
study of 119,336 cases. Asian J Transfus Sci. 2016;10:105-110. doi:
35. Impact. (n.d.). Positive and negative aspects of genetic testing.
Retrieved from http://www.impactstudy.co.uk/public/geneticsandcancer/
18. Centers for Disease Control and Prevention (CDC). 2016b. Thalassemia.
Retrieved from https://www.cdc.gov/features/international-thalassemia/
36. Ross C. Genetic test costs taxpayers $500 million a year, with little to
19. Genetics and Nutrition. 2017. The impact of genetic information
show for it. 2016. Retrieved from https://www.statnews.com/2016/11/02/
on the family. Retrieved from http://www.nchpeg.org/nutrition/index.
37. National Institutes of Health (NIH). 2016. Regulation of genetic
20. World Health Organization (WHO). 2017a. Economic implications
tests. Retrieved from https://www.genome.gov/10002335/regulation-
of genomics. Retrieved from http://www.who.int/genomics/policy/
38. Genetic Alliance. (n.d.). Genetic testing. Retrieved from
21. National Institutes of Health (NIH). 2017c. What are the different
ways in which a genetic condition can be inherited? Retrieved from
39. Thompson H, Brooks M. Genetics and genomics in nursing: evaluating
Essentials implementation. Nurse Educ Today. 2011;31:623-627. doi:
22. Kelly N, Chehayeb Makarem D, Wasserstein M. Screening of
newborns for disorders with high benefit risk ratios should be mandatory.
40. Djurdjinovic L, Peters JA. Special issue introduction: dealing with
J Law Med Ethics. 2016;44:231-240. doi: 10.1177/1073110516654133
psychological and social complexity in genetic counseling. J Genet Couns.
23. Centers for Disease Control and Prevention (CDC). 2012.
2017;26:195-198. doi: 10.1007/s10897-017-0080-0
CDC Grand rounds: Newborn screening and improved outcomes.
41. March of Dimes. Newborn screening saves lives and money. 2014.
Retrieved from https://www.cdc.gov/mmwr/preview/mmwrhtml/
Retrieved from http://www.marchofdimes.org/Issue-Brief-newborn-
are screened for these disorders. Retrieved from http://dshs.texas.gov/ newborn/screened_disorders.shtm 25. Badzek L, Henaghan M, Turner M, Monsen R. Ethical, legal, and social issues in the translation of genomics into health fare. J Nurs Scholarsh. 2013;45:15-24. doi:10.1111/jnu.12000 26. Pitt J. Newborn screening. Clin Biochem Rev. 2010;31:57-68. 27. Calzone K, Cashion A, Feetham S, et al. Nurses transforming health care using genetics and genomics. Nurs Outlook. 2010;58:26-35. doi: http://doi.org/10.1016/j.outlook.2009.05.00 28. Jimenez-Sanchez G. Genomics innovation: transforming healthcare, business, and the global economy. Genome. 2015;58:511-517. doi: dx.doi. org/10.1139/gen-2015-0121 29. Kirk M, Calzone K, Arimori N, Tonkin E. Genetics-genomics competencies and nursing regulation. J Nurs Scholarsh. 2011;43:107-116. doi: 10.1111/ j.1547-5069.2011.01388.x
“Everyone I know has a crazy long commute.”
32 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
© The New Yorker Collection 2018 from cartoonbank.com. All Rights Reserved.
24. Texas Department of State Health Services. 2017. All Texas newborns
The Clinical Advisor
is celebrating its 20th Anniversary! This special section includes perspective and commentary on the past 20 years and the changes that have occurred for nurse practitioners, as well as a look back at old articles from our archives.
www.ClinicalAdvisor.com â€˘ THE CLINICAL ADVISOR â€˘ JUNE 2018 S1
SPECIAL ANNIVERSARY SECTION
Nurse practitioners: 20 years of change
Laura A. Foster, MSN, FNP, practices in family medicine with Palmetto Primary Care Physicians in Charleston, SC.
y original ambition was to become a nurse anesthetist. However, while working as a registered nurse on a cardiac step-down unit, I realized that I enjoyed the clinical aspect of patient care, and the wide variety of maladies kept my interest.Therefore, I reset my goal to become a nurse practitioner (NP). So in 1999, I completed the required coursework, joined a family practice group, and was proud to be one of the nation’s 68,300 NPs.Today, according to the American Association of Nurse Practitioners (AANP), there are more than 234,000 NPs in the United States. The NP profession has evolved significantly throughout the past 20 years.These changes involve not only the growth of our profession, but the way that we practice and the patients whom we diagnose and treat. Changes in education, job growth, and salary
Loretta Ford, EdD, RN, and Henry Silver, MD, established the first NP program in 1965 at the University of Colorado. A few years later, Boston College ushered in a master’s program for NPs. In 2004, the American Association of Colleges of Nursing sanctioned the Position Statement on the Doctorate of Nursing Practice (DNP). This document supported the transition of education from the master’s level to the doctorate level by 2015. Merritt Hawkins, a national healthcare firm specializing in recruitment for physicians and advanced practitioners, stated in its 2017 annual report that NPs are third on the list of most requested recruiting assignments, their highest position ever.The average compensation offered was $123,000, up from $105,000 in 2013. Earlier this year, US News and World Report ranked NPs as #4 of the best 100 jobs. These rankings are based on work–life balance, salary, job growth, and job satisfaction. Just 8 years ago, our profession was not even listed among the top 10 in either of these publications. The Bureau of Labor Statistics (2018) predicted a 31% job growth for NPs during the next 10 years, which would lead to 56,000 new positions.The impetus for this robust growth may be a 2017 report by the Association of American Medical Colleges (AAMC) that projected a physician shortage of between 40,800 and 104,900 by the year 2030. A primary cause for this alleged shortage is America’s aging population and physician retirement. Up to one-third of practicing physicians will be older than age 65 within the next 10 years.
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During the past decade, NP salaries have outpaced the rate of inflation. According to the AANP (2015), salaries have increased by 10% since 2011.The Bureau of Labor Statistics (2016) reported that NPs in all care settings earned a median annual salary of $100,910. Changes in the clinical arena
Today’s patient Over the years, several changes in the clinical arena have unfolded. Online websites make it easy to access medical information. Therefore, many of today’s patients come in prepared to discuss options about their care. Encountering the prepared patient, in my opinion, has some advantages. A 2012 survey by Blue Shield of California Foundation found that well-informed, low income patients were more likely to take an active role in their care. As clinicians, we can offer perspective and assign value to the information they have gathered. A patient’s baseline understanding is a fertile foundation on which we can build, enhancing a productive conversation. Patients empowered by knowledge tend to take responsibility for some aspects of their well-being, yielding better outcomes. Disease burden According to the Centers for Disease Control and Prevention (CDC, 2017), heart disease, stroke, cancer, type 2 diabetes, and obesity are the most common, costly, and preventable health problems. Overall mortality rates differ from state to state.A study by Pew Charitable Trusts (2016) found that West Virginia, Alabama, and Mississippi have the highest overall mortality rates, while Hawaii, California, and Connecticut have the lowest. Currently, 48% of American adults have one or more chronic illness, up from 45.4% in 2000. The CDC asserted that by eliminating 3 risk factors—poor diet, inactivity, and cigarette smoking—would prevent 80% of heart disease, stroke, and type 2 diabetes and 40% of cancers. The rate of adult-onset type 2 diabetes has nearly doubled in recent years. In 2000, approximately 4.5% of American adults were diagnosed. By 2015, that number had swelled to nearly 9.5% (CDC, 2017). The prevalence of diabetes varies considerably by education and race/ethnicity; for example, there is a higher prevalence among adults with less than or equal to a high school education, American Indians, Alaskans, and non-Hispanic blacks. During the past 13 years, the US Food and Drug Administration (FDA) has approved 3 new drug classifications, adding at least 17 antidiabetic medications. There has been a significant increase in the prevalence of obesity since 1980. The prevalence of adult obesity has increased by 30% between 2000 and 2016 (NIH). Obese
Expanding our clinical acumen and fine-tuning a myriad of skills is a continual, stimulating, and rewarding process. To me, this is one of the best features of our profession. Perhaps the most valuable skill I’ve developed over 19 years in clinical practice is listening.
persons have an increased risk for heart disease, stroke, and type 2 diabetes. Recent cohort studies found that obese persons have a 30% increased risk for colon cancers, a 20% to 40% increased risk for breast cancers, and are twice as likely to develop esophageal and liver cancers. Behavioral disorders Mood disorders have also been increasing throughout the past two decades. “America’s State of Mind: A Report by Medco Health Solutions, Inc” reviewed prescription drug claims of 2 million Americans to determine the use of antidepressants, antipsychotics, attention-deficit/hyperactivity disorder (ADHD) drugs, and anxiolytics from 2001 to 2010. The authors concluded that more than 1 in 5 adults were taking at least one of these drugs in 2010, a 22% increase from 10 years prior. The southeastern region of the nation had the highest use of psychotropic drugs (23%), whereas the eastern north-central region had the lowest use (15%). The CDC announced a 22% increase in ADHD diagnosis between 2003 and 2007. The number of physician office visits for ADHD had increased by 66%, accounting for nearly 10.5% of office visits between the years 2000 and 2010 (NIH). However, following reports of psychosis and mania by the FDA, there was a 10% decrease in the amount of psychostimulants prescribed by 2010. Change is constant
Expanding our clinical acumen and fine-tuning a myriad of skills is a continual, stimulating, and rewarding process. To me, this is one of the best features of our profession. Perhaps the most valuable skill I’ve developed over 19 years in clinical practice is listening. And, when addressing the “difficult patient,” it is best to listen to the whisper and not the roar. ■
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SPECIAL ANNIVERSARY SECTION
At the time of this writing, Joan Unger had four decades of primary care nursing experience that culminated as a supervisor. She had served on the Certification Commission of the AANP and was writing and consulting.
FROM THE ARCHIVES: APRIL 1998
One too many words in our name?
they may think of someone who is feminine, gentle, caring, powerless, compliant, and dependent. Granted, today’s images of these stereotypes are blurring, but I’d wager that most of the lay public is still unaware of the education, expertise, and scope of practice of today’s nurse practitioner. One evening a few months back, while peeling potatoes and half-listening to the nightly news, I caught the words “nurse practitioner.” I dropped my peeler and dashed to the living room in time ight years ago, I was at the beauty to watch the end of a segment featuring shop getting a haircut.The person two nurse practitioners. Both were procutting my hair asked me what I fessional, articulate, and personable. They had been up to since the last time she One too many explained advanced nursing practice, its saw me. I enthusiastically told her about Words in our name? requirements and demands, its benefits for receiving my license and beginning a new patients, and its complementary and coljob as a nurse practitioner. She looked laborative relationship with physicians. It puzzled and said, “But you were already was an excellent feature, and I wished I had an RN, weren’t you?” What an opening recorded it — especially when the camera to discuss the scope of my new skills! I bounced back to the news anchor, whose explained the advanced education and expression projected considerable doubt clinical experience a registered nurse as he cautioned listeners to remember needs to become a nurse practitioner. I how many years of education and clinical discussed our roles in the medical comexperience physicians have. Even after the munity and mentioned our efforts to gain segment, the anchor had not a clue as to prescriptive authority. what “nurse practitioner” really means. I didn’t realize that the lady in the next During the past year, I’ve read a number of articles dischair had been listening in on our conversation until she spoke up: “I wouldn’t want a nurse to prescribe medication cussing the need for a short, succinct explanation of what for me.” Thinking she may not have heard all I had said nurse practitioners do. One writer challenged readers to about nurse practitioners, I reiterated. She shook her head describe what nurse practitioners do in five words or less. stubbornly and said, “I still wouldn’t want a nurse to treat One morning, a simple phrase popped into my head: Nurse practitioners diagnose, treat, and care for patients.There was me. When I’m sick, I want a doctor.” A name creates an image of who you are and what you do. still one extra word, so I dropped the “and.” It’s not profound, In fact, the dictionary defines “nameless” as “indescribable.” it’s not memorable, but for me it captures the essence, if When people think of the word “doctor,” they may think of not the magnitude, of who we are and what we do. Now if a person who is masculine, knowledgeable, skillful, powerful, someone would only come up with a name for our profesauthoritative, and independent.When people think of a nurse, sion that would do the same. ■
Granted, today’s images of these stereotypes are blurring, but I’d wager that most of the lay public is still unaware of the education, expertise, and scope of practice of today’s nurse practitioner. One evening a few months back, while peeling potatoes and half-listening to the nightly news, I caught the words “nurse practitioner.” I dropped my peeler and dashed to the living room in time to watch the end of a segment featuring two nurse practitioners. Both were professional, articulate, and personable. They explained advanced nursing practice, its requirements and demands, its benefits for patients, and its complementary Joan Unger, MS, ARNP-C and collaborative relationship with physicians. It was an excellent feature, and I wished Eight years ago, I was at the beauty shop getting I had recorded it — especially when the cama haircut. The person cutting my hair asked me what era bounced back to the news anchor, whose expresI had been up to since the last time she saw me. I sion projected considerable doubt as he cautioned enthusiastically told her about receiving my license listeners to remember how many years of education and beginning a new job as a nurse practitioner. She and clinical experience physicians have. Even after looked puzzled and said, “But you were already an the segment, the anchor had not a clue as to what RN, weren’t you?” What an opening to discuss the “nurse practitioner” really means. scope of my new skills! I explained the advanced During the past year, I’ve read a number of artieducation and clinical experience a registered nurse cles discussing the need for a short, succinct explananeeds to become a nurse practitioner. I discussed our tion of what nurse practitioners do. One writer roles in the medical community and mentioned our challenged readers to describe what nurse practiefforts to gain prescriptive authority. tioners do in five words or less. One morning, a simI didn’t realize that the lady in the ple phrase popped next chair had been listening in on our my head: Nurse The word “nurse” still into conversation until she spoke up: “I practitioners diagnose, wouldn’t want a nurse to prescribe medi- conjures up images of a treat, and care for cation for me.” Thinking she may not patients. There was professional who is have heard all I had said about nurse pracstill one extra word, titioners, I reiterated. She shook her head caring yet powerless. so I dropped the stubbornly and said, “I still wouldn’t want “and.” It’s not proa nurse to treat me. When I’m sick, I want a doctor.” found, it’s not memorable, but for me it captures the A name creates an image of who you are and essence, if not the magnitude, of who we are and what what you do. In fact, the dictionary defines “namewe do. Now if someone would only come up with a less” as “indescribable.” When people think of the name for our profession that would do the same. ■ word “doctor,” they may think of a person who is Joan Unger has four decades of primary-care nursing masculine, knowledgeable, skillful, powerful, authorexperience that culminated as a supervisor. She has itative, and independent. When people think of a served on the Certification Commission of the AANP nurse, they may think of someone who is feminine, and currently writes and consults. gentle, caring, powerless, compliant, and dependent.
THE CLINICAL ADVISOR / April 1998
S4 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
A LOOK BACK...
Through the years
ADViSORforum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Reviewers are identified on the last page of this feature.
Persistent Hemoglobinuria Dilemma LORENZO R. HOLGUIN, NP, PA-C, Sanger, California, asks: “What would be your approach for an asymptomatic patient with persistent hemoglobinuria who tests positive for hemoglobin on a dipstick, negative for red blood cells (RBCs) and white blood cells upon microscopic analysis, and has a negative urine culture?”
When urinalysis results are positive for occult blood, but no RBCs are seen on microscopic analysis of the urine specimen, several causes should be investigated. The most benign cause is that the urine dipstick results are inaccurate, which is usually due to old or expired dipsticks. If there are no visible RBCs by microscopic exam, causes of this state of hemoglobinuria (not hematuria) or myoglobinuria need to be correlated to the patient’s history. Crush injuries, burns, electrical shock, poisonous mushrooms, fish poisoning, snake bites, carbon monoxide poisoning, transfusion reactions, and malaria all cause hemoglobin or myoglobin in the urine. If the condition persists without symptoms, consider hemolytic anemia, muscular dystrophy, and vascular occlusion to a muscle. A chemical test for free myoglobin and a hematocrit would be a good place to start. — VHJ (1-1)
Feeling the Cervix of an Obese Woman “What is the best method for accurately feeling or visualizing the cervix of an extremely obese patient?” That question comes from VICTORIA HELMANDOLLAR, MSN, FNP, Acton, California.
Examining the cervix of an obese woman poses several clinical challenges. You may wish to try the following: Use the largest Graves’ speculum and spongettes (large Q-tips) to hold back the vaginal wall. Another option is to use a condom with the tip cut out and place it over the speculum to hold the vaginal wall in place. Instead of a condom, you can also use the finger of a latex glove. — MAZ (1-2) ■ Please send your letters with questions, comments, and ideas to: Advisor Forum, The Clinical Advisor, 7 Skyline Drive, Hawthorne, NY 10532-2119. You may also fax (914) 347-3801, phone (888) 762-7370, or contact us through the Internet at email@example.com. If you are writing in response to a published letter, please indicate so by the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.
THE CLINICAL ADVISOR / January 1998
CLINICAL CHALLENGE WAVEBREAKMEDIA / GETTY IMAGES
This retrospective section features our very first Clinical Challenge and Advisor Forum from 1998, as well as other departments, including a Derm Clinic, Legal Advisor column, and CME article, from the past 20 years.
Mr. W got sick on the Fourth of July. He had gone to a company picnic and developed nausea, vomiting, and abdominal pain several hours later. However, neither friends nor relatives nor anyone else who attended the picnic became ill. After five days of nausea, vomiting, and crampy epigastric pain that worsened with eating, the 44-year-old man developed intractable vomiting, despite taking Compazine (prochlorperazine), a medication he had on hand. Every time he ate, he vomited, and his abdominal pain increased. The vomitus was not bitter or green. He had no fever but felt chilled and sweaty during episodes of vomiting. There was no history of unusual travel. He had not drunk alcohol for the previous four months.
A Very Bad Fourth of July Case and analysis by Christina M. Surawicz, MD
THE CLINICAL ADVISOR / January 1998
From our inaugural issue in January 1998, our first Clinical Challenge explored the case of a patient who had become sick during a holiday company picnic. After 5 days of nausea, vomiting, and crampy epigastric pain that worsened with eating, the 44-year-old man developed intractable vomiting. Clinicians ruled out food poisoning due to the timing of symptoms and persistent vomiting. Ultimately, the patient was diagnosed with Reiter syndrome, a rheumatologic condition that often presents with a sterile chronic synovitis following a documented enteric, urogenital, or pharyngeal infection.
1998 Also from January 1998, our first Advisor Forum included discussion about persistent hemoglobinuria, examining the cervix in an obese woman, developing diabetes after cytomegalovirus infection, and proper timing for the measles, mumps, and rubella vaccine. Our advisors also weighed in on recurrent yeast infections, poison ivy, and whether a strep culture was necessary for pharyngitis. Recommendations for poison ivy included tepid Aveeno baths, calamine lotion, topical antihistamines, topical steroids, oral antihistamines, and oral corticosteroids. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 S5
SPECIAL ANNIVERSARY SECTION
In this Legal Advisor case, from November 2006, a 30-year-old man had visited a clinic 3 times within 1 month with complaints of abdominal pain, chills, fever, cough, vomiting, and diarrhea. The patient had been diagnosed with gastroenteritis at a local emergency department, but the clinician at the clinic questioned the diagnosis. However, the clinic’s physician did not take the clinician’s concerns seriously enough to re-examine the patient, which resulted in a delayed diagnosis and a malpractice suit.
LEGAL ADVISOR CASE #1
Revenge of Big Foot By Mohammed Bagheri, MD, and Mehran Alagheband, MD
severe but painless swelling of his left foot. On examination, several draining sinuses were noted in the indurated foot. The patient stated that the first sign that anything was amiss had been a “small bump,” which
In a case featuring obvious negligence, would an earlier admission of liability have helped the defendant? PUNCHSTOCK
A 42-year-old African American farmer presented with
Pathologist mislabels skin lesion
enlarged over the next few months. There was no other significant medical history. What is your diagnosis? ➙
THE CLINICAL ADVISOR / August 2003
From an August 2003 Dermatology Clinic, “Revenge of Big Foot,” a 42-year-old African American farmer presented with severe but painless swelling on his left foot. A small bump had become enlarged in a period of a few months. The patient was diagnosed with mycetoma, a chronic infection characterized by tumefaction, draining sinuses, and the presence of vegetative aggregates (sclerotia).The infection occurs most often on the feet (Madura foot) and legs. The organisms that cause mycetoma are associated with soil and woody plants and are introduced following a penetrating injury.
Having been a physician assistant in Arizona for several years before moving north, Mr. G had considerable experience in diagnosing skin lesions. One of his patients was a 51-year-old factory worker. At his annual exam, he presented with a raised,pigmented skin lesion on the right side of his back. Mr. G believed it was either a stable pigmented nevus or an early malignant melanoma. He thought there was some hyperpigmentation deep in the lesion, but he was not sure. There was no enlargement of the axillary lymph nodes as far as he could tell. In any case, Mr. G felt the patient’s lesion should be reviewed by his supervising physician and, if necessary, referred for excision biopsy to a dermatologist. After examining the lesion, the supervising physician agreed with Mr. G’s assessment.The patient was sent to a general surgeon, who removed the lesion with a small margin of skin and sent it to pathology.The pathologist was inexperienced in the diagnosis of malignant melanoma and mistakenly declared the sample benign. (Later review showed the sample to have early invasion of the subdermal layer, indicating a malignant lesion.) The erroneous report was forwarded to Mr. G and
A plaintiff’s expert concluded that early diagnosis would have allowed for wide re-excision of the original lesion and a greater chance of cure.
the patient. Mr. G was surprised at the finding but relieved that the skin mass was benign. He did not give the case another thought until four years later when the patient arrived with an axillary lump he discovered while in the shower. A lymph node biopsy showed metastatic malignant melanoma. Further studies indicated that the metastases were spread all over the body, including the brain and lungs. Facing staggering medical bills, the patient and father of two consulted a plaintiff ’s lawyer, who called for the chart from the pathologist, Mr. G, and his supervising physician.A review of the slides taken by the original pathologist revealed that he had made a mistake — the slides showed early invasion by the cancer.The pathologist maintained, and continued to insist throughout the case, that the early invasion was vascular; therefore wide excision would not have altered the outcome. A plaintiff ’s expert examined the patient’s records Cases presented are composites of 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.
THE CLINICAL ADVISOR • NOVEMBER 2006 97
Whereas my early practice was definitely focused more on treating disease state with medications, now I focus more on emphasizing lifestyle measures to improve health and well-being. It is a joy to see people make healthy choices that will benefit themselves for the rest of their life. —Jeanne Chase, DNP, APRN, FNP-BC, Stanford, KY
S6 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
CME CE FEATURE
■ LEARNING OBJECTIVES : • Become familiar with the cognitive assessment tools available to primary-care clinicians. • Explain the benefits of acetylcholinesterase inhibitors in the treatment of Alzheimer’s. • Recognize how drug formulation affects the tolerability of the chosen treatment. • Identify the preferred approach to treatment of behavioral problems. ■ COMPLETE THE POSTTEST: Page 66 ■ ADDITIONAL CME/CE: Pages 43, 63
BY FREDDI SEGAL-GIDAN, PA, PHD
Alzheimer’s management from diagnosis to late stage Caring for a patient with Alzheimer’s disease involves more than assessment and treatment. Education and legal issues must also be considered.
© PDSN / PHOTOTAKE
Brain CT of a woman with Alzheimer’s disease shows large areas of hypodensity in the frontal, temporal, and parietal lobes.
ith the aging of the population, the incidence and prevalence of Alzheimer’s disease (AD), already the most common type of dementia, are projected to rise. A diagnosis of AD has implications for ongoing care across all settings and providers—whether you are the primarycare provider (PCP) and made the diagnosis, assuming the care of a new patient with AD, or a consultant asked to provide input for a chronic problem of someone with AD. A diagnosis of AD adds to the complexity and cost of care. This article focuses on post-diagnostic care and is based on the 2008 report from the California Workgroup on Guidelines for Alzheimer’s Disease Management.1 Because it is a slowly progressive neurodegenerative condition that may continue for a decade or more after diagnosis, management of AD must change over time. The majority of patients with AD (and their caregivers) receive their medical care from PCPs.2 PCPs are key to ensuring the care provided is appropriate to the patient’s needs and situation.
2010 This feature, from July 2010, focused on managing patients with Alzheimer’s disease, from diagnosis to the late stages.The author addressed the importance of assessing a patient’s ability to adhere to a regimen when prescribing medications, integrating medical care with education that connects patients and caregivers with support organizations, and trying to make legal and financial decisions early in the course of the disease while the patient is still capable of understanding these issues.
Continues on page 24
www.clinicaladvisor.com • THE CLINICAL ADVISOR • JULY 2010 23
THE CLINICAL ADVISOR • MAY 2015
■ Feature: Meningococcal meningitis outbreaks ■ Stat Consult: Measles ■ Clinical Challenge: More than a cold ■ Commentary: Vaccine safety and parents
M AY 2 015
PREVENTING AND REPORTING
COMMUNICABLE DISEASES A case of measles on a child’s torso.
AANP FIRST REPORT
NP profession at 50: Full practice authority is a priority
✶ FREE CE COURSES!
■ Dermatology Clinic
BLISTERING PATCH ON FOREARM PAGE 71
■ Dermatologic Look-Alikes VOLUME 18, NUMBER 5
Our May 2015 issue was a special issue devoted to infectious diseases. Our cover story, which focused on prevention and screening, noted that acute respiratory infections such as pneumonia and influenza were the primary cause of infection-related deaths and the 8th leading cause of death in the United States, according to the CDC.The issue also included a feature on meningococcal meningitis outbreaks, a Stat Consult on measles, a Clinical Challenge on methicillin-susceptible Staphylococcus aureus, and a Commentary on vaccine safety.
A P E E R - R E V I E W E D F O RU M F O R N U R S E P R AC T I T I O N E R S
SPECIAL ISSUE: INFECTIOUS DISEASES
WELL-DEMARCATED PINK PLAQUES PAGE 75 Where do you rank in our Salary Survey? To find out the results, turn to page 46.
4/28/15 11:40 AM
In 1979, I was awarded a certificate as an adult and geriatric nurse practitioner. I could not admit patients to facilities. It required a collaborative MD agreement —compared to the truly autonomous role NPs fill now in hospitals, skilled nursing facilities, ambulatory primary care positions, and emergency rooms. The profession has evolved in the way envisioned to serve populations across the healthcare spectrum. —B. Betts, MS, ARNP, PsyD, LP, Mankato, MN
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 S7
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IBgard® is a medical food specially formulated for the dietary management of IBS. IBgard can help to manage the accompanying and often distressing group of symptoms of IBS. These include, at varying times**: • Abdominal pain, discomfort, or cramping • Urgency of bowel movement • Bloating or gas • The sense of an incomplete bowel movement • Diarrhea, constipation, or bouts of diarrhea interrupted by constipation • Pain during bowel movement
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Functional Dyspepsia (FD) is a relatively common condition, often associated with digestion issues after a meal. FDgard® is a medical food clinically proven to provide rapid relief of FD symptoms (postprandial fullness and/or early satiation, and epigastric pain and burning), in as early as 24 hours.2 Functional Dyspepsia symptoms include, at varying times**:
Fiber Choice® is a daily prebiotic fiber supplement. Each serving of Fiber Choice is packed with the same fiber found in many fruits and vegetables. With two tablets or gummies, patients get the general benefits of fiber. Fiber Choice can help to*:
• Abdominal pain, discomfort, or cramping • Difficulty finishing a meal • Bloating • Nausea • Burning • Belching
• Promote regularity • Promote satiety • Increase absorption of calcium • Lower blood cholesterol levels • Attenuate post-meal glucose levels • Improve digestive and immune health
Nightly Sleep CompanionTM
REMfresh® is the first and only continuous release and absorption formulation of UltraMel™ melatonin. REMfresh, for patients experiencing occasional sleeplessness, uses ionpowered science to deliver up to 7 hours of sleep support. REMfresh can*: • Mimic the body’s natural release of melatonin • Help patients fall asleep faster, stay asleep longer • Help patients experience quality sleep (i.e. deep sleep and REM sleep)
To request patient samples, visit IMHsamples.com/CA or contact firstname.lastname@example.org for more information. **With no known organic cause. † Among gastroenterologists who recommended peppermint oil for IBS. Alpha ImpactRx ProVoice September 2017 survey. ‡ Among gastroenterologists who recommended herbal products for Functional Dyspepsia. Alpha ImpactRx ProVoice May 2017 survey. ‡‡ Among gastroenterologists who recommended a chewable fiber tablet. Alpha ImpactRx ProVoice March 2018 survey. § Among primary care physicians with a certification in sleep disorders who recommended a brand of modified release melatonin. QuintilesIMS ProVoice July-Sept. 2017 survey. 1 REMfresh melatonin is 99.9% pure (via synthesis), and it is the same sleep ingredient found in humans. 2 Lacy B, et al. A caraway oil/menthol combination improves functional dyspepsia (FD) symptoms within the first 24 hours: Results of a randomized controlled trial, which allowed usual FD treatments. Peer-reviewed and presented at Digestive Disease Week®, Chicago,IL, May 2017.
Individual results may vary. Use under medical supervision. Medical foods do not require prior approval by the FDA but must comply with regulations. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on IBgard.com, FDgard.com, FiberChoice.com, and REMfresh.com.
*THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE. 2018 IM HealthScience®
Release Date: April 27, 2018
CME FEATURED COURSE EDUCATIONAL OBJECTIVES After completing the activity, the participant should be better able to: • Implement appropriate strategies for diagnosing gout • Utilize individualized, evidence-based approaches to gout management • Counsel patients with gout regarding lifestyle interventions and the importance of therapeutic adherence COMPLETE THE POSTTEST: Page 44
Expiration Date: June 30, 2019 Estimated Time to Complete: 30 minutes Maximum Credits: 0.50 AMA PRA Category 1 Credit(s)TM 0.50 CE for Pharmacists (0.05 CEUs) Accredited Provider: This activity is jointly provided by Haymarket Medical Education and the University of Wisconsin-Madison Division of Pharmacy Professional Development. Commercial Supporter: This activity is supported by an educational grant from Ironwood Pharmaceuticals, Inc. Program Description: Gout is a common and chronic disease, affecting more than 8 million individuals in the United States; its prevalence has increased in recent decades and will continue to increase as the population ages. It is now known that hyperuricemia can not only precipitate gout but also lead to a host of serious health consequences if left undiagnosed, untreated, or undertreated.Thus, evidence-based recommendations advise that, for chronic gout, serum urate levels should be lowered with the use of both pharmacologic and nonpharmacologic measures and maintained below a specific target, which should be individualized for each patient. As understanding of the pathophysiology of hyperuricemia and gout has increased, more precisely targeted therapeutic approaches have emerged and promise to improve outcomes and QoL, especially in patients with gout that is considered refractory to traditional therapies. This article will provide learners with an overview of the current state of gout management, inclusive of diagnosis and treatment. Learners will be encouraged to reflect on their own practice relative to how they manage the care of patients with gout and to identify areas in which they require education to improve their knowledge, competence, practice, and, by extension, health outcomes for their patients. Intended Audience: Family medicine and internal medicine (IM) clinicians (MDs/DOs, physician assistants [PAs], nurse practitioners [NPs]), pharmacists, rheumatologists, and nephrologists. Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, the University of Wisconsin-Madison and Haymarket Medical Education (HME) require 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.
Jointly provided by
Faculty Michael Pillinger, MD Professor of Medicine and Biochemistry and Molecular Pharmacology Director, Crystal Disease Study Group Director, Masters of Science in Clinical Investigation Director, Rheumatology Training New York University School of Medicine New York, NY Dr. Pillinger is a consultant to Horizon Pharmaceuticals and Ironwood Pharmaceuticals, Inc. Accredited Provider Disclosures: The staff of Haymarket Medical Education have nothing to disclose with regard to commercial support.
The staff of the University of Wisconsin-Madison Interprofessional Continuing Education Partnership (ICEP) have nothing to disclose with regard to commercial support. Publishing Staff Disclosures: Krista Sierra and Susan Basilico of Haymarket Medical Education have nothing to disclose with regard to commercial support. 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 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Accreditation Statement: In support of improving patient care, the University of Wisconsin-Madison ICEP is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. Designation Statement: A total of 0.50 hours (0.05 CEUs) of pharmacy CE credit will be provided for successful completion of this knowledge-based program.To receive CE credit, you must complete the program; complete the evaluation; and complete the post-test with a minimum score of 70%.Verification of completion will be provided to NABP within 60 days of completion of this program. No credit will be provided 60 days after this program expires. Universal Program #JA0000358-9999-18-078-H01-P Disclosure of Unlabeled Use: This CME activity will 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 this educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education, University of Wisconsin-Madison, and Ironwood. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period April 27, 2018 through June 30, 2019, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; and 5) complete the post-test and evaluation form and submit it online. 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/June18feature. If you have any questions relating to the accreditation of this activity, please contact cmequestions @ haymarket medical.com (for CME credits) or cemail @ pharmacy. wisc.edu (for CPE credits).
CME FEATURED COURSE: MICHAEL PILLINGER, MD
Viewpoints in gout and hyperuricemia: Updated treatment guidance Gout presents a classic conundrum: Despite the fact that effective treatments are available, the management of the disease is widely recognized as suboptimal.
The site most commonly involved in gout flares is the first metatarsophalangeal joint.
out is a form of inflammatory arthritis that affects nearly 4% of all adults in the United States. It is nearly twice as common in men as in women, with a US prevalence of nearly 6% among men and 2% in women. However, the prevalence of gout in postmenopausal women approaches that in men. Gout becomes more common with age, so that it affects up to 9.8% of those age 65 and older.1 Gout significantly impacts a patient’s health and functionality. It is associated with joint damage,1 work absenteeism,2 disability,3 poor quality of life (QoL),3 multiple comorbidities (eg, hypertension, cardiovascular disease, renal impairment, diabetes, obesity, and hyperlipidemia),4,5 and premature death.6
© DU CANE MEDICAL IMAGING LTD/SCIENCE SOURCE
The pathology leading up to gout typically progresses from asymptomatic hyperuricemia to asymptomatic monosodium urate (MSU) crystal deposition, to crystal deposition with acute flares, to advanced disease featuring chronic gouty arthritis, tophi, and radiographic erosions.7 Hyperuricemia is essential to the development of gout,8 though most people with hyperuricemia do not have gout. About 21.2% of men and 21.6% of women in the United States have hyperuricemia, according to National Health and Nutrition Examination Survey (NHANES) data. This analysis defined hyperuricemia as serum uric acid (sUA) >7.0 mg/dL www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 35
CME FEATURED COURSE
for men and >5.7 mg/dL for women.9 The American College of Rheumatology (ACR) guidelines define hyperuricemia as >6.8 mg/dL [408 μmol/L]) for all individuals, the concentration at which urate solutions saturate at pH 7.4.10,11 Serum uric acid concentrations strongly predict the development of gout, according to a recent analysis of data from 4 large cohorts (18,889 participants gout-free at baseline, followed for a mean of 11.2 ± 4.2 years).12 In this analysis, roughly half of those with sUA concentrations ≥10.0 mg/dL developed gout over 15 years.12 These findings underline the long duration of hyperuricemia prior to the development of gout and suggest that other factors play a role in the onset of the condition. Primary hyperuricemia can result from hepatic overproduction of purines, from renal or gut underexcretion of uric acid, or both.7 Underexcretion is the major cause of primary hyperuricemia in gout, accounting for roughly 90% of cases.13 Roughly two-thirds of urate is excreted through the kidneys; the remainder is excreted by the gut.7 In secondary hyperuricemia, diseases that induce rapid cell turnovers, such as some malignancies and hemolytic anemias, may result in aberrant urate overproduction. Alternatively, impairment of urate excretion may be caused by glomerular failure, dehydration, certain medications, or acidosis. Diet may also affect urate levels by providing purine substrate or by increasing metabolic generation of purines. One large prospective cohort study found that the risk of incident gout increased with increasing intake of sugarsweetened soft drinks. The risk was significantly increased with an intake level of 5 to 6 servings a week, and the risk rose even further as intake increased above 6 servings per week.14 The impact of sugar appears to be most profound in the case of fructose, whose metabolism promotes urate generation by several mechanisms. Consumption of alcohol has long been believed to trigger gout flares. The results from one prospective study of 724 patients with gout who had at least 1 flare during the 1-year of follow-up confirmed that all types of alcoholic beverages (wine, beer, and liquor) were associated, to varying degrees, with a greater risk for recurrent gout flares. The association was stronger in the presence of high purine intake (including high-purine alcoholic beverages, such as beer) and diuretic use, and was mitigated to varying degrees by the use of allopurinol and colchicine. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) did not modify the effects of alcohol intake on risk of recurrent gout flares.15 COMORBIDITIES
Diabetes, renal impairment, and cardiovascular comorbidities (eg, hypertension, heart failure, and history of myocardial
infarction or stroke) are common in gout patients.4,5 The prevalence of comorbidities rises with sUA levels.4 Patients should be screened for comorbidities associated with gout.10,16,17 CLINICAL PRESENTATION
Gout generally presents as an acute episode of inflammatory arthritis, with early flares most commonly affecting the foot or ankle.10 Symptoms (eg, joint warmth, swelling, redness, and difficulty with movement) result when (typically predeposited) MSU crystals in the joints and soft tissues activate leukocytes and their complement, leading to acute and chronic inflammation and joint damage.7 Severe cases of crystal deposition can lead to mechanical disruption of the joints.1 The first acute episode of gout generally resolves spontaneously after about 1 or 2 weeks. Recurrent, often more persistent flares may develop and affect other joints (including multiple joints in a single episode) if hyperuricemia remains untreated. Some individuals progress to advanced gout, with tophi and radiographic erosions.7 DIAGNOSIS
The gold standard for the diagnosis of gout is the confirmation of the presence of MSU crystals in synovial fluid or tophaceous material.7,17 If aspiration of fluid for this evaluation is not possible, the diagnosis can be suspected based on clinical features such as involvement of the first metatarsophalangeal joint, palpable tophi, rapid response to colchicine, or imaging findings.7,17 Imaging findings may be nonspecific on first presentation of an acute flare, with radiographs showing only swollen soft tissue. Bone erosions on x-ray are typical of late-stage disease. Ultrasonography may reveal the double-contour sign, consistent with urate crystal deposition on articular cartilage.10 Dual-energy computed tomography can specifically detect occult urate deposits.18 These features also have been detected in up to 29% of individuals with asymptomatic hyperuricemia (double-contour sign and urate deposits, respectively).16,17 One group of authors postulate that “these data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.”18 The tophus, a sign of advanced disease, represents an inflammatory response to aggregates of MSU crystals.Tophus penetration into bone has been associated with bone erosions on imaging.19,20 Dual-energy computed tomography evidence suggests that among patients with palpable tophi, the number of occult deep-tissue lesions may exceed the number of palpable tophi by as much as 400%.21 The ACR and the European League Against Rheumatism (EULAR) have established clinical, laboratory, and imaging classification criteria for gout (Table 1), summarized in an online
36 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
▶ Apply the criteria below only in the setting of at least 1 episode of swelling, pain, or tenderness in a peripheral joint or bursa. Patients with demonstrated presence of MSU crystals in a symptomatic joint or bursa (ie, in synovial fluid) or tophus are considered to have gout; further criteria need not be applied. The maximum possible score is 23. A threshold score of ≥8 classifies an individual as having gout. TABLE 1. ACR/EULAR gout classification criteria20 Clinical
Pattern of joint/bursa involvement during symptomatic episode(s), evera
Ankle or midfoot (as part of monoarticular or oligoarticular episode without involvement of the first metatarsophalangeal joint) Involvement of the first metatarsophalangeal joint (as part of monoarticular or oligoarticular episode)
Characteristics of symptomatic episode(s), ever • Erythema overlying affected joint (patient-reported or physician-observed) • Can’t bear touch or pressure to affected joint • Great difficulty with walking or inability to use affected joint
One point per characteristic
Time course of episode(s), ever Presence (ever) of ≥2, irrespective of anti-inflammatory treatment: • Time to maximal pain <24 hours • Resolution of symptoms in ≤14 days • Complete resolution (to baseline level) between symptomatic episodes
One typical episode Recurrent typical episodes
Clinical evidence of tophus (ie, draining or chalk-like subcutaneous nodule under transparent skin, often with overlying vascularity, located in typical locations: joints, ears, olecranon bursae, finger pads, tendons [eg, Achilles])
sUA: • Measured by uricase method • Ideally should be scored at a time when the patient was not receiving urate-lowering treatment and it was >4 weeks from the start of anepisode (ie, during intercritical period); if practical, retest under those conditions • The highest value irrespective of timing should be scored
<4.0 mg/dL (<0.24 mmol/L)b 6.0 to 8.0 mg/dL (0.36 to <0.48 mmol/L) 8.0 to <10.0 mg/dL (0.48 to <0.60 mmol/L) ≥10.0 mg/dL (≥0.60 mmol/L)
−4 2 3 4
Synovial fluid analysis of a symptomatic (ever) joint or bursa (should be assessed by a trained observer)c
Imaging evidence of urate deposition in symptomatic (ever) joint or bursa: ultrasound evidence of double-contour signe or DECT demonstrating urate depositionf
Present (either modality)
Imaging evidence of gout-related joint damage: conventional radiography of the hands and/or feet demonstrates ≥1 erosiong
ACR, American College of Rheumatology; DECT, dual-energy computed tomography; EULAR, European League Against Rheumatism; MSU, monosodium urate; sUA, serum uric acid. Symptomatic episodes are defined as periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral joint or bursa. If sUA level is <4.0 mg/L (<0.24 mmol/L), subtract 4 points; if sUA is ≥4.0 mg/dL but <6.0 mg/dL (≥0.24 mmol/L but <0.36 mmol/L), score this item as 0. If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to show MSU crystals, subtract 2 points. If synovial fluid was not assessed, score this item as 0. d If imaging is not available, score these items as 0. e Hyper-echoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation angle of the ultrasound beam (note: false-positive double-contour sign [artifact] may appear at the cartilage surface but should disappear with a change in the insonation angle of the probe). f Presence of color-coded urate at articular or periarticular sites. Images should be acquired using a DECT scanner, with data acquired at 80 kV and 140 kV and analyzed using gout-specific software with a 2-material decomposition algorithm that color-codes urate. A positive scan is defined as the presence of color-coded urate at articular or periarticular sites. Nail bed, submillimeter, skin, motion, beam-hardening, and vascular artifacts should not be interpreted as DECT evidence of urate deposition. g Erosion is defined as a cortical break with sclerotic margin and overhanging edge, excluding distal interphalangeal joints and gull-wing appearance. a
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 37
CME FEATURED COURSE
While diet and lifestyle measures may be useful in gout, these interventions alone are insufficient to manage the disease in most patients. calculator (http://goutclassificationcalculator.auckland.ac.nz/).22 These criteria define a patient diagnosis of gout, but they do not define the specific etiology of any single flare of acute inflammatory arthritis. APPROACHES TO GOUT MANAGEMENT Patient education
Disease-state education includes explaining to affected individuals that gout is a lifelong, chronic, inflammatory form of arthritis linked to hyperuricemia, with potential consequences including joint damage and disability.1,3 Patients should be educated about diet and lifestyle measures to lower sUA.10 Generally, these interventions alone are insufficient to manage the disease in patients with sUA substantially above 7.0 mg/dL.10 The decision to start therapy to lower sUA (ie, urate-lowering therapy [ULT]) should be shared between the clinician and patient. Understanding the rationale for therapy may promote adherence.23,24 Evaluate concomitant medications
© DR P. MARAZZI/SCIENCE SOURCE
There are many drugs capable of inducing hyperuricemia and gout; these include diuretics, nicotinic acid, salicylates (<2g/ day), ethanol, pyrazinamide, levodopa, ethambutol, cytotoxic drugs, and cyclosporine.25 Concomitant medications that may raise sUA levels or interact with medications prescribed for gout should be identified and adjusted or substituted where possible (eg, substituting an alternative medication such as losartan [urate-lowering] for a thiazide diuretic [urate-raising] to treat hypertension).
Reduction of uric acid levels is key to avoiding gout flares.
Treatment of acute flares10,26,27 Acute gout flares should be treated promptly, as early initiation is believed to promote greater effectiveness.16 The ACR guidelines recommend starting therapy within 24 hours of symptom onset. EULAR recommends initiating treatment as soon as possible.16,26 Colchicine, NSAIDS, or corticosteroids (oral or intra-articular) are first-line therapy for gout flares (Table 2).The ACR advises using colchicine when it can be started within 36 hours of symptom onset; EULAR recommends that colchicine be initiated within 12 hours of a flare onset. EULAR guideline authors recommend that patients prescribed colchicine for this purpose carry a pill with them to facilitate the earliest possible initiation. 16,26 Off-label considerations for treatment of acute flares
For individuals with frequent flares who fail or cannot tolerate any of the above agents, biologics that block interleukin (IL)-1 (eg, anakinra and canakinumab) may be considered.16 These agents are available in the United States but have not received US Food and Drug Administration (FDA) approval for use in gout. Current ACR guidelines characterize the risk-benefit ratio of these agents in gout as “unclear.”26 Canakinumab (150 mg subcutaneously, 1 dose) has been approved in Europe for patients with gout flares and a contraindication to, intolerance of, or nonresponse to NSAIDs and/or colchicine.16 Urate-lowering therapy Xanthine oxidase inhibitors. Both the ACR and EULAR guidelines recommend xanthine oxidase inhibitors as first-line therapy for ULT. EULAR lists allopurinol as the first choice;ACR considers allopurinol and febuxostat as equivalent first choices for ULT.10,16 These agents work by inhibiting urate production.7 Allopurinol is appropriate in patients with normal kidney function who can tolerate the drug. Dosing should be started low (100 mg/day) and raised by 100-mg increments every 2 to 5 weeks as needed to reach the sUA target, with a maximum dose of 800 (US) or 900 (Europe) mg/day.10,16,28 A low starting dose of allopurinol is advised because a high initiation dose may increase the risk of a potentially fatal hypersensitivity reaction.16,29-31 The estimated incidence of allopurinol hypersensitivity syndrome is 1 in 1000,10,29,30 with a US mortality rate of 25% to 30%.30 Potential manifestations of this reaction include Stevens-Johnson syndrome, toxic epidermal necrolysis, systemic disease with eosinophilia,
38 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
The decision to initiate urate-lowering therapy for patients with gout should be made after a discussion between the clinician and patient. vasculitis, rash, major end-organ disease, and death. A larger group of patients (2%) manifest hypersensitivity with a milder maculopapular eruption.30 Risk factors for hypersensitivity include time from start of therapy (highest risk within the first few months of initiation), genetic factors (HLA-B*5801), and factors that raise drug concentration (eg, renal impairment, concomitant pharmacotherapy).30 ACR guidelines currently recommend considering HLA-B*5801 testing prior to allopurinol therapy initiation, in Asian subpopulations at elevated risk for allopurinol hypersensitivity reaction, specifically in individuals of Korean descent with stage 3 or higher chronic kidney disease (CKD) and in those of Han Chinese and Thai descent irrespective of renal function.10 Febuxostat, a newer xanthine oxidase inhibitor, is recommended as first-line-equivalent therapy with allopurinol in the ACR guidelines or as second-line therapy (for those who cannot tolerate allopurinol or attain their sUA target with allopurinol) in the EULAR guidelines.10,16 Febuxostat 40 mg is approximately equipotent to allopurinol 300 mg; relative potency at higher doses of each drug has not been formally studied.32 In March 2018, results of the CARES trial, an FDA-mandated study comparing allopurinol with febuxostat for cardiac outcomes, were published in the New England Journal of Medicine. Among 6190 patients with gout and cardiovascular disease,
febuxostat was found to be noninferior with regard to the primary outcome: rates of adverse cardiovascular events.The secondary outcomes of all-cause mortality and cardiovascular mortality were higher in the febuxostat group, although the study could not distinguish between a potential allopurinol benefit and a potential febuxostat risk. The significance of these observations is an area of ongoing evaluation.33 Uricosuric agents. Many patients cannot attain or maintain their target sUA level on xanthine oxidase inhibitor therapy alone.34-35 Uricosuric agents are considered second-line therapy for such patients.These medications increase uric acid excretion by inhibiting renal urate reabsorption.7 Until recently, probenecid was the only drug in this class approved in the United States to treat gout-related hyperuricemia. Its use requires multiple daily dosing and aggressive hydration as well as potential alkalization of urine with potassium citrate to prevent urolithiasis.10 It is not effective in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] ≤30 mL/min).36 Benzbromarone, a more potent medication in this class, is approved in Europe but not in the United States. Either probenecid or benzbromarone can be combined with allopurinol in patients who do not achieve their sUA target with allopurinol therapy alone.16 A newer agent in this class, lesinurad, was approved by the FDA in December 2015 and by the European Medicines Agency in February 2016. Given as one 200-mg tablet once
TABLE 2.Therapies for acute flares of gout: recommended dosing Therapy
• Start at a loading dose of 1.2 mg on day 1, followed 1 hr later by 0.6 mg. • Subsequent dosing is 0.6 mg once or twice daily until the attack resolves. • In countries with 1 mg pills, the doses are 1 mg followed by 0.5 mg.26
• Use full approved dosing for the treatment of acute pain or acute gout.26 • NSAID therapy can be combined with a proton pump inhibitor. • A COX-2 inhibitor class also can be chosen.16
• Oral, US dosing: 0.5 mg/kg/day of prednisone or its equivalent for 3 to 5 days. • Oral, European dosing: 30 to 35 mg/day of equivalent prednisolone for 3 to 5 days.16,26 • Intramuscular steroid injection triamcinolone acetonide 60 mg, followed by oral prednisone.26 • Intra-articular aspiration and corticosteroid injection—for 1 or 2 large joints.26
COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs. *European League Against Rheumatism guidelines indicate that colchicine and NSAIDs can be used alone or in combination for gout flares.16
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CME FEATURED COURSE
Adding lesinurad to either febuxostat or allopurinol has led to more patients achieving sUA targets compared with xanthine oxidase therapy alone. daily, it can be added to allopurinol or febuxostat therapy for patients with hyperuricemia and gout who have not achieved their target sUA levels with a xanthine oxidase inhibitor alone. It is not approved as monotherapy and should not be used alone.37 A fixed-dose coformulation of 200 mg lesinurad and 300 mg allopurinol (1 pill once daily) received FDA approval in August 2017 and may be considered for patients who have been titrated to 300 mg allopurinol without achieving their sUA target. Patients should be instructed to stay well hydrated (2 L liquid/day) during the initiation of therapy. Increased serum creatinine was observed in some patients during clinical trials, though most cases resolved without stopping lesinurad.38,39 Adding lesinurad to either febuxostat or allopurinol has led to higher proportions of patients achieving their sUA target compared with xanthine oxidase therapy alone. Significantly larger proportions of patients with tophi achieved an sUA of <5.0 mg/dL at 6 months with lesinurad 400 mg plus febuxostat compared with febuxostat alone in a phase 3 clinical trial (76.1% vs 46.8%; P<.0001). At all other time points assessed except month 6, patients receiving the lower dose of lesinurad (200 mg) along with febuxostat were more likely to achieve their sUA target than those receiving febuxostat alone.11 Adding either dose of lesinurad (200 mg or 400 mg) to allopurinol therapy significantly increased the percentage of patients achieving sUA <6.0 mg/dL at 6 months, compared with allopurinol alone (54.1%, 59.5%, and 27.9%; lesinurad 200 mg, lesinurad 400 mg, and placebo, respectively, added to allopurinol; P<.0001).40 Because the 400-mg dose demonstrated a higher rate of adverse renal outcomes, only the 200-mg dose is approved for patient use. Uricase. Pegloticase, a recombinant, pegylated uricase, degrades uric acid into a water-soluble compound (allantoin).7 It is administered as an intravenous infusion every 2 weeks. After 12 biweekly infusions (6 months of therapy), 42% of patients maintained a plasma uric acid level of <6.0 mg/dL, compared with none in the placebo group.41 Anaphylaxis occurred in 6.5% of those receiving pegloticase during clinical trials. Patients should be premedicated with antihistamine and corticosteroid therapy. Infusion reactions were relatively common (26% of patients treated biweekly in clinical trials). Hemolysis and methemoglobinemia occurred during pegloticase therapy in patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Candidates for pegloticase therapy should be screened for G6PD levels; those with a deficiency should not receive the drug. The ACR and EULAR
guidelines recommend pegloticase in patients with clinically severe, crystal-proven gout who cannot be adequately treated with other therapies.10,16 Flare prophylaxis during ULT
Because the early months of ULT have been associated with an increased rate of gout flares, both the ACR and EULAR guidelines recommend flare prophylaxis. EULAR advises prevention during the first 6 months of ULT.16 ACR guidelines recommend prophylaxis for whichever of the following is the longest duration: a) 6 months, b) 3 months after achieving the target sUA level in the absence of tophi on physical examination, or c) 6 months after achieving the target sUA level where tophi previously detected on physical examination have resolved.25 Both ACR and EULAR guidelines emphasize that the risks and benefits of flare prophylaxis therapy should be discussed fully with the patient so that he or she can make an informed decision about whether to consent to prophylaxis.16,25 Colchicine (0.5-1.0 mg/day, EULAR; 0.5 or 0.6 mg once or twice daily, ACR) is recommended for prophylaxis. This dose should be adjusted in patients with renal impairment. There is an increased risk of neurotoxicity and/or muscular toxicity in patients with renal impairment or in those receiving statin treatment. Other cautions include avoiding colchicine in conjunction with strong P-glycoprotein and/or CYP3A4 inhibitors and avoiding colchicine and NSAIDs in patients with severe renal impairment.10,16,17 A consulting or community pharmacist may be able to assist with this evaluation and suggest possible substitutions. Low-dose NSAIDs offer an alternative for those in which colchicine is not tolerated or is contraindicated.16,25 For patients in which neither colchicine nor NSAIDs are options, the ACR recommends use of prednisone or prednisolone (≤10 mg/day).25 INDIVIDUALIZED STRATEGIES FOR GOUT MANAGEMENT
Guidelines issued by rheumatology societies within the last several years share broad agreement about the role of ULT in gout management (Table 3).The EULAR guideline concludes that long-term ULT reduces gout flares and avoids their recurrence while also shrinking the size and number of tophi and improving patient QoL.3,16,34,35,41,42 It also states that ULT therapy may reduce cardiovascular risk and slow the rate of renal disease progression.16,43 For this reason, it recommends
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Educating patients with gout about their disease and the reasons for urate-lowering therapy are associated with improved rates of adherence. “possible initiation of ULT close to the first presentation (ie, in most cases, close to the first flare).”16 Rheumatology guidelines advocate long-term ULT for appropriate patients (Table 2), with an sUA target of <6.0 mg/dL in most cases.10,16,17 Some individuals (eg, those with severe gout) may benefit from a target of <5.0 mg/dL until total crystal dissolution has occurred.10,16 The British Society of Rheumatology (BSR) advocates an initial target of <5.0 mg/dL to dissolve crystals and prevent their formation with <6.0 mg/dL as the long-term maintenance goal.27 Serum uric acid level should be monitored regularly;ACR guidelines suggest measurement every 2 to 5 weeks during ULT titration and every 6 months once the target is achieved.10 Patients with tophi, at least 2 flares per year, renal impairment, and/or a history of uroliathiasis meet the criteria for ULT according to the ACR, BSR, and EULAR guidelines. Individual
guidelines recommend ULT in patients with other characteristics (Table 3).10,19,27 EULAR and BSR guidelines advise discussing with, and considering or offering ULT therapy to, every patient who has a diagnosis of gout.16,27 The American College of Physicians (ACP) guideline offers a different viewpoint (Table 3). It notes that evidence associating the maintenance of sUA at <6.0 mg/dL for 1 year with reduction in gout flares comes from a post hoc analysis and retrospective cohort studies rather than from long-term randomized controlled trials.3,26,34,35 The guideline states that these studies “did not establish that urate-lowering therapy rather than other underlying patient characteristics caused the reduction in flares. Further, even if urate-lowering therapy does reduce gout flares, these studies do not help us understand the tradeoff between the magnitude of benefit and the harms and costs incurred by treatment and monitoring. Thus, we
TABLE 3. Comparison of guidelines for use of long-term urate-lowering therapy (ULT) in patients with gout Criteria
History of urolithiasis
Chronic gouty arthritisd
Diuretic therapy use
Primary gout starting at a young agee
Presenting with sUA >8.0 mg/dL (480 mmol/L) and/or comorbiditiesf
ACP, American College of Physicians; ACR, American College of Rheumatology; BSR, British Society of Rheumatology; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; EULAR, European League Against Rheumatism; NA, not addressed; SDM, shared decision-making between patient and clinician warranted to consider the benefits and harms of ULT; sUA, serum uric acid. Or tophus. CKD stage ≥2 in patients with prior gout attacks and current hyperuricemia. eGFR <60 mL/min. d Defined as or including ≥2 attacks/year. e Defined as <40 years old in EULAR guidelines. f Renal impairment, hypertension, ischemic heart disease, heart failure.10,16,27,28 a
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CME FEATURED COURSE
remain uncertain about the value of a treat-to-target strategy compared with a strategy of basing treatment intensity on minimizing symptoms.”26 The ACP advises against starting long-term ULT in most patients after a first gout flare or in patients with infrequent flares.The decision about starting ULT should be a shared one between patients and clinicians, based on a risk-benefit analysis. The guideline suggests that comparative effectiveness studies should compare the treat-to-sUA-target strategy espoused by rheumatology guidelines with a treat-to-avoid-symptoms strategy involving no sUA monitoring.26 PROMOTING QUALITY CARE THROUGH PATIENT EDUCATION
Low levels of adherence to gout therapy are common. A systematic review and meta-analysis reported that 46% of patients with gout were adherent.Treatment persistence also was problematic, with nonpersistence rates of 54% to 87% found in published studies.44 Educating patients about the disease state and the reasons for therapy was associated with high rates of patient adherence to and persistence with ULT in a UK-based nurse-led model of care. Patients received individually tailored information about gout and its management, agreed jointly with the physician about a care plan, and received ULT if agreed upon in accordance with BSR recommendations. More than 92% of 106 patients achieved sUA <6.0 mg/dL at 1 year in a pilot study of the intervention. Quality of life measures, including pain, also improved at 1 year.23 Five years later, 75 of those patients returned a questionnaire seeking follow-up data. Self-reported persistence with ULT was 90.7%. Mean sUA was <5.0 mg/dL in the 65 patients who returned for a study visit.24
Gout is a common form of inflammatory arthritis that can result in joint damage, disability, and reduced QoL in the absence of effective therapy. Hyperuricemia strongly predicts the development of gout. Therapy for acute flares should be started as early as possible after symptom onset. Rheumatology society guidelines recommend ULT with a goal of treating to a target sUA level in patients with tophi or chronic gouty arthritis; some societies advise consideration of ULT therapy in all patients.The ACP guideline states that, because evidence for the benefit of ULT therapy comes from observational data rather than long-term randomized controlled trials, it cannot endorse ULT.All guidelines recommend that decisions about gout management be based on shared decision-making with the patient and clinician after the clinician has fully informed the patient about the disease and the rationale for therapy. Patient education has been associated with high levels of adherence to ULT therapy and reduced levels of pain.24 ■ References 1. Dalbeth N, Aati O, Kalluru R, et al. Relationship between structural joint damage and urate deposition in gout: a plain radiography and dual-energy CT study. Ann Rheum Dis. 2015;74(6):1030-1036. 2. Sigurdardottir V, Drivelegka P, Svard A, et al. Work disability in gout: a population-based case-control study. Ann Rheum Dis. 2018;77(3):399-404. 3. Becker MA, Schumacher HR, Benjamin KL, et al. Quality of life and disability in patients with treatment-failure gout. J Rheumatol. 2009;36(5):1041-1048. 4. Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med. 2012;125(7): 679-687.e1. 5. Keenan RT, O’Brien WR, Lee KH, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med. 2011; 124(2):155-163. 6. Fisher MC, Rai SK, Lu N, et al. The unclosing premature mortality gap
Diet and lifestyle measures for gout
in gout: a general population-based study. Ann Rheum Dis. 2017;76(7): 1289-1294.
• Limit consumption of purine-containing meats/seafood and of high-fructose corn syrup–sweetened drinks10,16 • Avoid alcohol overuse (2 servings/day for men, 1 serving/ day for women); abstain from alcohol consumption during active arthritis attacks or periods of frequent attacks— especially beer and spirits10,16 • Consume plenty of vegetables and eat low-fat/nonfat vs full-fat dairy products10,16 • Be aware that weight loss can reduce serum uric acid levels16 • Engage in regular physical activity • Initiate smoking cessation (for patients who smoke)
7. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016;388(10055): 2039-2052. 8. Neogi T. Clinical Practice. Gout. N Engl J Med. 2011;364(5):443-452. 9. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10):3136-3141. 10. Khanna D, FitzGerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for Management of Gout Part I: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446. 11. Dalbeth N, Jones G, Terkeltaub R, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol.2017;69(9):1903-1913.
42 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
12. Dalbeth N, Phipps-Green A, Frampton C, et al. Relationship between
27. Qaseem A, Harris RP, Forciea M; Clinical Guidelines Committee of the
serum urate concentration and clinically evident incident gout: an individual
American College of Physicians. Management of acute and recurrent gout: a
participant data analysis [published online February 20, 2018]. Ann Rheum
clinical practice guideline from the American College of Physicians. Ann Intern
Dis. doi: 10.1136/annrheumdis-2017-212288. http://ard.bmj.com/content/
28. Hui M, Carr A, Cameron S, et al. The British Society for Rheumatology
13. Perez-Ruiz F, Calabozo M, Erauskin GG, et al. Renal underexcretion of
Guideline for the Management of Gout. Rheumatology (Oxford). 2017;56(7):
uric acid is present in patients with apparent high urinary uric acid output.
Arthritis Rheum. 2002;47(6):610-613.
29. Zyloprim [package insert]. Greenvile, NC: DSM Pharmaceuticals Inc; 2003.
14. Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of
30. Stamp LK, Day RO, Yun J. Allopurinol hypersensitivity: investigating the
gout in men: prospective cohort study. BMJ. 2008;336:309-312.
cause and minimizing the risk. Nat Rev Rheumatol. 2016;12(4):235-242.
15. Neogi T, Chen C, Niu J, et al. Alcohol quantity and type on risk of
31. Stamp LK, Taylor WJ, Jones PB, et al. Starting dose is a risk factor for allopu-
recurrent gout attacks: an internet-based case-crossover study. Am J Med.
rinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol.
Arthritis Rheum. 2012;64(8):2529-2536.
16. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-
32. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering
based recommendations for the management of gout. Ann Rheum Dis.
efficacy and safety of febuxostat in the treatment of the hyperuricemia of
gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63.
17. Sivera F, Andrés M, Carmona L, et al. Multinational evidence-based
33. White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat
recommendations for the diagnosis and management of gout: integrating
or allopurinol in patients with gout. N Engl J Med. 2018;378:1200-1210.
systematic literature review and expert opinion of a broad panel of
34. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared
rheumatologists in the 3e initiative. Ann Rheum Dis. 2014;73(2):328-335.
with allopurinol in patients with hyperuricemia and gout. N Engl J
18. Dalbeth N, House ME, Aati O, et al. Urate crystal deposition in
asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT
35. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat
study. Ann Rheum Dis. 2015;74(5):908-911.
versus allopurinol and placebo in reducing serum urate in subjects with
19. Howard RG, Pillinger MH, Gyftopoulos S, et al. Reproducibility of
hyperuricemia and gout: a 28-week, phase III, randomized, double-blind,
musculoskeletal ultrasound for determining monosodium urate deposition:
parallel-group trial. Arthritis Rheum. 2008;59(11):1540-1548.
concordance between readers. Arthritis Care Res (Hoboken). 2011;63(10):
36. Probenecid [package insert]. Parsippany, NJ: Actavis Pharma; 2016.
37. Uloric [package insert]. Deerfield, IL: Takeda Pharmaceuticals America
20. Dalbeth N, Clark B, Gregory K, et al. Mechanisms of bone erosion in gout:
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38. Zurampic [summary of product characteristics]. Aachen, Germany:
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Grünenthal GmbH; 2016. http://www.ema.europa.eu/docs/en_GB/document_
21. Modjinou DV, Krasnokutsky S, Gyftopoulos S, et al. Comparison of
dual-energy CT, ultrasound and surface measurement for assessing tophus
39. Zurampic [package insert]. Cambridge, MA: Ironwood Pharmaceuticals
dissolution during rapid urate debulking. Clin Rheumatol. 2017;36(9):
40. Saag KG, Fitz-Patrick D, Kopicko J, et al. Lesinurad combined with allopu-
22. Neogi T, Jansen T, Dalbeth N, et al. 2015 Gout classification criteria: an
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with an inadequate response to standard-of-care allopurinol (a US-based
collaborative initiative. Arthritis Rheumatol. 2015;67(10):2557-2568.
study). Arthritis Rheumatol. 2017;69(1):203-212.
23. Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative
41. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase
treatment if informed appropriately: proof-of-concept observational study.
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Ann Rheum Dis. 2013;72(6):826-830.
treatment: two randomized controlled trials. JAMA. 2011;306(7):711-720.
24. Abhishek A, Jenkins W, La-Crette J, et al. Long-term persistence and
42. Strand V, Khanna D, Singh JA, et al. Improved health-related quality of life
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care-5-year follow-up of a proof-of-concept study. Rheumatology (Oxford).
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25. Wells BG, Di Piro JT, Schwinghammer TL, Dipiro CV. Pharmacotherapy
43. Goicoechea M, Garcia de Vinuesa S, Verdalles U, et al. Allopurinol and
Handbook, 9E. 2016; McGraw-Hill Publishing.
progression of CKD and cardiovascular events: long-term follow-up of a
26. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of
randomized clinical trial. Am J Kidney Dis. 2015;65(4):543-549.
Rheumatology guidelines for management of gout. Part 2: therapy and antiin-
44. Scheepers LEJM, van Onna M, Stehouwer CDA, et al. Medication adher-
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ence among patients with gout: a systematic review and meta-analysis. Semin
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Arthritis Rheum. 2018;47(5):689-702.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 43
POSTTEST Expiration date: June 30, 2019
A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/June18feature. CREDITS: 0.50 | Viewpoints in gout and hyperuricemia: Updated treatment guidance
1. Which of the following statements is true? a. Gout is nearly twice as common in women as in men. b. Gout affects nearly 4% of all adults in the United States. c. Gout affects 30% of all individuals over the age of 65. d. Gout does not damage the joints of most affected people.
b. Febuxostat should not be used in patients who cannot tolerate allopurinol. c. Febuxostat is associated with a hypersensitivity syndrome in approximately 25% of patients with gout. d. All of the above
2. The majority of patients with hyperuricemia: a. Also have gout. c. Do not have medical comorbidities. b. Do not have gout. d. Are women.
8. Uricosuric agents: a. Are recommended by the ACR as first-line ULT for individuals with gout. b. Are recommended by the ACR for only a very small subset of individuals with chronic gout. c. Should not be used with allopurinol or febuxostat. d. Are recommended by the ACR for patients with gout who cannot reach or maintain their target serum uric acid (sUA) level on xanthine oxidase inhibitor monotherapy.
3. The major cause(s) of primary hyperuricemia in gout is/are: a. Hepatic overproduction of purines b. Malignancies c. Hemolytic anemia d. Renal or gut underexcretion of uric acid 4. The gold standard for diagnosis of gout is: a. Confirmation of the presence of monosodium urate crystals in synovial fluid b. Palpable tophi c. Rapid response to colchicine d. Diagnostic imaging (eg, ultrasound) 5. According to the American College of Rheumatology (ACR) guidelines for gout management: a. Biologics that block interleukin-1 are first-line therapy for acute gout flares. b. Colchicine should be used for acute gout flares but must be started within 8 hours of symptom onset. c. Acute gout flares should be treated within 24 hours of symptom onset. d. There is no correlation between how early therapy for acute gout flares is initiated and the efficacy of therapy. 6. According to the ACR, first-line options for urate-lowering therapy (ULT) include: a. Allopurinol c. Lesinurad b. Probenecid d. All of the above 7. According to results from the CARES Study published in 2018: a. All-cause mortality and cardiovascular mortality were higher in patients treated with febuxostat vs allopurinol.
9. Which of the following statements is true? a. Adding lesinurad to febuxostat is approved as an initial approach to ULT. b. Adding lesinurad to allopurinol is approved as an initial approach to ULT. c. Adding lesinurad to either febuxostat or allopurinol has no impact on the proportion of patients achieving their sUA target compared with xanthine oxidase therapy alone. d. Adding lesinurad to either febuxostat or allopurinol has led to higher proportion of patients achieving their sUA target compared with xanthine oxidase therapy alone. 10. Which of the following statements accurately summarizes key differences between gout guidelines issued by the ACR and those issued by the American College of Physicians (ACP)? a. The ACP advises considering or offering ULT therapy to every patient who has a diagnosis of gout. b. The ACP recommends that all gout patients with tophi, at least 2 attacks per year, renal impairment, and/or a history of urolithiasis should receive ULT. c. The ACP advocates an initial sUA target of <5.0 mg/dL to dissolve crystals and prevent their formation, with <6.0 mg/dL as the long-term, maintenance goal. d. The ACP advises against starting long-term ULT in most patients after a first gout attack or in patients with infrequent attacks.
TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/June18feature
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Dermatology Clinic CASE #1
Dry, scaly skin in a young boy DANIEL COLCHADO, BA, JOAN FERNANDEZ, BS, CHRISTOPHER RIZK, MD
A 6-year-old Caucasian boy is brought to the clinic by his parents for dry, scaly skin that has persisted for the past 2 years despite the use of commercial moisturizers. His scaly skin is especially notable over his lower extremities, back, and elbows. The patient denies any pain over the affected areas and reports only a mild itch that is soothed with cold water or lotions. The parents report that he had a similar condition as an infant throughout his entire body and that he has siblings who also have persistently dry skin. His parents have tried exfoliating the scales with moderate success, but the scales recur shortly thereafter. What is your diagnosis? Turn to page 46
Ecchymosis and bullous lesions on a young male’s back MICHELLE LEE, BA, JOAN FERNANDEZ, BA, CHRISTOPHER RIZK, MD
A 20-year-old male with a medical history of diabetes mellitus type 1 presents with ecchymosis and bullous lesions on his back, posterior legs, and buttocks. He was playing football when he ran into another player and became unconscious. He was immobile in the hospital for 3 days before he regained consciousness. He has about 7 tense blisters with areas of surrounding erythema on the back, buttocks, and posterior thighs. What is your diagnosis? Turn to page 48 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 45
Dermatology Clinic CASE #1
Ichthyoses are a group of genetic skin disorders that share the common feature of the appearance of scaly skin, which has frequently been likened to fish scales (ichthys meaning “fish” in Greek). Although many variants exist, most appear early in infancy or childhood with only rare cases presenting for the first time in adulthood. Ichthyoses vary widely in appearance, from mild hyperkeratosis to severe hyperkeratosis with bullae. Some forms of ichthyoses, such as harlequin-type ichthyosis, are often fatal in early infancy due to severe dehydration and respiratory failure as the chest fails to expand. Most of the more common ichthyoses variants, however, can be managed with only minor lifestyle modifications and a set skin care regimen.The most common form of ichthyosis is known as ichthyosis vulgaris (IV).1,2 Similar to the majority of the other forms of ichthyoses, IV generally presents in infants, with the most common age of initial presentation at 3 to 5 months. IV occurs in about 1 in 250 to 1 in 1000 cases with varying degrees of severity.2 IV is characterized by extremely xerotic skin, scaling, and occasional eczema and pruritus. Often patients will bleed as a result of cracks in the skin secondary to disease.These cracks allow for excess loss of moisture from the skin surface, which further exacerbates the lesions.1 The etiology of the lesions seen in IV is primarily genetic. Specifically, IV results from a mutation in the FLG gene, which encodes for the protein profilaggrin. Profilaggrin is the precursor to filaggrin, a cross-linking protein in the stratum corneum that helps to form an insoluble barrier against epidermal water loss and environmental insults.The genetic mutation present in IV leads to the loss of the epidermal integrity resulting in the appearance of scaly, cracked skin.2,3 Although IV is generally considered to be inherited in an autosomal dominant fashion, mutations in a single copy of FLG seem to result in much milder forms of IV compared to when both copies are mutated.3 Thus, it is possible that IV resulting from FLG mutations displays incomplete expression in humans.4 Apart from the underlying genetic factors that lead to the development of IV, multiple environmental factors contribute to the disease course as well. Factors that have been shown to worsen the severity of IV include exposure to cold temperatures, dry climate, and poor skin moisturization.1,4 In addition to exacerbating existing IV, these factors can also trigger the recurrence of this condition in adults who may have experienced it as infants.
In a majority of cases, the diagnosis of IV can often be made based on the gross appearance of the skin and historical information, particularly a family history of disease, obtained from the patient. If the diagnosis is uncertain, a biopsy of the skin may be performed, which would show hyperkeratosis of the stratum corneum and hypoplasia of the stratum granulosum with a normal dermis.4 When considering a diagnosis of IV, the differential should include the multiple different types of ichthyoses, which may have a similar presentation to that of IV. X-linked ichthyosis is the closest in presentation to IV, as it also appears as scaling of the skin in similar body regions and also primarily occurs during infancy. X-linked ichthyosis is due to a mutation in the gene encoding steroid sulfatase (STS) found on the X chromosome.
In a majority of cases, the diagnosis of IV can often be made based on the gross appearance of the skin and history. The identification of this mutation can be used to differentiate X-linked ichthyosis from IV.These two diagnoses can be further differentiated via biopsy examination, which will show a normal stratum granulosum in X-linked ichthyosis as opposed to the diminished stratum granulosum seen in IV.5 Other disorders to consider on the differential include lamellar ichthyosis, epidermolytic hyperkeratosis, and xerotic dermatitis.Typically, lamellar ichthyosis presents with a thicker, darkened stratum corneum and an increased stratum granulosum, secondary to transglutaminase 1 mutations.6 Epidermolytic hyperkeratosis is another disease that can present with the same hyperkeratosis as seen IV; however, epidermolytic hyperkeratosis is usually accompanied by the formation of bullae as a result of destruction of the cells in the stratum granulosum that arises due to collagenVII mutations.7 Furthermore, xerotic dermatitis can be differentiated from IV based on the age at initial presentation, as xerotic dermatitis often has onsets later in life.8 Currently, there is no definitive treatment for IV that serves to cure the disease. Instead, treatment focuses on preserving epidermal integrity and minimizing the evaporation of water from the surface of the skin. Thick moisturizers and topical medications with 10% lactic acid (eg, AmLactin) or 10% urea (eg, Ureacin-10) have proven to be helpful in the management of disease.3 Additionally, maintaining a warm, moist environment has also proven to be beneficial in controlling this condition.1
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Continues on page 48
Dermatology Clinic In this case, the patient’s parents were educated regarding the typical course of IV and the steps that could be taken to manage their son’s disease.They were instructed to moisturize the affected areas and apply a 10% lactic acid lotion daily to the affected areas.The parents were also advised to avoid dry, cold weather, and to be hyper-vigilant about applying moisturizers in situations in which these conditions could not be avoided. Daniel Colchado, BA, is a medical student, Joan Fernandez, BA, is a medical student, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston. References 1. Takeichi T, Akiyama M. Inherited ichthyosis: non‐syndromic forms. J Dermatol. 2016;43:242-251. 2. Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses—an update. J Dtsch Dermatol Ges. 2014;12:109-121. 3. Smith FJ, Irvine AD,Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38:337-342. 4. Monahan TP, Cohen BA, Siegfried EC. Congenital and hereditary disorders of the skin. In: Avery’s Diseases of the Newborn. 8th ed. Philadelphia: Elsevier; 2004:1483-1502. 5. Hand JL, Runke CK, Hodge JC.The phenotype spectrum of X-linked ichthyosis identified by chromosomal microarray. J Am Acad Dermatol. 2015;72:617-627. 6. Elias PM, Schmuth M, Uchida Y, et al. Basis for the permeability barrier abnormality in lamellar ichthyosis. Exp Dermatol. 2002;11:248-256. 7. Hernández-Martín A, Cuadrado-Corrales N, Ciria-Abad S, et al. X-linked ichthyosis along with recessive dystrophic epidermolysis bullosa in the same patient. Dermatology. 2010;221:113-116. 8. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441-446.
Pressure bullae (coma bullae)
Pressure bullae, also known as coma bullae, are tense, subepidermal blisters caused by prolonged pressure applied to an area.As such, they are commonly associated with barbiturate overdose and comatose patients. These lesions were first described by Dr. Larrey, Napoleon’s surgeon in the 19th century. He noted blisters in comatose soldiers after exposure to carbon monoxide.1 Recently, these lesions have been seen with increasing frequency in the wake of the
current opioid epidemic. Cases have recently been published describing patients who overdosed on diazepam, methadone, heroin, carbon monoxide, caffeine, alcohol, and tricyclic antidepressants who subsequently develop pressure bullae after prolonged periods of inactivity.2,3 Patients with neurologic disorders such as strokes, brain tumors, traumatic brain injuries, spinal cord disease, and encephalitis also frequently have coma bullae. Other associated conditions include chronic renal failure, hyperparathyroidism, and diabetic ketoacidosis, all of which share a common underlying theme of decreased movement and activity.4 Overall, the most common risk factor for pressure bullae is prolonged periods of impaired consciousness. Coma bullae often initially present as erythematous lesions that evolve to become tense bullae or vesicles.The lesions most often develop 2 to 3 days after the onset of altered consciousness or impaired mobility.5 The bullae usually resolve on their own in 2 to 4 weeks, either after the patient regains mobility or measures are taken to relieve pressure from the affected area.4 Skin biopsies taken from coma bullae reveal subepidermal bullae, epidermal and eccrine sweat gland necrosis with many neutrophils and dermal vessel thrombosis.5,6 The sweat gland degeneration that is seen in coma blisters has been found to have CD45RO and M30 immunoreactivity. As a result, these immunohistochemical stains can be used to identify sweat gland apoptosis in coma bullae.7 Although the exact pathogenesis leading to the formation of coma bullae is unclear, it is known that their development is multifactorial. Hypoxia and tissue ischemia combined with local pressure at the site of the lesion are the most significant contributors to the development of the bullae.This decreased oxygen supply can be seen as a result of arterial hypotension associated with shock, vascular control changes seen in comatose patients, or secondary to the vasoactive changes seen with certain drug ingestions.6 The low flow of oxygen to the area leads to necrosis, which most noticeably affects the cells with highest metabolic activity: eccrine sweat glands.8 When these damaged areas of skin are subjected to prolonged pressure forces, coma bullae may result. Infection and autoimmune processes are not thought to be involved in pathogenesis, and, surprisingly, reports have argued that frictional forces are unlikely to be involved either as blisters secondary to friction produce intraepidermal rather than subepidermal lesions.2 Other conditions to consider on the differential diagnosis when coma bullae are suspected are other blistering diseases that may also occur in dependent areas. Bullous disease of diabetes, or bullosis diabeticorum, results in the acute formation of tense, subepidermal bullae, most commonly on the
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Dermatology Clinic feet or lower legs.These lesions can have diameters extending several centimeters, and histopathologic examination will show intraepidermal and subepidermal blisters. These lesions also spontaneously resolve during the course of a few weeks. Stasis blisters are another diagnosis to consider, and these form in edematous areas, most commonly on the lower legs. Histologic studies have demonstrated that stasis blisters show epidermal spongiosis and dermal edema. Treating the patient’s edema typically leads to resolution of the blisters. Another etiology to consider on the differential should be bullous leukocytoclastic vasculitis, which presents
References 1. Ruiz‐Rivero J, Pulido‐Pérez A, Suárez‐Fernández RM. Coma blisters with deep soft tissue involvement after drug overdose. Int J Dermatol. 2017;56:881-883. 2. Herschthal D, Robinson MJ. Blisters of the skin in coma induced by amitriptyline and clorazepate dipotassium: Report of a case with underlying sweat gland necrosis. Arch Dermatol. 1979;115:499-499. 3. Arndt KA, Mihm MC, Jr, Parrish JA. Bullae: a cutaneous sign of a variety of neurologic diseases. J Invest Dermatol. 1973;60:312-320. 4. Sami N, Yeh SW, Ahmed AR. Blistering diseases in the elderly: diagnosis and treatment. Dermatol Clin. 2004;22:73-86. 5. Bosco L, Schena D, Colato C, Biban P, Girolomoni G. Coma blis-
In establishing a diagnosis of coma bullae, the clinical setting and history alone are oftentimes sufficient to make the diagnosis.
ters in children: case report and review of the literature. J Child Neurol. 2013;28:1677-1680. 6. Chacon AH, Farooq U, Choudhary S, et al. Coma blisters in two postoperative patients. Am J Dermatopathol. 2013;35:381-384. 7. Kashiwagi M, Ishigami A, Hara K, et al. Immunohistochemical investigation of the coma blister and its pathogenesis. J Med Invest. 2013;60:256-261.
Michelle Lee, BA, is a medical student, Joan Fernandez, BS, is a medical student, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston.
8. Rocha J, Pereira T, Ventura F, Pardal F, Brito C. Coma Blisters. Case Rep Dermatol. 2009;1:66-70. 9. Kato N, Ueno H, Mimura M. Histopathology of cutaneous changes in non-drug-induced coma. Am J Dermatopathol. 1996;18:344-350. 10. Arndt KA. Coma blister (comma bullae, drug-induced coma blisters, barbiturate blisters, neurologic blisters). 2017. Available at: https://www.clinicaladvisor.com/dermatology/coma-blister-commabullae-drug-induced-coma-blisters-barbiturate-blisters-neurologic-blisters/ article/593874/ (Accessed May 7, 2018).
“For my birthday, my parents are giving me a driverless car that’s always home by 10.”
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© Harley Schwadron, 2018
with subepidermal, hemorrhagic bullae, or vesicles that overlay purpuric plaques. This cutaneous presentation is due to necrosis of the skin in areas of small vessel vasculitis.4 Other conditions to rule out include friction blisters, as well as more unusual cases of bullous disease such as bullous amyloidosis, epidermolysis bullosa, and bullous pemphigoid. In establishing a diagnosis of coma bullae, the clinical setting and history alone are oftentimes sufficient to make the diagnosis. However, histologic findings of subepidermal bullae and necrosis of eccrine sweat glands can also confirm the diagnosis. In nondrug-induced coma blisters, the most frequent histologic finding is the lack of epidermal inflammation and the presence of vessel thrombosis in the dermis.9 Treatment of this condition includes mobilizing the patient and relieving pressure. Wound care to prevent infection is recommended, including sterile drainage, maintaining the overlying skin flap to cover most of the lesion, and hydrocolloid dressings.10 If these treatments are pursued promptly, the lesions typically resolve in 2 to 4 weeks. Systemic complications are rare if pressure is eliminated and proper wound care is followed. The 20-year old patient in this case was rotated from side to side and given a pressure relief cushion to lay on until he could ambulate.The patient’s bullae resolved after about 3 weeks with supportive care and ambulation. ■
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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.
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.
X-RAY FOR CHRONIC COUGH A pediatrician once passed on this clinical pearl to me, and it has helped me in my 35 years of practice: get a chest X-ray if you ever have a young child with chronic cough (think neoplasm or foreign body). I will never forget a 3-year-old jumping actively in the office who had no active cough or wheeze but a mother who said that he coughed nightly for more than 3 weeks. It turned out that he had a nickel lodged near the bifurcation of his airway. When he was lying down, it would impinge the trachea and cause him to cough. I never would have guessed. He looked too well.—CINDY BALTRUN, MSN, DNP, FNP Certified, Salado, Texas (236-1) SEASONAL ALLERGIES If affected by seasonal allergies after returning from outside during high allergy season, wash your hands. Then splash water on your face with your eyes open 8 times, dry your face and hands, blow your nose, drink water, and refrain from touching your eyes and face.—KARIN KRAUSZER, BSN, RN, CSN-NJ, Edison, NJ (236-2) LIQUID STOOL SOFTENER AS AN EARWAX REMOVAL AGENT Liquid stool softener is quite effective as an earwax removal agent. It works by dissolving or loosening the cerumen, allowing it to be more easily removed upon irrigation. Lie on your side with the affected ear facing up and instill 1 mL (about 15 drops) of liquid Colace into the ear. Let the liquid sit in the ear for 15 minutes so it can work.After 15 minutes, rinse the affected ear with warm water so that you can get the softened earwax out of your canal. This is a very effective and inexpensive option instead of prepared earwax removal products. (Do not use the syrup
formulation in the children’s laxative section.) If you can’t find a bottle of liquid formula, use the stool softener capsules. Cut the tip off and use the liquid inside, 1-3 capsules. Works like a charm!—PATRICIA EDWARDS, MSN, ANP, Commack, NY (236-3)
POSTPRANDIAL INSULIN For patients on insulin who still have a high A1c despite normal fasting blood sugars, have them check their postprandial insulin, which is 2 hours after eating, to see if more mealtime insulin is needed. A postprandial blood sugar level should be less than 180 mg/dL.—GINA LUNA, FNPBC, BC-ADM, Palmdale, Calif. (236-4)
CASE FILES ARTHRALGIAS AFTER CANCER Contributed by Sherril Sego, FNP-C, DNP Pam was a 54-year-old woman who had recently been diagnosed with endometrial and ovarian cancer. She had surgery and then underwent radiation and chemotherapy treatments. Approximately 2 months after she had finished her chemotherapy, she noticed annoying, mildto-moderate arthralgias. Her oncologist explained to her that this was a fairly common phenomenon.The literature suggests that early treatment with NSAIDS is usually effective and that the condition usually resolves. In a small percentage of patients, this pain continues for years. It appears to be more common in certain kinds of cancers, including breast cancer, ovarian cancer, and non-Hodgkin’s lymphoma. Pam’s condition gradually resolved over the next few months. The exact etiology of this syndrome is not wellunderstood. It does not appear to be inflammatory or immune-based. (236-5) ■
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 51
LEGAL ADVISOR CASE
Patient test results never received
BY ANN W. LATNER, JD
Ms Q was a 32-year-old nurse practitioner (NP) working for a very busy family practice in a large city. She had been employed there for 5 years, and although she liked the work, she did not like the fact that she had to see so many patients in one day. When she was hired, she had been told that she had to get patients in and out of the examination room in about 15 minutes. Clinicians who spent too much time with each patient or those who saw fewer patients than expected per day would be spoken to by the managing physician. Because of this, the practice sometimes felt like working in a factory to Ms Q. One afternoon, Mrs C, one of Ms Q’s patients, showed up for an appointment. The 58-yearold woman complained of chest pain and that she had heard a crack and thought she might have injured a rib. Ms Q examined the patient. Mrs C was in relatively good health, with no chronic illnesses, and was not on any medication other than synthetic thyroid replacement. After evaluating the
© RUNSTUDIO / GETTY IMAGES
A clinician fails to follow up after ordering diagnostic tests for a patient.
According to the experts, the 16-month delay in diagnosing the patient’s cancer had compromised her chances of survival.
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patient, Ms Q decided to send her for a chest radiograph. “I don’t see any obvious problem,” said Ms Q to her patient, “but I’d like you to get a chest X-ray to be sure.” She handed the patient a referral, ushered her out of the exam room, and brought in the next patient. Mrs C went for the radiograph a few days later, which revealed that she had a 1.5-cm mass in the right middle lobe of her lung. The radiologist put this information in his report, as well as his recommendation that the patient go for a CT scan, and sent the report to Ms Q’s practice. Had the practice received the report, the office policy was to notify the clinician whose patient it was, have the clinician sign off on the results, and then file the results in the patient’s file. Continues on page 56
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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LEGAL ADVISOR However, the report never arrived at the practice, and there was no policy in place as to how to handle test results that are ordered but which never arrive. Ms Q, who assumed she would be notified when the results came in, forgot about it entirely. The patient assumed that since she had not heard from Ms Q, the radiograph results must have been fine. Sixteen months after her initial visit, Mrs C returned to the practice to see Ms Q. This time she complained of a cough and chest pain that had been occurring for the past few weeks. Ms Q noticed that the original chest radiograph results were not in the file, although she had a note that she had given the patient a referral. “Did you go for that chest X-ray I ordered last time?” Ms Q asked the patient. Mrs C looked surprised. “Yes, of course I did,” she replied. “When I didn’t hear from you, I assumed that it was all okay. Isn’t it?” “I’m sure it’s fine,” said Ms Q, reassuringly. “I don’t see the results here. Let’s send you for another X-ray since the problem hasn’t resolved.”
A procedure should be instituted so that the office is aware of what results have come in and what are expected to arrive. She wrote another referral for Mrs C and sent her to the radiologist. This time the results were received by the office, and they showed a 4-cm mass in the right middle lobe. A CT scan revealed enlarged mediastinal lymph nodes. Mrs C underwent a biopsy, which showed invasive adenocarcinoma, and a PET scan confirmed that it was stage IV disease. Mrs C’s prognosis was extremely poor due to the late stage at which the cancer was identified. Before long, Mrs C developed brain metastases and died soon thereafter, leaving a husband and 2 college-aged children. Legal background
The widower contacted a plaintiff’s attorney and asked whether they might have a case against the NP and her practice. “My wife went for an X-ray almost a year and a half earlier and they never told her the results!” Mrs C’s widower
exclaimed. “What if she had the cancer then and it could have been treated?” The attorney subpoenaed the medical records, including the radiograph results and hired medical experts to review them. The experts told the attorney that the first X-ray had shown a mass, which had more than doubled in size by the time of the second X-ray. According to the experts, the 16-month delay in diagnosing the cancer compromised Mrs C’s chances of survival, and the delay was directly attributable to Ms Q’s failure to follow up on an X-ray that she had ordered. With this information in hand, the attorney told the widower that they had a case, and he filed a malpractice lawsuit against Ms Q and the practice. Ms Q met with the defense attorney provided by her malpractice insurance. This attorney also hired medical experts to review the records. The experts were critical of Ms Q’s treatment of the patient, specifically her failure to follow up on a test that she had ordered. The experts were also critical of the practice’s failure to have a procedure in place to verify that reports that are ordered are received and reviewed by the clinician. Based on this, the attorney advised Ms Q to settle the case out of court. Ms Q and the practice settled prior to trial for an amount within their malpractice limits. Protecting yourself
It should go without saying that if you order a test, you must review the results. Tests are ordered for a reason. Ignoring the results, or not bothering to look for them, negates the whole purpose for ordering them in the first place. Time is often of the essence with medical problems. Delays in getting and reviewing results can have a tremendously negative impact on a patient, as they did here. If you order a test, put a mechanism in place to remember to check for the results, whether it is a note, a memo on your computer, or a reminder on your phone. A procedure should be instituted so that the office is aware of what results have come in and what results are expected to arrive, so that follow-up can occur if the results do not appear. Mrs C’s options for treatment and chances of survival were significantly affected by the 16-month delay. Avoid this by ensuring that you follow up on every test ordered, and make sure that your practice has a policy not only to deal with results that arrive, but also to deal with those that do not. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.
56 THE CLINICAL ADVISOR • JUNE 2018 • www.ClinicalAdvisor.com
Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept. We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit. CLINICAL FEATURES update our readers on the latest information about conditions seen in everyday practice. Running approximately 2,500 to 5,000 words, including the references, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view. If at all possible, articles should be accompanied by clinical photos. Charts, tables, and algorithms are also encouraged. Please include your title and affiliation. CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general. The length should be about 1,500 words, and accompanying images are encouraged. Please include your title and affiliation. Dermatology Clinic CASE #1
Fingernail dystrophy in a young child SIMO HUANG, BS, CHRISTOPHER RIZK, MD
The patient is a 12-year-old Hispanic girl who presents with a 6-month history of nail dystrophy involving all of her fingernails. On examination, all 10 of her fingernails exhibit longitudinal ridging, pitting, fragility, thinning, and distal notching. The patient’s mother is very concerned about the cosmesis of her daughter’s nails. The patient has no systemic symptoms. On review of systems, the patient’s mother noted that her daughter has started to develop circular patches of hair loss that appear to resolve on their own. The patient has no relevant social or family history and does not take any medications. What is your diagnosis? Turn to page 54
Headache, malaise, and a rash ZACHARY SOLOMON, BS, DAVID RIZK, BA, CONNIE WANG, MD
A 42-year-old man presents with a four-day history of experiencing headache, malaise, and stabbing right-sided headache. Two days after his initial symptoms appeared, he developed a rash over the area of pain. He reports that he went hiking through the Texas hill country prior to becoming ill. The patient is otherwise in good health and has an unremarkable medical history. Physical examination reveals unilateral erythematous, thin, raised plaques over the right forehead. In addition, he has no relevant social or family history. What is your diagnosis? Turn to page 55 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 53
DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a 75-to-100-word description of the patient presentation, without giving away the diagnosis. This is followed by a 750-to-1,000-word summary that includes a fuller description of the ailment, an explanation of how the correct diagnosis was reached, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. Please include your title and affiliation. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. A typical Commentary runs about 600 words in length. Please include your title and affiliation. To discuss your editorial ideas, contact us by phone at 646.638.6078; by e-mail to editor@ClinicalAdvisor.com; or by mail to The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2018 57