December 2017 Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Hypertension guideline ■ LARC recommendations ■ Warfarin in older adults ■ Statins and diabetes risk ■ Cord clamping in infants LEGAL ADVISOR

A contract dispute between clinicians in practice together

n Dermatology Clinic

HEADACHE, MALAISE, AND A RASH PAGE 53

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n Feature

EMERGING THERAPIES FOR MS PAGE 30

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DECEMBER 2017

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DISORDERS OF PRIMARY

HEMOSTASIS Scanning electron microscope image showing red blood cells in a fibrin clot.

Editor Colby Stong editor@clinicaladvisor.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production manager Krassi Varbanov Circulation manager Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Editorial director Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085.

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EXPERTS 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.

CLINICAL PEARLS

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.

Advisor F

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.

orum

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.

NICAL

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

Write us today.

OUR CO

NSULTA

PEARLS

NTS

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

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

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Copyright © 2017

4 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

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.

CAL ADVI

SOR • SEPTE

MBER 2015

Abimbo la Farinde

, PhD,

is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

• www.Clinic

alAdvisor.c

om

Laura A.

Foster,

practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

.indd 62

9/29/15

2:44 PM

CONTENTS DECEMBER 2017

NEWS AND COMMENT

FEATURES

10

2 Treatment of disorders of 1 primary hemostasis An evaluation begins with a focused history and physical examination, a CBC count with platelet trend, and examination of the peripheral smear.

Newsline ■■The American Heart Association

and the American College of Cardiology publish a new clinical practice guideline for managing hypertension in adults, which redefines hypertension as 130 mm Hg/80 mm Hg from the previous level of 140 mm Hg/ 90 mm Hg. ■■The American College of Obstetricians and Gynecologists (ACOG) issues recommendations for long-acting reversible contraception. The practice bulletin provides information for appropriate patient selection and evidence-based recommendations for intrauterine devices and contraceptive implants.

■■Statins are associated with nearly a 30% increased risk of type 2 diabetes in individuals who are at high risk for the disorder, according to a study in BMJ Open Diabetes Research & Care.

■■Warfarin use is associated with a lower risk of cancer, according to results from a large study of persons older than 50 years published in JAMA Internal Medicine.

■■Delaying umbilical cord clamping in preterm infants delivered prior to 30 weeks of gestation shows no significant difference in death or severe morbidity rates compared with immediate cord clamping when monitored 36 weeks postmenstrual age, according to a study in the New England Journal of Medicine.

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

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CME Evolving expectations in the

44

CME Feature posttest

New clinical guideline for hypertension 10

management of MS Emerging therapies for RRMS raise the bar from the current therapeutic goal of minimal disease activity to none at all.

DEPARTMENTS 8

Rash on the upper extremities 59

53

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com Dermatology Clinic n Fingernail dystrophy in a

young child n Headache, malaise, and a rash

Continues on page 6

A contract dispute between two NPs 64

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CONTENTS 59

Dermatologic Look-Alikes A rash on the upper extremities

64

Legal Advisor Clinicians in a contract dispute.

One nurse practitioner partner loses her license after improperly writing prescriptions and abusing controlled substances. As the case shows, courts seek to honor the original intent of a contract and the language when interpreting it.

Top: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved. Bottom: © Harley Schwadron 2017.

DEPARTMENTS cont’d

ADVISOR FORUM 50

Your Comments ■ An individualized breast cancer screening strategy for women

51

My most memorable patient ■ Depression screening after a stroke

“Mom and Dad, can I borrow the wheel tonight?”

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■ Hyperte nsion ■ LARC reco guideline mmendatio ns ■ Warfarin in older adu lts ■ Statins and diabetes risk ■ Cord clam ping in infa nts LEGAL AD VISOR

A contract dispute bet wee clinicians in practice toge n ther

■ Dermatolo gy Clinic

HEADACHE , MALAISE AND A RA , SH PAG E 53

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DISORDER

S OF PRIM

HEMOSTA ARY

SIS

Scanning elec microscope tron image showing red blood cells in a fibrin clot .

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

Multimedia

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ClinicalAdvisor.com/Multimedia

Diminished ovarian reserve not associated with infertility Biomarkers of diminished ovarian reserve are not associated with reduced fertility in women of a reproductive age without a history of infertility who have been trying to conceive for less than 3 months.

Dermatology guideline authors frequently fail to disclose sizable industry payments Discrepancies were observed in disclosure forms of industry payments to authors of dermatology clinical practice guidelines.

Dabigatran, rivaroxaban associated with increased risk of major gastrointestinal bleeding Data suggest possible variability across NOACs regarding gastrointestinal bleeding risk, with an increased risk associated with rivaroxaban and dabigatran.

© The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.

Cartoon Archive The Clinical Advisor’s monthly cartoons are also available online.

ClinicalAdvisor.com/cartoons

Is group exercise more effective than individual workouts?

A study conducted by the American Osteopathic Association found that individuals who work out in a group have a 26% lower stress rate and improved quality of life compared with people who work out by themselves.

Watch the video here: ClinicalAdvisor.com/GroupExerciseVideo

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Sean L’Huillier Nurse practitioner treatment of hepatitis C in primary care Modern treatment for hepatitis C, including an oral tablet, has improved the outcomes and experiences of patients with the condition.

L. Gail Curtis, MPAS, PA-C, DFAAPA AAPA: Reducing the obesity rate through effective care delivery Obesity is a chronic, progressive disease, and continued communication on prevention and treatment is paramount to reversing the status quo.

Jim Anderson, MPAS, PA-C, DFAAPA Where’s the databank of biased providers?

A national databank is necessary and would include names of medical providers who have publicly expressed opinions indicating biases about certain populations.

“Take a look—that’s us in ninety years.”

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Advisor Dx

EXCLUSIVE TO THE WEB

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

Ortho Dx

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Neck pain after a motor vehicle accident A 46-year-old man presents to the emergency department with severe neck pain after a motor vehicle accident. He was a restrained driver when his car was struck from behind. He denies loss of consciousness and arrived by ambulance in a hard cervical collar after the accident.

WHAT IS THE BEST TREATMENT OPTION?

• Philadelphia collar for 6-12 weeks • Halo thoracic vest for 6-12 weeks • Posterior C1-C2 fusion • Anterior odontoid screw osteosynthesis ● See the full case at ClinicalAdvisor.com/OrthoDx_Dec17

Derm Dx Flesh-colored lesions on an infant A mother brings in her 13-day-old baby for evaluation of facial lesions. Noted on examination are flesh-colored lesions located in front of both ears. No other facial or body lesions are visible. The baby was carried to term, and the pregnancy was uneventful for the mother.

CAN YOU DIAGNOSE THIS CONDITION?

• Acrochordon • Chondroid syringoma • Cavernous hemangioma • Accessory tragus ● See the full case at ClinicalAdvisor.com/DermDx_Dec17

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 9

Newsline D E C E M B E R 2 017

Warfarin use is linked to reduced cancer risk page 11

Statins associated with higher risk of diabetes page 11

Delayed vs immediate cord clamping page 11

THE A M ERICAN Heart Association (AHA) and the American College of Cardiology (ACC) have released a new clinical practice guideline on managing high blood pressure in adults, redefining hypertension as 130 mm Hg/80 mm Hg from the previous level of 140 mm Hg/90 mm Hg. With this new definition of hypertension, approximately 14% more US adults are categorized as hypertensive (from 32% to 46%).

The new guideline, published in the Journal of the American College of Cardiology and in Hypertension, divides systolic blood pressure (SBP) and

diastolic blood pressure (DBP) into categories, giving patients a more specif ic def inition of hypertension and the associated recommendations: • Normal BP is defined as <120 mm Hg/<80 mm Hg. According to the guideline, this group of patients practices healthy living styles and should have yearly checks to monitor their BP. • Elevated BP is defined as 120 to 129 mm Hg/<80 mm Hg. This group is advised to make healthy changes in lifestyle and to reassess their BP in 3 to 6 months.

• High BP is subcategorized into two stages: ——Stage 1: BP ranging from 130 to 139 mm Hg/80 to

© ARIEL SKELLEY / GETTY IMAGES

New clinical guideline for managing hypertension

Hypertension is now defined as 130 mm Hg/ 80 mm Hg, versus the previous rate of 140 mm Hg/ 90 mm Hg.

89 mm Hg. Clinicians must assess 10-year heart disease and stroke risk. If the risk is <10%, the patient is highly encouraged to make immediate lifestyle changes, including medication with follow-ups until the BP is well-controlled.

——Stage 2: BP ≥140 mm Hg/≥90 mm Hg. Clinicians must stress lifestyle changes with 2 different classes of medications and monthly follow-ups until BP is well-controlled.

ACOG issues recommendations for long-acting reversible contraception THE AMERICAN COLLEGE of Obstetricians and Gynecologists has released a new practice bulletin regarding long-acting reversible contraception.

The following recommendations are graded as Level A: • Insertion of an intrauterine device (IUD) immediately after first-trimester uterine aspiration should be offered routinely as a safe and effective contraceptive option.

• Insertion of the contraceptive implant on the same day as first-trimester or second-trimester–induced or spontaneous abortion should be offered routinely as a safe and effective contraceptive option.

• Routine antibiotic prophylaxis is not recommended before IUD insertion.

The following recommendations are based on limited or inconsistent scientific evidence (Level B):

• Intrauterine devices and the contraceptive implants should be offered routinely as safe and effective contraceptive options for nulliparous women and adolescents.

• Insertion of an IUD or an implant may occur at any time during the menstrual cycle as long as pregnancy may be reasonably excluded.

• Insertion of an IUD immediately after confirmed completion of first-trimester medication-induced abortion should be offered routinely as a safe and effective contraceptive option.

• Immediate postpartum IUD insertion (ie, within 10 minutes after placental delivery in vaginal and cesarean births) should be offered routinely as a safe and effective option for postpartum contraception.

• Intrauterine devices may be offered to women with a history of ectopic pregnancies.

10 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

WARFARIN USE is associated with a lower risk of cancer, according to results from a large, population-based study of persons older than 50 years published in JAMA Internal Medicine.

The study cohort (n = 1,256,725) was divided into 2 groups: warfarin users and nonusers. Warfarin users received a warfarin prescription at least 2 years before any cancer diagnosis and had an interval between first and last prescription of at least 6 months. For warfarin users without a cancer diagnosis, the interval between first and last prescription had to be at least 6 months.

From the cohort, 607,350 (48.3%) were male, 649,375 (51.7%) were female, 132,687 (10.6%) had cancer, 92,942 (7.4%) were classified as warfarin users,

Among adults older than age 50, those who use warfarin have a lower risk of multiple types of cancer.

and 1,163,783 (92.6%) were classified as nonusers. Warfarin users were older, with a mean age of 70.2 years, and were predominantly men (57,370 [61.7%]), compared with nonusers, who had a mean age of 63.9 years and were mostly women (613,803 [52.7%]).

Warfarin users had a significantly lower age- and sex-adjusted incidence rate ratio (IRR) in all cancer sites (IRR, 0.84) and in prevalent organ-specific sites: lung, 0.80; prostate, 0.69; and breast, 0.90. No significant effect was observed in colon cancer (0.99).

In a subgroup analysis of patients with atrial fibrillation or atrial flutter, the IRR was lower in all cancer sites (IRR, 0.62) and in prevalent sites: lung, 0.39; prostate, 0.60; breast, 0.72; and colon, 0.71.

Delayed vs immediate cord clamping DELAYING UMBILICAL cord clamping in preterm infants delivered prior to 30 weeks of gestation shows no significant difference in death or severe morbidity rates compared with immediate cord clamping when monitored 36 weeks postmenstrual age, according to a study in the New England Journal of Medicine.

Of 1,634 randomized early expectant fetuses, 1,566 (95.8%) were categorized into either delayed (784 patients) or immediate cord clamping (782 patients).

Clamping time occurring for delayed and immediate actions was categorized as ≥60 seconds and ≤10 seconds, respectively.

Delayed cord clamping in preterm infants shows no significant difference in death rate compared with immediate clamping.

A tertiary outcome test monitored weight at birth, red blood cell transfusions by 36 weeks, infant temperature, primary week peak bilirubin and hematocrit levels, duration of hospital stay (for live discharged patients only), uterotonic drug usages, and maternal blood transfusion for postpartum hemorrhage, all of which resulted in statistically insignificant data.

Delayed cord clamping proved to have no major difference in levels of death (delayed, 6.4%; immediate, 9.0%). Morbidity in all three outcomes showed no statistical significance between the two groups (primary outcome relative risk, 1.00; secondary outcome relative rise, 0.69).

Statins are associated with diabetes risk Statins are associated with nearly a 30% increased risk of type 2 diabetes among individuals who are at high risk for the disorder, according to a study in BMJ Open Diabetes Research & Care.

Researchers conducted the Diabetes Prevention Program Outcomes Study (DPPOS), a longterm follow-up to the Diabetes Prevention Program (DPP). They assessed 3,234 patients—20% were aged 60 years and older.

Eligible participants received standard advice regarding healthy diet and physical activity and were randomly assigned to an intensive lifestyle intervention, metformin, or placebo. At the end of the main trial (mean follow-up, 3.2 years), all subjects were offered a group-administered version of the lifestyle intervention and were invited to enroll in the DPPOS. For the DPPOS, all participants were offered quarterly lifestyle sessions, the former metformin group received open-label metformin, and the former intensive lifestyle group was offered 2 additional lifestyle programs per year.

The investigators found that the cumulative incidence of statin initiation prior to a diagnosis of diabetes was 33% to 37% among the randomized treatment groups at 10 years. Statin use was associated with an increased diabetes risk irrespective of treatment group, and the pooled hazard ratio (HR) for incident diabetes was 1.36 (1.17 to 1.58). n

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 11

© VIDKA / GETTY IMAGES

Warfarin linked to lower cancer risk

FEATURE: DANIELLE KRUGER, PA-C, MS ED

Treatment of disorders of primary hemostasis An evaluation begins with a focused history and physical examination, a CBC count with platelet trend, and examination of the peripheral smear.

© DAVID M. PHILLIPS / SCIENCE SOURCE

D

isorders of primary hemostasis have a vast differential diagnosis and may present in a variety of medical, obstetric, surgical, and critical care settings. When evaluating patients with thrombocytopenia or evidence of qualitative platelet dysfunction, clinicians must determine the significance of the platelet count as well as the risk for bleeding, thrombosis, and other potential complications. In one study, thrombocytopenia was observed in approximately 1% of adult inpatients in acute care hospitals.1 Surgical bleeding is of concern when platelet counts are <50,000/µL, or <100,000/µL in patients undergoing some high-risk cardiac, orthopedic, or neurosurgical procedures.2 In intensive care units (ICUs), thrombocytopenia develops in 13% to 44% of patients during their admission.2 Clinicians must be familiar with the conditions leading to disorders of primary hemostasis because swift, accurate identification of the underlying cause is crucial for appropriate management. This article reviews disorders of primary hemostasis that range in severity from benign to life-threatening, focusing on pathophysiology, distinguishing features, diagnostic assessment, and treatment.

Physiology of primary hemostasis

Red blood cells in a fibrin clot.

Megakaryocytes, which are derived from hematopoietic stem cell precursors in bone marrow, form and release platelets; these circulate in the blood for 8 to 10 days before they are removed by hepatic or splenic macrophages. The Continues on page 14

12 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

ADVERTISEMENT

Identifying Appropriate Pain Management Options for Patients With Osteoarthritis Contributor: Christopher M. Chappel, MD | Medical Director, Chappel Group | Kissimmee, FL

27 million It is estimated that

Americans are living with osteoarthritis (OA).

1

Acetaminophen and oral nonsteroidal antiinflammatory drugs (NSAIDs) are among the pharmacologic therapies recommended for initial management of pain associated with OA.2,3

A stepwise approach helps ensure that patients receive the appropriate analgesic for their OA pain.5,6

41%

of people with OA

use opioids to manage pain associated with OA.4 The Osteoarthritis Research Society International recommends that weak opioids be considered where other pharmacological agents have been ineffective or are contraindicated.3

A Stepwise Approach to the Management of Pain Associated With OA

1

Assess Patient Profile

• Identify current medications (including over-the-counter medications, herbals, and supplements) and coexisting medical conditions.

2

Develop Pain Management Plan

• Educate patients on pain management options.

• Incorporate nonpharmacologic measures, such as physical therapy, assistive devices (eg, canes, walkers), or braces, as appropriate.2 • Consider options such as acetaminophen or NSAIDs.2 – Utilize information obtained in Step 1 to help identify an appropriate choice.

3

Introduce Nonopioid Pharmacologic Agents

The maximum dose of acetaminophen that a healthcare provider (HCP) can recommend for adults is 4000 mg/24 hours.

It is recommended that NSAIDs be given at the lowest effective dose for the shortest period of time.7

4

Assess Opioid Options for Appropriate Patients

• Start with weak opioids before escalating to stronger opioid options.5,6 • Consider use of acetaminophen or other over-the-counter analgesics to help manage breakthrough pain.8

5

Evaluate for Specialty Referral

• Consider referral to an orthopedic specialist or rheumatologist for further treatment options, such as surgery.

GetReliefResponsibly.com has more information for HCPs and patients.

References: 1. Centers for Disease Control and Prevention. Osteoarthritis. http://www.cdc.gov/arthritis/basics/osteoarthritis.htm. Updated May 16, 2014. Accessed October 20, 2015. 2. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-474. 3. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137-162. 4. Gore M, Tai KS, Sadosky A, Leslie D, Stacey BR. Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis. J Med Econ. 2011;14(4):497-507. 5. World Health Organization. WHO’s pain ladder for adults. http://www.who.int/cancer/palliative/painladder/en/. Accessed June 22, 2016. 6. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56(6):514-517. 7. US Food and Drug Administration.

Medication guide for nonsteroidal anti-inflammatory drugs (NSAIDs). http://www.fda.gov/downloads/Drugs/DrugSafety/UCM387559.pdf. Revised May 2016. Accessed June 21, 2016. 8. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130. © Johnson & Johnson Consumer Inc. 2016

TREATMENT OF DISORDERS OF PRIMARY HEMOSTASIS

Deficiency or dysfunction of platelets causes defects in primary hemostasis, characterized by superficial mucocutaneous bleeding. concentration of circulating platelets is normally 150,000 to 450,000/µL. A platelet count <150,000/µL traditionally defines thrombocytopenia; however, 2.5% of the population has a baseline concentration <150,000/µL.2 Clinicians should repeat the platelet count for trending; if the count is stable for 6 months, it is usually a normal variant.1 Normal vascular endothelium opposes thrombosis by resisting interactions with platelets and coagulation factors. Damage to vessels exposes collagen fibrils that trigger a series of adhesive reactions, allowing platelets to bind to the subendothelium and to other platelets to form a temporary hemostatic plug. A large protein, von Willebrand factor (vWF), is synthesized, stored in, and secreted by vascular endothelial cells following stimulation. Plasma vWF binds platelets to the subendothelial collagen via its platelet glycoprotein Ib complex. Platelets also have receptors that bind directly to collagen. Normal engagement of these receptors enhances platelet activation and signals extension of the plug. Activated platelets release pro-aggregatory granules containing adenosine 5’-diphosphate (ADP) and thromboxane A2 to amplify recruitment and aggregation. Fibrinogen and vWF also bind activated platelets together via the platelet glycoprotein IIb/IIIa complex. The hemostatic plug stops bleeding in a superficial wound. Initiation of the clotting cascade triggers secondary hemostasis, which culminates in the formation of a fibrin mesh that cross-links, reinforces, and further stabilizes the platelet plug. As a carrier protein for clotting factor VIII, vWF also functions in secondary hemostasis by protecting this factor from degradation.

Manifestations of disorders of primary and secondary hemostasis

Platelets play an essential role in preserving vessel wall integrity. Deficiency or dysfunction of platelets causes defects in primary hemostasis, characterized by superficial mucocutaneous bleeding and a prolonged bleeding time. Petechiae result from capillary bleeding and are likely to develop on dependent body regions. Confluence of petechiae results in the formation of purpura, which is “dry” when located on the skin and “wet” when located on mucous membranes.

Wet purpura signifies potentially more serious hemorrhage.2 The common bleeding manifestations of primary hemostasis disorders (Table 1)occur frequently in many of the disorders discussed in this review. Because the normal values for platelets are >150,000/µL, the blood has a large protective

reservoir. Mild thrombocytopenia is defined by platelet levels of 100,000 to 150,000/µL, moderate thrombocytopenia by levels of 50,000 to 100,000/µL, and severe thrombocytopenia by levels <50,000/µL. Significant spontaneous bleeding usually does not occur until platelet counts are <10,000 to 20,000/µL.1 Severe thrombocytopenia confers a greater risk for bleeding, but correlation between the platelet count and risk for bleeding varies with the underlying condition.

Comparatively, clotting factor deficiency or dysfunction results in disorders of secondary hemostasis and may cause delayed, deep, or prolonged bleeding. Bleeding into the central nervous system (CNS), hemarthrosis (bleeding into the fingers, wrists, knees, feet, and spine), deep muscle hematomas, or retroperitoneal bleeding usually indicates a clotting factor disorder. Clinically, no specific type, location, or quantity of bleeding is certain to differentiate a primary from a secondary disorder of hemostasis, and both can be severe, even life-threatening. Laboratory testing will reveal a prolonged bleeding time with or without thrombocytopenia in a disorder of primary hemostasis; disorders of secondary hemostasis are characterized by prolongation of the partial thromboplastin time (PTT) with or without prolongation of the prothrombin time (PT), depending on the clotting factors affected. In disorders of secondary hemostasis, the bleeding time and platelet count will be normal. Disorders of secondary hemostasis are outside the scope of this article but may be discussed in the differential diagnoses as appropriate.

TABLE 1. Clinical manifestations of disorders of primary hemostasis Mucocutaneous bleeding: petechiae, ecchymoses, purpura, bleeding gums, epistaxis, hemorrhagic bullae, and metromenorrhagia, all classically worsened by nonsteroidal anti-inflammatory drug (NSAID) use Wound bleeding, episodes of bleeding following surgery or trauma Other possible presentations: hemoptysis, gastrointestinal bleeding, and hematuria, which are rarely initial symptoms of a bleeding disorder but rather indicate an exacerbation of bleeding at a pre-existing lesion Symptoms depend on platelet level: • 20,000-50,000/µL: petechiae and ecchymoses following mild trauma • <10,000/µL: risk for intracranial hemorrhage, spontaneous generalized mucocutaneous bleeding • <2000/µL: widespread ecchymoses, hemorrhagic bullae, and retinal hemorrhage, which are harbingers of internal and intracranial bleeding2,6

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Aspirin, nonsteroidal anti-inflammatory drugs, and anticoagulants are common causes of bleeding or factors that exacerbate bleeding in the elderly.

History and physical examination

The history and physical examination are imperative to guide the differential diagnosis and focus the laboratory assessment.

Conduct a full mucocutaneous survey to search for signs of platelet dysfunction, and carefully assess the patient for hepatosplenomegaly, lymphadenopathy, and/or signs of thrombosis because the presence of these abnormalities influences the workup. Inquire about easy bruising or excessive bleeding, determine the location and duration of bleeding and whether it occurs spontaneously or after trauma (immediate vs delayed), and assess for evidence of volume loss or anemia. Extensive bruising or bruising in unusual locations where trauma is less likely (trunk, inner arms, thighs) is suspect. Obtain previous platelet counts if possible to determine if the level is stable or decreasing. An acute drop in the platelet count of >50%, even if the count is still within normal range, may herald a severe disorder and requires close follow-up.2 Lifelong bleeding or a family history of a bleeding disorder may indicate a familial or congenital disorder. Congenital platelet defects are strongly associated with consanguinity. Bleeding should not be overlooked in the elderly because age-related changes in hemostasis parameters (shortened bleeding time and PTT; increased levels of factors II, VIII, and X; and decreased levels of antithrombin III) favor thrombosis, not bleeding. Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and anticoagulants are common causes of bleeding or factors that exacerbate bleeding in the elderly. Clinicians may use a validated, objective bleeding score, such as the one derived from the Condensed MCMDM-1 VWD Bleeding Questionnaire,3 which grades the worst episode for each of the following: epistaxis; cutaneous manifestations; bleeding from minor wounds or the oral cavity; gastrointestinal bleeding; bleeding following tooth extraction or surgery; menorrhagia; postpartum hemorrhage; muscle hematoma; hemarthrosis; and CNS bleeding.4,5 The higher the bleeding score, the greater the likelihood of a bleeding disorder. In von Willebrand disease (vWD), the most common bleeding disorder, a score >4 has a sensitivity of 100% and a specificity of 87%, with a positive predictive value of 0.2.5 Uneventful molar tooth extraction is unlikely in a patient with a severe bleeding disorder.6 Assess for past medical history and for underlying diseases or their risk factors, particularly the following: • Autoimmune and connective tissue disorders: systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome

• Blood disorders and/or malignancy: leukemia, lymphoma, myeloproliferative disorders • Infections: human immunodeficiency virus (HIV) infection; hepatitis A, B, or C; disease caused by cytomegalovirus; other viral or rickettsial disease • Recent vaccinations; medication use (prescribed, overthe-counter, and alternative medications) • Pregnancy status, recent transfusion, surgery or organ transplant • Recent travel (malaria, rickettsial infection, leptospirosis, dengue or viral hemorrhagic fever) • Alcohol and drug use, liver or kidney disease A variety of infections may induce thrombocytopenia via immune-mediated platelet destruction, bone marrow suppression, or platelet consumption. In many viral infections (eg, rubella; mumps; varicella; infection with parvovirus, Epstein-Barr virus, or cytomegalovirus), thrombocytopenia is an incidental finding and spontaneously resolves with recovery. In some chronic infections, however, such as those caused by Helicobacter pylori, HIV, or hepatitis C virus (HCV), the thrombocytopenia may persist.2 Adults with the new onset of isolated thrombocytopenia should be screened for these chronic conditions. In many vector-borne diseases (eg, malaria, babesiosis, brucellosis, and anaplasmosis), thrombocytopenia is part of the clinical constellation, and parasites may be seen on peripheral blood smear.

Clinicians should know the mechanism and duration of action of common medications that affect platelet function. Aspirin irreversibly inactivates cyclooxygenase in platelets, and the effect lasts for the lifetime of the platelets.

Bleeding time generally normalizes within 3 days after the discontinuation of aspirin. NSAIDs competitively inhibit cyclooxygenase, and the effect is related to the drug halflife, usually 1 day. Clopidogrel irreversibly inhibits the P2Y12 ADP receptor on platelets, impairing the activation of platelets and cross-linking of fibrin. The bleeding time gradually returns to baseline within about 5 days after the discontinuation of clopidogrel. Anticoagulants (heparin, warfarin, dabigatran, apixaban, rivoraxaban) and antiplatelet agents increase the tendency for bleeding and impair hemostasis at sites of hemorrhage. This is particularly important in the management of victims of head trauma. A strong index of suspicion is required in managing mild head trauma in patients treated with anticoagulants to minimize the risk for missed intracranial bleeding.

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TREATMENT OF DISORDERS OF PRIMARY HEMOSTASIS

The first step in the assessment of primary hemostasis disorders is a review of the platelet count, bleeding time, PT, and PTT. Alcohol abuse may cause thrombocytopenia through direct bone marrow toxicity, nutrient deficiencies, or hypersplenism.

Binge drinking may precipitate severe thrombocytopenia, particularly in those with alcoholic liver disease.6 Deficiency of the nutrients required for hematopoiesis (folate, vitamin B12, copper) secondary to malnutrition, veganism, or bariatric or gastrointestinal surgeries usually induces pancytopenia, but isolated thrombocytopenia may be seen.2 Similarly, clinicians will see thrombocytopenia in bone marrow disorders (myelodysplastic syndromes, infections, sepsis, or infiltrative disease) in which pancytopenia is expected. Classification of thrombocytopenia as an isolated blood cell deficiency or as part of a constellation of pancytopenia is imperative in guiding the differential diagnosis. Uremia is a common cause of qualitative platelet dysfunction and is related to several dialyzable platelet-inhibitory factors that cause the bleeding time to be very prolonged. Gastrointestinal bleeding is the most frequent bleeding symptom, and vigorous dialysis is used to treat the manifestations.

Clinicians may also generate a differential diagnosis for platelet disorders by categorizing the mechanism of platelet loss or dysfunction (Table 2).

Diagnostic testing

The first step in the assessment of primary hemostasis disorders is a review of the platelet count, bleeding time, PT, and PTT, in addition to a careful examination of the peripheral blood smear. Some authors suggest that the basic laboratory evaluation should also include liver and renal function tests,

a coagulation panel with D-dimer, and measurement of the lactate dehydrogenase (LDH) level. Historically, bleeding time was quantified by measuring the hemostasis time in a fresh, superficial cut to the volar forearm. This test is unreliable and its use discouraged; it has largely been replaced by objective closure time assays such as the PFA-100 (Platelet Function Analyzer). Prolonged bleeding time indicates a disorder of primary hemostasis. The platelet count will then determine if the disorder is a qualitative dysfunction (the patient has normal platelet counts) or a quantitative dysfunction (thrombocytopenia is present). The bleeding time is generally prolonged with platelet counts <75,000/ µL.6 Platelet aggregation tests can distinguish disorders of platelet function and are discussed below together with the relevant diseases. In disorders of secondary hemostasis, such as hemophilia, the bleeding time is usually normal.

The PT and PTT may be prolonged in patients with a clotting factor deficiency or dysfunction. The PT evaluates the activity of the extrinsic and common pathway factors of the clotting cascade and is prolonged in patients with a deficiency of these factors, most notably factor VII. The PTT evaluates the activity of the intrinsic and common pathway clotting factors; hemophilia, for example, will cause prolongation of the PTT, but the PT will be normal. In some coagulopathies, multiple clotting factors are consumed, prolonging both the PT and PTT. The peripheral blood smear may show morphologic abnormalities relevant to an underlying diagnosis. If thrombocytopenia is due to platelet destruction, large or giant platelets may

TABLE 2. Mechanisms of induction of thrombo­cytopenia and/or platelet dysfunction Mechanism

Associated conditions

Increased destruction

Infection (human immunodeficiency virus, hepatitis C virus), immune-mediated mechanism (idiopathic thrombocytopenic purpura), heparin-induced thrombocytopenia

Decreased production

Bone marrow failure (infiltrative disease, aplastic anemia, leukemia, myeloproliferative disorders, granulomatous disorders, tuberculosis)

Increased consumption

Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation

Splenic sequestration or redistribution

Normally one-third of the platelet mass found in spleen in equilibrium with circulating platelets3; conditions causing congestive splenomegaly (eg, portal hypertension) redistribute circulating platelets into splenic pool; severe thrombocytopenia or bleeding rare3

Dilutional

Hemodilution due to failure to replace platelets during fluid and blood component transfusion following massive hemorrhage or massive fluid resuscitation; massive transfusion protocol recommendations include administration in a ratio of 1:1:1 of platelets, red blood cells, and fresh frozen plasma

Medications/toxins

Commonly antibiotics, antiepileptic agents, cytotoxins, and quinine

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Von Willebrand disease, the most common inherited bleeding disorder, is caused by a deficiency or qualitative abnormality of von Willebrand factor. be seen in addition to platelets of normal size. Fragmented red blood cells (schistocytes) suggest thrombotic microangiopathy, and teardrop-shaped cells (dacryocytes) suggest myelofibrosis. Blast cells are seen in acute leukemia, atypical lymphocytes in various viral infections, and rouleau formation in multiple myeloma. Clinicians should consider that conditions such as bone marrow failure and acute leukemia rarely present with isolated thrombocytopenia. Bone marrow analysis is reserved for patients with thrombocytopenia of unclear etiology, an atypical or a prolonged course, suspected malignancy, or a worrisome abnormality (hepatosplenomegaly, lymphadenopathy, or pancytopenia). A normal or increased number of megakaryocytes on bone marrow analysis accompanied by large platelets in the peripheral blood suggests that thrombocytopenia is due to peripheral platelet destruction and that marrow activity is normal or compensatory. A decreased number of megakaryocytes and decreased bone marrow cellularity suggest bone marrow failure or aplastic anemia.

How swiftly a subsequent evaluation should take place depends on the patient’s presentation and platelet count. If the patient is symptomatic with acute bleeding or the level of thrombocytopenia confers a high risk for bleeding, an assessment should be performed immediately. Otherwise, outpatient testing can occur over 1 to 2 weeks, with the patient counseled that he or she should return immediately or report to an emergency department if any changes in clinical status or bleeding occur. Patient education is imperative in the management of congenital platelet disorders or moderate to severe thrombocytopenia. Mucocutaneous bleeding is common, but serious hemorrhage requires immediate treatment, and clinicians should review a plan of action with patients. Patients should avoid medications that interfere with platelet function (aspirin, NSAIDs, ginko biloba) and should not engage in extreme athletics (football, boxing, rugby, martial arts). Women with severe menorrhagia may benefit from hormonal suppression of the menses.

Differential diagnosis of disorders of primary hemostasis

Von Willebrand Disease. vWD, the most common inherited bleeding disorder, is caused by a deficiency or qualitative abnormality of vWF. vWD affects about 1 in 1000 persons6 or 0.5% to 1.6% of the population in Western countries.7 It has an autosomal-dominant or autosomal-recessive inheritance

and is equally distributed between the sexes. vWD results in defective platelet adhesion to the vascular subendothelium and may lead to the degradation of coagulation factor VIII in the circulation. Manifestations vary, with bleeding that ranges from mild to life-threatening. Patients have bleeding manifestations (Table 1) with normal platelet counts and a prolonged bleeding time. vWD is classified as follows: partial quantitative deficiency (type 1: 60%-80% of cases per Western data distribution), qualitative dysfunction (type 2: 7%-30% of cases), and total deficiency (type 3: 5%-20% of cases).7 Patients should be at optimal baseline for laboratory testing because stressors (illness, anxiety, recent exercise, acute inflammation) and estrogen (pregnancy and oral contraceptives) may transiently elevate vWF and factor VIII levels.5 Accurate subtyping of vWD requires laboratory investigations including, but not limited to, quantitative vWF antigen (vWF:Ag) level, vWF ristocetin cofactor activity (vWF:RCo), and factor VIII levels.

The vWF:RCo measures the ability of plasma to agglutinate platelets in the presence of ristocetin, which is proportional to the hemostatic activity of vWF. Defective aggregation with ristocetin is the characteristic abnormality in vWD. Levels of vWF:RCo <30 IU/dL are designated as definitive for vWD, although some patients with type 2 vWD have higher levels.5 A very simplified analysis of the variables used to determine the type of vWD appears in Table 3. In type 1 vWD, the plasma vWF level (vWF:Ag) is low but sufficient to mediate some platelet adhesion (vWF:RCo) and stabilize factor VIII levels. Type 1 vWD is asymptomatic and may TABLE 3. Laboratory analysis of von Willebrand disease Condition

vWF:Ag (IU/dL)

vWF:RCo (IU/dL)

Factor VIII

Normal

50-200

50-200

Normal

Type 1 vWD

<30

<30

Low/normal

Types 2A, 2B, 2M vWD

<30-200

<30

Low/normal

Type 2N vWD

30-200

30-200

Very low

Type 3 vWD

<3

<3

Extremely low

vWD = von Willebrand disease; vWF:Ag = quantitative von Willebrand factor antigen; vWF:RCo = von Willebrand factor ristocetin cofactor activity.

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TREATMENT OF DISORDERS OF PRIMARY HEMOSTASIS

For patients with type 1 vWD, the preferred prophylaxis in anticipation of minor surgery is intravenous or intranasal desmopressin. result in relatively mild bleeding symptoms. Type 3 vWD is characterized by undetectable vWF:Ag and vWF:RCo and factor VIII levels usually <10 IU/dL7 with prolonged PTT and risk for bleeding indistinguishable from that of hemophilia A. Type 2 vWD is subdivided into four variants (2A, 2B, 2M, 2N) on the basis of specific defects that impair platelet adhesion or factor VIII binding. In-depth factor ratios, collagen binding studies, mutation analysis, and inhibitor assays are required to distinguish the type 2 vWD subtypes.

For patients with type 1 vWD, the preferred prophylaxis in anticipation of minor surgery or dental procedures is intravenous or intranasal desmopressin (DDAVP), which stimulates the release of vWF from endothelial cells. A trial dose of DDAVP is given before anticipated use to determine responsiveness. Therapy should achieve a vWF:RCo level >30 IU/dL, preferably >50 IU/dL, and DDAVP should be discontinued 2 to 3 days after the procedure to prevent tachyphylaxis.5,6 Most patients with type 1 vWD respond to DDAVP, but if the response is inadequate, vWF concentrates should be used. For severe bleeding or prophylaxis before major surgery, patients receive vWF concentrates or cryoprecipitate. The target VWF:RCo level is >100 IU/dL; levels >50 IU/dL should be maintained for at least 7 to 10 days.5 Factor VIII levels often rise following the infusion of vWF concentrate and remain elevated for about 40 hours, reflecting the half-life of vWF.6 Bernard-Soulier syndrome and Glanzmann thrombasthenia. If vWD is ruled out, additional aggregation tests can define the platelet defect in qualitative platelet disorders.

Bernard-Soulier syndrome (BSS) and Glanzmann thrombasthenia are rare, autosomal-recessive congenital disorders associated with a history of familial consanguinity and may cause lifelong bleeding manifestations (Table 1). In BSS, a molecular defect alters the platelet glycoprotein complex Ib/ IX/V, preventing the normal adhesion of platelets to vWF and to ristocetin, although the platelets aggregate normally in response to other agonists (ADP, collagen, epinephrine).

Patients have a prolonged bleeding time and more severe bleeding than expected for the mild thrombocytopenia associated with the condition. Giant circulating platelets are seen on peripheral smear. The severity of bleeding in BSS varies; the prognosis is related to the severity of the disease, which may change over time in response to hormones and aging.8 Glanzmann thrombasthenia results from deficiency or dysfunction of the platelet glycoprotein IIb/IIIa complex.

Platelets can adhere to exposed subendothelium and aggregate with ristocetin but have a limited ability to form platelet microthrombi without the ability of this receptor to bind vWF and fibrinogen. Typically, aggregation tests show poor aggregation to ADP, epinephrine, collagen, and thrombin.

Absent or severely reduced platelet aggregation leads to a prolonged bleeding time and severe mucocutaneous bleeding despite the normal numbers and size of platelets. In cases of severe bleeding, platelet transfusions are usually effective, but the benefit-to-risk ratio should be evaluated. Repeated exposure to normal platelets in conditions in which platelet glycoprotein is absent (BSS or Glanzmann thrombasthenia) can result in the development of autoantibodies to the missing proteins. This renders subsequent transfusions of normal platelets ineffective. To minimize sensitization, blood products should have few or no leukocytes.8 Bone marrow transplant has been used in rare cases of serious, repetitive bleeding.

Idiopathic thrombocytopenic purpura. The two most common causes of isolated thrombocytopenia are idiopathic thrombocytopenic purpura (ITP) and drug-induced thrombocytopenia (DIT).1 In ITP, platelet autoantibodies (immunoglobulin G, or IgG) to the target of the platelet glycoprotein IIb/IIIa complex are produced. Once tagged, the platelets are damaged, trapped in the spleen, and removed from the circulation. Additionally, antibodies may interact with megakaryocytes in bone marrow, suppressing thrombopoiesis. ITP commonly occurs in persons with other autoimmune disorders and in patients with chronic HIV or HCV infection. All adult patients with newly diagnosed ITP should undergo screening for HIV and HCV infection.9 The acute, self-limited form of ITP has no gender predilection, is usually observed in healthy children (5/100,000 persons6) 3 to 5 years of age, and may follow a viral upper respiratory infection. The chronic form of ITP occurs in adults 20 to 50 years of age (3/100,000-5/100,000 persons6), has an insidious onset, often persists for longer than 6 months, and has a female predilection. Bleeding manifestations (Table 1) vary depending on the platelet count. ITP usually causes no constitutional symptoms (weight loss, bone pain, night sweats), lymphadenopathy, or hepatosplenomegaly. The presence of splenomegaly or these other findings suggests another condition. Abdominal ultrasound may support ITP by ruling out chronic liver disease with hypersplenism and the presence of organomegaly or abdominal lymphadenopathy.1

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Only 2% of adults with idiopathic thrombocytopenic purpura have a spontaneous remission, but 60% to 90% of these patients respond to first-line therapy.

Peripheral blood smear will show giant platelets reflective of thrombopoietin-induced bone marrow stimulation, and antiplatelet IgG assays are about 90% specific for ITP.1 The American Society of Hematology (ASH) guidelines consider bone marrow studies unnecessary regardless of age in patients with typical features of ITP. Overall, >80% of untreated children exhibit spontaneous remission within 2 to 8 weeks.10 The rest have a course similar to that of individuals with adult-onset, chronic ITP. In children, factors associated with the development of chronic ITP include the following: female gender, age >11 years at onset, lack of precedent infection/vaccination, insidious onset, presence of antinuclear antibodies, and treatment with intravenous immunoglobulin (IVIG) plus steroids vs IVIG alone.10 The ASH guidelines specify that children with mild mucocutaneous bleeding require only observation, regardless of the platelet count. In children who require therapy, a single dose of IVIG or a short course of corticosteroids is first-line treatment. There is no evidence supporting the benefit of a prolonged course of steroids rather than very brief courses in children.9 IVIG is preferred over steroids if a rapid increase in the platelet count is desired, although the combination of IVIG with high-dose dexamethasone is synergistic in cases of imminent hemorrhage.6 The risk for intracranial hemorrhage in children with ITP is minimal (<0.1%), and intracranial hemorrhage generally occurs with platelet counts <20,000/µL.6 Platelet transfusions are used supportively if the platelet counts are <20,000/µL. Anti-D immunoglobulin (anti-D) is first-line treatment in Rh-positive children with an intact spleen, but the Food and Drug Administration (FDA) cautions about risk for severe hemolysis, and anti-D should not be used if posthemorrhagic anemia or autoimmune hemolysis is present.

Children with refractory ITP and significant or persistent bleeding may be candidates for rituximab, high-dose dexamethasone, or splenectomy. Because spontaneous remission is so common, splenectomy should be avoided in children younger than 6 years of age because of future risk of severe sepsis.6 The ASH guidelines recommend splenectomy only if a child has had ITP for longer than 1 year with bleeding and platelet counts <30,000/µL. Only 2% of adults with ITP have a spontaneous remission, but 60% to 90% respond to first-line therapy.10 Adults should be treated when the platelet counts are <30,000/µL, or higher in those with active bleeding or a risk for bleeding (eg, peptic

ulcer disease, hypertension). In adults, longer courses of steroids are preferred over shorter courses or IVIG.9 IVIG may be paired with steroids if a rapid rise in platelets is required.

Anti-D is as effective as IVIG in Rh-positive adults with an intact spleen, and either may be used as first-line therapy in adults if steroids are contraindicated. Second-line therapies for adults include splenectomy, rituximab, thrombopoeitin receptor agonists, or more potent immunosuppression.

The platelet response to thrombopoeitin receptor agonists (eltrombopag) averages 10 to 15 days; thus, they are unlikely to replace steroids or IVIG. Severe ITP with platelet counts <5000/µL is associated with fatal hemorrhages in the brain and internal organs. Elderly patients, those with refractory disease or a previous history of hemorrhage, and patients with concomitant bleeding disorders (hemophilia, uremia) are at higher risk for life-threatening hemorrhage.6 Drug-induced thrombocytopenia. In DIT, drugdependent antibodies against platelet glycoprotein epitopes form, induce the immune-mediated destruction of platelets, and impair thrombopoiesis. DIT is a misnomer because the “drug” may be a prescribed or over-the-counter medication, herb, food, beverage, or other substance (eg, walnuts, cow’s milk, cranberry juice, tonic water).1,11 This exposure variability can make it difficult to distinguish DIT from ITP. A database of DIT associations can be found at http:// www.ouhsc.edu/platelets/ditp.html. Patients usually present with moderate to severe thrombocytopenia (<50,000/ μL) and associated bleeding manifestations (Table 1). DIT usually occurs within 2 to 3 days (sometimes within hours) after a previously taken drug has been taken or within 1 to 2 weeks of daily exposure to a new drug. Once the drug is discontinued, thrombocytopenia resolves in 5 to 10 days.

In patients exposed to a single drug and with no other explanation for thrombocytopenia, recovery after drug discontinuation provides empiric evidence of DIT; recurrent thrombocytopenia following re-exposure to the drug is confirmatory. Recurrent, symptomatic thrombocytopenia with recovery within days, even in the absence of specific treatment, should prompt investigation of DIT.1 Many laboratory methods can detect the presence of drug-dependent antiplatelet antibodies.

Heparin-induced thrombocytopenia (HIT), a special case of DIT, is a clinical emergency that occurs in 0.5% to 5% of heparintreated patients and approximately 1 in 5000 hospitalized patients. HIT accounts for <1% of cases of thrombocytopenia

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TREATMENT OF DISORDERS OF PRIMARY HEMOSTASIS

Notably, up to 20% of cases of thrombosis occur before or during the decrease in the platelet count and may not be preventable. forms of TTP, whereas chronic or recurrent episodes suggest a congenital deficiency. The ultra-large hyperactive multimers remain attached to the endothelial cell surface and induce platelet aggregation and consumption. Platelet and hyaline thrombi with complete or partial blood vessel occlusion are the histopathologic finding.14 The incidence of TTP is greater in black female patients,14 and the peak incidence is in the fourth decade. The mnemonic for the classic pentad of TTP clinical manifestations is FART’N: fever, anemia, renal failure, thrombocytopenia, and neurologic dysfunction; however, only 20% to 30% of patients have the complete pentad. The most common presentation is petechiae with fluctuating neurologic symptoms.6 Fever is present in 50% of patients, and 10% to 40% report “flulike symptoms” in the preceding weeks.14 TTP must be considered in cases of thrombocytopenia and microangiopathic hemolytic anemia alone. Neurologic dysfunction may present as fluctuating levels of consciousness, altered mental status, headache, Continues on page 22

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in the ICU.1,12 In HIT, IgG antibodies form a complex with platelet factor 4 to activate platelets, alter endothelial cells, and increase thrombin generation. Although ITP and usually DIT may lead to bleeding complications, HIT paradoxically induces a hypercoagulable state. Early identification is paramount because thromboembolic complications develop in about 50% of cases, most commonly deep vein thrombosis and pulmonary embolus.12 HIT should be suspected in any patient who while on heparin therapy has a >50% decrease in the platelet count from baseline, particularly if the onset is 5 to 10 days after exposure or if hypercoagulability develops. Thrombocytopenia is usually moderate, with median platelets counts at 50,000 to 80,000/µL and nadir counts rarely <20,000/µL.1,13 Two risks for HIT include the administration of unfractionated heparin rather than lowmolecular-weight heparin (LMWH; incidence of HIT is 10 times higher12) and the administration of heparin during or after major surgery. In about 30% of cases, HIT has an acute onset.1 These patients usually received heparin within the previous 3 months and may have circulating platelet factor 4 antibodies. Pre-existing antibodies may also cause anaphylactoid reactions within 30 minutes of the intravenous bolus. Clinicians should review platelet counts on days 5, 7, and 9 following the initiation of heparin or following major surgery while the patient is on heparin to monitor for HIT. Notably, up to 20% of cases of thrombosis occur before or during the decrease in the platelet count and may not be preventable.12 Clinicians can use clinical scoring systems such as the 4 T’s: thrombocytopenia, thrombosis (venous and arterial thrombosis, necrotic skin lesions at heparin injection sites), timing, and exclusion of other causes of thrombocytopenia to estimate the probability of HIT. Patients with intermediate- or high-probability scores should discontinue heparin and start argatroban, the direct thrombin inhibitor approved for the treatment of HIT.12 Duplex ultrasound can be used to evaluate for deep venous thrombosis, and platelet factor 4–heparin IgG immunoassays aid in confirmation.

Thrombotic thrombocytopenic purpura. Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder in which platelet microthrombi occlude the microvasculature, causing ischemia in the brain, kidneys, heart, and other organs. TTP is initiated by ultra-large precursors of von Willebrand protein that are usually cleaved to normal size by plasma enzyme ADAMTS13. Inhibition of this enzyme by an autoantibody or toxin accounts for acquired

Purpura rash on a patient’s back. Purpura may be due either to defects in the capillaries or to a deficiency of blood platelets.

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seizures, paresthesias, hemiplegia, visual changes, aphasia, dysarthria, and/or coma (Table 4).

A critical step in the assessment of TTP is to rule out other consumptive coagulopathies, such as disseminated intravascular coagulation (DIC). Fibrinogen degradation products are elevated in 50% of patients with TTP.14 In TTP, the normal values for D-dimer, fibrinogen, parameters of liver function, PT, and PTT help to distinguish it from DIC. Baseline laboratory tests should be ordered, but treatment with plasma exchange should be initiated as soon as possible, before the results are obtained and preferably within 4 to 8 hours.15 Severely reduced ADAMTS13 activity (<5%) with or without an inhibitor or antibody confirms the TTP diagnosis and has a specificity of 90% in distinguishing acute TTP from hemolytic uremic syndrome (HUS). Measurement of ADAMTS13 is necessary in the workup for TTP but is not a diagnostic criterion because the levels may be normal in patients who otherwise have all the features of TTP.14 Elevated levels of troponin T are seen in 50% of cases of acute idiopathic TTP and are a poor prognostic indicator because coronary artery occlusion is a frequent cause of early death.15 TTP is a medical emergency; the untreated mortality rate of 90% can be reduced to 10% to 20% with prompt plasma exchange (PEX; 3-5 L/d). PEX removes antibodies and replenishes normal plasma proteins. Early death still occurs, in half of these cases within 24 hours of presentation, primarily in women.15 It is critical to differentiate TTP from other causes of thrombocytopenia early because platelet

transfusions, which may increase the risk for vascular microocclusion, are contraindicated (unless life-threatening bleeding is present). The incidence of symptomatic heart failure is increased in patients who have received a recent platelet transfusion.15 Fresh frozen plasma can be initiated if there is any delay in PEX; however, PEX is preferred because a larger amount of plasma can be given without fluid overload.

Packed red blood cells and oral folic acid can be given to correct anemia. Immediately after PEX, adjunct corticosteroids are administered. Daily PEX is continued until the platelet count and LDH level are normal for a minimum of 2 days after complete remission (platelet count >150,000/µL).15 Rituximab is increasingly being used as a first-line agent for acute TTP and is preferred for patients with neurologic or cardiac involvement15; early administration is associated with faster remission and fewer cycles of PEX.6 Once the platelet count is >50,000/µL, initiate LMWH thromboprophylaxis.15 Patients with frequent relapses of TTP are candidates for splenectomy.

Hemolytic uremic syndrome. HUS is a major thrombotic microangiopathy characterized by signs of microangiopathic hemolysis (as in TTP), thrombocytopenia, and variable manifestations of organ involvement. Clinically and pathologically, TTP and HUS overlap, but these entities are distinctly different in pathogenesis. Severe deficiency of ADAMTS13 is the hallmark of TTP but is not seen in HUS. Additionally, the severe thrombocytopenia of TTP is not present in HUS, in which ADAMTS13 levels are >5% to 10%.16 Most commonly, HUS is associated with diarrhea due

TABLE 4. Clinical manifestations, pathophysiology, and associated laboratory findings of thrombotic thrombocytopenic purpura Manifestation

Pathophysiology

Associated laboratory findings+

Microangiopathic hemolytic anemia (with fatigue, pallor, jaundice, hemoglobinuria)

Red blood cells damaged as they pass through occluded vessels, resulting in fragmentation

Schistocytes on peripheral blood smear, hemoglobin levels 8-9 g/dL, ↓haptoglobin, ↑LDH, ↑indirect bilirubin, ↑reticulocyte count, negative direct Coombs

Renal failure

Renal microthrombi

Proteinuria, hematuria, granular or red cell casts in urine, ↑BUN and creatinine*

Thrombocytopenia (mucocutaneous bleeding [Table 1])

Consumption in microthrombi

Prolonged bleeding time, platelet level usually in range of 10,000-30,000/µL15

Neurologic dysfunction

Cerebral microthrombi; variable causes and fluctuating symptoms depending on areas affected and whether cerebral vessels are occluded

CT of head/MRI of brain may show abnormality

BUN = blood urea nitrogen; CT = computed tomography; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; TTP = thrombotic thrombocytopenic purpura. * Mild azotemia may occur; 60% of patients with TTP have renal dysfunction, but acute renal failure requiring dialysis is rare in TTP.14,15 +

dditional laboratory tests: ADAMTS13 level; D-dimer level; fibrinogen level; liver function tests; prothrombin time and partial thromboplastin time; troponins I and T; amylase; A thyroid function; pregnancy; type and screen; hepatitis A, B, and C virus and human immunodeficiency virus serology.15

22 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

© ISM / PR J.L. KEMENY / MEDICALIMAGES.COM

to enteric infection with Shiga toxin–producing Escherichia coli 0157:H7 (STEC-HUS, the most common serotype) or Shigella species. These pathogens are potent activators of the alternative complement pathway. STEC-HUS is the most common cause of acute renal failure in children and accounts for 90% of all cases of HUS in this population.17 In North America, the incidence is highest in children 1 to 5 years of age: 6.1/100,000 in children <5 years vs 2/100,000 in adults.16,17 Cattle and sheep are the main reservoirs, and the major mode of transmission is the ingestion of food contaminated with animal feces. After a 3- to 8-day incubation period, watery or bloody diarrhea, nausea, vomiting, and fever may occur. The risk for the development of HUS after bloody diarrhea due to E. coli infection is about 15%.17 Factors associated with HUS evolution include the use of anti-motility agents and antibiotics, bloody diarrhea, leukocytosis, young age, and female gender.17 There is also a rarer form of infection-related HUS that is caused by disseminated Streptococcus pneumoniae, often associated with sepsis, meningitis, or pneumonia. Recovery is often spontaneous, but acute renal failure that lasts about 2 weeks develops in 26% of patients.17 About 80% of patients recover, and STEC-HUS carries a 3% to 5% mortality rate.17 Atypical HUS is due to a chronic deficiency of complement regulatory proteins, particularly factor H, factor I, and thrombomodulin (membrane cofactor protein). The alternative pathway is active in plasma and will cause a minor attack on body tissues unless it is downregulated by these regulatory proteins. Here, the pathway is continuously stimulated by the activation of C3, which leads to a cascade reaction potentiating platelet activation, aggregation, and complement-mediated endothelial cell injury throughout the microvasculature. Atypical HUS accounts for only 5% of all HUS cases, with an incidence of 2/million in adults and 3.3/million in children younger than 18 years; in 70% of pediatric cases, the onset is before age 2 years.16,17 Infection (respiratory or diarrheal) triggers the onset of atypical HUS in 50% of adults and 80% of pediatric cases.17 As such, the presence of diarrhea cannot reliably distinguish STECHUS from atypical HUS or TTP because diarrhea occurs in one-third of atypical HUS cases and is not uncommon in TTP. Atypical HUS has a worse outcome than STECHUS, with up to 50% of cases progressing to end-stage renal failure within a year and 25% of patients dying during the acute phase.16 The same organs are affected in HUS and TTP, but in HUS the lesions are most numerous in the renal vasculature and there is minimal neurologic dysfunction. Acute kidney

Hemolytic uremic syndrome is a major thrombotic microangiopathy characterized by signs of microangiopathic hemolysis.

injury supports a diagnosis of HUS rather than TTP; acute renal failure affects <5% of patients with TTP at presentation.16 Of note, in 20% of patients with an initial presentation of atypical HUS, although some proteinuria or hematuria may be present, renal function is preserved.16 The lungs are almost never involved in TTP, whereas pulmonary disease is frequent in untreated atypical HUS.16 It is essential to differentiate between these disorders quickly because the PEX that is standard for TTP has no role in HUS. Overall, patients with thrombocytopenia (<150,000/µL or >25% decrease from baseline) plus signs of microangiopathic hemolysis and at least one manifestation of organ damage (neurologic, renal, or gastrointestinal most commonly) should be treated for thrombotic microangiopathy, and time-sensitive PEX should be initiated. Subsequent laboratory analysis will confirm the diagnosis; the detection of toxin-producing bacteria in stool culture or via serology or the presence of an anti-0157 antibody titer supports a diagnosis of STECHUS; ADAMTS13 activity <5% to 10% is likely TTP, and if >5% to 10% is likely atypical HUS. Further investigation of atypical HUS includes screening for complement system abnormalities (serum C3 and C4 levels, factor H and factor I levels). As in TTP, platelet transfusions are strongly contraindicated in HUS unless a severe hemorrhagic condition is present. For STEC-HUS, treatment includes (intravenous) fluid hydration, supportive care, and hemodialysis, with renal transplant as needed. Antibiotic therapy is not needed.

In atypical HUS, PEX is the first-line treatment per expert opinion, although the efficacy is variable according to mutated factor.17 Eculizumab, a monoclonal anti-C5 antibody, was recently approved for atypical HUS therapy; the data report Continues on page 26

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 23

TREATMENT OF DISORDERS OF PRIMARY HEMOSTASIS

In patients with disseminated intravascular coagulation, an underlying condition leads to the systemic intravascular activation of coagulation. success in early use as well as in the prevention and treatment of post-transplant recurrence.17 Renal transplant in atypical HUS may not be recommended for patients with certain mutations.

Disseminated intravascular coagulation. In disseminated intravascular coagulation (DIC), an underlying condition leads to the systemic intravascular activation of coagulation; the simultaneous generation of thrombin and fibrin results in thrombosis in small to medium-size vessels.

The process culminates in organ ischemia and dysfunction and/or severe bleeding due to platelet and clotting factor consumption. The frequency of DIC in hospitalized patients is about 1.72%.18 The most common association is severe sepsis or septic shock. Clinically overt DIC may occur in 30% to 50% of patients with gram-negative sepsis18 but is estimated to be as common in patients with gram-positive sepsis. Other causes include the following: major trauma, burns, prolonged surgery, massive blood transfusion or ABO-incompatible transfusion, malignancy (especially acute promyelocytic leukemia or non-Hodgkin lymphoma), and obstetric complications (most commonly pre-eclampsia; also retained fetus, amniotic fluid embolism, placental abruption). An increase in tissue factor production and activity is paramount in initiating DIC and is found to be significant in injured tissue and in leukemic cells and solid tumors.18 Other contributors, particularly in cases of septic DIC, include elevated cytokines, elevations of plasminogen activator inhibitor 1, endothelial activation, lipopolysaccharides, histones, and activated leukocytes.

POLL POSITION

Which of the following bleeding disorders do you encounter most frequently?

■ Von Willebrand disease ■ Idiopathic thrombocytopenic purpura ■ Thrombotic thrombocytopenic purpura

29% 13% 58%

For more polls, visit ClinicalAdvisor.com/Polls.

Guidelines highlight four types of DIC based on the predominance of hyperfibrinolysis or hypercoagulation.19 The diagnosis and treatment of these types differ, and clinicians must be aware that types may shift or change. In cases of hyperfibrinolysis, as seen in patients with leukemia, obstetric disease, or aortic aneurysm, bleeding-type DIC develops.

In cases ofhypercoagulation, as seen in patients with sepsis, organ failure-type DIC develops. When both hypercoagulation and hyperfibrinolysis have a weak presence, patients may be asymptomatic. However, the strong presence of both factors, as seen in major bleeding after surgery or in obstetric disease, leads to massive bleeding or consumptive-type DIC. Guidelines recommend that DIC be diagnosed with a combination of laboratory markers trended serially rather than a single test. In clinical practice, the diagnosis may be based on the following: an underlying disease associated with DIC, an initial platelet count <100,000/μL or rapidly declining, prolongation of the PT and PTT (>1.5 times the normal value), the presence of fibrin degradation products, and low levels of coagulation inhibitors such as antithrombin III.18 The PT is prolonged in 50% of patients during the clinical course.19 Elevated levels of fibrin degradation products indicate ongoing hyperfibrinolysis together with low levels of plasminogen and α2-antiplasmin. Serial monitoring of fibrin degradation products may be used to evaluate the response to therapy. A decreased fibrinogen level (<1.5 g/dL) is observed in cases of DIC due to leukemia or obstetric disease but is rare in patients with sepsis.19 Levels of major physiologic anticoagulants, such as antithrombin III, protein C, and tissue factor pathway inhibitor, are low in DIC and are associated with increased mortality, particularly in sepsis.18 New assays monitoring thrombin generation and its activation of the protein C and fibrinolytic pathways are also being used to monitor DIC. It is critical to identify and treat the underlying disorder because DIC commonly spontaneously resolves once the trigger is removed. Otherwise, treatment is individualized according to the hemodynamic status of the patient and the type of DIC. Guidelines recommend platelet transfusion and fresh frozen plasma in patients who have DIC with active bleeding or those at high risk for bleeding, particularly when the platelet count is <50,000/µL.19 Large volumes of plasma (up to 6 units per day) may be required to correct coagulation defects; an initial dose of fresh frozen plasma of 15 mL/kg is clinically recommended. Deficiencies in fibrinogen associated with the massive bleeding type of DIC can be corrected

26 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

Pregnant women with platelet counts >30,000/μL without bleeding do not require any treatment until week 36 of gestation unless delivery is imminent. with the administration of purified fibrinogen concentrates or cryoprecipitate. The standard of care in nonbleeding types of DIC is prophylaxis with unfractionated heparin or LMWH and/or mechanical methods. Small studies suggest that LMWH is superior to unfractionated heparin for treating DIC because it has at least the same antithrombotic potential with a decreased risk for bleeding.18,19 Heparin mitigates the high risk for venous thromboembolism in DIC and has the benefit of partially inhibiting the activation of coagulation.

It is particularly useful in those with clinically overt venous thromboembolism or extensive fibrin deposition evidenced by acral ischemia.18,19 Clinical studies have not shown that heparin treatment significantly increases the incidence of bleeding, but it is not recommended in patients with the bleeding type of DIC.18,19 In studies of DIC in patients with severe sepsis, the 28-day mortality was lower in the heparintreated group than in the placebo group.19 Particularly in cases of sepsis-related DIC, the administration of antithrombin III and activated protein C concentrates, which have anticoagulant and anti-inflammatory effects, has been shown benefit in reducing DIC and mortality and improving organ function.18

No laboratory parameter predicts the platelet count in the fetus. Pregnant women with platelet counts >30,000/μL without bleeding do not require any treatment until week 36 of gestation unless delivery is imminent.10 First-line management of ITP does not change during pregnancy. Steroids or IVIG is recommended, and these have relatively few fetal complications; oral prednisone and prednisolone cross the placenta at a lower rate than dexamethasone. Refractory ITP in pregnancy is treated with combination steroid/IVIG or splenectomy, although splenectomy should be avoided if possible. A platelet count >50,000 /µL is usually sufficient for cesarean delivery.6 Pregnant patients with vWD usually have no problems during pregnancy but may be at risk for postpartum hemorrhage, even with treatment, because vWF and factor VIII activity decrease after childbirth.6 Severe thrombocytopenia or associated hypertension, renal insufficiency, and/or microangiopathic hemolytic anemia should prompt an evaluation for a more serious obstetric condition, such as pre-eclampsia, TTP, or HELPP (hemolysis, elevated liver enzymes, low platelet count) syndrome.

Conclusion

Considerations for pregnant patients

Platelet counts <150,000/µL are seen in 6% to 15% of women at the end of pregnancy, and counts <100,000/µL are observed in 1%.1 These counts are most commonly gestational thrombocytopenia (70% of cases, mild in an otherwise healthy pregnancy); other causes are pre-eclampsia (21%) and ITP (3%)1.

Gestational thrombocytopenia is observed in the mid-second to third trimester of pregnancy and is an extreme variation of the physiologic decrease in platelets normally observed; counts <70,000/µL are rare,1,2 and gestational thrombocytopenia requires no change from routine obstetric care.

If there is no past history of thrombocytopenia except in a former pregnancy, the thrombocytopenia should resolve spontaneously within 1 to 2 months after delivery with no sequelae or thrombocytopenia in the newborn. ITP occurs in 1/1000 to 2/1000 pregnancies but is the most common cause of isolated thrombocytopenia in the first and early second trimesters.1 One-third of cases are diagnosed during pregnancy, whereas two-thirds of patients report pre-existing disease.1 In ITP, IgG autoantibodies may cross the placenta and cause severe neonatal thrombocytopenia in 9% to 15% of cases.1 A platelet count <50,000/µL in pregnancy should be diagnosed as ITP.

The evaluation of most disorders of primary hemostasis begins with a focused history and physical examination, complete blood cell count with platelet trend, and examination of the peripheral smear. The most common conditions encountered include ITP and DIT, but clinicians must be aware of the extensive differential diagnosis if they are to determine the relevance of the platelet count as well as the patient’s risk for bleeding, thrombosis, and other complications. n Danielle Kruger, PA-C, MSEd, is an associate professor in the Physician Assistant, Bachelor of Science program at St. John’s University College of Pharmacy and Health Sciences, and a physician assistant practicing emergency medicine, and Director of Physician Assistant Development at Coney Island Hospital in Brooklyn, NY. References 1. Stasi R. How to approach thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2012;2012:191-197.

2. George JN, Arnold DM. Approach to the adult with unexplained thrombocytopenia. UpToDate. https://www.uptodate.com/contents/ approach-to-the-adult-with-unexplained-thrombocytopenia. Updated October 19, 2017. Accessed October 26, 2017.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 27

TREATMENT OF DISORDERS OF PRIMARY HEMOSTASIS

3. Bowman M, Mundell G, Grabell J, et al. Generation and validation of the Condensed MCMDM1-VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost. 2008;6:2062-2066.

4. Ballas M, Kraut EH. Bleeding and bruising: a diagnostic work-up. Am Fam Physician. 2008;77:1117-1124.

5. American Society of Hematology. 2012* clinical practice guidelines on the evaluation and management of von Willebrand disease (VWD). http:// www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference. aspx#a3. Accessed October 26, 2017.

6. Thiagarajan P. Platelet disorders: overview of platelet disorders.

Medscape.http://emedicine.medscape.com/article/201722-overview.

Updated August 5, 2017. Accessed October 26, 2017.

7. Mohanty D, Shetty S. Von Willebrand Disease: an update. J Blood Disorders Transf. 2014;5:238. doi:10.4172/2155-9864.1000238

“Keep loopholes and entitlements just the way they were...”

8. Simon D, Kunicki T, Nugent D. Platelet function defects. Hemophilia.

2008;14:1240-1249.

9. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207.

10. Kessler CM. Immune thrombocytopenic purpura (ITP). Medscape. www.emedicine.medscape.com/article/202158-overview. Updated December 2, 2016. Accessed October 26, 2017.

11. Visentin GP, Liu CY. Drug-induced thrombocytopenia. Hematol Oncol 12. Solomon CG. Heparin-induced thrombocytopenia. N Engl J Med. 2015;373:252-261.

13. Cuker A, Crowther M. 2013 Clinical practice guideline on the evaluation and management of adults with suspected heparin-induced thrombocytopenia (HIT). American Society of Hematology. Accessed October 26, 2017.

14. Saifan C, Nasr R, Mehta S, Acharya PS, El Sayegh S. Thrombotic thrombocytopenic purpura. J Blood Disord Transfus. 2012;S3:001. doi:10.4172/2155-9864.S3-001 15. Scully M, Hunt B, Benjamin S, et al; British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158:323-325. doi:10.1111/j.1365-2141.2012.09167.x 16. Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis. Clin Adv Hematol Oncol. 2012;10(10 Suppl 17):1-12.

17. Salvadori M, Bertoni E. Update on hemolytic uremic syndrome: diagnostic and therapeutic recommendations. World J Nephrol.

2013;2:56-76.

18. Dalainas I. Pathogenesis, diagnosis and management of disseminated intravascular coagulation: a literature review. Eur Rev Med Pharmacol Sci. 2008;12:19-31.

19. Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014,2:15.

“You sold our cow for magical beanbags?”

28 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

Top: © Harley Schwadron 2017. Middle, bottom: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.

Clin North Am. 2007;21:685-696.

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CME FEATURED COURSE

n EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be better able to: • Analyze the disease course of relapsing-remitting multiple sclerosis (RRMS) and the impact of early diagnosis • Describe how the introduction of disease-modifying therapy—including oral ­ sphingosine-1-phosphate (S1P) receptor modulators—has transformed expectations for reducing inflammatory lesion activity in patients with RRMS • Explain the mechanisms of action of S1P receptor modulators and their rationale for treatment for patients with RRMS • Interpret the efficacy and safety of current and emerging S1P receptor agents, including their benefit/risk profiles and effects on cardiac health • Utilize shared decision-making with patients when discussing a new treatment and/or a change in therapeutic regimen • Address nonmotor symptoms of MS such as depression and fatigue n COMPLETE THE POSTTEST: Page 44

Release Date: October 31, 2017 Expiration Date: December 31, 2018 Estimated Time to Complete: 1 hour Accredited Provider: This activity is provided by Haymarket Medical Education.

Commercial Supporter: This activity is supported by an educational grant from Celgene Corporation.

Program Description: Incomplete recovery from relapses in individuals with relapsing-remitting multiple sclerosis (RRMS) contributes to stepwise disability worsening, underscoring the importance of early, effective intervention. After many years in which first-line disease-modifying therapies (eg, glatiramer acetate, interferon-β) were the principal treatment options, a plethora of new agents for MS treatment—including next-generation sphingosine-1-phosphate (S1P) receptor modulators—are now approved or under investigation. These emerging options are raising the bar from the current therapeutic goals of achieving minimal evidence of disease activity to the potential, albeit ambitious, goal of achieving no evidence of disease activity—meaning no relapses, no disability worsening, and no new or enlarging lesions on magnetic resonance imaging.

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 1.00 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs.

Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition.

Intended Audience: Neurologists and other clinicians who manage patients with MS

Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education or Celgene Corporation.

Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities.

Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period October 31, 2017 through December 31, 2018, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete the post-test and evaluation form and submit it online.

Faculty Patricia K. Coyle, MD Professor and Vice Chair, Clinical Affairs Department of Neurology Director, Multiple Sclerosis Comprehensive Care Center Stony Brook University Medical Center Stony Brook, NY

A statement of credit will be issued only upon receipt of the above elements and a posttest score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Dec17feature.

Dr. Coyle receives consulting fees from Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Novartis, Sanofi Genzyme, and Serono and is a primary investigator for Actelion, Alkermes, Genentech/Roche, MedDay, National Institute of Neurological Disorders and Stroke (NINDS), and Novartis.

Accredited Provider Disclosure: Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose.

If you have any questions relating to the CME certification of this activity, please contact cmequestions@haymarketmedical.com.

If you have any questions relating to your certificate or other issues with this activity, please contact myCME.Support@haymarketmedical.com.

Provided by

CME

FEATURED COURSE: PATRICIA K. COYLE, MD

Evolving expectations in the management of MS Emerging therapies for relapsing-remitting multiple sclerosis raise the bar from the current therapeutic goal of minimal disease activity to none at all.

T

© ZEPHYR / SCIENCE SOURCE

oday’s characterizations of multiple sclerosis (MS) phenotypes include both disease activity (based on the clinical relapse rate and imaging findings) and disease progression. Relapsingremitting MS (RRMS), clinically isolated syndrome (CIS), and secondary progressive MS (SPMS) are categorized into the relapsing MS phenotype. Primary progressive MS (PPMS) is a unique phenotype, which is part of the spectrum of progressive disease (Table 1).1 Relapsing-remitting MS, which is the focus of this article, involves clearly defined attacks of new or recurrent neurologic symptoms and signs with full, partial, or no recovery, and lack of disease worsening between relapses.2 Patients with RRMS experience acute attacks of symptoms. Usually, a relapse develops over a few days, before the symptoms plateau and remit over the proceeding weeks to months.

During this time, central nervous system (CNS) repair mechanisms operate and neurologic reserve is used up to remodel and compensate for damage. Complete physical recovery from a relapse is often the case; however, relapse can be associated with a sustained increase in disability. Incomplete recovery from relapses contributes to stepwise disability worsening.3 Diagnosis and early intervention

Colored MRI of the brain in a patient with MS

The earlier that MS can be diagnosed, the sooner treatment can be initiated. Today, MS can be diagnosed 10 times more quickly than what was possible decades earlier by using data from magnetic resonance imaging (MRI), as well as with clinical assessments.3 Positive cerebrospinal fluid (CSF) www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 31

CME

FEATURED COURSE

TABLE 1. Contemporary multiple sclerosis phenotypes1 Relapsing-remitting disease

Progressive disease Primary progressive (progressive accumulation of disability from onset)

Not active CIS Activea Not active RRMS Activea CIS, clinically isolated syndrome; Gd, gadolinium; RRMS, relapsing-remitting multiple sclerosis. b Progression measured by clinical evaluation at least once yearly.

findings (≥2 oligoclonal bands or elevated immunoglobulin G index) can be an important marker to support the inflammatory demyelinating nature of the underlying condition, to evaluate other diagnoses, and to predict clinically definite MS.4 More recently, a number of candidate CSF biomarkers, such as CXCL13, fetuin A, Nf L, GFAP, and osteopontin, have been shown to correlate with disease activity, disease progression, and response to treatment. Further evaluation and standardization is needed before these biomarkers can be applied in individualized assessment and treatment decision-making.5 Contrast lesions can occur late in the disease process; these include breakdown of the blood-brain barrier, multifocal inflammation, demyelination, oligodendrocyte loss, reactive gliosis, and axonal degeneration. In line with imaging studies, actively demyelinating white-matter lesions are often seen in patients with RRMS. When it comes to diagnosis, time may be of the essence to preserve brain volume and physical function. Many people with CIS and early MS already experience brain atrophy more rapidly than the general population.6 This loss of brain tissue is often subclinical, owing to repair mechanisms in the CNS and neurologic reserve, which allow the brain to reorganize itself and reroute pathways to avoid damaged areas, even when repair is incomplete.3 After a number of years, many RRMS cases will have advanced to SPMS. Inflammation contributes to the brain and/or spinal cord lesions, which are evidenced on MRI. The “window of opportunity” for use of current diseasemodifying therapy (DMT) is optimally soon after clinical presentation. Treatment in later stages of MS is still possible, although it may be considerably less effective.7 In the absence of a cure for MS, the goal of starting treatment with a DMT should be to reduce subclinical disease activity, preserve brain volume, and slow or prevent disability progression.8,9 It is important to keep in mind the distinction

a

Activea and with progressionb Activea but without progression

Progressive disease

Not active but with progressionb

Secondary progressive (progressive accumulation of disability after an initial relapsing course)

Not active and without progression (stable disease)

Activity = clinical relapses and/or MRI (Gd-enhancing MRI lesions; new/enlarging T2 lesions).

between microscopic and macroscopic injury because abnormal brain tissue may appear to be normal. Early diagnosis means that early DMT initiation can be accompanied by other interventions to preserve brain tissue and optimize brain health (eg, exercise, smoking cessation, weight loss, and control of comorbidities). This approach maximizes the chances of modifying the disease course before further relapses or disability progression occur.

A recent meta-analysis of published randomized-clinical trials in RRMS provides evidence that DMTs are most effective early on. Results showed that DMTs are more effective at slowing worsening—including disability—in younger people compared with older people. In addition, DMTs also reduce the relapse rate most effectively in younger people vs older people, in patients with low Expanded Disability Status Scale (EDSS) scores vs high scores, and in those with active lesions vs no active lesions.10 The introduction of DMTs, including oral sphingosine-1-phosphate receptor (S1PR) modulators, which are discussed in greater detail in this article, have transformed the expectations for reducing inflammatory lesion activity in patients with MS.11,12 Current and emerging RRMS treatment approaches

Over the past 2 decades, the MS treatment landscape has greatly expanded and continues to evolve. After many years in which first-line DMTs, such as glatiramer acetate (GA) and interferon β (IFNβ), were the principal treatment options, a plethora of new agents for MS treatment are now approved or under investigation. Table 2 outlines the current US Food and Drug Administration-approved DMTs. It is common practice for clinicians to prescribe IFNβs, GA, or oral agents as initial therapy. Although monoclonal antibodies are highly efficacious treatments approved for treating MS, they tend to be reserved for patients with more active disease because of autoimmune reactions and immunosuppression.11

32 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

In clinical practice, the therapeutic goal in RRMS has been to achieve minimal evidence of disease activity. Recently, however, an aspirational therapeutic goal is to achieve no evidence of disease activity (NEDA), meaning no relapses, no disability worsening, and no new or enlarging lesions on MRI. This emerging strategy of treating to target to achieve NEDA is aligned with management concepts in other autoimmune diseases, in which treatment algorithms aim to suppress as much inflammation as possible and to induce long-term remission for prevention of irreversible end-organ damage.14 Although NEDA may be difficult to achieve in practice, the availability of new and emerging treatments makes it a potential—albeit ambitious—benchmark.15 Injectable/intravenous agents

First-line DMTs Interferon β and GA were shown to have comparable efficacy and reduce the relapse rate (RR) by about 30% in their initial clinical trials, with even better results in more recent trials.16 IFNβ drugs are often used as upfront DMTs for RRMS. Each of the IFNβ drugs was approved based on findings from single multicenter, double-blind, placebo-controlled, phase 3 trials.17-19 IFNβ is well tolerated; side effects include flu-like symptoms, increased liver enzymes, and injection-site reactions.

Glatiramer acetate is a 4 amino acid synthetic copolymer based on the composition of myelin basic protein.20 GA has positive effects on regulatory T cells, modulates B cell cytokine secretion, and mediates a T-cell shift toward an anti-inflammatory phenotype 2 T helper.21 Several clinical trials have demonstrated positive GA effect.22 GA is safe; side effects include local injection-site reactions and post-injection reactions, which occur in fewer than 20% of patients.23 IFNs and GA require regular, long-term self-injection administration. It is important that the patient accepts this to minimize adherence concerns.16 US Food and Drug Administration-approved next-line therapies, such as natalizumab and mitoxantrone, are more effective in the treatment of RRMS. Natalizumab is usually

reserved for highly active MS, and mitoxantrone is now rarely used to treat MS.24 These agents are administered parenterally and are associated with potentially severe side effects. These include progressive multifocal leukoencephalopathy (PML) with natalizumab, and cardiotoxicity and acute leukemia with mitoxantrone. Given the risk of these serious side effects, mitoxantrone is rarely used in the treatment of MS. Natalizumab, which is a humanized recombinant monoclonal antibody against α4-integrin and the first monoclonal approved for treatment of MS, diminishes leukocyte migration from the peripheral blood into the CNS by preventing its binding via α4-integrin to the ligand vascular cell adhesion molecule found on endothelial surfaces.20 This blocks the adhesion and subsequent migration of lymphocytes across the blood-brain barrier, attenuating CNS inflammation.

In the pivotal placebo-controlled phase 3 trial, intravenous (IV) natalizumab 300 mg monthly reduced RR by 68% and confirmed disability at 2 years by 42%.25 Contrast lesion MRI activity was reduced by 92% in the natalizumab-treated group, new or enlarging T2 lesions were reduced by 83%, and T1 hypo intense lesions were reduced by 76% compared with placebo (P<.001).26 PML risk stratification for patients with MS who were treated with natalizumab is feasible by evaluating anti-John Cunningham ( JC) virus antibody status, antibody index,27,28 treatment duration, and prior immunosuppressant use.20 In some instances, discontinuation of natalizumab may trigger rebound disease activity with marked clinical and radiologic worsening.29 Alemtuzumab Alemtuzumab, a humanized monoclonal antibody targeting CD52 expressed on lymphocytes, natural killer cells, monocytes, and some granulocytes, produces antibody-dependent cellular cytotoxicity with rapid and profound lymphopenia lasting for years.30,31 Alemtuzumab is given by IV infusion for 2 treatment courses: the first treatment course is 12 mg/ day for 5 consecutive days (60-mg total dose), and the second treatment course is 12 mg/day for 3 consecutive days

TABLE 2. FDA-approved, off-label, and investigational DMTs (in alphabetical order)13 Injectable • Glatiramer acetate • IFNβ-1a (IM and SC) • IFNβ-1b (SC) • Pegylated IFNβ-1a

Oral • Dimethyl fumarate • Fingolimod • Teriflunomide

Monoclonal • Alemtuzumab • Daclizumab • Natalizumab

• Ocrelizumab • Ofatumumaba • Rituximabb

Anthracenedione • Mitoxantrone

FDA, US Food and Drug Administration; IFNβ, interferon β; IM, intramuscular; SC, subcutaneous. a Investigational. bOff-label.

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(36-mg total dose) administered 12 months after the first treatment course. If necessary, additional courses may be given 12 months after the latest treatment course. Two phase 3 trials of RRMS demonstrated that alemtuzumab 12 mg/ day reduced the RR by 49% to 55%, the rate of confirmed disability worsening by 30% to 42%, and MRI gadoliniumenhancing (GdE) lesions by 61% to 63% when compared with subcutaneous (SC) IFNβ-1a 44 μg 3 times weekly.32,33 Patients commonly experience infusion-associated reactions with alemtuzumab treatment (eg, flushing, headache, urticaria, and tachycardia.32-35 Herpes virus reactivation has been observed; therefore, antiviral prophylaxis starting on the first day of each treatment course and continued for a minimum of 2 months after treatment with alemtuzumab or until the CD4+ lymphocyte count is 200 cells/μL or higher, whichever occurs later, is recommended.36 Alemtuzumab treatment is associated with increased risk of upper respiratory tract infection and urinary tract infection.

Emergent autoimmune complications are common but seem to follow a known temporal sequence and usually can be effectively managed during long-term monitoring. There is increased risk of autoimmune-mediated conditions including thyroid disorders (41%), immune thrombocytopenic purpura (3.5%), or rarely, nephropathies (eg, antiglomerular basement membrane disease; <1%).37 Given the risk of autoimmunemediated conditions, monthly blood and urine analyses are recommended for 4 years after the last dose.

Daclizumab Daclizumab, which is a humanized monoclonal antibody against CD25, the interleukin (IL)-2 receptor expressed on the surface of T cells, works by blocking the IL-2 receptor on T cells and preventing their activation. A randomized, double-blind, active-controlled, phase 3 study in patients with RRMS compared daclizumab 150 mg every 4 weeks with intramuscular (IM) IFNβ-1a 30 μg once weekly for up to 144 weeks. Results from this study showed that the annualized relapse rate (ARR) was lower with daclizumab than with IM IFNβ-1a (0.22 vs 0.39; 45% lower rate with daclizumab; P<.001). Serious adverse events, excluding relapse of MS, were reported in 15% of the patients in the daclizumab group and in 10% of patients in the IFNβ-1a group. Infections were more common in the daclizumab group vs the IFNβ-1a group (65% vs 57%, including serious infection in 4% vs 2% of patients), as were cutaneous events, such as rash or eczema (37% vs 19%, including serious events in 2% vs <1% of patients) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal (ULN) range (6% vs 3%).38

Ocrelizumab Ocrelizumab, which is the latest entrant in the monoclonal class, is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed on pre-B cells, mature B cells, and memory B cells but not on lymphoid stem cells and plasma cells.39 It depletes B cells by antibodydependent cell-mediated cytotoxicity and to a lesser extent compliment-dependent cytotoxicity. Given that ocrelizumab is derived mostly from human antibodies, it induces less of an immune response to foreign antigens. Moreover, because ocrelizumab is thought to bind more avidly to CD20 and expected to be less immunogenic than rituximab, it might have a more favorable benefit-to-risk profile.40 In 2 phase 3 trials, patients with RRMS were randomized to receive IV ocrelizumab 600 mg every 24 weeks or SC IFNβ-1a 44 μg 3 times weekly for 96 weeks. Findings from this study showed a lower ARR with ocrelizumab vs IFNβ-1a in trial 1 (0.16 vs 0.29; 46% lower rate with ocrelizumab; P<.001) and in trial 2 (0.16 vs 0.29; 47% lower rate; P<.001). In addition, the percentage of patients with disability worsening confirmed at 12 weeks was significantly lower with ocrelizumab than with IFNβ-1a (9.1% vs 13.6%; hazard ratio [HR], 0.60; 95% CI, 0.45-0.81; P<.001), as was the percentage of patients with disability worsening confirmed at 24 weeks (6.9% vs 10.5%; HR, 0.60; 95% CI, 0.43-0.84; P=.003). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab.

Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with IFNβ1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with IFNβ-1a.39 Investigational agents Ofatumumab is a fully human anti-CD20 antibody, which binds to a different epitope of CD20 than ocrelizumab or rituximab; it depletes B cells by complement-dependent cytotoxicity. A phase 2, double-blind, placebo-controlled, parallel-group study assessed the safety and efficacy of 4 different SC ofatumumab regimens (3 mg, 30 mg, or 60 mg every 12 weeks, or 60 mg every 4 weeks) in patients with RRMS. All patients continued in the study for 24 weeks of treatment and until B-cell repletion. The cumulative number of new T1 GdE lesions for each ofatumumab dose regimen from baseline to week 12 was reduced by 65% (P<.001), and the corresponding data analysis of weeks 4 to 12 estimated reductions of at least 90% for each dose of 30 mg or higher (P<.001). A dose-dependent CD19 B-cell depletion was seen across all regimens. The rate of repletion of B cells following cessation of dosing was similar, with a delay of approximately 4 weeks in the 60-mg every-4-weeks group.41

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Rituximab, a chimeric anti-CD20 monoclonal antibody, which is approved in other disease states, is thought to deplete B cells by antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and induction of apoptosis.40 Data from a phase 2, double-blind, placebocontrolled trial in RRMS showed that compared with placebo, rituximab showed a significant reduction in total number of GdE lesions of 91% (P<.001) and a significant reduction of ARR of 58% at week 24.42 Oral agents

Given that injectable drugs may have adherence and tolerance issues, oral therapies provide an advancement in convenience.

Oral therapies for RRMS include fingolimod, teriflunomide, and dimethyl fumarate.

Fingolimod Fingolimod, which was the first entrant in a new class of agents known as S1PR modulators, is described in greater detail in the following section.

Teriflunomide Teriflunomide, which is the metabolite of leflunomide, is administered once daily and has an oral bioavailability of nearly 100%. It inhibits dihydroorotate dehydrogenase and blocks rapidly dividing lymphocytes, both B and T cells, and is cytostatic.20,43 Results from a phase 3 trial in RRMS showed that the ARR was significantly reduced by teriflunomide (0.54 for placebo vs 0.37 for either 7- or 14-mg teriflunomide, indicating a 31% RR reduction).44 Other phase 3 studies showed similar effects with teriflunomide 7 and 14 mg and IFNβ, as well as a 36.3% reduction in ARR and a 31.5% reduction in the risk of 12-week confirmed disability with 14-mg teriflunomide vs placebo. The most common adverse events with teriflunomide include gastrointestinal effects (nausea, diarrhea), elevated alanine transaminase (ALT), and hair thinning in the first 6 months.45 To date, no cases of PML have been seen in patients with MS that are attributable to teriflunomide.43 Dimethyl fumarate Dimethyl fumarate, an ester of dimethyl fumaric acid, is almost completely absorbed in the small intestine and is hydrolyzed to the active metabolite monomethyl fumarate. Its exact mechanism of action is not fully understood. It may polarize the immune system toward a phenotype 2 T helper; increase the production of anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist; or attenuate production of tumor necrosis factor-α, IL-1β, IL-6, and nitric oxide.20 It may also exert neuroprotective

effects via activation of the NF-E2–related factor 2 antioxidant pathway.46 Results from a phase 3 trial in RRMS showed that a daily dose of 480-mg and 720-mg dimethyl fumarate was superior to placebo by reducing the proportion of patients who relapsed within 2 years (P<.0001) and by reducing the ARR (53% and 48% for the 480 mg and 720 mg daily dose, respectively) and the MRI outcomes vs placebo.47 In another phase 3 study, there was a significant reduction in ARR in all active arms of the trial at 2 years compared with placebo, but it was more prominent with dimethyl fumarate than with GA (51% with 720 mg, 44% with 480 mg, and 29% with GA); this study was only powered for comparison to the placebo arm. The most common adverse events were gastrointestinal symptoms and flushing usually within 30 minutes of administration.48 Although rare, several cases of PML with the use of dimethyl fumarate in patients with MS have been reported in the peer-reviewed literature; one of these cases was fatal.49-51 In-depth look at S1PR modulators

Sphingosine-1-phosphate (S1P), which is active phospholipid resulting from phosphorylation of sphingosine by sphingosine kinase-1 or -2, regulates diverse cellular responses involved in immunity, heart rate, smooth muscle tone, and endothelial barrier function. S1P is abundant in erythrocytes, the brain, the spleen, and the eyes. S1PRs have 7 transmembrane segments and are coupled to G proteins, which transduce their actions.

Mechanisms of action and nuances of receptor selectivity

There are 5 receptor subtypes: subtypes S1P1 to S1P3 are present throughout the body, whereas S1P4 is expressed in lymphoid tissue and S1P5 is expressed in the spleen and oligodendrocytes (Figure 1).52,53 B and T lymphocytes mainly express S1P1, although they also express S1P3 and S1P4 to a lesser extent. S1PRs are important in lymphocyte trafficking, particularly from lymph nodes. S1P concentration is typically low in lymph nodes and lymphocytes upregulate their S1PR expression. When S1P agonistically interacts with its receptor, the bound product is internalized, which leads to activation and transient retention of the T cell in the lymph node. The S1PR is then recycled back to the surface. The re-expression of the S1PR allows emergence from the lymph nodes in response to the efferent lymph-lymph node chemotactic gradient.54 Fingolimod efficacy and safety

Fingolimod was the first FDA-approved oral for treatment of RRMS. Its clinical efficacy results from modulation of subtype 1 S1P (S1P1) receptors, leading to lymphocyte sequestration

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FIGURE 1. Selectivity of S1P receptor modulators52 S1P1 modulator

S1P1/5 dual modulator

AUY954, KRP-203, CS-0777, SEW2871, MT-1201, Ponesimod (ACT-128800)

Ceralifimod (ONO-4641), GSK2018682, Siponimod (BAF312), Ozanimod, (RPC1063)

S1P1

prodrug Fingolimod

S1P5

in vivo phosphorylation SK2

S1P4

active drug Fingolimod-phosphate

S1P3

endogenous ligand Sphyingosine 1-phosphate

S1P2

JTE-013

S1P, sphingosine-1-phosphate

in the lymph nodes and reduced migration to the CNS. The intended mechanism of action of fingolimod is via binding of the S1P1 receptor on lymphocyte surfaces, but its nonselective modulation of S1P3, S1P4, and S1P5 may result in untoward adverse effects. Phase 3 trials have demonstrated the efficacy of fingolimod in RRMS. Results from FREEDOMS showed that fingolimod 0.5 mg and 1.25 mg decreased the ARR by 54% and 60%, respectively, vs placebo.55 Results on time to first relapse and confirmed EDSS worsening also favored fingolimod. Treatment with fingolimod also significantly reduced GdE MRI lesions (≈90%) and new/enlarged T2 lesions (≈50%) at 24 months. In addition, there was significant preservation of brain volume in participants treated with the 0.5-mg dose vs placebo (-0.84% vs -1.31% from baseline to 24 months).

These findings were confirmed in FREEDOMS II, which was the second placebo-controlled phase 2 trial.56 In the TRANSFORMS trial, fingolimod 0.5 mg and 1.25 mg were found to be superior to IM IFNβ-1a 30 μg weekly in decreasing the ARR by 52% and 38%, respectively. The proportion of relapse-free patients and time to confirmed relapse were greater in both fingolimod groups. The number of GdE lesions and new/enlarged T2 lesions was significantly lower in the fingolimod groups vs IFNβ-1a. Brain volume reductions were significantly less with both fingolimod doses vs IFNβ-1a.57 Fingolimod was also evaluated in PPMS; however, pursuit in this

disease course has been abandoned because it did not improve disability or reduce loss in brain volume in a phase 3 study.58 Although fingolimod is an efficacious S1PR and is generally well tolerated, it is not without safety concerns, which have emerged in clinical trials and in post-marketing surveillance studies. Many of these adverse events are attributed to its nonselective modulation of S1PRs. Among the most common adverse effects were first-dose bradycardia or atrioventricular (AV) block, macular edema, hypertension, cough, dyspnea, headache, back pain, diarrhea, and influenza. Pooled analysis from FREEDOMS and TRANSFORMS showed a mean decrease in heart rate of 8 beats per minute (BPM), reaching a nadir 4 to 5 hours after the first dose. The incidence of first-degree AV block was 4.7%, Mobitz type 1 second-degree AV block occurred in 0.2% of participants, and symptomatic bradycardia occurred in 0.5% of participants.59 Discontinuation of fingolimod for more than 2 weeks requires repeating first-dose monitoring given the recurrence of bradycardia. The mechanism of the effect on heart rhythm is via transient agonistic effects on S1P1 receptors in atrial myocytes followed by desensitization due to receptor down-modulation.60 Table 3 summarizes important cardiac considerations when contemplating use of fingolimod in patients with RRMS. Several other adverse effects of fingolimod have been observed, although the exact mechanisms are less clear and

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they may be due to off-target effects via other S1PR subtypes.

Among these were macular edema, infections in a minority of patients (herpes zoster/varicella zoster virus, and cryptococcal infection, as well as at least 9 reported cases of PML), asymptomatic elevation of liver transaminases, and lymphoma.61 LONGTERMS was a multicenter, open-label, single-arm, long-term safety and tolerability study of patients in the phase 2 and phase 3 fingolimod studies treated with the 0.5-mg dose. Results from this study showed that the incidence rate of adverse events was lower in the long-term cohort vs the core phase 3 cohort, and included infections, cardiac events, skin cancer and other malignant neoplasms, thromboembolic events, hypertension, respiratory conditions, and macular edema. In addition, no new adverse events were seen and although there was a greater incidence rate of leukopenia and lymphopenia in the long-term cohort, it did not appear to be associated with an increased risk of infection.62 Fingolimod has been used in patients with highly active RRMS who have antibodies to the JC virus, as well as for a switch option for patients taking natalizumab who are at increased risk for PML due to JC virus seropositivity.

When switching from natalizumab to fingolimod, the risk of relapse increases with a longer washout period; however, in most patients, fingolimod maintains good control of relapse activity.63 Ideally, the washout period should be less than 3 months; practically, many clinicians suggest 1 month. Severe disease reactivity has been documented after discontinuation of fingolimod, particularly in patients with previously high disease activity.64 Generic versions of fingolimod are expected to be available as early as 2019.65 Rationale for next-generation S1PR modulators

Fingolimod’s interactions with other S1PR subtypes in other tissues and off-target pharmacologic effects have prompted

research into the feasibility of more selective S1PR modulators.

Selectivity for S1P1 receptors is favored to preserve efficacy and minimize adverse events associated with S1PR subtypes.

These small-molecule S1PR modulators have shorter halflives, similar broad tissue distribution, preserved efficacy, more S1PR selectivity, and hopefully, fewer adverse effects due to avoidance of the S1P3 and S1P4 receptor subtypes.

Several of the next-generation S1PR modulators that have been investigated have considerably shorter half-lives than fingolimod (Table 4),52,53,66-68 allowing for more rapid lymphocyte recovery post discontinuation. This might provide greater flexibility in retreatment with other agents, aid in washout to treat opportunistic infections or eliminate the drug in unplanned pregnancy, and address other treatment-related complications.

Investigational S1PRs include ponesimod, siponimod, ozanimod, ceralifimod, GSK2018682, and amiselimod, although not all of these drugs are in active development.52-54 Ponesimod Ponesimod binds to the S1P1 receptor. The efficacy, safety, and tolerability of 10 mg, 20 mg, and 40 mg of ponesimod was evaluated in a 24-week phase 2b double-blinded, placebocontrolled trial. The 20-mg and 40-mg arms included a titration schedule, whereas the 10-mg and placebo groups consisted of mock titrations. The primary endpoint was cumulative number of new GdE lesions from weeks 12 to 24. Among the secondary endpoints were ARR, time to first confirmed relapse over 24 weeks, cumulative number of new or enlarging T2 lesions at 12 to 24 weeks, combined unique active lesions (CUALs [GdE and new or enlarging T2 lesions]), and change in brain volume from baseline. A total of 464 participants were randomized into the 4 study arms (≈79%-90% of patients completed each arm). Results showed a significant reduction in new GdE lesions from week 12 to 24 with all 3 doses of

TABLE 3. Fingolimod cardiac considerations43 Higher risk of cardiac adverse events

Contraindications

Prior history of: • Ischemic heart disease • Congestive heart failure • Cerebrovascular disease • Symptomatic bradycardia • Recurrent syncope • Severe untreated sleep apnea • Atrioventricular block • Sino-atrial heart block • Prolonged QT interval

• Recent history (<6 months) of: —— MI, unstable angina, stroke, transient ischemic attack, decompensated heart failure • Mobitz type II second degree atrioventricular block, third degree atrioventricular block, or sick sinus syndrome if no pacemaker • QTc interval >500 ms • Use of class Ia (quinidine, procainamide) or class III anti-arrhythmics (amiodarone, sotalol, dofetilide, ibutilide)

• Risk factors for prolonged QT interval: —— Hypokalemia —— Hypomagnesemia —— Congenital long QT syndrome —— Drugs known to prolong QT interval (citalopram, chlorpromazine, haloperidol, and other antipsychotics, methadone, erythromycin) —— Use of beta blockers, digoxin, some calciumchannel blockers (verapamil, diltiazem)

MI, myocardial infarction; QTc, corrected QT interval.

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TABLE 4. Half-lives of next-generation S1P receptor modulators vs fingolimod Drug name

S1P receptor activity52

Half-life (hours)

Amiselimod

S1P1

380-42066

Ceralifimod

S1P1 and S1P5

Data not available

Ozanimod

S1P1 and S1P5

1953

Ponesimod

S1P1

3067

Siponimod

S1P1 and S1P5

2666

Fingolimod

S1P1, S1P3, S1P4, and S1P5

144-21666

ponesimod vs placebo, but more so with 20 mg and 40 mg (83% and 77% reduction, respectively). Significant benefits for ARR reduction and time to first confirmed relapse were only significant in the 40-mg arm at 52% (P=.0363) and 58% (P=.0189), respectively. The 20-mg and 40-mg doses showed significant reduction in CUAL but not in new or enlarging T2 lesions; all 3 doses preserved brain volume at 24 weeks compared to placebo. Ponesimod seems to have a dose-dependent effect, although not at doses exceeding 20 mg.69 With regard to safety, the 10-mg and 20-mg doses appeared to be well tolerated vs the 40-mg dose. Only 2% of participants on ponesimod experienced bradycardia (≈15 BPM decrease), and 1.2% and 0.9% of the respective cohorts had first- and seconddegree heart block, all of which occurred only on the first day of the 10-mg dose and within 2 to 3 hours of administration.

Among the other adverse effects reported in the ponesimod cohorts were anxiety, dizziness, dyspnea, increased ALT (>3x ULN), influenza, insomnia, and peripheral edema. Dyspnea and peripheral edema were dose-dependent, and 7 patients prematurely discontinued due to dyspnea (n=6 in the 40-mg group).

A decrease in forced expiratory volume in 1 second (FEV1) was seen in 0.6% to 10% of patients treated with ponesimod.

FEV1 returned to baseline within 1 week of discontinuation.

Macular edema was documented in 4 participants (n=3 in the 20-mg cohort and n=1 on placebo). The average reduction in lymphocyte count up to week 24 was 50% to 69% for ponesimod vs 3% for placebo and most of the reduction occurred by day 8 and recovered within the first week of discontinuation.69 Siponimod Siponimod binds to both S1P1 and S1P5. The phase 2 BOLD trial was a double-blind, randomized trial that evaluated multiple doses of siponimod (0.25 mg, 0.5 mg, 1.25 mg, 2 mg, and 10 mg) vs placebo. The primary endpoint was CUAL (new GdE and new/enlarged T2 lesions without double counting) during the first 3 months. Among the secondary endpoints

were total monthly new GdE lesions, total monthly new or enlarging T2 lesions, ARR, and proportion of patients who were relapse-free. The efficacy of siponimod 2-mg and 10-mg doses was about the same, with a reduction in CUAL by 72% and 82% respectively, but was submaximal for the 0.5-mg dose.

The ARR was significantly lower with the 2-mg and 10-mg doses (0.2 and 0.3, respectively) vs placebo (0.58). Yet the ARR reduction was statistically significant for the 2-mg dose only.70 In terms of safety, 5% of patients treated with the higher doses (2 mg and 10 mg) experienced second-degree AV block and 17% had bradycardia. One patient with a history of coronary artery disease (CAD) treated with the 1.25-mg dose died 27 days after discontinuing the medication. The cause of death was thought to be the result of a combination of the study drug and underlying CAD. Another participant taking the 10-mg dose had a nonfatal myocardial infarction 45 days after treatment discontinuation, which was related to siponimod. Elevation in ALT (>3x ULN) was more frequent in the higher doses. The magnitude of reduction in lymphocyte count at day 7 plateaued with the 2-mg dose, suggesting maximal S1P modulation. Based on these data, the 2-mg dose appears to be the most appropriate dose for future trials, especially if titrated to lessen its cardiac effects.70 Siponimod also has been evaluated in the treatment of SPMS. Results from the phase 3 EXPAND study involving 1651 patients with SPMS, showed that the 2-mg siponimod dose reduced the risk of 3-month confirmed disability progression by 21% vs placebo (HR [95%CI]: 0.79 [0.65-0.95]; P=.013).71 There was a similar overall incidence of treatmentemergent AEs in the siponimod and placebo groups (89% and 82%, respectively).72 Ozanimod Ozanimod is a selective oral modulator of S1P1 and S1P5,53 which is being evaluated in the RADIANCE and SUNBEAM phase 2/3 trials. RADIANCE is a phase 2/3 trial of ozanimod in adults with RRMS. In this 24-week placebo-controlled trial, 258 patients were randomized to receive ozanimod 0.5 or 1 mg, or placebo. The primary efficacy endpoint was the cumulative number of GdE lesions on monthly scans from weeks 12 to 24. Among the secondary measures were cumulative number of new or enlarging T2 lesions from weeks 12 to 24, the number of GdE lesions at week 24, ARR, and the safety and tolerability of ozanimod. Results from this study had a high rate of completion (>96%). RADIANCE met its primary endpoint with an 86% reduction in cumulative number of GdE lesions from weeks 12 to 24 for both doses vs placebo. Secondary endpoints favored ozanimod with 91%

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and 94% reduction in the total number of GdE lesions at week 24 (0.5-mg and 1-mg doses, respectively). The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% and 91%. ARR was reduced by 31% and 53%, respectively, approaching significance for the higher dose.73 Three serious adverse effects unrelated to therapy were reported in the 0.5-mg dose: optic neuritis, somatoform autonomic dysfunction, and uterine cervical squamous metaplasia.

All 3 of these were not related to ozanimod. Among the other adverse reactions were nasopharyngitis, headache, and urinary tract infection (no significant difference in incidence among the treatment groups). Rare elevation in ALT (>3x ULN) was noted in both ozanimod groups (1%-2%). The first-dose effects on cardiac conduction were minimal. Second-degree AV block was seen in less than 3% of both the ozanimod and placebo groups, and 74% of the ozanimod cohort maintained a heart rate higher than 60 BPM within the first 24 hours.73 Updated results from the 96-week blinded extension of RADIANCE were recently reported.62 Patients originally randomized to ozanimod continued their assigned dose (0.5 mg: n=85; 1.0 mg: n=81), and placebo patients were rerandomized (1:1) to ozanimod 0.5 mg (n=41) or 1.0 mg (n=42).

Ninety percent of patients entering the blinded extension completed the week 96 visit; 5 discontinued due to adverse events. Results showed that ozanimod 0.5 mg and 1.0 mg dose-dependently reduced mean (±SD) GdE lesions at weeks 48 (0.4±1.6 and 0.1±0.5) and 96 (0.3±1.3 and 0.1±0.5) and the mean new/enlarging T2 lesions at weeks 48 (1.3±3.7 and 0.7±3.8) and 96 (1.8±4.4 and 0.6±1.2). The 0.5-mg and 1.0-mg groups maintained reductions in unadjusted ARR at weeks 48 (0.26 and 0.15) and 96 (0.30 and 0.19). No evidence of disease activity during years 1 and 2 of the extension was seen in 44% and 39% (0.5 mg) and 62% and 47% (1.0 mg) of patients.

Safety profiles were comparable across groups; 75% had at least 1 adverse event, with 20 serious adverse events (none were ozanimod-related). The most common adverse events were minor infections and headache. With regard to cardiac safety, no first-dose adverse events of bradycardia, second-degree or higher AV block, or macular edema were reported. Elevated ALT occurred in 11 patients (4.4%) and approximately evenly across the doses. RADIANCE researchers concluded that both the 0.5-mg and 1.0-mg doses of ozanimod were efficacious over 2 years based on MRI and clinical measures of RRMS disease activity in patients continuing ozanimod or switching from placebo.

The efficacy, tolerability, and safety of ozanimod prompted ongoing phase 3 studies.74 These are RADIANCE Part B and SUNBEAM, which are randomized, double-blind,

double-dummy studies of ozanimod vs IM IFNβ-1a in RRMS. Patients were randomized (1:1:1) to ozanimod 0.5 mg every day, ozanimod 1 mg every day (with 7-day dose escalation), or IFNβ1a 30 μg weekly. The primary study endpoint is the ARR at 24 months (RADIANCE Part B) and at 12 months (SUNBEAM).

Among the secondary endpoints are number of new/newly enlarging T2-weighted lesions, number of GdE lesions, time to disability progression, brain atrophy, patient-reported outcomes, and safety/tolerability. To date, both RADIANCE Part B and SUNBEAM have completed enrollment, and baseline patient characteristics are outlined in Table 5.75 Early in 2017, the study sponsor reported that the phase 3 RADIANCE trial met its primary endpoint in reducing ARR with ozanimod compared with weekly IFNβ-1a. In addition, in a prespecified pooled analysis of time to confirmed disability progression in both the RADIANCE and SUNBEAM phase 3 trials, a very low rate of disability progression was observed across both doses of ozanimod (0.5 mg and 1 mg) as well as IFNβ-1a, and ozanimod did not reach statistical significance compared to IFNβ-1a. Additionally, both doses of ozanimod demonstrated statistically significant reductions in brain atrophy compared to IFNβ-1a in each phase 3 trial.

The overall safety and tolerability profile was consistent with results from the recently completed phase 3 SUNBEAM RMS trial and previously reported phase 2 trials. Researchers concluded that results from the phase 3 RADIANCE trial confirmed results seen in SUNBEAM and were consistent with the long-term phase 2 RADIANCE trial.76 TABLE 5. RADIANCE Part B and SUNBEAM phase 3 baseline characteristics75 Higher risk of cardiac adverse events

RADIANCE Part B

SUNBEAM

1312

1346

Mean age, years

35.5

35.6

Female, %

67.1

66.4

White, %

98.3

99.6

Mean duration since MS symptom onset, years

5.9

6.4

Mean duration since MS diagnosis, years

3.2

3.2

Mean baseline EDSS scores

2.5

2.6

1.3; 1.8

1.3; 1.7

1.7

1.7

Completed enrollment

Mean number of relapses in past 12 months; 24 months Mean number of GdE lesions

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 39

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TABLE 6.Treatment and access considerations13 Treatment • Initiating treatment with an Food and Drug Administration (FDA)approved DMT is recommended: —— As soon as possible following a diagnosis of RRMS or PPMS, regardless of age —— For individuals with a first clinical event and MRI features consistent with MS, in whom other possible causes have been excluded —— For individuals with progressive MS who continue to demonstrate clinical relapses and/or demonstrate inflammatory activity • Treatment with any given medication should be continued indefinitely unless any of the following occur (in which case an alternative DMT should be considered): —— Suboptimal treatment response as determined by the individual and the treating clinician —— Intolerable side effects —— Inadequate adherence to the treatment regimen —— Availability of a more appropriate treatment option • Movement from one DMT to another should occur only for medically appropriate reasons as determined by the treating clinician and patient.

• When evidence of additional clinical or MRI activity while on treatment suggests a suboptimal response, an alternative regimen (eg, different mechanism of action [MOA]) should be considered to optimize therapeutic benefit.

• The factors affecting choice of therapy at any point in the disease course are complex and most appropriately analyzed and addressed collaboratively by the individual and his or her treating clinician.

Access • Due to significant variability in the MS population, people with MS and treating clinicians require access to the full range of treatment options for several reasons: —— Different MOAs allow for treatment change in the event of a suboptimal response.

—— Potential contraindications limit options for some individuals.

—— Risk tolerance varies among people with MS and their treating clinicians.

—— Route of delivery and side effects may affect adherence and quality of life.

—— Individual differences related to tolerability and adherence may necessitate access to different medications within the same class.

• Individuals’ access to treatment should not be limited by their frequency of relapses, level of disability, or personal characteristics such as age, sex or ethnicity.

• Absence of relapses while on treatment is a characteristic of treatment effectiveness and should not be considered a justification for discontinuation of treatment.

• Treatment should not be withheld to allow for determination of coverage by payers as this puts the patient at risk for recurrent disease activity.

DMT, disease-modifying treatment; FDA, US Food and Drug Administration; MOA, mechanism of action; MRI, magnetic resonance imaging; MS, multiple sclerosis; PPMS, primary progressive MS; RRMS, relapsing-remitting MS.

Two-year data from the blinded extension of RADIANCE, which included both patients continuing ozanimod and those switching from placebo, show that both doses of ozanimod (0.5 mg and 1 mg) demonstrated sustained efficacy at 48 and 96 weeks on MRI and clinical measures of MS disease activity.

Serious adverse effects (AEs), none of which were considered to be related to ozanimod, were reported by 20 patients. The safety profile was consistent with previous studies of ozanimod, with minor infection and headache being the most common AEs. A rise in ALT of 3 times the upper limit of normal occurred in 16 patients, 12 of whom continued to receive the study drug.77 Other agents in development Other S1PR modulators that have been evaluated in RRMS include ceralifimod (ONO-4641), GSK2018682, and amiselimod. Ceralifimod is an oral, selective S1P1 and S1P5 modulator.

In the phase 3 DreaMS trial that was completed in 2012, 407 patients were randomized to 0.05-mg, 0.1-mg, or 0.15-mg ceralifimod, or placebo. The primary endpoint was total number of GdE lesions on monthly scans over 26 weeks.

Results showed promising efficacy on MRI measures (82%, 92%, and 77% fewer GdE lesions for the 0.05-mg, 0.1-mg, and 0.15-mg doses [all P<.0001], respectively); however, it appears that development efforts of this modulator are on hold.54 GSK2018682 is a selective S1P1 receptor modulator with some activity at S1P5. Three phase 1 studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK2018682 in humans. GSK2018682 is tolerated after single oral doses of 0.6 mg to 24 mg, although it appears that the study sponsor will not continue development of this agent.54 Amiselimod is a selective S1PR (subtype not known) modulator, which was tested in a phase 2 dose-finding trial; however, akin to ceralifimod and GSK2018682, development efforts have been discontinued.54 Overall, S1PR modulators’ effects on lymphocyte reduction, development of GdE lesions (which was a primary endpoint across phase 2/3 trials), and ARR are similar to fingolimod.

Selective S1PRs seem to have the advantage of a shorter halflife and more rapid lymphocyte recovery after discontinuation, which might allow for flexibility in retreatment with other agents, aid in washout to treat potential opportunistic infections, and address other treatment-related complications and/ or eliminate the drug in unplanned pregnancy.52,54 Shared decision-making in RRMS

Once MS is diagnosed, the goal should be to initiate and continue treatment with the DMT that is most appropriate to the disease course, values, needs, limitations, and lifestyles of the

40 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

given patient. Treatment selection should be an informed, shared decision between the clinician and the patient. Table 6 highlights key considerations from the MS Coalition for clinicians and patients with regard to treatment initiation and switching.13 Most patients with RRMS want to be informed about their conditions and share in the clinical decision-making process.78 The principles of shared decision-making are effective communication and recognition of patient preferences.

Effective communication is key to patient-centered care as it allows for the opportunity to address other symptoms (eg, depression, fatigue, and impaired cognition) that may impair quality of life. Clinicians should engage patients and caregivers in the discussion of all available treatment options.

Shared decision-making recognizes the importance of patient preferences in treatment decisions to79-81: • Ensure consideration of patient needs, values, and preferences regarding treatment; • Involve patients to the extent they desire; and • Provide balanced, evidence-based, and understandable information.

Many treatment decisions in RRMS are preference sensitive, particularly when it comes to DMTs. As such, shared decision-making factors in patient knowledge, values, and risk tolerance. Patients with MS usually prefer higher efficacy against the risk of adverse events. They may tend to dismiss low-frequency risks with treatments. Shared decision-making acknowledges that values/preferences may differ between the patient and clinician. Clinicians should evaluate not only the risks of DMT but also the natural history of MS.82-84 Shared decision-making helps clinicians counsel patients about symptom management, prognosis, and new and emerging treatments that positively affect the clinical course of the disease, are well tolerated, convenient, and may improve outcomes.

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POSTTEST Expiration date: December 31, 2018

A statement of credit will be issued only upon receipt of a completed preassessment test, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Dec17feature.

CREDITS: 1.00 | Evolving expectations in the management of MS

1. Which of the following statements about relapsing remitting multiple sclerosis (RRMS) is true? a. In the contemporary understanding of MS phenotypes, clinically isolated syndrome (CIS) and primary progressive MS are considered separate phenotypes from RRMS. b. The window of opportunity for disease-modifying therapy (DMT) is typically from the time of a CIS suggestive of MS through the early to middle stages of clinically definite RRMS. c. DMT should be reserved for patients with evidence of disease worsening or progression. d. Meta-analyses of randomized clinical trials in RRMS provide evidence that DMTs are most effective in older patients as compared with younger patients.

2. In current clinical practice, which of the following has been a widely accepted therapeutic goal in RRMS? a. Slowing or prevention of disability worsening/progression and reducing the relapse rate b. Reducing inflammatory lesion activity on imaging c. Achieving minimal evidence of disease activity d. Achieving no evidence of disease activity 3. Which of the following classes of DMT approved for treatment of MS tends to be reserved for patients with more active disease? a. Oral agents b. Injectable non–monoclonal antibodies c. Injectable anthracenedione d. Injectable monoclonal antibodies 4. Which of the following next-line therapies is rarely used in the treatment of MS due the potential for cardiotoxicity and acute leukemia? a. Alemtuzumab c. Natalizumab b. Mitoxantrone d. Rituximab

5. Which of the following statements about sphingosine1-phosphate (S1P) receptor modulators is correct? a. There are 5 different S1P receptor modulator subtypes, which are distributed relatively evenly throughout the body. b. S1P receptor subtypes 1 through 3 are present throughout the body, whereas S1P4 is expressed in lymphoid tissue and S1P5 is expressed in the spleen and oligodendrocytes. c. Fingolimod, which was the first US Food and Drug Administration (FDA)-approved oral agent for the treatment of RRMS, is highly selective for S1P subtype 1 receptors. d. There is no difference in relative S1P receptor modulators selectively among the various approved and investigational S1P receptor modulators.

6. A higher risk of cardiac adverse events has been associated with which of the following approved or investigational S1P receptor modulators? a. Fingolimod c. Siponimod b. Ponesimod d. Ozanimod 7. Treatment selection in MS should be an informed, shared decision between the clinician and the patient. The principles of shared decision-making are meant to: a. Enhance symptom management and increase treatment convenience for the patient b. Minimize any differences in values/preferences between the patient and the clinician c. Promote effective communication and recognition of patient preferences d. Emphasize patient-centricity in treatment selection in situations of clinical certainty

TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/Dec17feature

44 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

ADVERTISEMENT

What Should You Consider

Before Recommending an Over-the-Counter (OTC) Analgesic?

Pain is one of the top reasons patients seek care from a healthcare provider (HCP).1

The right OTC analgesic recommendation matters.

In a survey of US adults,

58% of patients

discussed OTC medications with their physicians.2

Consider a Few Important Factors for Safe and Efficacious Pain Management

1

Assess coexisting medical conditions According to the Centers for Disease Control and Prevention,

133 million Americans have at least one

• 6.2% of US adults are undergoing therapy for ulcers4 • Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), may promote ulcer formation and bleeding5 • Acetaminophen is recommended as an alternative to NSAIDs in patients with gastrointestinal (GI) risks6 More than 26 million people (13%) in the United States have chronic kidney disease (CKD), and most are undiagnosed.

Another 20 million are at increased risk for CKD.7

RENAL

• Acetaminophen is recommended as the analgesic of choice for patients with kidney disease8 • NSAIDs may cause kidney disease if taken long term and may increase the risk of sudden kidney failure8

An estimated 85.6 million US adults (>1 in 3) have ≥1 type of cardiovascular (CV) disease.7

CV

HEPATIC

81% of 2590

US adults surveyed

claimed to have used at least one medication in the prior week.12

chronic illness or disease.3

Some OTC analgesic options may exacerbate the risk of adverse events in patients with certain coexisting medical conditions.

GI

2

Assess concomitant medications

• 18.7% of US adults are undergoing therapy for hypertension4 • NSAIDs may increase blood pressure9 • Acetaminophen and aspirin are both recommended as the least risky pain medications for patients with CV risks9; however, any existing GI and renal concerns should also be considered • Although most people take acetaminophen appropriately,10 exceeding the recommended dose of acetaminophen poses a risk of liver damage11

OTC Analgesic Concomitant Medication Risk NSAID

• May cause GI bleeding when taken with anticoagulants6 • May cause GI bleeding when taken with steroids6 • May cause GI bleeding when taken with other NSAIDs6 • May interact with and decrease the efficacy of certain antihypertensive agents9

Acetaminophen

• May increase hepatic risk when taken with other acetaminophen-containing products

Ibuprofen

• May decrease the benefit of low-dose aspirin heart therapy9

3

Ensure patient understanding In a survey of pharmacy customers,

53.2%

were not aware of potential interactions between their prescription and OTC medications.13 It is important to help your patients understand all factors involved in making a safe and appropriate OTC analgesic choice.

They need to know that your recommendations for an OTC analgesic are influenced by their coexisting medical conditions as well as current prescription and OTC medications. Each recommendation should be specific to a unique patient profile.

GetReliefResponsibly.com has more information for HCPs and patients.

References: 1. Prunuske JP, et al. Opioid prescribing patterns for non-malignant chronic pain for rural versus non-rural US adults: a population-based study using 2010 NAMCS data. BMC Health Serv Res. 2014;14:563. 2. Sleath B, et al.

Physician–patient communication about over-the-counter medications. Soc Sci Med. 2001;53(3):357-369. 3. Centers for Disease Control and Prevention. Chronic diseases and health promotion. http://www.cdc.gov/chronicdisease/overview/ index.htm. Updated August 13, 2012. Accessed March 12, 2014. 4. Aitken M, et al. Declining Medicine Use and Costs: For Better or Worse? A Review of the Use of Medicines in the United States in 2012. Parsippany, NJ: IMS Institute for Healthcare Informatics; May 2013. 5. Bhatt DL, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008;118(18):1894-1909. 6. American College of Gastroenterology.

Ulcers and gastrointestinal bleeding: protecting your health: what you should know about the safe and appropriate use of common pain medications. http://s3.gi.org/patients/pdfs/ulcerprotect.pdf. Accessed January 28, 2015. 7. Mozaffarian D, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29-e322. 8. National Kidney Foundation. Pain medicines (analgesics). http://www.kidney.org/atoz/content/painMeds_Analgesics.cfm. Reviewed June 2009. Accessed January 28, 2015. 9. Antman EM, et al; American Heart Association. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12):1634-1642. 10. Kaufman DW, et al. Prevalence and correlates of exceeding the labeled maximum dose of acetaminophen among adults in a U.S.-based internet survey. Pharmacoepidemiol Drug Saf. 2012;21(12):1280-1288. 11. Bower WA, et al. Population-based surveillance for acute liver failure. Am J Gastroenterol. 2007;102(11):24592463. 12. Kaufman DW, et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287(3):337-344. 13. Indermitte J, et al. Prevalence and patient awareness of selected potential drug interactions with self-medication. J Clin Pharm Ther. 2007;32(2):149-159. © Johnson & Johnson Consumer Inc. 2016

Beyond Rx : OTC Corner A S U P P L E M E N T TO T H E C L I N I C A L A DV I S O R

Benefit-to-Risk Ratio of PPI Therapy: A Roundtable Review FACULTY Sharon Dudley-Brown, PhD, FNP-BC, FAAN

Assistant Professor Gastroenterology and Hepatology Division School of Nursing The Johns Hopkins University Baltimore, Maryland Ronnie Fass, MD

Professor of Medicine Case Western Reserve University School of Medicine Cleveland, Ohio Brooke Fidler, PharmD

Associate Professor LIU Pharmacy The Arnold and Marie Schwartz College of Pharmacy and Health Sciences Brooklyn, New York Robert Sheeler, MD

Next Level Concierge Care Fountain Hills, Arizona

Adapted from Dudley-Brown S, Fass R, Fidler B, Sheeler R. Clinical roundtable review: rational counsel on the benefitto-risk ratio of PPI therapy.

Gastroenterol Endosc News.

2017; 68(10).

P

roton pump inhibitors (PPIs) are some of the most commonly prescribed medications for gastrointestinal (GI) diseases, including gastroesophageal reflux disease (GERD) and nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers.1 PPIs are also available over the counter (OTC) for short-term use in managing heartburn experienced twice weekly.2 In controlled trials, PPIs have repeatedly been shown to be safe, with an adverse event (AE) profile typically indistinguishable from placebo.1,3,4 However, a number of large observational studies found associations between their chronic use and a disparate range of clinical risks.5-9 Although these studies did not establish causality, clinicians should weigh the therapeutic benefit of a PPI against the risk of any type of adverse event.

In August 2017, the PPI Roundtable Summit Panel convened to weigh the clinical benefits and risks of PPI therapy.

The panel—consisting of a gastroenterologist, a pharmacist, a nurse practitioner, and a family physician—offered a critical review of the evidence in providing guidance for prescription and OTC indications and provided insight specific to each field on advising colleagues and patients about the role of PPIs in the context of potential risks identified in retrospective observational studies.

46 SUPPORTED BY AN EDUCATIONAL GRANT FROM P&G

Epidemiology of Acid-Related GI Diseases

Acid-related GI symptoms are extremely common, accounting for 8.9 million outpatient visits.10 Heartburn, a manifestation of GERD, is experienced monthly by approximately 40% of US individuals.11 Frequent GERD substantially impairs quality of life,12 but it also can lead to potentially serious complications including stricture and Barrett’s esophagus, a precancerous condition.13 Peptic ulcer disease (PUD) remains common.14 Despite declining rates of Helicobacter pylori infection, a major etiologic factor, NSAIDs and aspirin, which can induce PUD through injury to the gastric mucosa, continue to be used to control inflammatory diseases.1,15 Like GERD, PUD can progress to a serious condition with complications that include perforation and life-threatening upper GI bleeding.16 According to guidelines from the American College of Gastroenterology (ACG), a presumptive diagnosis of GERD can be established on the basis of typical symptoms of heartburn and regurgitation.17 Endoscopy is not required except in patients at risk for complications, such as those with unexplained weight loss or other alarm symptoms.17 In patients with typical symptoms of GERD, about 13% will demonstrate esophagitis, Barrett’s

esophagus, or other visible pathology on endoscopic examination.18 Symptomatic patients with GERD in the absence of esophagitis (non-erosive disease) still benefit from acid suppression therapy through symptom control and improved quality of life.17 Not all patients with a potential diagnosis of GERD present with typical symptoms, a consideration for empirical treatment with therapies that suppress acid. Patients may describe a range of complaints that include dyspepsia, bloating, or other forms of abdominal pain or discomfort. In controlled trials, a proportion of patients with endoscopynegative dyspepsia (non-ulcer dyspepsia) showed symptom improvement with antacid therapies.19 Patients with other functional upper GI disorders defined by symptomatic complaints without visible pathology, such as noncardiac chest pain, also have responded to acid suppression in controlled studies.17,20 Descriptions of heartburn, regurgitation, dyspepsia, bloating, and abdominal discomfort are subjective. The ACG guidelines included a strong recommendation for empirical PPI therapy in the setting of typical GERD symptoms based on the principle that symptom relief identifies an acid-related process.17 In patients with symptoms that include but are not confined to heartburn and regurgitation, it has become common practice to offer an empirical trial of PPI therapy for the same reason.

Acid Suppression: PPI Efficacy and Safety

For healing of esophagitis or peptic ulcers, no class of therapy for acid suppression is more effective than PPIs. In

trials comparing PPIs with H2-receptor antagonists (H2RAs), which were a previous standard for both GERD and PUD, PPIs provided a large gain in healing of both esophagitis and peptic ulcers. In GERD-related esophagitis, the therapeutic gain for PPIs relative to H2RAs was approximately 50% and the rate of both healing (11.7% vs 5.9%) and complete heartburn relief (11.5% vs 6.4%) was nearly doubled.21 Similar relative efficacy has been demonstrated when PPIs were compared with H2RAs for PUD.22 In PUD a­ ssociated

with the tachyphylaxis reported with repeat dosing of H2RA agents.27 The ACG guidelines identify PPIs as the therapy of choice for symptom relief and healing of erosive esophagitis based on a high level of evidence.17 H2RA therapy is acknowledged as an option for GERD without esophagitis if heartburn is relieved, but the reliable control of acid provided with PPIs is the basis for identifying a trial of PPIs as a diagnostic test for GERD. Heartburn relief occurs almost twice as quickly with a PPI than an H2RA agent.21 Antacids, the most

For healing of esophagitis or peptic ulcers, no class of therapy for acid suppression is more effective than PPIs. with H. pylori eradication, combination regimens with PPIs are more effective than those with H2RAs.23 PPIs also are far more effective for preventing peptic ulcers induced by NSAIDs, as well as controlling and preventing upper GI stress ulcers and bleeding.24,25 PPIs are more effective than H2RAs in suppressing gastric acid secretion. H2RA agents block the histamine receptors, which are one of several triggers of gastric acid production taking place in the parietal cell, while PPIs inhibit the acid pump itself.26 By binding irreversibly to these acid pumps, PPIs stop acid production on the final pathway and prevent further acid production until new acid pumps are formed.

Additionally, PPIs are not associated

common therapy used for acid-related symptoms before H2RAs, have no role in treating esophagitis and are not listed as a therapeutic option for GERD in the ACG guidelines.

In OTC labeling for PPIs derived from clinical trials, drugs in this class are indicated for frequent heartburn, defined as 2 or more days per week.2 The drug should be taken once daily in the morning with water 30-60 minutes before the first meal of the day.A course of therapy is defined as 14 days and a 4-month interval is recommended between courses.28 PPI Safety and Tolerability in Controlled Trials

For almost 30 years, PPIs have shown favorable safety and tolerability in trials

SUPPORTED BY AN EDUCATIONAL GRANT FROM P&G 47

Beyond Rx : OTC Corner that include both placebo arms and active H2RA comparative treatment arms,1 with no significant differences in AEs between study arms over study periods 8 to 16 weeks in duration.29,30 Although low rates of nausea, diarrhea, and other self-limited events were reported in the PPI arms of some trials,

exceptions in which patients have been followed on PPIs taken over years.34 In one of these studies, chronic omeprazole therapy was compared with antireflux surgery over a 12-year period.35 In the other, chronic esomeprazole therapy was compared with surgery over a 5-year period.36 In the combined analysis of

reported, a biological gradient that associates greater exposure with more risk, and coherence with experimental data. For example, the most recent observational study testing the association between PPIs and dementia failed to show a relationship, conflicting with data produced by two previous studies but supporting the conclusion of a fourth.37 Placing PPIs Into Context

For almost 30 years, PPIs have shown favorable safety and tolerability in trials that include both placebo arms and active H2RA comparative treatment arms. the rates were generally comparable to those observed with placebo.31 PPIs were not associated with any serious AEs in these studies.

A large body of data showing placebolike tolerability and safety led to the FDA approval of an OTC formulation of omeprazole for the control of heartburn in 2003.32 Safety warnings are restricted to potential drug-drug interactions and allergic reactions.28 Postmarketing safety surveillance continues to support the safety and tolerability of OTC use. In response to observational studies suggesting a potential association between long-term PPI use and altered bone metabolism, a statement issued by the FDA reconfirmed the safety of OTC PPIs when used as directed.33 In patients with chronic acid-related symptoms, long-term or indefinite PPI therapy has been common practice.

Although controlled trials conducted over periods longer than 16 weeks have been uncommon, there are two notable

these studies, which were prospective but not randomized, there was no difference between strategies over the course of follow-up for risk for serious AEs or change in baseline for a variety of laboratory markers, including homocysteine, routine blood tests, and liver enzymes.

Long-Term PPIs: Safety in Observational Studies

As with many pharmaceutical agents, the list of potential but unproven risks in using PPIs is long. For AEs with the strongest biological plausibility, such as diminished absorption of vitamin B12 and other specific nutrients, Clostridium difficile infection, osteoporosis, and chronic kidney disease, the association studies indicate a modest increase that may be concentrated among individuals with other risk factors. For AEs with a more tenuous link to biological plausibility, such as dementia and myocardial infarction, the weaknesses in the evidence prevent meaningful conclusions about risk avoidance. These weaknesses include lack of consistency in data so far

48 SUPPORTED BY AN EDUCATIONAL GRANT FROM P&G

A number of journal articles describe the overuse of PPIs in ambulatory and hospital settings. In one analysis of hospital prescriptions, only 39% were guideline compliant.38 One of the most important consequences of these observational studies associating PPIs with potential risks, may be the impetus for health care providers to ensure that PPIs are being appropriate prescribed and utilized. In response to the observational studies, numerous papers have been published to provide rational guidance for clinical use of PPIs. Most, including two of the most recent, emphasize that PPIs should continue to be used for established indications as confirmed by the PPI Roundtable Summit Panel.27,39 REFERENCES 1. Vanderhoff BT, Tahoub RM. Proton pump inhibitors: an update. Am Fam Physician.

2003;66(2):274-280.

2. Centers for Medicare & Medicaid. Proton pump inhibitors: use in adults. August 2013.

3. Reilly JP. Safety profile of the proton-pump inhibitor. Am J Health Syst Pharm.1999;56(23 suppl 4):S11-S17.

4. McDonagh MS, Carson S, Thakurta S. Drug class review: proton pump inhibitors: final report update 5. Oregon Health & Science University; 2009.

5. Zhou B, Huang Y, Li H, et al. Protonpump inhibitors and risk for fractures: an update metaanalysis. Osteoporos Int. 2016;27(1):339-347.

6. Lazarus B, Chen Y, Wilson FP, et al.

18. Kuipers EJ. Barrett esophagus and life

28. Prilosec OTC [prescribing information].

Proton pump inhibitor use and the risk of

expectancy: implications for screening?

29. Abraham NS. Proton pump inhibi-

chronic kidney disease. JAMA Intern Med.

Gastroenterol Hepatol (NY). 2011;7(10):689-691.

tors: potential adverse effects. Curr Opin

2016;176(2):238-246.

19. Moayyedi P, Delaney BC, Vakil N, et al.

Gastroenterol. 2012;28(6):615-620.

7. Shah NH, LePendu P, Bauer-Mehren A, et

The efficacy of proton pump inhibitors in

30. Simon TJ, Bradstreet DC. Comparative tol-

al. Proton pump inhibitor usage and the risk of

nonulcer dyspepsia: a systematic review

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and economic analysis. Gastroenterology.

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2004;127(5):1329-1337.

31. Thomson AB, Sauve MD, Kassam N,

8. Gomm W, von Holt K, Thome F, et al.

20. Cremonini F, Wise J, Moayyedi P, et

et al. Safety of the long-term use of pro-

Association of proton pump inhibitors with risk

al. Diagnostic and therapeutic use of pro-

ton pump inhibitors. World J Gastroenterol.

of dementia: a pharmacoepidemiological claims

ton pump inhibitors in non-cardiac chest

2010;16(19):2323-2330.

data analysis. JAMA Neurol. 2016;73(4):410-416.

pain: a metaanalysis. Am J Gastroenterol.

32. Department of Health and Human

9. Xie Y, Bowe B, Li T, et al. Risk of death

2005;100(6):1226-1232.

Services. Prilosec OTC Approval Letter. NDA

among users of proton pump inhibitors: a lon-

21. Chiba N, De Gara CJ, Wilkinson JM,

21-229. June 2003.

gitudinal observational cohort study of United

etal. Speed of healing and symptom relief

33. FDA. FDA Drug Safety Communication:

States veterans. BMJ Open. 2017;7(6):e0157735.

in grade II to IV gastroesophageal reflux

possible increased risk of fractures of the hip,

10. Peery AF, Dellon ES, Lund J, et al. Burden

disease: a meta-analysis. Gastroenterology.

writse, and spine with the use of proton pump

of gastrointestinal disease in the United

1997;112(6):1798-1810.

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States: 2012 updated. Gastroenterology.

22. Eriksson S, Langstrom G, Rikner L, et al.

34. Attwood SE, Ell C, Galmiche JP, et al. Long-

2012;143(5):1179-1187.

Omeprazole and H2-receptor antagonists

term safety of proton pump inhibitor therapy

11. Sandler RS, Everhart JE, Donowitz M,

in the acute treatment of duodenal ulcer,

assessed under controlled, randomised clini-

et al. The burden of selected digestive dis-

gastric ulcer and reflux oesophagitis: a

cal trial conditions: data from the SOPRAN

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and LOTUS studies. Aliment Pharmacol Ther.

2002;122:1500-1511.

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2015;41(11):1162-1174.

12. Wiklund I, Carlsson J, Vakil N.

23. Gisbert JP, Khorrami S, Calvet X, et al.

35. Funk LM, Kanji A, Scott Melvin W, et al.

Gastroesophageal reflux symptoms and

Meta-analysis: proton pump inhibitors vs.

Elective antireflux surgery in the US: an analysis

well-being in a random sample of the general

H2-receptor antagonistsâ&#x20AC;&#x201D;their efficacy with

of national trends in utilization and inpatient

population of a Swedish community. Am J

antibiotics in Helicobacter pylori eradication.

outcomes from 2005 to 2010. Surg Endosc.

Gastroenterol. 2016;101(1):18-28.

Aliment Pharmacol Ther. 2003;18(8):757-766.

2014;28(5):1712-1719.

13. Triadafilopoulos G. Proton pump

24. Rostom A, Dube C, Wells G, et al.

36. Muthusamy VR, Lightdale JR, Acosta

inhibitors for Barrettâ&#x20AC;&#x2122;s oesophagus. Gut.

Prevention of NSAID-induced gastro-

RD, et al; ASGE Standards of Practice

2000;46(2):144-146.

duodenal ulcers. Cochrane Database Syst Rev.

Committee. The role of endoscopy in the

14. Lau JY, Sung J, Hill C, et al. Systematic review

2002:CD002296.

management of GERD. Gastrointest Endosc.

of the epidemiology of complicated peptic ulcer

25. Alshamsi F, Belley-Cote E, Cook D, et al.

2015;81(6):1305-1310.

disease: incidence, recurrence, risk factors and

Efficacy and safety of proton pump

37. Goldstein FC, Steenland K, Zhao L, et al.

mortality. Digestion. 2011;84(2):102-113.

inhibitors for stress ulcer prophylaxis in

Proton pump inhibitors and risk of mild

15. Kurata JH, Nogawa AN. Meta-analysis of

critically ill patients: a systematic review and

cognitive impairment and dementia [published

risk factors for peptic ulcer. Nonsteroidal anti-

meta-analysis of randomized trials. Crit Care.

online June 7, 2017]. J Am Geriatr Soc.

inflammatory drugs, Helicobacter pylori, and

2016;20(1):120.

38. Eid SM, Boueiz A, Paranji S, et al. Patterns

smoking. J Clin Gastronterol. 1997;24(1):2-17.

26. Shin JM, Sachs G. Pharmacology of pro-

and predictors of proton pump inhibitor over-

16. Lau JY, Barkun A, Fan DM, et al. Challenges

ton pump inhibitors. Curr Gastroenterol Rep.

use among academic and non-academic hospi-

in the management of acute peptic ulcer bleed-

2008;10(6):528-534.

talists. Intern Med. 2010;49(23):2561-2568.

ing. Lancet. 2013;381(9882):2003-2043.

27. McRorie JW, Kirby JA, Miner PB.

39. Freedberg DE, Kim LS, Yang YX. The risks and

17. Katz PO, Gerson LB, Vela MF. Guidelines

Histamine2-receptor antagonists: rapid

benefits of long-term use of proton pump inhibi-

for the diagnosis and management of gastro-

development of tachyphylaxis with repeat

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2013;108:308-328.

2014;5(2):57-62.

Gastroenterology. 2017;152(4):706-715.

SUPPORTED BY AN EDUCATIONAL GRANT FROM P&G 49

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

YOUR COMMENTS AN INDIVIDUALIZED BREAST CANCER SCREENING STRATEGY FOR WOMEN I am often concerned about articles summarizing screening mammography data. Without fail, organizations that materially benefit most from performing mammography conclude and advocate more frequent and earlier screening mammography. Organizations composed of primary care or with minimal material benefit conclude that a more conservative screening program and more personalization, such as shared decision making, has the greatest net benefit.

The cost alone, from the most aggressive screening design to the most conservative design, is in the billions of dollars. No tradeoff analysis of alternative uses of such cost is entertained.

The article, “Mammography: a review of current guidelines” [November, p. 17], characterizes the review as an effort “to minimize the morbidity and mortality of breast cancer.” The incidence of breast cancer increases with age, 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.

peaking after 50 years of age and waning after 75 years of age. The article uses relative mortality reduction as a metric of effectiveness of screening, yet the incidence in women younger than age 50 overall is low, increasing from 40 to 50 years of age. The use of relative rate reduction of mortality for a 40-year-old woman mischaracterizes the benefit of screening at that age.

Mammography started in the early 1950s with a study from HIP of New York, among others. The use of screening mammography increased precipitously during the ensuing decades typical of new technology, often for assumed or wished for benefits. A major industry was born. As happens with most new technologies, finding the optimal use or non-use takes time but almost always perseveres past the optimal benefit point or in some cases full retirement.

I was struck by the poll results with more than 60% of respondents opting for annual mammography starting at age 40 for all women. The profile of the respondents is unknown. If this reflects the opinion of physicians at large, unbiased personalized discussions with patients as to benefits and harms of screening mammography will not ensue. The same can be said for many diagnostics and therapeutics.

I had a conversation with a radiology friend the other day. He specializes in mammography. I asked why on all of the negative screening mammogram reports that I see, the summary of findings includes a statement that the person should return in 1 year for repeat screening mammogram.

OUR CONSULTANTS

Philip R. Cohen, MD,

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

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

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

Abimbola Farinde, PhD, PharmD,

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

50 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

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

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

He mentioned medical-legal reasons, habit, etc, but blurted out “if all physicians followed the USPSTF mammography guidelines, I would go out of business.”

So easy to ramp up, so arduous to ramp down. We owe women an unbiased discussion and most likely multiple discussions over the years about the benefits and harms of screening mammography. This effort requires acquiring the skills and the tools to perform such with excellence. Let us not be lazy and continue doing what we may have done for many years. Propagating annual screening mammography for all is not the answer. Creating individualized screening strategies for all is the answer with periodic review as the science evolves and personal values change.—MICHAEL MONTIJO, MD, MPH, FACP, Nashville (230-1)

MY MOST MEMORABLE PATIENT DEPRESSION SCREENING AFTER A STROKE I had been working as a nurse practitioner (NP) in stroke/ neurology for 3 years when I encountered a patient whom I will never forget. Mr B, aged 67, came to our hospital with acute onset of right-sided weakness and aphasia following a moderately sized left middle cerebral artery stroke.

Mr B’s course was typical of an acute stroke patient, and we proceeded through our workup and evaluation as usual.

Because Mr B’s language center was in the left side of his brain, he had language deficiencies that included profound expressive aphasia. During his stay in our hospital, he worked with our skilled therapy team. It was evident to all of his healthcare providers that he was extremely frustrated with his inability to communicate.

The day before we had scheduled to send him to acute rehab, I entered the room for daily rounds with another NP on our

Debra August King, PhD, PA,

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

Mary Newberry, CNM, MSN,

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

team. Mr B again seemed agitated and frustrated as he tried to communicate his wishes to us. I grabbed my notebook and a dry erase marker, which he was able to grip in his right hand in hopes that he would be able to write his question or request for me. To our surprise he was able to write, but the letters were jumbled, and we set the notebook page aside feeling unsuccessful in our attempt to communicate.

An hour later we were called back to Mr B’s room by his daughter. It turns out that when she was a child, her father had used mirror image writing to communicate with her as a special code. She saw the notebook page from earlier that morning lying on his bedside table and recognized the pattern immediately. We grabbed a mirror and were able to decode the message.

Unfortunately, he had written that he “wanted to die.”

My feeling of elation at having discovered this strange mirror writing from his younger years was immediately overwhelmed by the realization that my patient was very depressed. He had been a very active person before the stroke, and now that he was unable to communicate and unable to walk, he was dreadfully depressed. He wanted to die.

We immediately got neuropsychology in to see him, and he was treated for his depression. He did well in rehab and regained most of his motor function and his ability to communicate through speech. His clinical course in the hospital was unremarkable until the moment we discovered the backward writing, and his depression would likely have gone undetected for weeks longer if we had not been able to decode his cryptic message. I will never forget how strange, exciting, and then profoundly sad the experience was for me as a care provider, and I am much more aggressive in screening patients with stroke for signs of depression through all means possible.—ADRIENNE CLEMENTS, APRN, ACNP-BC, Hartford, Conn. (230-2) n

Claire O’Connell, MPH, PA-C,

an associate professor at the Rutgers University Physician Assistant Program, Piscataway, N.J.

is

Katherine Pereira, DNP, FNP,

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

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 51

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

CASE #2

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.

52 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

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

CASE #2

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 CASE #1

Trachyonychia

Trachyonychia, also known as “20-nail dystrophy,” is an abnormal nail condition characterized by longitudinal ridging, pitting, fragility, thinning, distal notching, and opalescent discoloration that mostly affects children, but can occur in people of all ages.1,2 It can result as a manifestation of other dermatologic conditions or it can be idiopathic. Although determining the exact cause can be challenging, the disorder is mostly self-limited and typically resolves with time.1 Longitudinal striations of the nail can be seen as a normal part of the aging process, appearing as accentuated ridges over the nail surface. However, when nails lose their opalescence and begin thinning, a diagnosis of trachyonychia must be considered. When all of the nails are affected, the condition is referred to as 20-nail dystrophy.2 Trachyonychia is more common in children, often presenting with an insidious onset between the ages of 3 and 12 years, but cases have been reported in patients of all ages.2,3 Associated conditions include alopecia areata, psoriasis, atopic dermatitis, and lichen planus. Alopecia areata has been the most commonly reported associated disease; an estimated 3.65% of patients have trachyonychia.4 Although the prevalence of idiopathic trachyonychia is unknown, it is likely more common than is reported in literature.5

Trachyonychia is more common in children, often presenting with an insidious onset between the ages of 3 and 12 years.

Clinically, trachyonychia is described as having 2 varieties—shiny and opaque— corresponding to mild and severe versions, respectively. The mild type is characterized by shiny nails with superficial longitudinal ridging and diffuse, small pitting. Importantly, the nails retain their luster. In the severe type, nails appear opaque and sandpaper like, with excessive longitudinal ridging caused by fine, paralleloriented superficial striations, and they have hyperkeratotic, irregular cuticles. In both the mild and severe variants,

fingernails are affected more than toenails, and koilonychia is a common finding.3 The range of severity seen in trachyonychia can be attributed to the extent of inflammation that occurs in the nail matrix.1,3 Severe and persistent inflammation results in nails showing diffuse damage and loss of luster, as seen in severe trachyonychia. Conversely, inflammation that is mild and intermittent results in multifocal damage and nails that retain their luster, as seen in milder variants of trachyonychia.

On biopsy, trachyonychia commonly shows generalized spongiosis and inflammatory cells in the nail epithelium.3 This is seen in patients with associated alopecia areata as well as idiopathic trachyonychia. In patients with associated lichen planus or psoriasis, histopathologic changes congruent with the associated disease are seen on nail biopsy, such as psoriasiform changes in patients with trachyonychia.3 Another histopathologic change seen in patients with trachyonychia is nail hypergranulosis. Inflammation and trauma to the nail matrix can result in increased expression of keratin granules in the nails. Although trachyonychia does not cause permanent scarring, hypergranulosis of the nail matrix may remain even after inflammation subsides.3 However, biopsy is generally not advised as the standard procedure for trachyonychia. Although trachyonychia rarely causes permanent nail damage, nail matrix punch and longitudinal nail biopsy can result in trauma and scarring.

In both adult and pediatric cases reported in literature, the majority of patients report improvement over time regardless of treatment.6,7 Differential diagnoses for trachyonychia include fungal infections, psoriasis, brittle nails, senile nails, lichen planus, psoriasis, eczematous nail changes, and nail changes of alopecia areata.1,8 Eczema and fungal infections rarely cause observable disease in all the nails simultaneously.

Brittle nails lack the pronounced ridging and roughness observed in trachyonychia.1 Senile nails may show mild longitudinal ridging, but lack diffuse involvement of the entire nail plate.8 Similar superficial, geometric pitting can be seen in both alopecia areata and the shiny variant of trachyonychia.3 In lichen planus, nails can also have pitting and longitudinal streaks, but formation of pterygium is not seen in trachyonychia.9 In psoriasis, observable nail changes include pitting, onycholysis, salmon spots, oil spots, splinter hemorrhages, and subungual hyperkeratosis.10 No universally accepted standard treatment exists for trachyonychia. Treatment is mainly cosmetic because it is not a permanently scarring condition; most patients

54 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

show resolution of symptoms regardless of treatment.5,6 Intralesional steroids, topical PUVA, biotin (2.5 mg/d for 6 mo), and 5% 5-fluorouracil cream have been shown to cause improvement in select patient cases in the literature.

In other patient cases, treatment with oral vitamin A and topical steroids under occlusion failed to show any changes in the patientâ&#x20AC;&#x2122;s disease.5 Ultimately, there is not a standardized guideline for the treatment of trachyonychia, and much of the published literature is aimed at targeting the underlying disorder, such as in psoriasis, lichen planus, and alopecia areata. Aside from treating an associated underlying condition, most cases are not treated and spontaneously resolve.

The patient in this case was diagnosed with trachyonychia of the fingernails. Her circular hair loss was diagnosed as alopecia areata and treated with a topical steroid solution.

The patient was advised that no treatment was necessary for her nail findings and that her nails would likely normalize with time. In the meantime, she was advised that she could apply cosmetic nail polish to her nails to assist with cosmesis.

Simo Huang, BS, is a medical student at the Baylor College of Medicine, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine.

References 1. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. St. Louis, MO: Mosby/

CASE #2

Herpes zoster (shingles)

Herpes zoster is one of the two clinical syndromes caused by the Varicella-zoster virus (VZV). Initial infection with VZV will result in varicella (chickenpox), a common pediatric infection that causes a widespread and extremely pruritic rash. After resolution, the VZV lays dormant in neural tissue.1-3 Shingles occurs when the virus reactivates in a sensory dorsal root ganglion and travels down the axon toward the skin.3 Patients with shingles can sometimes have a mild prodromal phase with fever, headache, and sensory changes in the dermatome corresponding to the affected ganglion.4,5 Before the appearance of the rash, this neuropathic pain can frequently lead the clinician toward incorrect diagnoses of angina, appendicitis, or early glaucoma.3 The condition usually progresses to the eruptive phase, in which groups of herpetiform vesicles gradually evolve from papules that appear over an erythematous base.3 These lesions can be immensely painful and are characteristically confined to a single dermatome, although it is not uncommon to have adjacent dermatome involvement or scattered lesions in other

Elsevier; 2008.

2. Scheinfeld NS. Trachyonychia: a case report and review of manifestations, associations, and treatments. Cutis. 2003;71:299-302.

3. Tosti A, Bardazzi F, Piraccini BM, Fanti PA. Idiopathic trachyonychia (twenty-nail dystrophy): a pathological study of 23 patients. Br J Dermatol.

1994;131:866-872.

Before the rash appears, shingles pain can frequently lead toward incorrect diagnoses of angina, appendicitis, or early glaucoma.

4. Tosti A, Fanti PA, Morelli R, Bardazzi F. Trachyonychia associated with alopecia areata: a clinical and pathologic study. J Am Acad Dermatol.

1991;25(2 Pt 1):266-270.

5. Tosti A, Piraccini BM, Iorizzo M. Trachyonychia and related disorders: evaluation and treatment plans. Dermatol Ther. 2002;15:121-125.

6. Kumar MG, Ciliberto H, Bayliss SJ. Long-term follow-up of pediatric trachyonychia. Pediatr Dermatol. 2015;32:198-200.

7. Sakata S, Howard A, Tosti A, Sinclair R. Follow up of 12 patients with trachyonychia. Australas J Dermatol. 2006;47:166-168.

8. Singh G, Haneef NS, Uday A. Nail changes and disorders among the elderly. Indian J Dermatol Venereol Leprol. 2005;71:386-392.

9. Nakamura R, Broce AA, Palencia DP, Ortiz NI, Leverone A. Dermatoscopy of nail lichen planus. Int J Dermatol. 2013;52:684-687.

10. Nakamura RC, Costa MC. Dermatoscopic findings in the most frequent onychopathies: descriptive analysis of 500 cases. Int J Dermatol.

2012;51:483-485.

areas of the body. The vesicles can become necrotic, bullous, or hemorrhagic, and eventually become pustular and heal.

The most frequently affected nerves are the thoracic (55%), cranial (20%), and lumbar nerves (15%). Involvement of the ophthalmic division of the trigeminal nerve (lesions on the tip of the nose) can lead to herpes zoster ophthalmicus, which can result in blindness; thus, an emergent ophthalmology referral is indicated.3-7 Although the presentation is classically that of dermatomal herpetiform vesicles, it is important to realize that varying presentations can occur (as in this patient presentation), such as unilateral erythematous plaques (without vesicles). In these nonclassic cases the presence of a prodrome preceding the rash, along with a dermatomal distribution, are instrumental in making the diagnosis.

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ DECEMBER 2017 55

Dermatology Clinic Approximately 95% of adults in the United States are seropositive for VZV infection, and therefore at risk for developing herpes zoster.4 The annual incidence is between 1.5 and 3 cases per 1000 persons, approximating 1 million cases per year in the United States.5 The primary risk factor is age; 66% of all new cases occur in adults older than 50 years. By age 75 years, the annual incidence increases to 10 cases per 1000 persons.7 This increase is partly explained by waning cellular immunity, which keeps varicella in a latent state.8 Accordingly, immunosuppression has been associated with a higher risk of developing herpes zoster. Both corticosteroids and immune-modulating biologic drugs have been shown to increase the risk of developing shingles; HIV-positive patients have an annual incidence of 29.4 cases per 1000.9,10 A herpes zoster diagnosis has also been shown to slightly increase the risk of being diagnosed with cancer within the following year, and herpes zoster is up to 4 times more common in patients with hematologic malignancies.11,12

Approximately 95% of adults in the US are seropositive for VZV infection and are at risk for developing herpes zoster.

With the advent of the varicella vaccination, primary infections have been reduced by approximately 90%, and the live attenuated vaccine has reduced the incidence of herpes zoster in immunized individuals.13 Herpes zoster vaccination is recommended by the Centers for Disease Control and Prevention (Atlanta, GA) for all immunocompetent nonpregnant adults over the age of 60 years, as it has been shown to reduce herpes zoster rates by up to 70%.13 Diagnosis of herpes zoster is relatively straightforward given the characteristic dermatomal rash and associated pain. A thorough differential in this case includes ruling out cellulitis, zosteriform herpes simplex, contact dermatitis (in particular exposure to urushiol from poison ivy), scabies, atopic dermatitis, and pediculosis or other insect bites. If necessary, a Tzanck smear can be useful in helping to rapidly confirm the diagnosis.3 Newer laboratory tests, such as polymerase chain reaction and direct fluorescent antibody testing, offer greater sensitivity and specificity, but are more expensive and take longer to obtain results.14 Biopsy can be performed for atypical lesions, and reveal large “balloon cells” lining the intraepidermal vesicles and cellular inclusions in the cells of the vesicular epithelium.3

Atypical lymphocytes, as well as multinucleated keratinocytes, can also be present.3 Treatment of herpes zoster consists of oral or intravenous antiviral therapy. Treatment within the first 3 days of symptom onset has been shown to lessen the pain and severity of the rash. Acyclovir or its prodrugs are typically used to treat herpes zoster infections.3 Herpes zoster is commonly complicated by postherpetic neuralgia, which can cause the patient significant pain for weeks to months after the resolution of the rash. Persistent herpes zoster pain is typically the same in nature as the pain present during the eruptive phase.3 The quality of the pain is heterogeneous, but can be roughly divided into burning-aching pain, shootinglancing pain, and allodynic or hyperalgesic pain produced by normal stimuli.3 Older individuals have a significantly higher risk for residual pain.13 Approximately 2% of patients under 40 years of age have residual pain 1 month after diagnosis, whereas in individuals aged over 60 and 70 years, these figures are 50% and 75%, respectively.3 The pain tends to recede gradually, but can last several years—although this is uncommon in any age group. Although there are many modalities used to treat the pain, the most widely prescribed medications are topical lidocaine 5% patch, tricyclic antidepressants (eg, nortriptyline), and gabapentin.

Aside from postherpetic neuralgia, herpes zoster includes a wide spectrum of complications, ranging from persistent herpes zoster to potentially fatal pneumonitis and chronic encephalitis.2 Fortunately, most of these complications are rare and occur more commonly in immunocompromised individuals.

After discussing treatment options with our patient, he was treated with a 7-day course of valacyclovir (oral 1000 mg every 8 h). His pain was treated with gabapentin, 100 mg three times daily. His rash gradually resolved over the subsequent 2 weeks and he reported no residual pain after 1 month. ■ Zachary Solomon, BS, is a medical student at the Baylor College of Medicine, David Rizk, BA, is a medical student at the University of South Alabama, and Connie Wang, MD, is a dermatology resident at the Baylor College of Medicine.

References 1. Goh CL, Khoo L. A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic. Int J Dermatol. 1997;36:667-672.

2. Gnann JW Jr. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002;186(suppl 1):S91-S98.

56 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

3. James WD, Berger TG, Elston DM, Neuhaus, DM, eds. Andrew’s Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.

4. Marin M, Meissner HC, Seward JF. Varicella prevention in the United States: a review of successes and challenges. Pediatrics. 2008;122:e744-e751.

5. Gnann JW Jr, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med. 2002;347:340-346.

6. Schmader K. Herpes zoster in older adults. Clin Infect Dis. 2001;32:1481-1486.

7. Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med. 1995;155:1605-1609.

8. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology. 2008;115(2 suppl):S3-S12.

9. Marra F, Lo E, Kalashnikov V, Richardson K. Risk of herpes zoster in individuals on biologics, disease-modifying antirheumatic drugs, and/or corticosteroids for autoimmune diseases: a systematic review and meta-

“You call this a resume? The school you graduated from lost every football and basketball game this year.”

analysis. Open Forum Infect Dis. 2016;3(4):ofw205.

10. Buchbinder SP, Katz MH, Hessol NA, et al. Herpes zoster and human immunodeficiency virus infection. J Infect Dis. 1992;166:1153-1156.

11. Ragozzino MW, Melton LJ 3rd, Kurland LT, Chu CP, Perry HO. Risk of cancer after herpes zoster: a population-based study. N Engl J Med. 1982;307:393-397.

12. Habel LA, Ray GT, Horberg M, et al. The epidemiology of herpes zos13. Oxman MN. Vaccination to prevent herpes zoster and postherpetic neuralgia. Hum Vaccin. 2007;3:64-68.

14. Ozcan A, Senol M, Saglam H, et al. Comparison of the Tzanck test and polymerase chain reaction in the diagnosis of cutaneous herpes simplex and varicella zoster virus infections. Int J Dermatol. 2007;46:1177-1179.

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Top, bottom: © Harley Schwadron, 2017. Middle: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.

ter in patients with invasive cancer. J Clin Oncol. 2009;27(15 suppl):9562.

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Dermatologic Look-Alikes A rash on the upper extremities POOJA REDDY, BA, DAVID RIZK, BA, CONNIE WANG, MD

CASE #1

CASE #2

A 48-year-old man presents with a rash on the upper extremities that has been worsening for 5 months. On examination, the patient has thin erythematous plaques with overlying scale on the upper extremities and dorsal hands. He also has patches of hypopigmentation. On questioning, the patient states that the areas of hypopigmentation correspond with previous sites of the rash. He also complains of low-grade fevers and malaise. Aside from the rash, the patient does not have any other medical problems or any relevant social or family history.

A 62-year-old man presents with an upper body rash that has been worsening during the past 4 to 5 years.

On examination, he has erythematous papules and plaques with overlying silvery, micaceous scale on the extensor surfaces and dorsal hands. The patient decided to seek a diagnosis due to recent nail changes. Physical examination reveals pitting, leukonychia, and oil spots of the fingernails. Aside from the rash, the patient does not have any other medical problems or any relevant social or family history.

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ DECEMBER 2017 59

Dermatologic Look-Alikes CASE #1

Subacute cutaneous lupus erythematous

Cutaneous lupus erythematous (LE) is an autoimmune inf lammatory skin disease that involves characteristic skin lesions.1 Subacute cutaneous lupus erythematosus (SCLE) falls into 1 of 3 subsets of cutaneous lupus; the other 2 are acute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus (CCLE).2-4 SCLE has certain features of both acute and chronic LE. Similar to CCLE, lesions tend to be more persistent, lasting for months, but they typically heal without scarring.2 SCLE is highly photosensitive, with predominant distribution on sun-exposed areas (eg, upper back, shoulders, anterior chest, neck, and extensor part of the upper extremities).3,5 The midface is typically spared, although the sides of the face may be involved.5 Lesions of SCLE have two morphologic varieties: a papulosquamous with psoriasiform appearance and an annular configuration with scale and erythematous borders.2,3,5 Although scarring is not generally associated with SCLE, dyspigmentation, particularly hypopigmentation, is a potential sequela.2,5 It is important to note that 40% to 50% of patients with SCLE may eventually meet 4 or more of the American Rheumatology Association’s criteria for systemic lupus erythematosus (SLE). Thus, patients diagnosed with SCLE are at high risk for developing SLE. Patients who do have underlying SLE also present with systemic symptoms, most commonly arthralgia, malaise, and low-grade fever.5 White women are most commonly affected by SCLE.2,4 These two factors—sex and ethnicity—help clinicians understand the risk factors for the development of SCLE. Sex is the strongest factor affecting risk; affected women outnumber men by a ratio of 3:1.4 Ethnicity is another important risk factor and prevalence differs among the subtypes of cutaneous LE; discoid lupus erythematosus, a subtype of CCLE, is predominant in African Americans and SCLE is predominant in white populations.4 Like many other autoimmune conditions, cutaneous LE is caused by the interplay of genetics and environment.6 Many of the genes responsible for cutaneous LE are involved with the innate immune system, including dendritic cells and neutrophils, as well as adaptive immune cells, including both B and T cells.5,7 Keratinocytes and endothelial cells are also involved in the pathogenesis of cutaneous LE.7 It is

thought that certain triggering factors, ultraviolet radiation being the most significant for SCLE, instigate an inflammatory cascade; this, in turn, manifests as the classical skin lesions of cutaneous LE. Other triggering factors implicated include medications and infections.7 Diagnosis is made by obtaining a relevant clinical history, performing a detailed skin and physical examination, and ordering proper laboratory and serologic tests.1,5 Because many cases of SLE initially present with cutaneous findings, a thorough work-up is indicated. A complete blood count, assessment of liver and kidney function, and an autoantibody profile are appropriate laboratory tests to order for patients presenting with cutaneous LE.1,3 For SCLE, specifically, medication history is of particular importance because, in some instances, lesions of SCLE have appeared in patients receiving certain medications. Hydrochlorothiazide and terbinafine are common culprits, although calcium channel blockers, nonsteroidal anti-inflammatory drugs, griseofulvin, and antihistamines have also been associated with SCLE.2,5 Serologic studies may be of particular significance for SCLE; approximately 70% of patients display the antiRo/Sjögren syndrome-related antigen A antibody.4,5 Skin biopsy reveals epidermal atrophy and superficial inflammatory infiltrate; hyperkeratosis, periadnexal infiltrate, and follicular plugging are not commonly associated with SCLE.5 Several different disease processes may have presentations similar to that of SCLE. As previously stated, there are two morphologic variants of SCLE. Important differential diagnoses to consider for the annular variant are granuloma annulare, tinea corporis, and psoriasis. For the papulosquamous variant, a differential may include psoriasis, erythema annulare centrifugum, and photolichenoid drug eruption.

Granuloma annulare involves erythematous or flesh-colored annular plaques and papules, commonly found on the dorsal hands or feet. Unlike the lesions of SCLE, granuloma annulare lesions do not have scaling. In addition, patients with granuloma annulare are ordinarily asymptomatic and the disease is self-limited.8 Scaly, annular, erythematous plaques or papules with central clearing and pustules are classic presentations of tinea corporis.9 Definitive diagnosis of tinea is made via skin scrapings and preparation with potassium hydroxide.

Microscopic analysis reveals the presence of dermatophytes.5 Psoriasis is characterized by erythematous plaques, usually covered by silvery, white scales.5 In patients with psoriasis, scaling tends to be thicker and has a micaceous appearance, meaning the scales peel in layers. In addition, the distribution of plaques in psoriasis, which are not limited

60 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

by photodistribution, tend to affect classic areas such as the extensor surfaces of the elbows and knees. Nondermatologic manifestations, including involvement of the joints and the nails, are also commonly noted in patients with psoriasis.10 Results of a skin biopsy provide definitive diagnosis.

Erythema annulare centrifugum is characterized by annular patches with erythematous borders, a trailing scale, and central clearing.11 The clinical course of erythema annulare centrifugum is highly variable, ranging from a few weeks to several decades. The histologic features are more specific, characteristically showing a perivascular lymphohistiocytic infiltrate known as “coat-sleeving”; thus, a skin biopsy for definitive diagnosis is warranted.12 As previously mentioned, ultraviolet radiation may act as a triggering factor for SCLE. Thus, sun protection is a vital part of therapy.1,4 The mainstays of pharmacotherapy are topical/intralesional corticosteroids and oral antimalarial therapy (eg, hydroxychloroquine sulfate).1,4,5 Notably, antimalarial therapy takes several weeks before any effects may be appreciated, so bridging with topical or intralesional steroids should be considered.1 Immunosuppressive agents, such as systemic corticosteroids, methotrexate, mycophenolate, and cyclophosphamide, as well as immunomodulators, such as dapsone and thalidomide, are also used for systemic therapy, but are generally reserved for antimalarial-resistant cases.1 The patient in this vignette was diagnosed with SCLE. He was started on topical triamcinolone 0.1% ointment along with hydroxychloroquine, 200 mg twice daily. After several weeks, his lesions began to clear and he is currently doing very well.

CASE #2

Psoriasis

Psoriasis is a chronic and recurrent inflammatory disease that is caused by the interaction of various genetic, environmental, and immunologic factors.

The overall world prevalence of psoriasis is 2% to 4%, although there is significant geographic and ethnic variation.10 Although psoriasis can appear at any age, bimodal peaks at 20 to 30 years and 50 to 60 years of age have been reported. Women tend to have an earlier age of onset, but the natural history of chronicity coupled with intermittent remissions is similar for both sexes.5,13

Diagnosis is based on the typical erythematous plaques of various sizes, usually covered by silvery white scales.5,14,15 A positive Auspitz sign, pinpoint bleeding resulting from the removal of overlying scale, is suggestive of psoriasis.

Notably, the term psoriasis encompasses a number of distinct clinical phenotypes, which include plaque-type, guttate, erythrodermic, pustular, and inverse.5,10 These variants all share three important characteristics: erythema, thickening, and scale.5 The underlying histology, tortuous and elongated vessels close to the skin surface, acanthosis of the epidermis, and hyperkeratosis, reflects these hallmark features.5

Diagnosis of psoriasis is based on the typical erythematous plaques, which are usually covered by silvery white scales.

Plaque-type psoriasis is the most common variant, comprising approximately 90% of affected patients.10,14 It is characterized by sharp borders, erythema, and papulosquamous lesions.5,10 Plaques have a symmetric distribution and occur mainly on the extensor surface of elbows and knees, the scalp, nails, lower back, and umbilical region.10,15 Guttate psoriasis is characterized by multiple, small, widely dispersed papules and plaques that usually occur around the trunk and proximal extremities. The rash has a sudden onset and is often preceded by a bacterial infection of the upper airways, usually streptococcal pharyngitis in children and young adults.10,15 Erythrodermic psoriasis and generalized pustular psoriasis can be life threatening and are characterized by diffuse erythema with or without scaling and a multitude of diffuse, sterile pustules, respectively. The abrupt withdrawal of systemic steroids (or other systemic therapies) has been identified as a possible triggering factor in both presentations.5,10 Inverse psoriasis involves the intertriginous areas and often lacks the classic scale, due to the moistness of these regions.5 Nondermatologic manifestations include psoriatic arthritis and nail changes, both of which are used for clinical diagnosis. Psoriatic arthritis, which is distinguished from rheumatoid arthritis by its asymmetrical joint involvement, occurs in 5% to 30% of patients with cutaneous psoriasis5,15; 80% to 90% of patients with psoriasis develop nail disease over their lifetimes. Pitting, oil spots, leukonychia, subungual hyperkeratosis, and onycholysis are manifestations of psoriatic onychodystrophy.15

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Dermatologic Look-Alikes TABLE 1. Characteristics of subacute systemic lupus erythematosus and psoriasis Subacute systemic lupus erythematosus

Psoriasis

Dermatologic presentation

• Two morphologic varieties: scaly annular lesions or scaly papulosquamous plaques • Residual hypopigmentation is a potential sequela

• Typical erythematous, scaly skin lesions, often with additional nail and joint involvement • Several morphologic varieties: plaque-type, guttate, erythrodermic, pustular, and inverse

Associations

• Positive anti-Ro antibodies • May be induced by a variety of medications (particularly hydrochlorothiazide and terbinafine)

• Guttate psoriasis is associated with streptococcal pharyngitis in children and young adults • Several comorbidities may be implicated, including cardiovascular disease, metabolic syndrome, depression, and cancer

Etiology

Complex interplay between genetics and environmental factors, especially ultraviolet light in subacute cutaneous lupus erythematous

Complex interplay between genetics and environmental factors

Characteristic location

• Photosensitive distribution (upper back, shoulders, anterior chest, neck, and extensor part of upper extremities) • Tends to spare the central face

Plaque-type (the most common subtype) is commonly found on extensor surface of elbows and knees, the scalp, nails, lower back, and umbilical region

Histology

• Epidermal atrophy and superficial inflammatory infiltrate are characteristic • Hyperkeratosis, periadnexal infiltrate, and follicular plugging are uncommon findings

Subtypes share the following histologic findings: elongated and dilated capillaries superficially located, epidermal acanthosis, abnormal keratinization, and inflammatory infiltrate

Diagnosis

• History, biopsy, and physical examination • Relevant laboratory and serologic tests may assist in diagnosis

History and physical examination

Treatment

• Sun protection is vital • Topical and intralesional corticosteroids • Antimalarial therapy

• Topical therapies (glucocorticosteroids, vitamin D derivatives, and topical calcineurin inhibitors) for mild/moderate symptomology • Phototherapy plus systemic therapy (systemic retinoids, cyclosporine, methotrexate, and biologics) for severe cases

Several conditions may mimic psoriasis. Several differential diagnoses to consider include nummular dermatitis, mycosis fungoides, pityriasis rubra pilaris (PRP), SCLE, secondary syphilis, and pustular drug eruption (acute generalized exanthematous pustulosis; AGEP).

Nummular dermatitis is characterized by scaly, pruritic, coin-shaped lesions usually located on the extremities. The scale is much thinner and not as silver-colored as the one found in psoriasis. The Auspitz sign is also not present in nummular dermatitis.16-18 PRP is characterized by islands of normal skin within larger, well-demarcated, reddish-orange plaques with scale.

These islands of sparring are not characteristic of psoriasis.

In addition, PRP and psoriasis are histologically different and biopsy results aid in diagnosis.19 For guttate psoriasis, an important differential diagnosis to consider is secondary syphilis. A history of a primary chancre as well as systemic symptoms, such as malaise, myalgia, flu-like symptoms, and lymphadenopathy, is more suspicious of syphilis. A positive rapid plasma reagin test result confirms the diagnosis.5,20

For generalized pustular psoriasis, an important differential is AGEP, or pustular drug eruption. Clinical presentation may be similar to systemic symptoms such as fever and leukocytosis present in both. Time of onset and drug history may help differentiate AGEP from pustular psoriasis; the former shows a more temporal relationship between the initiation of a drug and the onset of symptoms. AGEP and generalized pustular psoriasis differ histologically; therefore, a skin biopsy may confirm diagnosis.21 Risk factors for psoriasis include a positive family history, trauma, infections, use of certain drugs, smoking, obesity, alcohol use, and psychogenic stress.5,10,22 These factors demonstrate the intricate pathogenesis of the disease, which involves both a genetic predisposition as well as exposure to certain environmental triggers. Though several gene studies have been undertaken, it is still unknown whether keratinocytes (which undergo abnormal proliferation and differentiation in psoriatic lesions) or certain cytokines and cells of the immune system (specifically tumor necrosis factor-α and the interleukin-23/T-helper 17 cell axis) are the initiating cause for the disease.22,23 Regardless of the

62 THE CLINICAL ADVISOR • DECEMBER 2017 • www.ClinicalAdvisor.com

etiology, several therapeutic advances have been made as a result of the current understanding of the disease process.

Treatment for psoriasis is primarily dependent on the severity of the disease as well as patient preference.14 For mild to moderate symptomology and for patients who do not want to be as aggressive with treatment, topical therapies are generally recommended. Such treatments include corticosteroids, vitamin D derivatives, and topical calcineurin inhibitors.5,14 Treatment for severe cases is typically phototherapy in combination with systemic therapy, which includes systemic retinoids, cyclosporine, methotrexate, and biologic agents.5,14 Biologic therapy is increasingly being used in the treatment of moderate to severe psoriasis and in psoriatic arthritis due to rapid clinical response.14 It is important to note that psoriasis, especially severe manifestations, is associated with various comorbidities, including cardiovascular disease, metabolic syndrome, depression, and cancer, and screening for these conditions may also be warranted.5,10 The patient in this vignette was diagnosed with mild plaque-type psoriasis. He was treated with topical triamcinolone ointment. After 1 month, the vast majority of his psoriasis had cleared. n

11. De Marchi S, Cecchin E, De Marchi SU. Erythema annulare centrifugum. Am J Med Sci. 2012;347:414.

12. Patterson JW. Weedon’s Skin Pathology. 4th ed. London, UK: Churchill Livingstone; 2016.

13. Perera GK, Di Meglio P, Nestle FO. Psoriasis. Ann Rev Pathol. 2012;7:385-422.

14. Weigle N, McBane S. Psoriasis. Am Fam Physician. 2013;87:626-633.

15. James WD, Berger TG, Elston DM, Neuhaus, DM, eds. Andrew’s Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.

16. Burgin S. Nummular eczema, lichen simplex chronicus, and prurigo nodularis. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012:182-184.

17. Haldberg, M. Nummular eczema. J Emerg Med. 2012;43:e327-e328.

18. Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol. 2014;70: 205.e1-205.e16 19. Pitman J, Muekusch G. Pityriasis rubra pilaris. Dermatol Nurs. 2005;17:302.

20. Miller AC, Rashid RM, Khachemoune A. Secondary syphilis. J Emerg Med. 2008;35:83-85.

21. Sidoroff A, Dunant A, Viboud C, et al. Risk factor for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-996.

Pooja Reddy, BA, is a medical student at the Baylor College of Medicine, David Rizk, BA, is a medical student at the University of South Alabama, and Connie Wang, MD, is a dermatology resident at the Baylor College of Medicine.

22. Boehncke WH, Schön MP. Psoriasis. Lancet. 2015;386:983-994.

23. Mahajan R, Handa S. Pathophysiology of psoriasis. Indian J Dermatol Venereol Leprol. 2013;79(suppl 7):S1-S9.

References 1. Chang AY, Werth VP. Treatment of cutaneous lupus. Curr Rheumatol Rep. 2011;13:300-307.

2. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy.

6th ed. Philadelphia, PA: Elsevier; 2016.

3. Walling HW, Sontheimer RD. Cutaneous lupus erythematosus: issues in diagnosis and treatment. Am J Clin Dermatol. 2009;10:365-381.

4. Grönhagen CM, Nyberg F. Cutanous lupus erythematosus: an update.

Indian Dermatol Online J. 2014;5:7-13.

5. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. St. Louis, MO: Mosby/ Elsevier; 2008.

6. Kirchhof, MG, Dutz JP. The immunopathology of cutaneous lupus erythematosus. Rheum Dis Clin North Am. 2014;40:455-474. tosus. Arthritis Res Ther. 2015;17:182.

8. Keimig EL. Granuloma annulare. Dermatol Clin. 2015;33:315-329.

9. Degreef H. Clinical forms of dermatophytosis (ringworm infection).

Mycopathologia. 2008;166:257-265.

10. Di Meglio P, Villanova F, Nestle FO. Psoriasis [published online August 1, 2014]. Cold Spring Harb Perspect Med. doi: 10.1101/cshperspect.a015354.

“Those were the good old days leading Santa’s sleigh. Then along came GPS…”

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© Harley Schwadron, 2017.

7. Achtman JC, Werth VP. Pathophysiology of cutaneous lupus erythema-

LEGAL ADVISOR CASE

© SIPHOTOGRAPHY / GETTY IMAGES

Clinicians in a contract dispute Two NPs in practice together end up in court after one loses her license.

ANN W. LATNER, JD

Ms G and Ms B were nurse practitioners (NPs) in their early 40s. They had worked together in the past and had been friends for several years when they went into business together. The two women, with the help of their attorney, formed a limited liability company, HealthWise Medical, to run a medical clinic that would be staffed by the two women, their supervising physician, and other medical professionals. Ms G and Ms B entered into an operating agreement governing HealthWise, which addressed what would happen in case either woman wanted to leave the company.

Specifically, the contract specified that, “Each Member agrees to adhere to the standards of personal and professional conduct and practice established by the profession and the Company. If a Member becomes legally disqualified to render the professional services rendered by the Company or accepts employment that, pursuant to existing law, places restrictions or limitations on his or her continued rendering of professional services, he or she shall withdraw from the Company pursuant to section 5.2 of this Article within a reasonable

One partner loses her license after improperly writing prescriptions and abusing controlled substances.

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period, not to exceed ten days, after the event giving rise to the disqualification, and thereby sever all association, employment and financial interest in the Company. If such Member shall fail to voluntarily withdraw, the Company shall take such action as may be required to compel resignation under the same terms.” Section 5.2 specified that in the event that a member is withdrawing from the company, the remaining member shall have one of two options: 1) buy out the withdrawing member’s share; or 2) liquidate the company and distribute the proceeds.

At first, the arrangement seemed to be working out. But as time passed, Ms G began to be concerned about her business partner, Ms B, who had begun to show up for work late and act erratically. One day, Ms G found that her partner had been prescribing controlled substances for a patient of Ms G’s, even though Ms G knew of 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.

no reason why the patient would require such medications.

Ms G suspected that Ms B was using the medications herself.

She confronted Ms B, who did not deny having improperly written prescriptions or having abused controlled substances.

Ms B reassured Ms G that she would contact the state’s Health Professional Recovery Program, which supported substance abuse recovery by health professionals. However, as weeks passed by without Ms B doing anything, Ms G contacted the Health Professional Recovery Program and reported Ms B. During the investigation by the Board of Nursing Disciplinary Committee, Ms B admitted to having written prescriptions for acetaminophen/hydrocodone and lorazepam for a patient, and then diverting and using the drugs. Following the investigation, Ms B’s supervising physician refused to supervise her, and her license was suspended and she could no longer practice.

The relationship between the two partners became toxic. Ms G hoped that Ms B would simply withdraw from the agreement, leaving her in control of the company, but Ms B did not voluntarily withdraw. Thus, Ms G had to hire an attorney and file a lawsuit against Ms B, asking that the trial court expel Ms B from HealthWise and sever her financial interest and employment with the clinic. Ms B filed a counterclaim, alleging defamation—specifically, Ms B alleged that when two of her former patients called HealthWise to schedule an appointment with her, they were told that she was “no longer practicing,” and was “no longer a nurse practitioner.”

The trial court dismissed Ms B’s allegations of defamation, holding that the statements were essentially true and thus not defamatory.

Then the trial court looked into Ms G’s claims seeking to expel Ms B from the agreement. Although the contract had language specifying what would happen if a party became legally disqualified to practice, and the contract specified that the person leaving the partnership would be bought out by the remaining partner, the trial court declined to enforce this. Instead, the court held that “neither the buyout nor the liquidation option provides a logical and just resolution,” and that because Ms B had breached the contract first, she should not be entitled to recover anything.

Ms G breathed a sigh of relief and planned how to keep the clinic going. Ms B appealed the trial court’s decision.

in interpreting a contract is to honor the intent of the parties by enforcing the plain and unambiguous language of the agreement,” wrote the court. “Clear and unambiguous language will be enforced as written.”

The court noted that the plain language of the HealthWise agreement indicated that the parties had contemplated this exact situation—a dispute over whether a member was legally disqualified from practicing—and had provided a contractual remedy—forced withdrawal with one of two options: the remaining member buying out the withdrawing member’s share, or liquidating the company. “Here, the parties contractually established that the remedy for a breach of the withdrawal-for-disqualification clause was to permit HealthWise to enforce the required withdrawal through legal action and to elect the form of compensation to be paid to the withdrawing member,” wrote the court in its decision. “We see no reason to apply an equitable remedy when a contractual remedy is available.”

Protecting yourself

The appeal

Ms G was ultimately forced to buy Ms B out, despite Ms B’s bad actions. Fair? Equitable? No—but a contract existed, and the contract specified exactly what would happen in this particular situation. Courts always seek to honor the original intent of a contract and the language when interpreting it.

If you are contemplating a partnership, or any contract, be sure to read it carefully and understand all the eventualities. If something happens, courts will always look to the language of the contract. Make sure that you have language that is fair and is what you would want. Speak to your lawyer. Try to work through the various possibilities and have contractual solutions.

In this case, Ms G would have been better off if her contract had specified that if a member becomes legally disqualified from practicing based on her own illegal actions, she must withdraw from the company without compensation. That scenario is far different from one partner deciding to leave and the other buying her out.

Language is powerful. Whether it is the language you write in a patient’s chart, or language in your employment contract, or in your partnership agreement, be sure that you understand what it says and that it is an accurate reflection of your intentions. n

On appeal, Ms B argued that she was entitled to compensation for her share of HealthWise based on the operating agreement. The appeals court agreed. “Our primary goal

Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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