COVID-19: Update for NPs and PAs 1 Learning Objectives Describe - - PDF document

COVID-19: Update for NPs and PAs

1 2020 PCE Symposia Series 2

COVID-19: Update for NPs and PAs

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Learning Objectives

• Describe what is currently known about COVID-19 transmission and how

to prevent it

• Assess current COVID-19 diagnostic strategies
• Discuss evolving therapeutic strategies for patients with COVID-19

infection

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US Incidence Rates (6/10/2020)

Johns Hopkins University & Medicine. coronavirus.jhu.edu/us-map. Accessed June 10, 2020.

• US Cases: 1,982,264
• US Deaths: 112,093

Key Concerns

• Transmission
• Diagnosis
• Therapeutics
• Prevention

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US Incidence Rates (6/04/2020) cont’d

Source: Wikimedia Commons. 5

TRANSMISSION

• Why do some infect many and others don’t?

‒ Superspreader events

• Churches, especially with choirs
• Migrant worker dormitories
• Zumba classes
• Nursing homes
• Meatpacking plants
• Ski resorts
• Restaurants
• Hospitals
• Prisons

‒ Tendency for tightly connected >>> outdoor activities

• Remains poorly understood

Clustering is a COVID Puzzle

Kupferschmidt K. Science 2020;368:808-09. 6

TRANSMISSION

• Reproduction number (R0)

‒ SARS-CoV-2 = ~ 3.0 if not socially distancing

• But, some spread lots, others not at all
• Healthy people make droplets when

talking, some >> others ‒ Indoor risk in Japan 19x than

• utdoor risk

‒ People with more social contacts

Clustering is a COVID Puzzle (cont’d)

Kupferschmidt K. Science 2020;368:808-09; Lloyd-Smith JO, et al. Nature 2005; 438:355-359.

• Another factor important (k)

‒ Dispersion factor: how much an infection clusters

• Lower k values = more transmission

comes from fewer people

• SARS-CoV-1  0.16
• MERS-CoV  0.25
• H1N1 1918 influenza  1.0
• SARS-CoV-2 varying estimates

‒ k = 0.1 (10% cases = 80% of spread)

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TRANSMISSION

• Human sneeze or cough

‒ 0.1 to 1000 microns

• Respiratory droplets mostly

‒ 5 to 10 microns ‒ Fall to ground, gravity (larger) or evaporate (smaller)

• Probably some aerosols?

‒ <5.0 microns ‒ May bypass protection by upper airway defenses

• Silent shedders as main drivers? Estimates up to 79%

‒ Infectious up to 6 days before symptoms

Masks Reduce Airborne Transmission

Prather KA et al. Science 10.1126/science.abc6197 (2020). 8

TRANSMISSION

• 6 feet doesn’t account for particles 1 micron
• r smaller

‒ May not be sufficient if indoors with poor circulation

• Uncovered intense coughs  20 ft. or further
• Universal masking as best weapon

‒ Surgical masks reduce transmission

Masks Reduce Airborne Transmission (cont’d)

Prather KA et al. Science 10.1126/science.abc6197 (2020). 9

TRANSMISSION

• Covid-19 Deaths

‒ Fatalities among confirmed coronavirus cases in Hong Kong and Singapore are extremely low

Masks Reduce Airborne Transmission (cont’d)

Prather KA et al. Science 10.1126/science.abc6197 (2020). Note: Data as of May 26, 2020. Sources: Johns Hopkins University, New York City Department of Health and Mental Hygiene, Hong Kong Department of Health.

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TRANSMISSION

• Key questions:

‒ How durable? ‒ Lessons from other coronaviruses

• Respiratory coronaviruses (229E, NL63, OC43, HKU1), ~1 year
• SARS-CoV-1: ~3 to 4 years
• MERS-CoV: 7 to 34 months
• Is reinfection possible?
• Severe COVID-19: China

‒ 285 patients

• ~ 95% developed SARS-CoV-2 IgM antibodies by week 3
• IgG appeared later (sustained immunity?)

What Do We Know About COVID-19 Immunity?

Alshukiari AN et al. Emerg Infect Dis. 2016;22:1113-1115; Long QX et al, Nat Med 2020;10.1038/s41591-020-0897-1. 11

TRANSMISSION

We are far from herd immunity

Popovich N et al. www.nytimes.com/interactive/2020/05/28/upshot/coronavirus-herd-immunity.html. Accessed June 4, 2020. 12

TRANSMISSION

We are far from herd immunity

Popovich N et al. www.nytimes.com/interactive/2020/05/28/upshot/coronavirus-herd-immunity.html. Accessed June 4, 2020.

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• Why rapid and global spread?

‒ Asymptomatic shedding

• Estimates 25% to 79% of infected?
• Role of asymptomatic cases affecting models/forecasts
• Second wave—worries about next respiratory season? High risk events?

‒ Mass gatherings ‒ Schools, Universities

Transmission and Contagiousness

CDC = Centers for Disease Control and Prevention. Redfield R. www.cdc.gov. Accessed June 4, 2020; Fauci A. www.niaid.nih.gov. Accessed June 4, 2020.

TRANSMISSION

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Range of COVID-19 Disease States and Potential Therapeutic Targets

Siddiqi HK, Mehra MR. J Heart Lung Transplant. 2020;39:405-407. ARDS = acute respiratory distress syndrome; CRP = C-reactive protein; IL = interleukin; JAK = Janus kinase; LDH = lactate dehydrogenase; SIRS = systemic inflammatory response syndrome.

DIAGNOSIS

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• Descriptions mostly limited to

hospitalized patients

• Signs, symptoms

‒ Fever (46%-98%) ‒ Cough (46%-82%, usually dry) ‒ Myalgia or fatigue (11%-44%) ‒ Shortness of breath at onset (31%) ‒ Chills

Clinical Presentations

• Less common symptoms

‒ Pharyngitis ‒ Loss of taste/smell ‒ Headache ‒ Productive cough ‒ GI symptoms

• May be heralding

‒ Hemoptysis – Leukopenia in ~70% hospitalized patients – LDH often elevated

Chan JF, et al. Lancet. 2020;395:514-523; Huang C, et al. Lancet. 2020;395:497-506; Wang D, et al. JAMA. 2020; [Epub ahead of print]; Zhu N, et al. N Engl J Med. 2020;382:727-733.

DIAGNOSIS

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• Increasing testing capacity, but still

limited in many places

• Issues with sensitivity of NP swabs

‒ 75% to 85%?

• Need for additional
• High clinical suspicion

? need for test

• Is (+) later in course reflective of

infectiousness?

• Lower vs upper samples

Diagnostics

• Rapid molecular diagnostic tests

‒ Cepheid COVID GeneXpert, <45 minutes ‒ Abbott ID Now COVID, <5 min (+), <15 min (–)

NP = nasopharyngeal.

DIAGNOSIS

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• FDA eased approvals, allowing laboratory-developed tests (LDTs)
• Serology: “No IMMUNITY PASSPORT” likely valid at this time

‒ Many tests now available—unclear how well validated; FDA warnings ‒ Tests have not been reviewed by the FDA ‒ Negative results do not rule out COVID-19 infection (molecular needed) ‒ Results from antibody testing should not be used as the sole basis to diagnose or exclude COVID-19 infection ‒ Results from antibody testing should not be used to inform infection status or protective immunity ‒ Positive results may be due to past or present infection with non-SARS-CoV-2 coronavirus strains, such as coronavirus HKU1, NL63, OC43, or 229E

Diagnostics (cont’d)

Food and Drug Administration. www.fda.gov. Accessed May 27 2020; Auwaerter P. Expert Opinion. 2020.

DIAGNOSIS

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Many Investigational Therapeutic and Preventive Approaches

Kupferschmidt K, Cohen J. Science. 2020;367:1412-1413.

THERAPEUTICS

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COVID-19: Update for NPs and PAs

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19 www.microbenotes.com/remdesivir/. Accessed May 27,2020. Image created with biorender.com.

Remdesivir: Potential Repurposed Drug Candidate for COVID-19 THERAPEUTICS

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Remdesivir: Potential Repurposed Drug Candidate for COVID-19

• Added data to reduced length of stay
• RDV patients 31% faster recovery vs placebo

(P <0.001, 11d vs 15 d)

• 14 d (28 d in analysis)
• No virologic data
• Appears safe
• Mechanically ventilated or ECMO patients don’t appear

to benefit

• O2 requiring (largest group) most benefit

ECMO = extracorporeal membrane oxygenation; RDV = remdesivir. Beigel JH, et al. N Engl J Med. May 22. doi: 10.1056/NEJMoa2007764. [Epub ahead of print].

THERAPEUTICS

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Several Vaccines in Development

• 115 candidates
• >90 currently at exploratory or preclinical stages

‒ 10 in human trials

• Most advanced candidates now in clinical

development ‒ mRNA-1273 (Moderna) ‒ Ad5-nCoV (CanSino Biologicals) ‒ INO-4800 (Inovio) ‒ LV-SMENP-DC and pathogen-specific aAPC (Shenzhen Geno-Immune Medical Institute)

• Many others have indicated plans to initiate

human testing in 2020 (eg, J&J, phase 1 testing anticipated Oct. 2020)

COVID-19: Vaccines in Development

Thanh LT, et al. Nat Rev Drug Discov. 2020 [Epub ahead of print].

9 22 2 4 4 8 4 2 5 2 9 7 6 8 2 5 2 2 2 2

10 20 30 40 50 60 Exploratory (confirmed) Exploratory (unconfirmed) Preclinical Phase I Number of Projects Current Stage of Development Live attenuated virus Inactivated Non-replicating viral vector Replicating viral vector Recombinant protein Peptide-based Virus-like particle DNA RNA Unknown

PREVENTION

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Clinical Phase Vaccine Candidates for COVID-19

www.microbenotes.com. Accessed May 27,2020. Image created with biorender.com.

PREVENTION

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Moderna Announces Positive Interim Phase 1 Data for its mRNA Vaccine (mRNA-1273) Against Novel Coronavirus

Moderna Press Release. investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its- mrna-vaccine. Accessed May 27, 2020.

• After 2 doses all participants evaluated to date across the 25g and 100g dose cohorts

seroconverted with binding antibody levels at or above levels seen in convalescent sera

• mRNA-1273:

⎻ Elicited neutralizing antibody titer levels in all 8 initial participants across the 25g and 100g dose cohorts, reaching or exceeding neutralizing antibody titers generally seen in convalescent sera ⎻ Was generally safe and well tolerated ⎻ Provided full protection against viral replication in the lungs in a mouse challenge model

• Anticipated dose for Phase 3 study between 25g and 100g: expected to start in

July 2020

PREVENTION

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PREVENTION

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• BARDA & AstraZeneca

‒ Candidate AZD1222 ‒ Phase 1/Phase 2 underway ‒ Phase 3, summer 2020 start

• 30,000 volunteers
• Partnerships to make 300M doses

‒ Goal to have first vaccine delivery by Oct 2020

• Supporting 14 vaccines  narrowed to 5 (6/4/20)

‒ No partnering with Chinese vaccine efforts ‒ Moderna, Astra Zeneca/Oxford U, JNJ, Merck, Pfizer

Operation Warp Speed

PREVENTION

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• Attenuated adenovirus

‒ Spike glycoprotein insert ‒ Phase 1/Phase 2 in 1112 volunteers

• Started enrollment 4/23/20

‒ Protection from pneumonia in challenge in rhesus macaques

• 5/23/20 Prof. Adrian Hill

‒ “It’s a race against the virus disappearing, and against time…there’s a 50% chance we get no result at all”

AZD1222 aka ChAdOx1 nCoV-19

PREVENTION

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• Speed
• Safety
• Production capacity
• >110 vaccine candidates

‒ How to test that many? ‒ 10 in human trials ‒ 16% (historical average) get to FDA approval

• Durability

Vaccine Big Picture Issues

PREVENTION

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

1 2020 PCE Symposia Series 2

Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Learning Objectives

• Identify available and emerging options for prevention of influenza
• Select influenza treatment for adult patients at high risk of

complications based on current recommendations and evidence

• Individualize influenza treatment in pediatric patients based on

current recommendations

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• Rates of serious illness and death from

seasonal influenza are highest in persons >65 years, in children <2 years, and in anyone with medical conditions at increased risk for complications

• In the 2017-2018 flu season, influenza killed

and hospitalized more people in the US than any other year since 2010

Epidemiology and Burden of Seasonal Influenza in the US

*Data for 2017-2018 and 2018-2019 are preliminary estimates. Centers for Disease Control and Prevention. cdc.gov/flu/about/burden/index.html. Accessed Apr 5, 2020; Centers for Disease Control and Prevention. gis.cdc.gov/GRASP/Fluview/FluHospRates.html. Accessed Apr 5, 2020; Rolfes MA, et al. Influenza Other Respir Viruses. 2018;12:132-137.

Burden of Influenza: Annual Estimates by the CDC From 9 Influenza Seasons (2010-2011 through 2018-2019)*

9.3 to 45 million illnesses caused 140,000 to 810,000 hospitalizations 12,000 to 61,000 deaths 14.2 to 21 million outpatient medical visits

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Influenza-Positive Tests Reported to CDC: National Summary, 2019-2020 Season

Centers for Disease Control and Prevention. cdc.gov/flu/weekly/index.htm. Accessed Apr 5, 2020. 500 1000 1500 2000 2500 3000 3500 4000 2019-40 2019-42 2019-44 2019-46 2019-48 2019-50 2019-52 2020-02 2020-04 2020-06 2020-08 2020-10 2020-12 2020-14 2020-16 2020-18 2020-20 Number of Positive Specimens Week B (Yamagata Lineage) B (Victoria Lineage) B (lineage not performed) A (H3N2) A (H1N1)pmd09 A (subtyping not performed) 5

Number of Specimens Tested and Percent Positive for SARS-CoV-2

SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Centers for Disease Control and Prevention. cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html. Accessed Apr 5, 2020. 1000 2000 3000 4000

2019-40 2019-42 2019-44 2019-46 2019-48 2019-50 2019-52 2020-02 2020-04 2020-06 2020-08 2020-10 2020-12 2020-14 2020-16 2020-18 2020-20

B (Yamagata Lineage) B (Victoria Lineage) B (lineage not performed) A (H3N2) A (H1N1)pmd09 A (subtyping not performed) 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 SARS-CoV-2 6

Outpatient Visits for Influenza-like Illness Reported to CDC: National Summary, 2009-2020

ILI = influenza-like Illness. Centers for Disease Control and Prevention. cdc.gov/flu/weekly/index.htm. Accessed Apr 5, 2020. 1 2 3 4 5 6 7 8 9 40 42 44 46 48 50 52 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 % of Visitors for ILI Week 2018-19 season 2017-18 season 2015-16 season 2014-15 season 2011-12 season 2009-10 season 2019-20 National Baseline 2019-20 season

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Influenza Pandemics

*As of May 18, 2020; COVID-19 = Coronavirus disease 2019. Dawood FS, et al. Lancet Infect Dis. 2012;12:687-695; Johnson NP, et al. Bull Hist Med. 2002;76:105-115; Saunders-Hastings PR, et al. Pathogens. 2016;5:e66; Simonsen L, et al. PLoS Med. 2013;10:e1001558; Taubenberger JK, et al. Emerg Infect Dis. 2006;12:15-22; COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University. coronavirus.jhu.edu/map.html. Accessed May 11, 2020; University of Washington Institute for Health Metrics and Evaluations. www.covid19.healthdata.org Accessed May 22, 2020.

Common Name Year Virus Estimated No. of Deaths (range) Spanish flu 1918 H1N1 50 million-100 million Asian flu 1958 H2N2 1 million-2 million Hong Kong flu 1968 H3N2 500,000-2 million H1N1 pandemic 2009 H1N1 151,700-575,400 COVID-19 pandemic estimate (for comparison to influenza pandemics) COVID-19 2020 SARS-CoV-2 143,357* (by Aug 4, 2020)

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• The family Orthomyxoviridae has 3 genera, or

types, that infect humans: influenza viruses A, B, and C

• Influenza A virus subtypes are based on

specific HA and NA glycoproteins that they express − 18 HAs (H1-H18) − 11 NAs (N1-N11) − Potential for 144 HA and NA combinations (some HAs and NAs cannot work together)

• Birds are reservoir for 16 HA and 9 NA

subtypes

Influenza Virus

HA = hemagglutinin; NA = neuraminidase; NS = nonstructural protein; ss = single stranded. Clancy S. Nature Education. 2008;1:83; Vemula SV, et al. Viruses. 2016;8:96. Hemagglutinin NA NS 2 Lipid bilayer Ion channel Matrix protein Negative-sense ssRNA 9

Case Study: Joanne, a 52-year-old female

• Joanne visits your primary care practice in November for an annual checkup
• She is 5 ft 6 in; 249 lb (BMI = 40.2 kg/m2)
• Her blood pressure is 128/78 mm Hg
• Unvaccinated against influenza and skeptical about the vaccine

⎻ She received the vaccine last year and “got the flu” the day after

• You recommend influenza vaccination, but she refuses

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Focus on Patients at Higher Risk for Influenza Complications

Demographic factors

• Adults aged ≥65 years
• Children <5 years (highest risk in children

<2 years, especially if <6 months)

• Pregnant women (and women up to 2 weeks

postpartum)

• American Indians/Alaska Natives
• Residents of nursing homes and other

long-term care facilities

Centers for Disease Control and Prevention. cdc.gov/flu/highrisk/index.htm. Accessed Apr 5, 2020.

Chronic Medical Conditions

• Asthma
• Neurologic and neurodevelopmental conditions
• Blood disorders (eg, sickle cell disease)
• Chronic lung disease (eg, COPD, cystic fibrosis)
• Diabetes
• Kidney disorders
• Liver disorders
• Morbid obesity (BMI ≥40 kg/m2)
• <19 years and on long-term aspirin- or salicylate-

containing medications

• Compromised immune system or on

immunosuppressive therapies

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Influenza Vaccination: Effective but Underutilized

• Most effective means of preventing seasonal influenza virus infection

– Recommended in all persons ≥6 months in the United States

• 38% to 61% of population gets vaccinated*
• Because of changes in circulating influenza strains, vaccine reformulated every year
• Vaccination can prevent serious illness

⎻ CDC estimates that during the 2018-2019 season, flu vaccine prevented an estimated:

• 4.4 million illnesses
• 2.3 million medical visits; 58,000 hospitalizations
• 35,000 deaths

*Estimated from percentage of patients with acute respiratory illness who were vaccinated for the 2019-2020 flu season. Dawood FS, et al. MMWR Morb Mortal Wkly Rep. 2020;69:177-182. 12

• Vaccination does not guarantee protection
• Interim data for vaccine effectiveness during 2019-2020 flu season (adjusted):

– 55% against influenza B/Victoria – 37% against influenza A(H1N1)pdm09 – 45% overall effectiveness against influenza A and B combined

• Despite overall vaccine effectiveness of 38% in 2017-2018 season, flu vaccine

prevented: ‒ 7.1 million illnesses, 3.7 million medical visits ‒ 109,000 hospitalizations, 8000 deaths

Interim Data for Influenza Vaccine Effectiveness During the 2019-2020 Season

Dawood FS, et al. MMWR Morb Mortal Wkly Rep 2020;69:177-182; Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21. 12

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Manufacturing Process Age Indication Route Formulations IIV4 standard dose Egg based† ≥6 months IM Prefilled syringe, MDV* IIV4 standard dose Cell culture based ≥4 years IM Prefilled syringe, MDV* IIV3 high dose Egg based† ≥65 years IM Prefilled syringe IIV3 standard dose with MF59 adjuvant Egg based† ≥65 years IM Prefilled syringe RIV4 Recombinant HA ≥18 years IM Prefilled syringe LAIV4‡ Egg based† 2 to 49 years Intranasal Single-use intranasal spray

Influenza Vaccines: 2019-2020 Influenza Season

*MDV = multidose vials containing ≤25 ug/0.5 mL thimerosal; †Contraindicated only if history of severe allergic reaction (eg, anaphylaxis) to egg;

‡Precautions in individuals with asthma, or underlying medical conditions that may predispose to complications after wild-type influenza infection;

IIV3 = inactivated influenza vaccine, trivalent; IIV4 = inactivated influenza vaccine, quadrivalent; IM = intramuscular; LAIV4 = Live attenuated influenza vaccine; RIV4 = recombinant influenza vaccine, quadrivalent. Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21. 14

• Vaccine composition:

‒ A/Brisbane/02/2018 (H1N1) pdm09-like virus ‒ A/Kansas/14/2017 (H3N2)-like virus ‒ B/Colorado/06/2017-like virus (B/Victoria/2/87 lineage) ‒ B/Phuket/3073/2013-like virus (B/Yamagata/16/88 lineage) [quadrivalent only]

• Clinicians may administer any licensed, age-appropriate influenza vaccine to all patients

‒ Includes those with egg allergy, except for history suggestive of anaphylaxis

ACIP Guideline Update for 2019-2020 Influenza Season

ACIP = Advisory Committee on Immunization Practices. Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21. 15

Influenza Vaccination in Children Aged 6 Months Through 8 Years

Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21.

Has the child received ≥2 doses of influenza vaccine previously (excluding the current influenza season)? 2 doses of 2019-2020 influenza vaccine (≥4 weeks apart) 1 dose of 2019-2020 influenza vaccine Yes No or don’t know

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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High-dose and MF59-adjuvanted Seasonal Influenza Vaccines in Patients ≥65 Years

RCT = randomized controlled trial. Centers for Disease Control and Prevention. cdc.gov/flu/professionals/acip/2019-2020/acip-table.htm. Accessed Apr 5, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03183908. Accessed Apr 5, 2020; Czaja CA, et al. Open Forum Infec Dis. 2019;6:ofz225; DiazGranados CA, et al. N Engl J Med. 2014;371:635-645; Gravenstein S, et al. Lancet Respir Med. 2017;5:738-746; Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21; Izurieta HS, et al. Lancet Infect Dis. 2015;15:293-300; Lapi F, et al. Expert Rev Vaccines. 2019;18:663-670; Reed C, et al. PLoS

• One. 2015;10:e0118369; Shay DK, et al. J Infect Dis. 2017;215:510-517; Van Buyunder PG, et al. Vaccine. 2013;31:6122-6128.
• Population accounts for up to 90% of seasonal flu-related deaths and 50% to 70% of hospitalizations
• High-dose vs standard-dose vaccine (RCTs and observational studies)

⎻ Higher immunogenic responses ⎻ Improved protection against influenza and related complications

• MF59-adjuvanted vaccine vs nonadjuvanted inactivated influenza vaccine (observational studies)

⎻ Greater vaccine efficacy for lab-confirmed influenza and influenza-related hospitalizations ⎻ Results of RCT comparing immunogenicity of MF59-adjuvanted to high-dose vaccines pending (NCT03183908)

• ACIP recommends no preference for particular vaccine types

⎻ Vaccination should not be delayed if a specific product is not available

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• Classic flu

– Abrupt onset of fever, chills, myalgia, headache, fatigue, nonproductive cough, sore throat, rhinitis – Some people may have GI symptoms (eg, nausea, diarrhea) – Typically resolves within 3 to 7 days – Cough, malaise can persist for >2 weeks

• Mild illness without fever may also occur
• Atypical presentations may occur in elderly,

immunocompromised hosts, infants

Influenza Symptoms and Clinical Course

CF = cystic fibrosis; CV = cardiovascular; MI = myocardial infarction. Centers for Disease Control and Prevention. cdc.gov/flu/symptoms/symptoms.htm. Accessed Apr 5, 2020; Kwong JC, et al. N Engl J Med. 2018;378:345-353; Rolfes MA, et al. Clin Infect Dis. 2018;67:485-492; Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902.

• Complications

– Sinusitis, otitis media – Pneumonia—primary viral or secondary bacterial – Coinfections with other bacterial/viral pathogens – Exacerbation of underlying medical conditions (eg, COPD, asthma, CF, diabetes) – Associations with CV events (eg, MI, stroke), parotitis

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Case Study (cont’d): Joanne

• Joanne returns to your office in early December after sudden onset of

symptoms the previous morning ⎻ Symptoms include fever (101.8°F), chills, body aches, intense headache, extreme fatigue, and cough

• Has missed work yesterday; unable to perform household chores
• Several coworkers have been sick with flu-like illness, and Joanne is concerned

that she may have the flu

• Adult daughter and a grandchild (newborn) will be visiting soon, and she wants

to avoid spreading her illness

• Husband, aged 60 years, has not been vaccinated

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Differential Diagnosis of Allergies, URIs, and Influenza in a Typical Influenza Season

Centers for Disease Control and Prevention. www.cdc.gov/flu.htm. Accessed Apr 5, 2020; National Institutes of Health. newsinhealth.nih.gov/2014/10/cold-flu-or-allergy. Accessed Apr 5, 2020. Symptom Allergy Acute URI (common cold) Influenza Itchy, watery eyes Common Rare; conjunctivitis may occur with adenovirus Soreness behind eyes, sometimes conjunctivitis Nasal discharge Common Very common Common Nasal congestion Common Very common Sometimes Sneezing Very common Very common Uncommon Sore throat Sometimes Very common Sometimes Cough Sometimes Common Very common Headache Sometimes Sometimes Common Fever Never Rare in adults, possible in children Very common Malaise Sometimes Sometimes Very common Fatigue, weakness Sometimes Sometimes Very common Myalgia Never Rare Very common Duration of symptoms Weeks 3 to 14 days 3 to 10 days; several weeks of cough, fatigue 20

Laboratory Diagnostic Methods to Detect Influenza A and B

Test Method Test Time Sensitivity Specificity Rapid molecular assay Nucleic acid amplification 15 to 30 minutes High High RIDT Antigen detection <30 minutes Low/Moderate* High Immunofluorescence assay Antigen detection 1 to 4 hours Moderate High Molecular assays, including RT-PCR Nucleic acid amplification 1 to 8 hours High High Multiplex molecular assays Nucleic acid amplification 1 to 2 hours High High Rapid cell culture (shell vials, cell mixtures) Virus isolation 1 to 3 days High High Viral cell culture Virus isolation 3 to 10 days High High

*Higher sensitivity with analyzer reader device. FDA now requires RIDTs to achieve 80% sensitivity. Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Apr 5, 2020; Uyeki TM, et

• al. Clin Infect Dis. 2019;68:895-902.

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RT-PCR RIDT Diagnostic accuracy  Higher sensitivity  fewer false negatives Specific  Limited false positives Lower sensitivity  more false negatives (newer tests have improved) Specific  Limited false positives Discriminate influenza A subtypes  Yes, if subtype primers used No Time to results ≤30 minutes to several hours  10 to 15 minutes Availability in office setting More expensive and less available  More likely to be available

RT-PCR Versus RIDT: Preferred Tests

✓ = preferred. Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Apr 20, 2020; Merckx J, et al. Ann Intern Med. 2017;167:394-409; Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902.

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Interpreting Influenza Testing Results

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/algorithm-results-circulating.htm. Accessed Apr 5, 2020; Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Apr 5, 2020.

• Initiate antiviral treatment if indicated
• Implement infection prevention and control measures
• Consider additional influenza testing if subtype info is desired
• Use information on local influenza activity (eg, from health

department), patient history and travel, clinical signs/symptoms, and physical examination to decide if treatment is indicated

• Initiate antiviral treatment if flu is suspected and patient is at high

risk for complications or is being admitted to the hospital

• Consider additional diagnostic testing for other pathogens

Cannot rule out flu, especially if test does not have high sensitivity

• r if specimen was

collected >4 days after illness onset Negative result Influenza virus infection likely Positive result (A or B)

23

Confirmed or suspected influenza

• Initiate antiviral treatment as soon as possible for patients who:

⎻ Have severe, complicated, or progressive illness ⎻ Require hospitalization ⎻ Are at higher risk for complications due to age or underlying conditions

• Do not wait for test results in patients who have a serious illness or are
• therwise at high risk
• Consider antiviral treatment for outpatients if treatment can be initiated

within 48 hours of onset without known risk factors for severe illness

When to Treat Influenza: Complicated vs Uncomplicated

Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902. 24

Why Is It Important to Treat Early?

Dobson J, et al. Lancet. 2015;385:1729-1737; Jain S, et al. N Engl J Med. 2009;361:1935-1944; McGeer A, et al. Clin Infec Dis. 2007;45:1568-

• 1575. Muthuri SG, et al. Lancet Respir Med. 2014;2:395-404; Venkatesan S, et al. Clin Infect Dis. 2017;64:1328-1334.
• RCTs show that antiviral treatment within 2 days of illness onset can lessen

symptoms, shorten disease course, and reduce complications and hospitalization risk

• Observational studies indicate that timely antiviral treatment can reduce

complications and hospitalization risk, and decrease mortality in hospitalized patients (up to 4-5 days after symptom onset)

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Influenza Antivirals: Mechanisms of Action

Finberg RW, et al. J Infect Dis. 2019;219:1026-1034; Li TC, et al. Viruses. 2015;7:4929-4944; Noshi T, et al. Antiviral Res. 2018;160:109-117.

Adsorption Packaging and budding Release

Cap snatching (baloxavir, pimodivir) mRNA RNA (+/-)

Endocytosis and fusion Uncoating Receptor containing sialic acid

NA inhibitors (oseltamivir, peramivir, zanamivir) M2 inhibition (adamantanes) Antibodies RNA polymerase inhibition (favipiravir)

26

FDA-approved Antiviral Agents for Influenza

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Apr 28, 2020; Grohskopf LA, et

• al. MMWR Recomm Rep. 2019;68:1-21; Wester A, et al. Infect Drug Resist. 2016;9:201-214
• Neuraminidase inhibitors: oseltamivir, peramivir, zanamivir

– Activity against both influenza A and B viruses – Oseltamivir, zanamivir also used as prophylaxis

• Baloxavir

– Activity against both influenza A and B viruses – Inhibits endonuclease, enzyme required for viral gene transcription

• Adamantanes: amantadine, rimantadine

– Activity against influenza A only – Widespread resistance, not recommended

27

Antivirals for Influenza: Age Indications and Dosage

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Apr 20, 2020; Rapivab [prescribing information]. BioCryst Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018; Tamiflu [prescribing information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019.

Antiviral Dosage Age Indication Route of Administration Precautions Baloxavir Single oral dose

• 40 mg for patients 40 to 80 kg
• 80 mg for patients ≥80 kg

≥12 years Tablets Do not take with:

• Dairy products or calcium-fortified

beverages

• Polyvalent cation-containing

laxatives Oseltamivir Twice daily for 5 days

• 75 mg (≥13 years)
• Weight based (1-12 years)
• 3 mg/kg (2 weeks-1 year)

≥2 weeks Capsule or oral suspension Peramivir Single dose of 600 mg over 15 min ≥2 years Intravenous Zanamivir 10 mg twice daily for 5 days ≥7 years Oral inhalation Do not use in patients with:

• Underlying respiratory disease
• History of milk protein allergy

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Drugs AEs Baloxavir Diarrhea, bronchitis, nausea, sinusitis, headache Postmarketing reports: Swelling of the face, eyelids or tongue; dysphonia; angioedema; anaphylactic reactions, anaphylactic shock, anaphylactoid reactions; rash, urticaria, erythema multiforme; vomiting, bloody diarrhea, melena, colitis; delirium, abnormal behavior, and hallucinations Oseltamivir Nausea, vomiting, headache Postmarketing reports: serious skin reactions; sporadic, transient neuropsychiatric events* Peramivir Diarrhea Postmarketing reports: serious skin reactions; sporadic, transient neuropsychiatric events* Zanamivir Oropharyngeal or facial edema; skin rash; bronchospasm, especially in the setting of underlying airways disease; sinusitis; dizziness; ear, nose, and throat infections Postmarketing reports: sporadic, transient neuropsychiatric events*

Antivirals for Influenza: Adverse Events (AEs)

*Self-injury or delirium; mainly reported among Japanese adolescents and adults; may be due to viral infection itself. Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Apr 20, 2020; Tamiflu [prescribing information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019; Rapivab [prescribing information], BioCryst Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018. 28 29 100 80 60 40 20

• Phase 3 study

‒ 1436 otherwise healthy patients ‒ 12 to 64 years of age ‒ Symptomatic uncomplicated flu

• Time to alleviation of symptoms

‒ Baloxavir group: 53.7 h ‒ Placebo group: 80.2 h (P <.001)

• Baloxavir generally well tolerated

‒ Diarrhea most common adverse event, but less frequent than with placebo

CAPSTONE-1: Time to Alleviation of Symptoms With Baloxavir Marboxil vs Placebo

Hayden FG, et al. N Engl J Med. 2018;379:913-923. Patients Who Did Not Have Symptom Alleviation (%) Hours From Start of Trial Regimen 0 30 60 90 120 150 180 210 240 270 300 330 Baloxavir Placebo + + + + + + + + + + + + + + ++ + + + + + + + + + + + 30

• Phase 3 Study in patients ≥12 years (N = 2184) presenting ≤48 hours of symptom onset and at high risk of influenza

complications (eg, asthma or chronic lung disease, age ≥65 years)

• Primary endpoint: Time to improvement of influenza symptoms in baloxavir vs placebo groups
• Adverse events were similar among groups

CAPSTONE-2: Baloxavir vs Placebo or Oseltamivir in Patients at High Risk for Influenza Complications

*All reported values are medians; **As determined by virus titer. NA = not available; TTIIS = Median time to improvement of influenza symptoms. Ison MG, et al. Abstract LB16, IDSA Week, Oct 6, 2018; Xofluza [prescribing information]. Genentech; 2019; Xofluza [approval letter], October 16,

• 2019. www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210854Orig1s001.pdf. Accessed Apr 13, 2020; ClinicalTrials.gov.

clinicaltrials.gov/ct2/show/NCT02949011. Accessed Apr 5, 2020. Measure* Baloxavir Placebo P Value (Baloxavir vs Placebo) Oseltamivir P Value (Baloxavir vs Oseltamivir) Overall TTIIS 73.2 h 102.3 h <.0001 81.0 h .8347 Influenza A/H3N2 TTIIS 75.4 h 100.4 h .0141 NA NA Influenza B TTIIS 74.6 h 100.6 h .0138 101.6 h .0251 Time to cessation of viral shedding** 48 h 96 h <.0001 96 h <.0001

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Joanne: Case Conclusion

• You prescribe baloxavir for Joanne, advising her not to take it with:

⎻ Dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (eg, calcium, iron, magnesium, selenium, or zinc)

• She feels better within a few days; 12 days later she feels almost completely

better, except for a slight lingering cough

• She’s looking forward to spending time with her daughter and new grandchild

during their upcoming visit

• She has urged her husband and her college-aged children to get vaccinated

and is committed to getting vaccinated herself early in the season each year

32

Case Study: Sarah, an 11-year-old Student

• Usually in excellent health
• Sudden onset of headache, pharyngitis, fever, chills, nasal congestion yesterday;

symptoms worse today and now include dry cough, fatigue, weakness

• Mother reports OTC meds providing limited relief
• Flu prevalent at her school and community
• Height: 5 ft, 4 in; weight: 105 lb (BMI: 18 kg/m2); blood pressure: 118/73 mm Hg
• Temperature: 103.5°F; heart rate: 95 beats/min; respiration rate: 14 breaths/min;

SpO2: 98% on room air

• Lungs: clear to auscultation
• Rapid strep test: negative

33

Case Study: Sarah

• Given Sarah’s symptoms and the fact that flu is currently circulating

in the community, your clinical judgment is that a flu test is: ‒ Not necessary for diagnosis ‒ Would not change your approach to management

• You discuss antiviral treatment options with Sarah and her mother

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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Case Conclusion: Sarah

• You prescribe Sarah oseltamivir, 75 mg twice daily for 5 days, because

it is approved for children of Sarah’s age and has more than 20 years

• f clinical use
• Her symptoms start to resolve over the next few days and by the

weekend she is feeling well enough to travel for her quiz bowl event

• You recommend she get vaccinated early in the next flu season

35

• Phase 3 multicenter in patients 1 to <12 years of age and influenza confirmed by RIDT
• Primary endpoint: Proportion of patients exhibiting AEs or severe AEs for up to day 29
• Patients randomized to baloxavir (single dose; N = 115) or oseltamivir (twice daily for 5 days; N = 58)
• No serious AE, deaths, adverse events of special interest, or new safety signals observed

MINISTONE-2: Baloxavir vs Oseltamivir in Pediatric Patients With Influenza-like Symptoms

*Determined via virus titer. Baker J, et al. OPTIONS X 2019. Abstract 11756; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03629184. Accessed Apr 5, 2020; Roche. www.roche.com/investors/updates/inv-update-2019-07-03.htm. Accessed Apr 5, 2020.

Measure Baloxavir Oseltamivir Patients with at least 1 AE 46.1% 53.4% Median time to cessation of viral shedding* (95% CI) 24.2 h (23.5 to 24.6) 75.8 h (68.9 to 97.8) Median time to alleviation of influenza signs and symptoms (95% CI) 138.1 h (116.6 to 163.2) 150.0 h (115.0 to 165.7)

36

• Phase 3 randomized study assessing post-exposure prophylaxis in unvaccinated household contacts of

influenza-infected patients (influenza confirmed by RIDT)

• Household contacts randomized to single-dose baloxavir vs placebo
• Primary endpoint: Proportion of participants testing positive for influenza (RT-PCR positive, with fever and ≥1

symptom[s]) during 10-day assessment period

• Serious AEs not observed

BLOCKSTONE: Baloxavir Prophylaxis vs Placebo in Subjects Living With Someone With Confirmed Influenza

Ikematsu H, et al. OPTIONS X 2019. Abstract 11718; Roche. www.roche.com/media/releases/med-cor-2019-09-02b.htm. Accessed Apr 5, 2020.

Measure Baloxavir (n = 374) Placebo (n = 375) P Value Subjects developing flu 1.9% 13.6% <.0001 Subjects at high risk of flu-associated complications developing flu 2.2% 15.4% .0435 Children <12 years of age 4.2% 15.5% .0339 Influenza A (H1N1) 1.1% 10.6% .0023 Influenza A (H3N2) 2.8% 17.5% <.0001 Incidence of AEs 22.2% 20.5% —

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Weighing the Options: Prevention and Management of Influenza in Patients at High Risk for Complications

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• Current FDA-approved indication

⎻ Treatment of acute uncomplicated influenza in patients ≥12 years who have been symptomatic for ≤48 hours and who are:

• Otherwise healthy, or
• At high risk for influenza-related complications
• Convenience of single oral dose
• Offers another option if/when viruses become resistant to NA inhibitors
• Quicker reduction of influenza B symptoms than oseltamivir
• Faster clearance of virus than oseltamivir
• CDC does not recommend use of baloxavir in pregnant, breastfeeding mothers, outpatients with

complicated or progressive illness, severely immunosuppressed people, or hospitalized patients because

• f lack of data in these groups

Considerations Regarding Baloxavir

Centers for Disease Control and Prevention. www.cdc.gov/flu/treatment/baloxavir-marboxil.htm. Accessed May 18, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02949011. Accessed Apr 5, 2020; Hayden FG, et al. N Engl J Med. 2018;379:913-923; Ison MG, et al. IDSA Week, Oct 6, 2018. Abstract LB16; Xofluza [prescribing information]. Genentech; 2019. 38

Tell Your Patients to Be Proactive…Get Flu Vaccination, Not the Flu

Oct Nov Dec Jan Feb

Month Cases

Optimal time for vaccination Height of flu season

39

PCE Action Plan

 Beware of potential for influenza complications, especially in higher risk patients  Strongly recommend influenza vaccination for all patients older than 6 months and GET YOURSELF VACCINATED  Confirm influenza using rapid molecular assay if available; RIDT 2nd choice  Consider clinical diagnosis without diagnostic lab testing for patients with signs and symptoms consistent with flu, especially during periods of influenza activity in the community  Initiate antiviral treatment as early as possible and preferably within 2 days to ensure best treatment

• utcomes

 Treat influenza A and B with an NA inhibitor or baloxavir

PCE Promotes Practice Change

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The Continuum of Care in Atopic Dermatitis: Advances in Management

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The Continuum of Care in Atopic Dermatitis: Advances in Management

2

• Apply recommended proactive approaches to the identification and

management of atopic dermatitis (AD)

• Identify treatment strategies for AD that include use of novel therapies as

appropriate

• Implement strategies for long-term management of AD, with a focus on

patient-centered management

Learning Objectives

3

• Affects 11% to 25% of children

‒ Onset most common between 3 and 6 months of age

• 60% develop AD by 1 year, 90% develop by 5 years
• Affects up to 10% of adults

‒ 10% to 30% of pediatric cases persist into adulthood ‒ 1 in 4 adults with AD report adult-onset of symptoms

Clinical Burden of AD

Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351; Ellis CN, et al. Semin Cutan Med Surg. 2012;31(3 Suppl):S18-S22; Kim JP, et al. J Am Acad Dermatol. 2016;75:681-687; Lee HH, et al. J Am Acad Dermatol. 2018;80:1526-1532; Shaw TE, et al. J Invest Dermatol. 2011;131:67-73; Silverberg JI, et al. J Allergy Clin Immunol. 2013;132:1132-1138.

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• Atopic diseases

‒ Asthma ‒ Hay fever/nasal allergies ‒ Food allergies

• Non-atopic diseases

‒ Skin infections ‒ Sleep disturbances ‒ Psychological burden (eg, depression, anxiety, ADHD)

Comorbidities

ADHD = attention deficit hyperactivity disorder. Czarnowicki T, et al. J Allergy Clin Immunol. 2017;139:1723-1734; Dalgard FJ, et al. J Invest Dermatol. 2015;135:984-991; Davidson WF, et al. J Allergy Clin Immunol. 2019;143:894-913; Jeon C, et al. Drmatol Ther (Heidelb). 2017;7:349-364; Legendre L, et al. J Am Acad Dermatol. 2015;72:992; Silverwood R, et al. BMJ. 2018;361:k1786; Strom MA. Br J Dermatol. 2016;175:920-929. 5

AD Is a Chronic, Pruritic, Inflammatory Skin Disease

IgE = immunoglobulin E. Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351; Paravar T. Clin Dermatol. 2018;36:525-532; Yew YW, et al. J Am Acad Dermatol. 2019;80:390-401.

American Academy of Dermatology Diagnostic Criteria Essential Features Important Features Exclusionary Conditions

• Pruritus  Hallmark
• Eczema

− Typical morphology and age-specific patterns − Chronic or relapsing history

• Usually early age of onset
• Atopy

− Personal/family history − IgE reactivity

• Xerosis
• Scabies
• Seborrheic dermatitis
• Contact dermatitis
• Ichthyoses
• Cutaneous T-cell lymphoma
• Psoriasis
• Photosensitivity dermatoses
• Immune deficiency diseases
• Erythroderma of other causes
• Connective tissue diseases

6

Age-Specific Patterns

Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351; Ricci G, et al. Dermatol Reports. 2011;4:e1; Sugerman DT. JAMA. 2014;311:636.

Adults

• Flexural creases
• Dorsum of hands
• Dorsum of feet

Children

• Flexural creases
• Dorsum of hands
• Dorsum of feet
• Cheeks

Infants

• Cheeks, forehead, scalp
• Extensor extremities

(arms, legs)

• Flexural creases

Adolescents

• Face
• Neck
• Palms
• Soles

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Pathogenesis of Atopic Dermatitis: Inside-out and Outside-in

FLG = filaggrin; Th2 = T helper 2; TLR2 = toll-like receptor 2. Huet F, et al. J Dermatol Sci. 2018;89:213-218; Silverberg JI. Dermatol Clin. 2017;35:327-334; Wang D, et al. Am J Clin Dermatol. 2016;17:425-443.

Inside-out Outside-in

IL-4, IL-13, others IL-4, IL-13, others Barrier dysfunction Cutaneous inflammation

Pro-inflammatory environment:

• Promotes IgE production
• ↓ cutaneous antimicrobial

peptides

• Inhibits expression of skin

barrier proteins (eg, FLG)

• Promotes Th2 differentiation

and immune cell recruitment

Inflammation induction Vulnerability to exogenous insults

Defect of the epidermis (↓ TLR2 expression):

• Impaired pathogen

elimination

• Impaired skin barrier

8

Barrier dysfunction

Adaptive Type 2 Immune Defects

TSLP = thymic stromal lymphopoietin. Brunner PM, et al. J Allergy Clin Immunol. 2017;139:S65-S76; Wang D, et al. Am J Clin Dermatol. 2016;17:425-443.

Scratching TSLP B cell IgE Mast cells and basophil degranulation ↑ expression of endothelial adhesion molecules FLG Pruritus IL-13 IL-13 IL-4 IL-31

B cell

9

Cytokine Activation of Th2 Lymphocyte

IL-4R𝛃 = interleukin 4 receptor alpha chain; JAK = Janus kinase; STAT = signal transducer and activator of transcription. Wang D, et al. Am J Clin Dermatol. 2016;17:425-443.

IL-4 IL-4 IL-13 JAK3 JAK1 JAK3 STAT6

IL-4 R𝛃

IL-13 IL-4 IL-4 R𝛃 GATA-3

↑ Transcription of:

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PDE4 Inhibitors Block the Degradative Action of PDE4 on cAMP

AMP = adenosine monophosphate; cAMP = cyclic adenosine monophosphate; PDE4 = phosphodiesterase type 4; PKA = protein kinase A. Brunner PM, et al. J Allergy Clin Immunol. 2017;139:S65-S76; Samrao A, et al. Arch Dermatol. 2012;148:890-897.

PDE4 AMP cAMP PKA

Inhibits proinflammatory cytokine transcription, neutrophil degranulation, chemotaxis, and adhesion to endothelial cells

11

Case Study: Jim, an 8-year-old boy with pruritus

BSA = body surface area.

Chief Complaint

• Severe itchiness that keeps him up at night
• Pruritic, erythematous, eczematous rash affecting face, flexural areas of

neck, chest, palms, flexural areas of knee (30% BSA) History

• AD since infancy
• Symptoms worse, more continuous in past year (flares every 4-6 weeks)
• Seasonal allergy

Social History

• Student, on gymnastics team
• Lives with parents; no pets

12

• At least one of the following features

‒ Involvement of ≥10% BSA ‒ Involvement of areas important for function or highly visible areas (soles, palms, genitals, neck, face) ‒ Significantly reduced QoL (interference with sleep or daily activities)

Definition of Moderate to Severe AD

Actively assess:

• Degree of pruritus
• Effects on sleep
• Impact on daily activities and work/school
• Disease persistence

QoL = quality of life. Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017;5:1519-1531; Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351; Eichenfield LF, et al.

• Pediatrics. 2015;136:554-565.

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AD Severity Assessment

DLQI = Dermatology Life Quality Index; POEM = Patient-oriented Eczema Measure; PO-SCORAD = Patient-oriented SCORAD. Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017;5:1519-1531; Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22; Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351.

Investigator’s Global Assessment Not validated, but a primary endpoint in many clinical trials and simple to document

• 0 = Clear
• 1 = Almost clear
• 2 = Mild
• 3 = Moderate
• 4 = Severe

Validated scoring systems used in clinical trials, but not routinely used in office

• EASI
• DLQI
• POEM
• SCORAD
• PO-SCORAD

14

AD Step-care Management

*Not FDA approved for AD; **FDA approved for AD but not for long-term maintenance. TCI = topical calcineurin inhibitor. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22.

AD Severity Non-lesional Mild Moderate Severe

Basic Management Basic Management Basic Management + Topical Anti-inflammatory Medication Basic Management + Referral to AD Specialist

• Skin care

− Liberal and frequent moisturizer − Warm baths/showers with non-soap cleansers

• Trigger avoidance
• Skin care

− Liberal and frequent moisturizer − Warm baths/showers with non-soap cleansers

• Antiseptics

− Dilute bleach bath up to 2x weekly − Antibiotics for infections

• Trigger avoidance
• Apply to areas of previous flares
• Maintenance TCS

− Low potency 1 to 2x daily (including face) − Medium potency 1 to 2x weekly (except face)

• OR Maintenance TCI (pimecrolimus,

tacrolimus) − 1 to 2x daily − 2 to 3x weekly (not FDA-labeled)

• OR Crisaborole 2% 2x daily
• Dupilumab
• Systemic immunosuppressants

− Cyclosporine* − Methotrexate* − Mycophenolate* − Azathioprine* − Corticosteroids**

• Consider acute treatment

− Wet wrap therapy − Hospitalization

• Phototherapy

15

• Avoid known irritants/triggers

‒ Allergy testing only when history suggests significant concern for allergies

• Warm baths/showers with non-soap cleansers or mild soaps, followed by

moisturizers (including uninvolved skin)

• Bleach baths (5-10 min, 2-3 times weekly) helpful for frequent bacterial infections

‒ Literature: ½ cup 6% bleach in full bathtub of water (40 gallons) or 50 mL in ¼ tub of water for children <12 years old ‒ In practice: ¼ cup 6% bleach in full bathtub of water, and rinse off

Nonpharmacologic Therapy — Foundational Management

Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132; Eichenfield LF, et al. Pediatrics. 2015;136:554-565.

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Nonpharmacologic Therapy — Foundational Management (cont’d)

• Moisturizers (including uninvolved skin)

‒ Apply liberally within 2 to 3 minutes after bathing to improve skin hydration ‒ Reapply liberally throughout the day ‒ May decrease cumulative incidence of AD by 50% at 6 months in infants at high risk for AD (first degree relative with AD, asthma, or allergic rhinitis)

• Ointments are best to seal and decrease evaporation

Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132; Eichenfield LF, et al. Pediatrics. 2015;136:554-565; Huang JT, et al. Pediatrics. 2009;123:e808-e814; Nichol NH. In: Dermatologic Nursing Essentials: A Core Curriculum. 3rd edition. 2016:114-130; Simpson EL, et al. J Allergy Clin Immunol. 2014;134:818-823. 17

• Mainstay of anti-inflammatory therapy for AD in children and adults

‒ Use after lack of response to good skin care and moisturizers alone ‒ Once- or twice-daily application

• Adult fingertip unit (~0.5 g) over affected area equal to 2 adult palms
• Address steroid “phobia”

‒ Determine adherence to adequate TCS prior to systemic therapies

Topical Corticosteroids

Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132. 18

• Short-term or non-continuous chronic treatment of AD, when TCS is ineffective
• r inadvisable (steroid sparing)
• Approved for age ≥2 years
• Inhibit calcineurin-dependent T-cell and mast-cell activation
• Available agents:

‒ Tacrolimus ointment for moderate to severe AD ‒ Pimecrolimus cream for mild to moderate AD

• Adverse effects: stinging/burning, potential risk of secondary infections,

rare cases of malignancy

Topical Calcineurin Inhibitors

Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132.

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• Topical PDE4 inhibitor for mild to moderate AD
• Initially approved by the FDA in 2016 based on results of two randomized,

placebo-controlled, phase 3 trials

• Expanded FDA approval in March 2020 for children aged 3 to <24 months based
• n the phase 4 CrisADe CARE trial
• Most common side effect: burning or stinging at the application site

Crisaborole

CrisADE CARE = Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to <24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22.e12; Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT03356977. Accessed May 28, 2020; Eucrisa [prescribing information]. Pfizer; 2020; Paller AS, et al. J Am Acad Dermatol. 2016;75:494-503.e6. Schlessinger J, et al.Am J Clin

• Dermatol. 2020;21(2):275-284.

20

• Second-line treatment
• Can be used as maintenance therapy in chronic disease
• Requires local access and clinician competence
• Dosing and scheduling of light based on minimal

erythema dose and/or Fitzpatrick skin type

• Clinician-directed home phototherapy possible
• Adverse effects: actinic damage, local erythema and

tenderness, pruritus, burning, stinging

Phototherapy

Sidbury R, et al. J Am Acad Dermatol. 2014;71:327-349. 21

Proactive Management

Eichenfield LF, et al. Pediatrics. 2015;136:554-565; Sidbury R, et al. J Am Acad Dermatol. 2014;71:1218-1233; Wollenberg A, et al. J Eur Acad Dermatol Venereol. 2016;30:729-747.

Proactive Approach (Prevention of Flares)

• Long-term, intermittent anti-inflammatory

therapy to previously affected skin ‒ Continue TCS 1-2 times/week or TCI 2-3 times/week after disease stabilization

• Ongoing emollient therapy of unaffected skin

Reactive Approach

• TCS application to affected

skin only

• Stop or taper once visible

lesions are cleared

z

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Wet Wrap Therapy

Bathe child Pat away excess water; immediately apply TCS to affected area + cream/ointment to non-lesional skin Apply wet layer (thin cotton or cotton-blend pajamas); in infants/small children, first place wet tube socks over hands Apply second (heavier PJs) dry layer; place second layer

• f dry tube socks over hands

Wrap head with warm, wet gauze, only if significantly affected Wrap same area with dry gauze Apply expandable surgical netting to hold wraps in place Make sure patient can see and move properly; comfort child and take steps to avoid chilling Brar K, et al. J Allergy Clin Immunol Pract. 2019;7:1-16; Nicol NH. Am J Nurs. 1987;87:1560-1563; Nicol NH. Immunol Allergy Clin N Am. 2017;37:123-139. Photos used with permission.

A B C D E F G H A B C D E F G H

23

• Do-it-yourself hypoallergenic mask
• Rice paper cut out improves hydration and

medication penetration

• 1. Cut to fit
• 2. Soak in warm water until a gel-like sheet
• 3. Apply over thin layer of emollient or TCS
• 4. Leave on 10 to 15 minutes
• Apply to volar forearm first to assess

tolerability

Rice Paper Facial Wet Wraps

Maarouf M et al. Pediatr Dermatol. 2018;35:748-753. 24

• Adjust to minimal effective dose once response is attained and sustained
• Continue adjunctive therapies
• Avoid systemic corticosteroids if possible

‒ Reserve for acute, severe exacerbations, or as a short-term bridge to

• ther systemic therapy

‒ Rebound flares

Traditional Systemic Immunomodulatory Agents

Sidbury R, et al. J Am Acad Dermatol. 2014;71:327-349.

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Cyclosporine A Azathioprine Methotrexate Mycophenolic Acid Starting dose, children 5 mg/kg/day 50 mg/day 10-15 mg/m2/week MMF: 20-50 mg/kg/day Maintenance dose, children 2.5-3 mg/kg/day 2-3 mg/kg/day ↑ by 2.5-5 mg/week to effective dose. Taper by 2.5 mg/week to lowest effective dose MMF: ↑ daily dose by 500 mg increments every 2 to 4 weeks Starting dose, adults 5 mg/kg/day 50 mg/day 5 mg/week MMF: 1000-2000 mg/day (EC-MPA 1440 mg/day) Maintenance dose, adults 2.5-3 mg/k/day 2-3 mg/kg/day ↑ to 25 mg/week max MMF: 2000 mg/day (EC-MPA 1440 mg/day) Time to symptom relief 2 weeks 8 to 12 weeks 8 to 12 weeks 4 to 12 weeks

Traditional Systemic Immunomodulatory Agents (cont’d)

MMF = mycophenolate mofetil; EC-MPA = enteric-coated mycophenolate sodium. Megna M. Dermatol Ther. 2017;7:1-23; Wollenberg A, et al. J Eur Acad Dermatol Venereol. 2016;30:729-747. 26

Drug Potential Toxicities Cyclosporine Renal impairment, hypertension, headache, tremor, paresthesia, hypertrichosis, gingival hyperplasia, nausea, vomiting, diarrhea, myalgias, hypertriglyceridemia, increased risk of infections and malignancies Azathioprine Bone marrow suppression, increased risk of infections and malignancies, nausea, vomiting, diarrhea, pancreatitis, hepatitis Methotrexate Elevated liver enzymes, cytopenias, interstitial pneumonitis, pulmonary fibrosis, ulcerative stomatitis, nausea, vomiting, diarrhea, fatigue, chills/fever, photosensitivity, alopecia, increased risk of infections and malignancies Mycophenolate mofetil Diarrhea, nausea, vomiting, abdominal cramps, leukopenia, anemia, increased risk of infections, thrombocytopenia, multifocal leukoencephalopathy, hypercholesterolemia, electrolyte abnormalities, peripheral edema, hypertension, increased risk of malignancies

Side Effect Profile of Traditional Systemic Immunomodulatory Agents

Sidbury R, et al. J Am Acad Dermatol. 2014;71:327-349. 27

Case Study (cont’d): Jim’s Therapy Over the Past 2 Years

• Jim is now 10 years old and embarrassed about his appearance
• Pruritus significantly disrupting sleep
• Feels “exhausted” and struggles to keep up with school and gymnastics
• His teacher recommends ADHD evaluation

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Case Study (cont’d): Jim’s Therapy Over the Past 2 Years

• Maintenance TCS

‒ Discontinued: made his face and hands greasy

• Tried topical tacrolimus and crisaborole

‒ Discontinued: intolerable burning and stinging from both agents

• AD became more persistent 1 year ago and cyclosporine A was started

‒ Discontinued: headaches

• Currently using hydrocortisone 2.5% cream (low potency TCS, group 7) for

his face and triamcinolone 0.1% (medium potency TCS, group 4) for his body for AD flares ‒ Dislikes the greasiness, but feels he “has no choice”

29

Unmet Needs in Moderate to Severe AD Management

Silverberg JI, et al. Dermatol Clin. 2017;35:327-334.

• Treating only AD flares is inadequate for frequent flares or persistent

disease with daily symptoms

• Topical therapies

‒ Not effective for severe disease ‒ Impractical for extensive disease ‒ Do not address systemic inflammation

• Systemic immunosuppressants (eg, oral corticosteroids, cyclosporine,

methotrexate, azathioprine) ‒ Poor side effect and tolerability profiles

30

• Fully human monoclonal antibody against IL-4 receptor α subunit: blocks IL-4

and IL-13

• FDA approvals

‒ Adults with moderate to severe AD not adequately controlled by topical therapies (March 2017) ‒ Patients ≥12 years with moderate to severe AD not adequately controlled with topical prescription therapies, with or without TCS (September 2019) ‒ Children age 6 to 11 with moderate to severe AD who have inadequate response to TCS (May 26, 2020)

Dupilumab

Barrett, J. www.drugtopics.com/autoimmune-diseases/fda-approves-dupilumab-atopic-dermatitis-children. Accessed May 26, 2020; Beck LA, et al. N Engl J Med. 2014;371:130-139; Blauvelt A, et al. Lancet. 2017;389:2287-2303;; Dupixent [prescribing information]. Regeneron; 2019; Sanofi US. www.news.sanofi.us/2020-05-26-FDA-approves-Dupixent-R-dupilumab-a. Accessed May 28, 2020; Simpson EL, et al. N Engl J Med. 2016;375:2335-

• 2348. Cork MJ, et al. Br J Dermatol. 2020;182:85-96.

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Dupilumab: Efficacy in Adults — SOLO 1 and SOLO 2

*P <.0001 compared with placebo. Simpson EL, et al. N Engl J Med. 2016;375:2335-2348. 80 60 40 20 80 60 40 20 Patients Achieving Qualifying IGA Score (%) Patients With EASI-75 (%) SOLO 1 SOLO 2 SOLO 1 SOLO 2 Placebo Dupilumab every

• ther week

Dupilumab every week

IGA Score EASI-75 * * * * * * * *

• Subcutaneous dupilumab (300 mg) administered weekly or every other week x 16 weeks
• Primary endpoints: patients (%) achieving IGA 0 (clear) or 1 (almost clear) and ≥2-point improvement from baseline;

patients (%) achieving at least 75% improvement in EASI score from baseline

32

Dupilumab: Efficacy in Adults — LIBERTY AD CHRONOS

*P <.0001 compared with placebo + topical steroids. Blauvelt A, et al. Lancet. 2017;389:2287-2303. 5 10 15 20 25 30 35 40 45 Week 16 Week 52 Patients Achieving Qualifying IGA Score (%)

IGA Score * * * *

10 20 30 40 50 60 70 80 Week 16 Week 52 Patients Achieving EASI-75 (%)

EASI-75 * * * *

• All groups used concomitant topical corticosteroids ± calcineurin inhibitors
• Dupilumab 300 mg subcutaneously every week or every other week, or placebo for 1 year

Placebo Dupilumab every

• ther week

Dupilumab every week

33

SOLO 1 and 2: 16 Weeks (pooled) LIBERTY AD CHRONOS: 52 Weeks With TCS LIBERTY AD CAFE: 16 Weeks With TCS Event, % Placebo (N = 222) Dupilumab Every Other Week (N = 229) Dupilumab Every Week (N = 218) Placebo (N = 315) Dupilumab Every Other Week (N = 110) Dupilumab Every Week (N = 315) Placebo (N = 108) Dupilumab Every Other Week (N = 107) Dupilumab Every Week (N = 110) ≥1 Adverse event (AE) 69 69 68 84 88 83 69 72 69 ≥1 Serious AEs 5 2 2 5 4 3 2 2 2 Injection site reaction 7 12 17 8 15 19 1 4 AD exacerbation 33 13 13 46 18 17 15 8 8 Headache 5 9 7 6 5 8 8 9 9 Conjunctivitis 2 10 7 8 14 19 3 11 7 Nasopharyngitis 9 9 10 19 23 19 17 21 16 Adjudicated skin infection 4 2 2 18 11 8 8 2 4 All infections/infestations 31 31 31 58 57 53 41 46 43

Dupilumab: Safety in Adults

Blauvelt A, et al. Lancet. 2017;389:2287-2303; Bruin-Weller, et al. Br J Dermatol. 2018;178:1083-1101; Thaci D. J Dermatol Sci. 2019;94:266-275. 33

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Dupilumab: Efficacy/Safety in Adolescents 12 to 17 Years

42 37 24 8 5 2 5 10 15 20 25 30 35 40 45 Reached EASI-75 from baseline Peak pruritus numeric rating scale (≥4-point improvement) IGA 0 or 1 Percentage of Patients Dupilumab 200 or 300 mg Q2W (N = 82) Placebo+TCS (n = 61)

* *

• Phase 3 trial in 251

adolescents with moderate to severe AD not adequately controlled with TCS

• Improvement seen as early as

week 4

• Primary EP: IGA 0 (clear) or

IGA 1 (almost clear) with ≥2 point improvement from baseline to week 16

• Safety profile similar to adults

*P<.001 Simpson EL, et al. JAMA Dermatol. 2020;156:44-56. Dupixent [prescribing information]. Bridgewater, NJ and Tarrytown, NY: sanofi-aventis US LLC and Regeneron Pharmaceuticals, Inc; 2020.

*

35

Dupilumab: Efficacy in Pediatric Patients Age 6 to 11 Years

Cork MJ, et al. Br J Dermatol. 2020;182:85-96. Dupixent [prescribing information]. Bridgewater, NJ and Tarrytown, NY: sanofi-aventis US LLC and Regeneron Pharmaceuticals, Inc; 2020. Clinicaltrials.gov. NCT03345914. 75 54 30 28 12 13 75 61 39 26 13 10 10 20 30 40 50 60 70 80 Reached EASI-75 from baseline Peak pruritus numeric rating scale (≥4-point improvement) IGA 0 or 1 Percentage of Patients Dupilumab 300 mg Q4W + TCS (n = 61) Placebo+TCS (n = 61) Dupilumab 200 mg Q2W + TCS (n = 59) Placebo+TCS (n = 62)

• Phase 2A and subsequent phase 3
• pen label extension (N = 367)
• Moderate to severe AD
• Pharmacokinetic profile consistent

with that of adults

• Primary EP: IGA 0 (clear) or IGA 1

(almost clear) at week 16

36

Adverse Reactions (≥5%) Dupilumab 300 mg Q4W + TCS n (%) Placebo + TCS n (%) Dupilumab 100/200 mg Q2W + TCS n (%) Placebo + TCS n (%) Upper respiratory tract infection 9 (15) 5 (8.3) 5 (8.5) 7 (11.7) Injection site reaction 6 (10) 4 (6.7) 8 (13.6) 3 (5) Nasopharyngitis 6 (10) 2 (3.3) 2 (3.4) 6 (10) Conjunctivitis 4 (6.7) 2 (3.3) 5 (8.5) 3 (5) Vomiting 3 (5) 4 (6.7) 4 (6.8) 4 (6.7) Pyrexia 3 (5) 4 (6.7) 1 (1.7) 0 (0)

Dupilumab: Safety in Pediatric Patients Age 6 to 11 Years

36 Cork MJ, et al. Br J Dermatol. 2020;182:85-96. Dupixent [prescribing information]. Bridgewater, NJ and Tarrytown, NY: sanofi-aventis US LLC and Regeneron Pharmaceuticals, Inc; 2020. Clinicaltrials.gov. NCT03345914.

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Nationaleczema.org lists treatments in development by phase and route, and clinical trial opportunities Mechanism Agent Route Status/Phase** Anti–IL-13 mAb Lebrikizumab SC 2 Tralokinumab SC 3 Anti–IL-31 mAb Nemolizumab SC 2 JAK1/2/3 inhibitor Delgocitinib (JTE-052) Topical 3 JAK1/2 inhibitor Baricitinib Oral 3 JAK 1 inhibitor PF-04965842 Oral 3 JAK 1-selective inhibitor Upadacitinib Oral 3

Emerging Options for Moderate to Severe AD

*For agents not yet approved by the FDA, AD severity information is derived from clinical trial population from ClnicalTrials.gov or manufacturer’s announcements; **as of May 20, 2020; mAb = monoclonal antibody. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT03349060?term=B7451012&rank=1. Accessed May 28, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03363854. Accessed May 28, 2020; Guttman-Yassky E, et al. JAMA Dermatol. 2020;156:411-420; Guttman-Yassky E, et al. J Allergy Clin Immunol. 2020;145:877-884; Kabashima K, et al. J Allergy Clin Immunol. 2018;142:1121-1130; Lilly. investor.lilly.com/news- releases/news-release-details/lilly-and-incyte-announce-positive-top-line-results-north. Accessed May 28, 2020; Nakagawa H, et al. J Am Acad

• Dermatol. 2020; 82:823-831.

38

Adherence to Therapies in AD

38 Stalder JF et al. Allergy. 2017;71:1713-1719.

Poor treatment adherence “Treatment failure” Further nonadherence

39

Strategies to Promote Adherence/Shared Decision-Making in AD Management

Bass A, et al. J Clin Med. 2015;4:231-242; Eichenfield LF, et al. Pediatrics. 2015;136:554-565; O’Toole A, et al. J Cutan Med Surg. 2013;17:276-282; Sidbury R, et al. J Am Acad Dermatol. 2014;71:1218-1233; Stalder JF et al. Allergy. 2017;71:1713-1719.

• Take time to listen to the patient and/or caregiver
• Quality of patient-provider relationship
• Shorter time to follow-up/check-in

Trust

• Solicit patient’s preference (eg, greasiness of an ointment)
• Understand the patient’s goals and expectations (eg, less

itching, better sleep, clearer skin, or other issues affecting QoL)

Individualized Treatment

• Treatment options: reduce fears and misconceptions
• Structured education, nurse-led workshops
• Written action plans

Education

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If Itching and Scratching Is Starting: Instead of scratching I can

• Apply moisturizer
• Apply cool compress

and moisturizer

• Pat the itchy skin

I can do something else I like to: ___________________ ___________________ ___________________

Sample Personalized AD Action Plan from National Jewish Health

Adapted from Brar K, et al. J Allergy Clin Immunol Pract. 2019;7:1-16.

Green Zone (doing well; skin is clear)

• Take a bath (or shower) with warm water once a day; soak for 10-15 minutes
• Use a gentle cleanser (labeled “sensitive skin”); avoid scrubbing
• Apply moisturizer at least twice a day
• Avoid triggers and irritants; keep fingernails short

Yellow Zone (mild rash and itching)

• Continue Green Zone care (daily bath and moisturizer)
• Face: Apply ____________ 2 times per day to the red itchy, rash areas
• Body: Apply ____________ 2 times per day to the red itchy, rash areas
• Do not put moisturizer over medicine
• For daytime itching take _________ For nighttime itching take _________
• Also take/do: ______________________________

Red Zone (severe rash and itching)

• Increase baths (2X day max) and moisturizers to 2-3 times a day
• Face: Apply _________ 2 times per day to the red, itchy, rashy areas
• Body: Apply _________ 2 times per day to the red, itchy, rashy areas
• For daytime itching take __________ For nighttime itching take __________
• Also take/do: ______________
• Watch for signs of infection (increase redness, pus-filled bumps or oozing,

cold sores or fever blisters)

• Call your healthcare provider

40

Name: _________________________ Clinician or Clinic: ________________ Clinic Phone: ____________________

41

Case Conclusion

• Since Jim is 10 years old and eligible for dupilumab therapy, he and his

mother elect to begin treatment after discussion with his clinician

• Jim continues to practice foundational hygiene and skin care
• He tolerates the medication without problems and has achieved good

results

• His sleep improves and he is functioning better socially, in school, and on

the gymnastics team

• You suggest that he return for follow-up in 3 to 6 months, or sooner if he

experiences a flare in the “red zone” that doesn’t resolve in 3 to 5 days

42

American Academy of Dermatology Guidance

• Patients already on biologic therapy who have not tested positive or

exhibited signs/symptoms of COVID-19 ‒ Insufficient evidence to recommend discontinuation of biologics

• Patients on biologic therapy who have tested positive for COVID-19

‒ Discontinue or postpone biologic therapy until patient recovers from COVID-19

• Patients being considered for biologic therapy initiation

‒ Assess risk vs benefits in low-risk patients; in high-risk patients consider deferring

Treating AD with Biologics During the COVID-19 Pandemic

American Academy of Dermatology. assets.ctfassets.net/1ny4yoiyrqia/PicgNuD0IpYd9MSOwab47/ 023ce3cf6eb82cb304b4ad4a8ef50d56/Biologics_and_COVID-19.pdf. Accessed May 20, 2020.

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PCE Action Plan

 Reconsider diagnosis of AD if pruritus is absent  Consider the underlying pathophysiology when treating AD  Use a simple scoring system such as IGA when evaluating AD  Optimize nonpharmacologic therapies for AD  Be proactive to prevent AD flares  Use systemic therapies for moderate to severe AD when appropriate  Create a personalized AD action plan for every patient

PCE Promotes Practice Change

43

Improving Glycemic and Cardiorenal Outcomes in T2DM: The Expanding Role of SGLT2 Inhibitors

2020 PCE Symposia Series 2 1

Improving Glycemic and Cardiorenal Outcomes in T2DM: The Expanding Role

• f SGLT2 Inhibitors

2

• Describe evidence supporting use of SGLT2 inhibitors in the setting of

existing cardiovascular disease (CVD), heart failure (HF), or renal disease

• Integrate SGLT2 inhibitors into the treatment plans of patients with type 2

diabetes (T2DM) according to evidence-based guidelines and patient- specific factors

• Implement patient-centered management for patients with T2DM within the

context of current guidelines

Learning Objectives

SGLT2 = sodium-glucose cotransporter 2. 3

• CVD is the leading cause of death among patients with diabetes

‒ Risk highest for individuals with prior history of CVD and with increasingly poorer glycemic control

• ~1/3 of patients with T2DM have comorbid CVD

‒ 68.4% of patients with T2DM are hypertensive ‒ 43.5% have high LDL-C

• Mitigating CVD risk is important to improving long-term outcomes for

patients with T2DM

• Updated guidance from the ADA recommends using treatments that convey

both glycemic and CVD benefits

CVD and T2DM

LDL-C = low-density lipoprotein cholesterol. Centers for Disease Control and Prevention. www.cdc.gov/diabetes/library/features/diabetes-stat-report.html. Accessed June 1, 2020; Einarson TR, et al. Cardiovasc Diabetol. 2018;17:83; Raghavan S, et al. J Am Heart Assoc. 2019;8:e011295.

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Case Study: Diane, a 57-Year-Old With 6-Year History of T2DM

• New patient presenting for annual physical
• Stent placement 2 years ago after hospitalization for ACS
• Physical exam

‒ Height 5 ft 6 in ‒ Weight: 165 lb ‒ BMI: 26.6 kg/m2 ‒ BP: 144/92 mm Hg on ACE inhibitor ‒ No overt retinopathy or neuropathy

ACE = angiotensin-converting enzyme; ACS = acute coronary syndrome. 5

Case Study (cont’d): Diane’s History and Laboratory Values

• Lab Results

‒ FPG: 136 mg/dL ‒ PPG: 196 mg/dL ‒ A1C: 7.8% ‒ LDL-C: 81 mg/dL on statin ‒ Mild renal impairment

• eGFR: 59 mL/min/1.732

‒ Albuminuria present

• A/C ratio = 360 mcg/mg on

spot test

A1C = glycated hemoglobin; A/C = albumin/creatinine; eGFR = estimated glomerular filtration rate; FPG = fasting plasma glucose; PPG = postprandial glucose.

• Current Medications

‒ Metformin 1500 mg/day ‒ Ramipril 10 mg/day ‒ Atorvastatin 80 mg/day ‒ Aspirin 81 mg/day

• Family/Social History

‒ Full-time office manager ‒ Engages in group exercise 3 days per week ‒ Enjoys traveling, visiting grandchildren

6

HF or CKD predominates PREFERABLY: SGLT2i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR is adequate OR If SGLT2i not tolerated or contraindicated or inadequate eGFR, add GLP-1 RA with proven CVD benefit Choose agent with CV safety; Avoid TZD in setting of HF ASCVD predominates PREFERABLY: GLP-1 RA with proven CVD benefit SGLT2i with proven CVD benefit if eGFR is adequate If further intensification required or patient unable to tolerate GLP-1 RA and/or SGLT2i, choose agents with CV safety For all patients: lifestyle modification For most patients: metformin Indicators of high-risk or established ASCVD, HF, or CKD

ADA 2020: Use Agents That Address Patient-Specific Comorbidities

EITHER/OR

CKD = chronic kidney disease; CVOT = cardiovascular outcome trial. Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

If A1C above target If A1C above target

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HF or CKD predominates PREFERABLY: SGLT2i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR is adequate OR If SGLT2i not tolerated or contraindicated or inadequate eGFR, add GLP-1 RA with proven CVD benefit Choose agent with CV safety; Avoid TZD in setting of HF ASCVD predominates PREFERABLY: GLP-1 RA with proven CVD benefit SGLT2i with proven CVD benefit if eGFR is adequate If further intensification required or patient unable to tolerate GLP-1 RA and/or SGLT2i, choose agents with CV safety For all patients: lifestyle modification For most patients: metformin Indicators of high-risk or established ASCVD, HF, or CKD

ADA 2020: Use Agents That Address Patient-Specific Comorbidities

EITHER/OR

CKD = chronic kidney disease; CVOT = cardiovascular outcome trial. Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

If A1C above target If A1C above target

8

Baseline Characteristics of SGLT2 Inhibitor CVOTs

*DAPA-HF enrolled patients with HF with and without T2DM; ~42% of included patients had diabetes at baseline. Cannon CP, et al. Am Heart J. 2018;206:11-23; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 2017;377:644-657; Wiviott SD, et al. N Engl J Med. 2019;380:347-357; Zinman B, et al. N Engl J Med. 2015;373:2117-2128.

Characteristics EMPA-REG Empagliflozin CANVAS & CANVAS-R Canagliflozin CREDENCE Canagliflozin DECLARE-TIMI 58 Dapagliflozin DAPA-HF* Dapagliflozin VERTIS-CV Ertugliflozin N 7020 10,142 4401 17,160 4744 9463 Established ASCVD, % 100 72 50 41 — 100 Renal impairment, % 11 Nephropathy 18 Nephropathy 100 Albuminuric CKD 7 eGFR <60 40.6 eGFR <60 22 CKD Baseline eGFR, mL/min/1.732 74 77 56 85 66 76 Baseline HF, % 11 14 15 10 100 23

9

Outcomes of SGLT2 Inhibitor CVOTs

9 *DAPA-HF enrolled patients with HF with and without T2DM; ~42% of included patients had diabetes at baseline. MACE = major adverse cardiovascular event (composite of CV death, MI, or stroke). Cannon CP, et al. Am Heart J. 2018;206:11-23; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 2017;377:644-657; Percovic V, et al. Lancet Diabetes Endocrinol. 2018;6:691-704; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Radholm K, et al. Circulation. 2018;138:458-468; Wiviott SD, et al. N Engl J Med. 2019;380:347-357; Zinman B, et al. N Engl J Med. 2015;373:2117-2128; Zoler ML. www.medscape.com/viewarticle/929647. Accessed June 1, 2020.

Characteristics EMPA-REG Empagliflozin CANVAS & CANVAS-R Canagliflozin CREDENCE Canagliflozin DECLARE-TIMI 58 Dapagliflozin DAPA-HF* Dapagliflozin VERTIS-CV Ertugliflozin Primary outcome MACE MACE Renal composite MACE + composite HHF or CV death MACE + CV death or HHF

• Est. ASCVD, %

100 72 50 41 — 100 MACE 0.86 (0.74-0.99) 0.86 (0.75-0.97) 0.80 (0.67-0.95) 0.93 (0.84-1.03) NR Noninferior CV death 0.62 (0.49-0.77) 0.87 (0.72-1.06) 0.78 (0.61-1.00) 0.98 (0.82-1.17) 0.82 (0.69-0.98) Noninferior HHF 0.65 (0.50-0.85) 0.67 (0.52-0.87) 0.61 (0.47-0.80) 0.73 (0.61-0.88) 0.70 (0.59-0.83) Pending CV death or HHF 0.66 (0.55-0.79) 0.78 (0.67-0.91) 0.69 (0.57-0.83) 0.83 (0.73-0.95) 0.75 (0.65-0.85) Noninferior Fatal/non-fatal stroke 1.18 (0.89-1.56) 0.87 (0.69-1.09) NR 1.01 (0.84-1.21) Pending

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Outcomes in Observational Studies Are Consistent With CV Benefit

• f Treatment With SGLT2 Inhibitors

HHF = hospitalization for heart failure; MI = myocardial infarction. Due to the timing of data collection, the majority of patients in these studies received either dapagliflozin or canagliflozin; smaller percentages received empagliflozin. EASEL also included a small percentage treated with SGLT2 inhibitors not currently approved in the US (ipragliflozin, tofogliflozin, luseogliflozin). Birkeland KI, et al. Lancet Diabetes Endocrinol. 2017;5:709-717; Kosiborod M, et al. Circulation. 2017;136:249-259; Kosiborod M, et al. J Am Coll

• Cardiol. 2018;71:2628-2639; Patorno E, et al. BMJ. 2018;360:k119; Udell JA, et al. Circulation. 2018;137:1450-1459.

Characteristics CVD-REAL Patorno et al EASEL CVD REAL 2 CVD REAL Nordic N 309,056 224,999 25,258 >400,00 91,930 Established ASCVD, % 13 16-18 100 27 25 All-cause death, MI, stroke — — 0.67 (0.60-0.75) 0.51 (0.37-0.70) 0.78 (0.69-0.87) All-cause death 0.49 (0.41-0.57) 0.66 (0.25-1.74) 0.57 (0.49-0.66) 0.51 (0.37-0.70) 0.51 (0.45-0.58) HHF 0.61 (0.51-0.73) 0.70 (0.54-0.92) 0.57 (0.45-0.73) 0.64 (0.50-0.82) 0.70 (0.61-0.81)

11

• CREDENCE evaluated effect of canagliflozin on progression of renal disease in patients

with T2DM and CKD; outcomes showed reduced risk on: ‒ Primary endpoint (sustained creatinine doubling, ESRD, or CV or renal death): 0.70 (0.59-0.82) ‒ Other endpoints

• Sustained creatinine doubling, ESRD, or renal death: 0.66 (0.53-0.81)
• ESRD: 0.68 (0.54-0.86)
• Dialysis, transplant, or renal death: 0.72 (0.54-0.97)

‒ Patients with baseline eGFR <45 had renal, but not glycemic, benefit with canagliflozin

Improvements in Renal Outcomes With SGLT2 Inhibitors

All data presented as hazard ratio (95% confidence interval). ESRD = end-stage renal disease. Herrington WG, et al. Clin Kidney J. 2018:749-761; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 2017;377:644-657; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Wanner C, et al. N Engl J Med. 2016;375:323-334; Wiviott SD, et al. N Engl J Med. 2019;380:347-357. 12

• Data from EMPA-REG, DECLARE-TIMI 58, and DAPA-HF suggest renal

benefit with empagliflozin and dapagliflozin in CVOTs

• Renal-specific trials ongoing

‒ EMPA-Kidney (NCT03594110) ‒ Dapa-CKD (NCT03036150)

Improvements in Renal Outcomes With SGLT2 Inhibitors (cont’d)

Herrington WG, et al. Clin Kidney J. 2018:749-761; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 2017;377:644-657; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Wanner C, et al. N Engl J Med. 2016;375:323-334; Wiviott SD, et al. N Engl J Med. 2019;380:347-357.

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Current Indications for SGLT2 Inhibitors in T2DM

Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020; Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020.

Agent FDA Indication in T2DM Empagliflozin

• Adjunct to diet and exercise to improve glycemic control
• Reduce risk of CV death in adults with T2DM and established CVD

Canagliflozin

• Adjunct to diet and exercise to improve glycemic control
• Reduce risk of MACE in adults with T2DM and established CVD
• Reduce risk of ESRD, doubling of serum creatinine, CV death, and HHF in

adults with T2DM and diabetic nephropathy with albuminuria Dapagliflozin

• Adjunct to diet and exercise to improve glycemic control in patients with T2DM
• Reduce risk of HHF in adults with T2DM and established CVD or multiple CV

risk factors Ertugliflozin

• Adjunct to diet and exercise to improve glycemic control

14

• Current recommendations:

̶ Achieving/maintaining appropriate weight ̶ Regular physical activity ̶ Smoking cessation, if applicable ̶ Reducing stress

Lifestyle Modifications: Cornerstone of Treatment for T2DM

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Garber AJ, et al. Endocr Pract. 2019;25:69-100. 15

Use of SGLT2 Inhibitors to Reduce CV Risk Is a “Paradigm Shift”

• Demonstrated reductions in risk for CV death, MI, stroke, HF

hospitalization, progression of renal disease, and associated mortality

• Choose agents based on evidence and established indications
• SGLT2 inhibitors may be considered as first-line oral option
• Recommended in guidelines from ADA/EASD, ACE/AACE, and ESC

ACE/AACE = American College of Endocrinology/American Association of Clinical Endocrinologists; ESC = European Society of Cardiology. American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Cosentino F, et al. Eur Heart J. 2020;41:255-323; Garber AJ, et al. Endocr Pract. 2019;25:69-100.

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Approach to Individualization of A1C Targets for Treatment

Readily available Limited High motivation/adherence Low motivation/adherence Absent Few/mild Severe Absent Few/mild Severe Long Short Newly diagnosed Long-standing Low High

A1C 7.0% More Stringent Less Stringent Usually not modifiable Potentially modifiable

Patient/Disease Features Risk of hypoglycemia/drug adverse effects Disease duration Life expectancy Relevant comorbidities Established vascular complications Patient attitude and expected treatment efforts Resources and support system

American Diabetes Association. Diabetes Care. 2020;43:S1-S212. 17

Factors to Consider When Choosing Treatment

• Treatment efficacy
• Hypoglycemia risk
• Impact on weight
• Potential side effects
• Renal effects

American Diabetes Association. Diabetes Care. 2020;43:S1-S212

• Cost
• Route of administration
• Patient CV history and risk
• Comorbidities
• Patient preferences

18

• Moderate renal impairment and reduced eGFR diminish efficacy, and may increase AEs

‒ Evaluate renal function prior to and periodically during treatment

• May cause acute kidney injury; discontinue and promptly treat if occurs

‒ Hypovolemia, CKD, NSAIDs, ACE inhibitors, ARBs, diuretics, HF increase risk

Using SGLT2 Inhibitors for Patients With Renal Impairment

AE = adverse event; ARB = angiotensin-receptor blocker; NSAID = nonsteroidal anti-inflammatory drug. Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020; Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020.

SGLT2 Inhibitor eGFR (mL/min/1.732) ≥60 <60 but ≥45 <45 but ≥30 <30 Canagliflozin All doses 100 mg only With albuminuria >300 mg/day:100 mg Contraindicated* Dapagliflozin All doses All doses Not recommended Contraindicated Empagliflozin All doses All doses Do not initiate, discontinue if persists Contraindicated Ertugliflozin All doses Do not initiate, discontinue if persists Do not initiate, discontinue if persists Contraindicated

*Patients already on canagliflozin whose eGFR declines <30, with albuminuria >300 mg/day, can continue 100 mg dose unless dialysis is initiated.

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Evaluate Patients’ Renal Status Before Initiating SGLT2 Inhibitor Therapy

• Monitor renal function periodically during treatment, and adjust/discontinue

if necessary

• Use baseline renal status in choosing an SGLT2 inhibitor, recommended

use varies

• Be aware of risk for acute kidney injury in patients at higher risk, and

discontinue SGLT2 inhibitor promptly if occurs

20

Normal Physiology of Renal Glucose Homeostasis

Glomerulus Distal tubule

Glucose filtration Minimal glucose excretion

Collecting duct

90% 10% Glucose reabsorption

Proximal tubule

S1 S3

SGLT1 Loop of Henle

Han S. Diabetes. 2008;57:1723-1729; Lee YJ, et al. Kidney Int Suppl. 2007;106:S27-S35; Wright EM. Am J Physiol Renal Physiol. 2001;280: F10-F18.

SGLT2

21

SGLT2 Inhibition Reduces Renal Glucose Absorption

SGLT2

Proximal tubule

S1

Glomerulus Distal tubule

Glucose filtration

S3

Collecting duct

90% 10% Glucose reabsorption Loop of Henle SGLT1

SGLT2 inhibitor

Increased glucose excretion –70-80 g/day (–280-320 Kcal/day)

Han S. Diabetes. 2008;57:1723-1729; Lee YJ, et al. Kidney Int Suppl. 2007;106:S27-S35; Wright EM. Am J Physiol Renal Physiol. 2001;280: F10-F18.

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Potential Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors

Zelniker TA, Braunwald E. J Am Coll Cardiol. 2020;75:422-434.

CV and Renal Protection Decrease arterial stiffness Reduce glucotoxicity Increase hematocrit and hemoglobin Increase weight loss Reduce plasma volume Decrease systolic blood pressure Decrease adiposity and inflammation Improve cardiac fuel energetics

23

• Alleviate glucotoxicity, improving β-cell function and insulin sensitivity
• Lower A1C as monotherapy (≤1.0%) or in combination with other T2DM

therapies

• Reduce both fasting and postprandial glucose levels
• Reduce glucose independent of insulin response
• Have a low risk of hypoglycemia, even when combined with basal insulin
• r sulfonylureas

Glycemic Efficacy of SGLT2 Inhibitors

Abdul-Ghani M, et al. Diabetes Care. 2016;39:717-725; Anderson JE, et al. Diabetes Ther. 2017;8:33-53; Consoli A, et al. Expert Opin Drug Saf. 2018;17:293-302; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26. 24

SGLT2 Inhibitors Provide Additional A1C Reductions When Added to Other Diabetes Medications*

*As a class; where they appear, ranges include different doses and agents. Frías JP, et al. Lancet Diabetes Endocrinol. 2016;1004-1016; Jabbour SA, et al. Diabetes Care. 2014;37:740-750; Nauck MA. Drug Des Devel Ther. 2014;8:1335-1380; Vivian EM. Drugs Context. 2014;3:212264.

Therapy A1C Reduction With Added SGLT2 Inhibitor Metformin –0.4% to –0.7% Glimepiride –0.5% to –0.68% Pioglitazone –0.4% to –0.55% DPP-4 inhibitor –0.5% to –0.79% GLP-1 RA –0.4% Basal insulin –0.4% to –0.89%

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• Body weight reductions
• Modest reduction in systolic and diastolic BP
• Small increase in LDL-C, greater increase in HDL-C, decrease in triglycerides
• Albuminuria: reductions of 30% to 40%
• Renal health: meta-analysis

‒ Among patients with renal impairment, initial decrease in eGFR, increase in serum creatinine levels followed by return to baseline ‒ Among those without impairment, no significant change in either parameter

Benefits Beyond Glycemic Reductions

Baker WL, et al. J Am Heart Assoc. 2017;6:e005686; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26; Grossman A, Grossman E. Cardiovasc

• Diabetol. 2017;16:3; Kelly MS, et al. Postgrad Med. 2019;131:31-42; Seidu S, et al. Prim Care Diabetes. 2018;12:265-283; Takenaka T. Diab Vasc

Dis Res. 2018;15:154-157; Zelniker TA, et al. Lancet. 2019;393:31-39. 26

• Body weight: glucose loss → calorie loss → weight loss
• Modest, dose-dependent weight loss: 1.5 to 2 kg (placebo-adjusted)
• Weight loss maintained in 4 years of follow-up
• Amount of weight loss due to glucosuria mitigated by compensatory

mechanisms

• Majority of weight loss is from subcutaneous and visceral fat tissue, not

lean tissue ‒ Reductions in waist circumference

Body Weight Loss With SGLT2 Inhibitors

Bolinder J, et al. J Endocrinol Metab. 2012;97:1020-1031; Cefalu WT, et al. Lancet. 2013;382;941-950; Neeland IJ, et al. Diab Vasc Dis Res. 2016; 13:119-126; Pereira MJ, Eriksson JW. Drugs. 2019;79:219-230. 27

SGLT2 Inhibitors in Context With Other T2DM Medications

*Potential for moderate weight loss; **Can occur in various stress settings. DPP-4i = DPP-4 inhibitor; MET = metformin; SU = sulfonylurea. American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Davidson JA. Mayo Clin Proc. 2010;85:S27-S37; Garber AJ, et al. Endocr Pract. 2019;25:69-100; Nathan DM. N Engl J Med. 2002;347:1342-1349.

Effect MET SGLT2i GLP-1 RA DPP-4i TZD SU Basal Insulin Typical A1C reduction, % 1.0 to 2.0 ≤1.0 0.6 to 1.5 0.5 to 0.8 0.5 to 1.0 1.0 to 2.0 1.5 to 2.5 Efficacy High Intermediate High Intermediate High High Highest Hypoglycemia No No No No No Yes Yes Weight ∆ Neutral* Loss Loss Neutral Gain Gain Gain Bone Neutral Neutral Neutral Neutral Moderate fracture risk Neutral Neutral Ketoacidosis Neutral Potential** Neutral Neutral Neutral Neutral Neutral

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SGLT2 Inhibitors: Glycemic and Nonglycemic Effects Contribute to Cardiorenal Benefits

Zelniker TA, Braunwald E. J Am Coll Cardiol. 2020;75:422-434.

Mechanism Glucose lowering ✓ Body weight reduction ✓ ✓ ✓ Blood pressure reduction ✓ ✓ ✓ Natriuresis ✓ ✓ Anti-inflammation ✓ ✓ ✓ Antifibrotic ✓ ✓ Extracellular matrix turnover reduction ✓ ✓ Intrarenal hypoxia amelioration ✓ Tubuloglomerular feedback restoration ✓ Natriuretic protein reduction ✓ ✓ Energy demand reduction ✓ ✓ Liver fat reduction ✓ HF ASCVD CKD

29 Avogaro A, et al. Diabetes Metab Res Rev. 2018;34:e2981; Cinti F, et al. Drug Des Devel Ther. 2017;11:2905-2919; Consoli A, et al. Expert Opin Drug Saf. 2018;17:293-302; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26; Lega IC, et al. Diabetes Obes Metab. 2019;21:2394-2404; McGill JB, Subramanian S. Am J Cardiol. 2019;124:S45-S52; Mosley JF, et al. P T. 2015;40:451-462; Patel S, et al. Diabetes Ther. 2020;11:1347-1367; Russo GT, et al. Int J Endocrinol. 2016;1615735; Simes BC, MacGregor GG. Diabetes Metab Syndr Obes 2019;12:2125-2136;

Potential AEs of SGLT2 Inhibitors and Their Management

Issue Notes Management Genital mycotic infections (GMI) 7% to 8% of women; 1% to 2% of men Standard antifungal treatment Urinary tract infection Triggered by glycosuria Standard treatment Polyuria 2% to 3% of patients; typically transient Educate patients Increase in LDL-C Usually offset by increase in HDL-C Monitor Hypoglycemia Rare with monotherapy, more common in combination with insulin or SU Educate patients regarding rarity with SGLT2 inhibitors

30

• SGLT2 inhibitors have a loop diuretic effect
• Due to increased diuresis, treatment may result in dehydration, initial transient

decrease in eGFR, hypotension, fainting, or falls ‒ Assess and correct volume status in at-risk patients ‒ Risk factors: older age, renal impairment, low systolic BP, on treatment with diuretics, ACE inhibitors, or ARBs ‒ Dehydration is also a factor in risk for amputation, diabetic ketoacidosis

• In patients with preexisting HF, consult with cardiologist to adjust all medications
• In patients with eGFR <45 mL/min/1.732, consult with nephrologist to ensure

treatment will not worsen any other aspects of renal function

Fluid Management for Patients Using SGLT2 Inhibitors

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020; Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020; Garber AJ, et al. Endocr Pract. 2019;25:69-100.

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Fracture and Amputation Risk With Canagliflozin

• CANVAS and other data suggest increased fracture risk with canagliflozin; data from CANVAS also

showed increased risk for amputation (especially toes)

• Only canagliflozin has boxed warning for amputation and warning for fractures
• No clear pathogenetic mechanism for either identified
• No increase in fracture or amputation was seen with other SGLT2 inhibitors
• Population-based cohort (N = 73,173) found no increased fracture risk with SGLT2 inhibitors as a

class versus use of DPP-4 inhibitors

Abrahami D, et al. Diabetes Care. 2019;42:e150-e152; Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26; Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020; Erythropoulou-Kaltsidou M, et al. Diabetes Ther. 2020;11:7- 14; Neal B, et al. N Engl J Med. 2017;377:644-657; Patel S, et al. Diabetes Ther. 2020;11:1347-1367; Ye Y , et al. Front Pharmacol. 2019;9:1517.

Outcome CANVAS: Canagliflozin vs Placebo, HR (95% CI) Amputation (toes, feet, or legs) 1.97 (1.41-2.75) All fractures 1.26 (1.04-1.52)

32

• Mechanism not clear; seen only with canagliflozin
• Avoid or discontinue SGLT2 inhibitor in patient with lower limb complications
• Closely monitor patients with risk factors for amputation

‒ Peripheral vascular disease ‒ Neuropathy ‒ Avoid in patients with previous amputations and diabetic foot ulcers

• Educate patients on foot care and include foot exams at office visits
• Avoid volume depletion: adequate hydration important
• Monitor patients for signs and symptoms of infection (including osteomyelitis),

new pain or tenderness, sores or ulcers involving the lower limbs

Clinical Considerations: Amputation Risk With Canagliflozin

Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020; Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020. 33

• Diabetic ketoacidosis risk

‒ Rare with T2DM: between 0.16 and 0.76 events/1000 patient-years ‒ Regardless of A1C level, assess patients with symptoms of malaise, nausea/vomiting ‒ Avoid very-low carbohydrate diets, excess alcohol intake, dehydration ‒ Treat promptly—may require insulin and fluid/carbohydrate replacement ‒ Recommendation: stop SGLT2 inhibitor 24 to 48 hrs prior to planned surgeries

• r metabolically stressful activities (eg, extreme sports)
• Risk of Fournier’s gangrene

‒ Assess patients presenting with pain, tenderness, erythema, swelling in genital area; treat promptly

Additional Concerns: Warnings on all SGLT2 Inhibitors

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Garber AJ, et al. Endocr Pract. 2019;25:69-100; McGill JB, Subramanian S. Am J Cardiol. 2019;124:S45-S52; Simes BC, MacGregor GG. Diabetes Metab Syndr Obes 2019;12:2125-2136.

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SGLT2 Inhibitors Generally Are Well-Tolerated, but Rare Serious Side Effects Can Occur

• GMIs are the most frequent side effect of treatment and respond to

antimycotic therapy

• Emphasize importance of adequate hydration due to potential for volume-

depletion side effects

• Consult with cardiologists and nephrologists to adjust BP and other

medications as needed

• Rare side effects include diabetic ketoacidosis, Fournier’s gangrene:

educate patients on signs and symptoms and treat promptly if occur

• Amputation and fracture risk cited in canagliflozin prescribing information,

but does not appear to be a class effect

35

• Individualize treatment based on goals and risks

‒ Partnership with patient, shared decisions ‒ Good communication and trust are essential

• Problem of nonadherence

‒ 20% to 30% of prescriptions for glucose-lowering drugs not filled ‒ ~50% of drugs not taken as prescribed ‒ Patients may feel fine and not perceive the need for treatment ‒ Patients may not understand consequences of nonadherence

Improving Outcomes With Patient-Centered Care

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Garber AJ, et al. Endocr Pract. 2019;25:69-100; Marden B. Martineau C. www.pharmacytimes.com/publications/health-system-edition/2019/September2019/emphasize-medication-adherence-to-patients. Accessed June 1, 2020; Polonsky WH, Henry RR. Patient Prefer Adherence. 2016;10:1299-1307. 36

• Explore and address patient needs and preferences
• Motivational interviewing techniques to identify underlying issues
• Emphasize importance of adherence
• Simplify regimen as much as possible

‒ Oral vs injected; less frequent dosing; combined drugs in one tablet

• Educate patients about treatment options and possible side effects

Fostering Adherence

Dandona P, Chaudhuri A. Int J Clin Pract. 2017;71:e12937; Polonsky WH, Henry RR. Patient Prefer Adherence. 2016;10:1299-1307.

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Reducing cardiorenal risk Weight loss Simplified regimens Manageable side effects Low hypoglycemia risk

Helping Patients Achieve Success

• Shared decision-making―educating patients while addressing concerns

about safety and efficacy―improves treatment adherence

• Greater adherence to therapy is associated with agents that meet other

personal or clinical goals, such as:

Battersby M, et al. Jt Comm J Qual Patient Saf. 2010;36:561-570; Dandona P, Chaudhuri A. Int J Clin Pract. 2017;71:e12937; Polonsky WH, et al. Diabetes Obes Metab. 2011;13:144-149; Polonsky WH, Henry RR. Patient Prefer Adherence. 2016;10:1299-1307. 38

PCE Action Plan

 Consider SGLT2 inhibitors for patients with established HF, CKD, or ASCVD  Use a patient-centered approach when collaborating on treatment goals and options  Assess renal status prior to and periodically during treatment with SGLT2 inhibitors  Consider SGLT2 inhibitors for patients who require glycemic control with weight loss and cardiorenal protection  Educate patients on side effect management and actions to minimize risk of volume depletion and rare side effects  Discuss patient priorities, ease of use, and formulary restrictions when selecting antihyperglycemic regimens—watch for new agents and indications

PCE Promotes Practice Change

37 38

2020 Vision: Implementing the New ADA 2020 Guidelines for GLP-1 RAs in Clinical Practice

1 2020 PCE Symposia Series 2

2020 Vision: Implementing the New ADA 2020 Guidelines for GLP-1 RAs in Clinical Practice

2

• Describe the pathophysiology of T2DM and the clinical utility of incretin therapy in

patients with T2DM

• Apply the 2020 ADA recommendations for GLP-1 RAs to the care of patients with

T2DM who require better glucose control, weight mitigation, and/or CVD risk reduction

• Partner with patients to use shared decision-making to select and improve

adherence to therapies

Learning Objectives

ADA = American Diabetes Association; CVD = cardiovascular disease; GLP-1 RA = glucagon-like peptide-1 receptor agonist; T2DM = type 2 diabetes mellitus. 3

• In a glucose-dependent manner, GLP-1 works to maintain

normal glucose levels by: ‒ Stimulating release of insulin from pancreatic β cells when glucose levels are elevated, particularly in response to food ‒ Suppressing glucagon secretion from pancreatic α cells

GLP-1 in T2DM: The Incretin Effect

3 0% 20% 40% 60% 80% 100% Non-T2DM T2DM Incretin Effect 0 60 120 180 240 12 10 8 6 4 2 Oral Isoglycemic IV Insulin Secretion Rate (pmol/kg/min) Time (minutes) DeFronzo RA. Diabetes. 2009;58:773-795; Drucker DJ, Nauck M. Lancet. 2006;368:1696-1705; Nauck M. Diabetes Obes Metab. 2016;18:203-216.

• This “incretin effect” is diminished in patients with

T2DM, contributing to hyperglycemia

• GLP-1 RAs restore this effect by potentiating the action
• f endogenous GLP-1

1 2 3

2020 Vision: Implementing the New ADA 2020 Guidelines for GLP-1 RAs in Clinical Practice

2 2020 PCE Symposia Series 2

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The “Ominous Octet”: Multiple, Complex Pathophysiologic Abnormalities in T2DM

4 Adapted from: Inzucchi SE, Sherwin RS. In: Cecil Medicine. 2011; DeFronzo RA. Diabetes. 2009;58:773-795.

Impaired insulin secretion Increased glucagon secretion Neurotransmitter dysfunction Increased lipolysis Increased glucose reabsorption Decreased glucose uptake Decreased incretin effect 𝞬-cell 𝛃-cell 𝛄-cell Increased hepatic glucose production

HYPERGLYCEMIA

5

The “Ominous Octet”: Multiple, Complex Pathophysiologic Abnormalities in T2DM

5 DPP-4i = dipeptidyl peptidase-4 inhibitor; SGLT2 = Sodium glucose co-transporter 2; SGLT2i = SGLT2 inhibitor; SU = sulfonylurea; TZD = thiazolidinediones. Adapted from: Inzucchi SE, Sherwin RS. In: Cecil Medicine. 2011; DeFronzo RA. Diabetes. 2009;58:773-795.

𝞬-cell 𝛃-cell SU Glinides TZD GLP-1 RA DPP-4i DPP-4i GLP-1 RA Insulin Metformin TZD GLP-1 RA GLP-1 RA Insulin TZD Insulin SGLT2i Insulin Metformin TZD GLP1-RA DPP-4i GLP-1 RA 𝛄-cell Impaired insulin secretion Increased glucagon secretion Neurotransmitter dysfunction Increased lipolysis Increased glucose reabsorption Decreased glucose uptake Decreased incretin effect Increased hepatic glucose production

HYPERGLYCEMIA

6

Case Study: Don, a 69-Year-Old With a 4-Year History of T2DM

• Don has not pursued regular medical care since his T2DM diagnosis. He was recently

diagnosed with peripheral arterial disease (PAD). At his wife Betty’s urging, he agrees to a telehealth appointment to assess his overall health

• Don is a retired machinist whose father died of an MI at 62. He enjoys woodworking and is a

former smoker who quit 15 years ago

• Physical exam findings

‒ Height: 5 ft 11 in ‒ Weight: 213 lb ‒ BMI: 29.8 kg/m2 ‒ BP: 148/96 mm Hg on an ACE inhibitor ‒ No history of MI, DVT/ PE ‒ Last ECG was normal

ACE = angiotensin-converting enzyme; DVT/PE = deep vein thrombosis/pulmonary embolism; MI = myocardial infarction.

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2020 Vision: Implementing the New ADA 2020 Guidelines for GLP-1 RAs in Clinical Practice

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Case Study (cont’d): Don’s Medications and Lab Values

• Lab results

‒ FPG: 190 mg/dL ‒ PPG: 205 mg/dL ‒ A1C: 8.3% ‒ LDL-C: 110 mg/dL on statin ‒ CBC, CMP/LFT: within normal ranges ‒ Mild renal impairment (eGFR: 55 mL/min/1.732) ‒ No albuminuria

CBC = complete blood count; CMP = comprehensive metabolic panel; FPG = fasting plasma glucose; LDL-C = low density lipoprotein cholesterol; LFT = liver function tests; PPG = post-prandial glucose.

• Current medications

‒ Metformin 1500 mg/day ‒ Ramipril 10 mg/day ‒ Atorvastatin 40 mg/day ‒ Aspirin 81 mg/day ‒ Clopidogrel 75 mg/day ‒ Cilostazol 100 mg twice/day

8

• Evaluate for complications and comorbidities
• Review previous treatment and risk factor control in patients with established diabetes
• Assess 10-year ASCVD risk using a validated pooled cohort equations tool
• Engage patient in creating and adhering to management plan
• Repeat at follow-up visits, plus:

‒ Assess diabetes self-management ‒ Conduct foot exam ‒ Discuss nutrition ‒ Explore psychosocial health (eg, depression, anxiety, eating disorders) ‒ Evaluate need for referrals, immunizations, routine health screening

• Assess patient’s familiarity with diabetes technology (eg, continuous glucose monitoring,

health apps)

ADA 2020: Comprehensive Medical Evaluation for Patients With T2DM

American Diabetes Association. Diabetes Care. 2020;43:S1-S212. 9

• Assess eating patterns and weight history, physical activity,

sleep behaviors

• Assess tobacco/alcohol/other substance use
• Consider referral for:

‒ Medical nutrition therapy education and support ‒ Diabetes self-management education and support ‒ Anxiety and stress reduction

Lifestyle Modifications Are a Cornerstone of Treatment for T2DM

American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

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2020 Vision: Implementing the New ADA 2020 Guidelines for GLP-1 RAs in Clinical Practice

4 2020 PCE Symposia Series 2

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• Among patients with T2DM who have established ASCVD or indicators of

high-risk, established kidney disease or heart failure (HF): ‒ An SGLT2i or GLP-1 RA with demonstrated CVD benefit is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors

Optimizing Glucose-Lowering Regimens Independent of A1C and in Consideration of Comorbidities

American Diabetes Association. Diabetes Care. 2020;43:S1-S212. 11

HF or CKD predominates PREFERABLY: SGLT2i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR is adequate OR If SGLT2i not tolerated or contraindicated or inadequate eGFR, add GLP-1 RA with proven CVD benefit Choose agent with CV safety; Avoid TZD in setting of HF ASCVD predominates PREFERABLY: GLP-1 RA with proven CVD benefit SGLT2i with proven CVD benefit if eGFR is adequate If further intensification required or patient unable to tolerate GLP-1 RA and/or SGLT2i, choose agents with CV safety For all patients: lifestyle modification For most patients: metformin Indicators of high-risk or established ASCVD, HF, or CKD

ADA 2020: Use Agents That Address Patient-Specific Comorbidities

EITHER/OR

CKD = chronic kidney disease; CVOT = cardiovascular outcome trial. Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

If A1C above target If A1C above target

12

HF or CKD predominates PREFERABLY: SGLT2i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR is adequate OR If SGLT2i not tolerated or contraindicated or inadequate eGFR, add GLP-1 RA with proven CVD benefit Choose agent with CV safety; Avoid TZD in setting of HF ASCVD predominates PREFERABLY: GLP-1 RA with proven CVD benefit SGLT2i with proven CVD benefit if eGFR is adequate If further intensification required or patient unable to tolerate GLP-1 RA and/or SGLT2i, choose agents with CV safety For all patients: lifestyle modification For most patients: metformin Indicators of high-risk or established ASCVD, HF, or CKD

ADA 2020: Use Agents That Address Patient-Specific Comorbidities

EITHER/OR

CKD = chronic kidney disease; CVOT = cardiovascular outcome trial;. Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

If A1C above target If A1C above target

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Compelling need to minimize hypoglycemia Compelling need to minimize weight gain/promote weight loss GLP1-RA with good efficacy for weight loss SGLT2i SGLT2i GLP1-RA with good efficacy for weight loss If triple therapy required or GLP-1 RA/SGLT2i not tolerable, use agent with lowest risk of weight gain If A1C above target If A1C above target If A1C above target If A1C above target, continue with addition of

• ther agents outlined above

DPP-4 GLP-1 RA SGLT2i TZD SGLT2i

• r

TZD SGLT2i

• r

TZD GLP-1 RA

• r

DPP-4i

• r

TZD SGLT2i

• r

DPP-4i

• r

GLP-1 RA

ADA 2020: Pathways for Patients Without Indicators of High-Risk

• r Established ASCVD, CKD, or HF

EITHER/ OR

.Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

First-line is metformin + lifestyle modification; if above A1C target, proceed as below If NO established ASCVD or CKD

14

GLP-1 RAs in Context With Other T2DM Medications

Effect MET SGLT2i GLP-1 RA DPP-4i TZD SU Basal Insulin Typical A1C reduction, % 1.0 to 2.0 ≤1.0 0.6 to 1.8 0.5 to 0.8 0.5 to 1.0 1.0 to 2.0 1.5 to 2.5 Efficacy High Intermediate High Intermediate High High Highest Hypoglycemia No No No No No Yes Yes Weight ∆ Neutral* Loss Loss Neutral Gain Gain Gain Bone Neutral Neutral Neutral Neutral Moderate fracture risk Neutral Neutral Ketoacidosis Neutral Potential** Neutral Neutral Neutral Neutral Neutral

MET = metformin. *Potential for moderate weight loss; **Can occur in various stress settings. American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Davidson JA. Mayo Clin Proc. 2010;85:S27-S37; Garber AJ, et al. Endocr

• Pract. 2019;25:69-100; Nathan DM. N Engl J Med. 2002;347:1342-1349.

15

GLP-1 RAs Are Recommended for Patients With Established ASCVD or at High Risk for ASCVD

• GLP-1 RAs address multiple aspects of T2DM pathophysiology
• All are safe for patients with CVD, and several have proven benefit in

CV risk reduction for patients with ASCVD or CV risk factors

• ADA 2020: For patients in whom ASCVD predominates or who have

indicators of high risk for ASCVD, use a GLP-1 RA with proven CVD benefit*

*Defined by ADA as having a label indication for reducing CV events. American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

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• PCE discussion guide/checklist developed to help clinicians step through options in a

patient-friendly manner, including ‒ Mode of administration ‒ injectable vs oral ‒ Frequency of administration ‒ twice daily, daily, weekly ‒ CV benefit ‒ A1C-lowering potential ‒ Weight mitigation potential ‒ Side-effect profile

• Tool is available in the resources section of today’s symposium and can also be

downloaded at PCE.is/GLPdecisiontool

GLP-1 RA Decision-Making Tool

17

GLP-1 RA Decision-Making: Frequency of Administration, Glycemic Control, Weight Reduction

Effect Exenatide Lixisenatide Liraglutide Exenatide LAR Dulaglutide Semaglutide SC Semaglutide Oral Administration frequency Twice daily Daily Daily Weekly Weekly Weekly Daily Typical A1C reduction,* % 0.5-0.9 0.7 1.0 1.6 1.0-1.4 1.5-1.8 1.0-1.3 FPG reduction, mg/dL 5.4-28.8 0-20.9 15.12-44.0 31.1-47.0 26.0-43.0 35.0-43.0 36 PPG reduction, mg/dL 30.0-52.2 55.8-143.3 29.0-49.0 NR 41.4-46.1 NR NR Weight reduction, kg 1.0-2.6 2.7 2.6-2.8 2.3 2.4-2.9 4.6-6.5 3.8

NR = not reported. *In trials with GLP-1 RA added to metformin. Ahren B, et al. Lancet Diabetes Endocrinol. 2017;5:341-354; Davidson JA. Postgrad Med. 2015;127:827-841; Lyseng-Williamson KA. Clin Drug Invest. 2019;39:805-819; Rodbard HW, et al. Diabetes Care. 2019;42:2272-2281. 18 GLP-1 RA Initial Dose* Maintenance Dose Relation to Meals Missed Dose Exenatide 5 mcg twice daily x ≥1 month 5 or 10 mcg twice daily, depending

• n clinical response

<60 min before 2 main meals Continue with next scheduled dose Lixisenatide 10 mcg daily x 14 day 20 mcg daily <60 min before 1st daily meal T ake dose within 1 hour before next meal Liraglutide 0.6 mg daily ≥1 week 1.2 to 1.8 mg daily None Continue with next scheduled dose Exenatide LAR N/A 2 mg weekly None ≥3 days until next scheduled dose: ASAP; <3 days: skip dose, take next planned dose Dulaglutide 0.75 mg weekly 0.75 or 1.5 mg weekly depending

• n clinical response

None ≥3 days until next scheduled dose: ASAP; <3 days: skip dose, take next planned dose Semaglutide 0.25 mg weekly x 4 weeks 0.5 or 1.0 weekly depending on clinical response None ≥5 days until next scheduled dose: ASAP; <5 days: skip dose, take next planned dose Semaglutide (oral) 3 mg daily x 30 days 7 or 14 mg daily depending on clinical response 30 minutes before 1st food/other intake of day Continue with next dose the following day

GLP-1 RA Decision-Making: Dosage and Administration

18 *Initial lower doses are used to minimize GI side effects for liraglutide and semaglutide subcutaneous/oral. These initial doses are not effective for glycemic reduction, and the dose must be increased as recommended for glycemic effect. Adlyxin [prescribing information]. Sanofi-Aventis US LLC; 2019; Bydureon [prescribing information]. AstraZeneca Pharmaceuticals LP; 2020; Byetta [prescribing information]. AstraZeneca Pharmaceuticals LP; 2020; Ozempic [prescribing information]. Novo Nordisk Inc; 2020; Rybelsus [prescribing information]. Novo Nordisk Inc; 2020; Trulicity [prescribing information]. Eli Lilly and Company; 2020; Victoza [prescribing information]. Novo Nordisk Inc; 2019.

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• Taken once daily in morning, 30 min before first food, beverage, or other oral

medications of the day (take with no more than 4 ounces of water)

• Starting dose: 3 mg once daily for 30 days
• After 30 days on 3 mg, increase to 7 mg once daily
• After 30 days on 7 mg, increase to 14 mg once daily if more glycemic control needed

‒ Taking two 7 mg tablets to achieve a 14 mg dose is contraindicated

• Studied as monotherapy and as add on to metformin, OADs, and basal insulin
• Shares characteristics with other GLP-1 RAs

‒ A1C reduction, weight loss, low hypoglycemia risk ‒ Noninferior to placebo in CVOT (PIONEER 6)

Oral Semaglutide: An Alternative to Injectable Therapy

OAD = oral antidiabetic drug. Rodbard HW, et al. Diabetes Care. 2019;42:2272-2281; Rybelsus [prescribing information]. Plainsboro, NJ: Novo Nordisk, Inc.; 2020; Theti TK, et

• al. Diabetes Obes Metab. 2020;1-15.

20

Characteristics ELIXA Lixisenatide LEADER Liraglutide SUSTAIN-6 Semaglutide PIONEER-6 Oral semaglutide EXSCEL Exenatide LAR REWIND Dulaglutide N 6068 9340 3297 3183 14,752 9901 Mean age, years 60.3 64.3 64.6 66 ± 7 62.0 66.2 Male, % 69.3 64.3 60.7 68.4 62.0 53.7 Established ASCVD, % 100 72.5 83.0 84.7 73.1 31.4 eGFR <60 23.2 23.1 28.5 26.9 21.6 22.2 History of HF, % 20.3 17.8 23.6 12.2 16.2 8.6 Median follow-up time, years 2.1 3.8 2.1 1.3 3.2 6.0

Baseline Characteristics of GLP-1 RA CVOTs

20 Gerstein HC, et al. Diabetes Obes Metab. 2018;20:42-49; Gerstein HC, et al. Lancet. 2019;394:121-130; Holman RR, et al. N Engl J Med. 2017;377:1228-1239; Husain M, et al. N Engl J Med. 2019;381:841-851; Marso SP, et al. N Engl J Med. 2016;375:1834-1844; Marso SP, et al. N Engl J Med. 2016;375:311-322; Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257. 21

Outcomea ELIXA Lixisenatide LEADER Liraglutide SUSTAIN-6 Semaglutide PIONEER-6 Oral semaglutide EXSCEL Exenatide LAR REWIND Dulaglutide Primary outcome 3 pt MACE 3 pt MACE 3 pt MACE 3 pt MACE 3 pt MACE 3 pt MACE

• Est. ASCVD, %

100 72.5 83.0 84.7 73.1 31.4 MACE 1.02 (0.0.89-1.17) 0.88 (0.79-0.97) 0.74 (0.58-0.95)b 0.79 (0.57-1.11) 0.91 (0.83-1.00) 0.896 (0.81-0.99) CV mortality 0.98 (0.78-1.22) 0.78 (0.66-0.93) 0.98 (0.65-1.48) 0.49 (0.27-0.92) 0.88 (0.76-1.02) 0.92 (0.79-1.06) Nonfatal MI 1.03 (0.87-1.22) 0.88 (0.75-1.03) 0.74 (0.51-1.08) 1.18 (0.73-1.90) 0.97 (0.85-1.10)c — Nonfatal stroke 1.12 (0.79-1.58) 0.89 (0.72-1.11) 0.61 (0.38-0.99) 0.74 (0.35-1.57) 0.85 (0.70-1.03)c — HHF 0.96 (0.75-1.22) 0.88 (0.74-1.05) 1.09 (0.76-1.56) 0.88 (0.49-1.57) 0.94 (0.78-1.13) 0.94 (0.78-1.13)

Outcomes in CVOTs: GLP-1 RA vs Placebo

21 HHF = hospitalization for heart failure; 3 pt MACE = major adverse CV event (death related to CV causes, nonfatal MI, or nonfatal stroke; EXSCEL included fatal or nonfatal MI, fatal or nonfatal stroke).

aData expressed as hazard ratio (95% confidence interval). bIn SUSTAIN-6, semaglutide reached superiority vs placebo, but the trial was not

powered for superiority; cFatal or nonfatal MI or stroke. Gerstein HC, et al. Lancet. 2019;394:121-130; Holman RR, et al. N Engl J Med. 2017;377:1228-1239; Husain M, et al. N Engl J Med. 2019;381:841-851; Marso SP, et al. N Engl J Med. 2016;375:1834-1844; Marso SP, et al. N Engl J Med. 2016;375:311-322; McKee A, et al. J Endocr Soc. 2020;4:bvaa037; Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257.

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Current Indications for GLP-1 RAs

Adlyxin [prescribing information]. Sanofi-Aventis US LLC; 2019; Bydureon [prescribing information]. AstraZeneca Pharmaceuticals LP; 2020; Byetta [prescribing information]. AstraZeneca Pharmaceuticals LP; 2020; Ozempic [prescribing information]. Novo Nordisk Inc; 2020; Rybelsus [prescribing information]. Novo Nordisk Inc; 2020; Trulicity [prescribing information]. Eli Lilly and Company; 2020; Victoza [prescribing information]. Novo Nordisk Inc; 2019.

Agent Year Approved FDA Indication in T2DM Exenatide 2005

• Adjunct to diet and exercise to improve glycemic control in adults

Lixisenatide 2016

• Adjunct to diet and exercise to improve glycemic control in adults

Liraglutide 2010

• Adjunct to diet and exercise to improve glycemic control
• Reduce risk of MACE in adults with T2DM and established CVD

Exenatide LAR 2005

• Adjunct to diet and exercise to improve glycemic control in adults

Dulaglutide 2014

• Adjunct to diet and exercise to improve glycemic control in adults
• Reduce risk of MACE in adults with T2DM and established CVD or multiple

CV risk factors Semaglutide SC 2017

• Adjunct to diet and exercise to improve glycemic control in adults
• Reduce risk of MACE in adults with T2DM and established CVD

Semaglutide oral 2017

• Adjunct to diet and exercise to improve glycemic control in adults

23

Factor Clinical Characteristics of GLP-1 RAs Into Shared Decision-Making

• Highly effective glucose-lowering agents, with some variability between agents
• Depending on the agent, treatment may have a greater or lesser effect in terms
• f reductions in A1C, FPG, and PPG
• Associated with low risk of hypoglycemia, unless administered in combination

with insulin or a sulfonylurea

• May support patients’ efforts to maintain or reduce weight
• Administration frequency and expected glycemic and nonglycemic benefits

should be part of patient-clinician discussion and shared decision-making

• 2020 ADA guidelines recommend reviewing and agreeing on management

plan with patient at least once or twice a year

24

Important Educational Points to Help Patients Understand, Avoid, and Manage Adverse GI Effects

• Nausea is usually transient
• Unfamiliar sense of fullness may be interpreted as “nausea”

Discuss expectations

• Persistent severe abdominal pain may indicate presence of pancreatitis
• No increased risk of pancreatitis was noted in CVOTs
• Discontinue GLP-1 RA and promptly report pain to healthcare provider

Severe abdominal pain is not normal or typical

• Titrate GLP-1 RA slowly
• Stop eating when fullness is first sensed

GI symptoms can be minimized

• Decrease portion sizes and fat content
• Keep a log of foods that cause nausea

Suggest behavioral changes

24 Gerstein HC, et al. Lancet. 2019;394:121-130; Holman RR, et al. N Engl J Med. 2017;377:1228-1239; Husain M, et al. N Engl J Med. 2019;381:841- 851; Kruger DF, et al. Diabetes Educ. 2010;36(Suppl 3):S44-S72; Lyseng-Williamson KA. Clin Drug Invest. 2019;39:805-819; Marso SP, et al. N Engl J

• Med. 2016;375:311-322; Marso SP, et al. N Engl J Med. 2016;375:1834-1844; Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257.

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• Injection site reactions may occur
• Adding to SU or insulin may increase hypoglycemia risk
• Do not use in patients with a history of pancreatitis
• Boxed warning for all long-acting GLP-1 RAs

‒ Contraindicated in patients with a history of medullary thyroid cancer or multiple endocrine neoplasia syndrome (MENS)

• Monitor patients with history of diabetic retinopathy for treatment-related changes

‒ Diabetic retinopathy complications reported in patients with semaglutide injection in SUSTAIN-6

• Not recommended for use during pregnancy

Other Considerations and Precautions

Adlyxin [prescribing information]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2019; Bydureon [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020; Byetta [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020; Ozempic [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc.; 2020; Rybelsus [prescribing information]. Plainsboro, NJ: Novo Nordisk, Inc.; 2020; Trulicity [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2020; Victoza [prescribing information]. Princeton, NJ: Novo Nordisk, Inc.; 2019. 26

GLP-1 RAs in Patients with Renal Impairment

Adlyxin [prescribing information]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2019; Bydureon [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020; Byetta [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020; Ozempic [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc.; 2020; Rybelsus [prescribing information]. Plainsboro, NJ: Novo Nordisk, Inc.; 2020; Trulicity [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2020; Victoza [prescribing information]. Princeton, NJ: Novo Nordisk, Inc.; 2019. 50 30 30 15 15 15 50 25 50 75 100 Exenatide QW Exenatide BID Lixisenatide Semaglutide Duluglutide Liraglutide Not recommended Use with caution Allowed use without dose adjustment

CKD Stages 5 4 3 2 1

eGFR (mL/min/1.73 m2/ Creatinine clearance (mL/min) <15 15-29 30-59 60-89 ≥90 27

Ongoing Management of T2DM

• Assess glycemic control: if not at goal, evaluate adherence or need for

therapy change

• Reinforce lifestyle modification recommendations
• Refer, if necessary, for additional support with self-management, nutrition,

psychosocial health, technology

• Refer for annual eye exams, regular dental care, and family planning as

needed

American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

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PCE Action Plan

 Consider a GLP-1 RA with proven benefit in CV risk reduction for patients with existing ASCVD or multiple CV risk factors  Match the GLP-1 RA to the patient’s needs, abilities, preferences, and support  Educate patients on the GI side effects associated with GLP-1 RAs and how to minimize them  To maintain progress, set date and goals for follow-up visit and reassess patient engagement, adherence, and need for referral, if not met PCE Promotes Practice Change

28

Rheumatoid Arthritis: Best Practices in Diagnosis and Management in the Era of Novel Agents

1 2020 PCE Symposia Series 2

Rheumatoid Arthritis: Best Practices in Diagnosis and Management in the Era of Novel Agents

2

Learning Objectives

• Assess patients for signs and symptoms of rheumatoid arthritis (RA)
• Identify novel therapies for RA and their appropriate use in clinical

practice

• Evaluate patients with RA for extra-articular manifestations and

comorbidities

3

• 1.5 MILLION ADULTS in the

United States have RA

• 3x as many women as men

Dadoun S, et al. Joint Bone Spine. 2013;80:29-33; Gonzalez A, et al. Arthritis Rheum. 2007;56:3583-3587; Humphreys JH, et al. Arthritis Care Res (Hoboken). 2014;66:1296-1301; Myasoedova E, et al. Arthritis Rheum. 2010;62:1576-1582; Sokka T, et al. Arthritis Res Ther. 2010;12:R42.

Prevalence of RA

= 10,000 people

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Environmental and Genetic Risk Factors for RA

• RA is thought to be associated with:

‒ Genetics ‒ Female sex

*Gut dysbiosis in patients with RA may result from an increased abundance of certain rare bacterial lineages. Managing RA by manipulating the gut microbiota is a new area of research. Abella V, et al. Life Sci. 2016;157:140-144; Chen J, et al. Genome Med. 2016;8:43; Yarwood A, et al. Rheumatology (Oxford). 2016;55:199-209.

Genetic background Environmental factors (eg, smoking, periodontitis, pollution, gut microbiota*, others) Asymptomatic Outcomes (disability, joint surgery) Intermittent mono- or oligo- arthritis Persistent symmetric polyarthritis Clinical (inflammation) Preclinical (autoimmunity)

5

Pathogenesis of RA

Anti-CCP = antibodies to citrullinated peptide; Cit = citrullinated peptide; DC = dendritic cell; MØ = macrophage; RF = rheumatoid factor. Adapted from: Smolen JS, et al. Nat Rev Drug Discov. 2003;2:473-488. 6

Importance of Early Diagnosis in RA

• RA is progressive, not benign
• Structural damage and disability occur within first 2 to 3 years of disease
• Slower progression of disease is linked to early treatment with DMARDs
• Once bone and cartilage are damaged, they never return to normal

Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637; Smolen JS, et al. Ann Rheum Dis. 2017;76:960-977.

Disease

• nset

Optimal window of opportunity

• Severe functional decline
• Radiographic damage
• Work disability
• Premature death

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Radiographic Progression of RA

1987

Radiographs courtesy of Brian Peck, MD and Rick Pope MPAS, PA-C.

2007

8

Radiographic Progression of RA (cont’d)

20 16 12 8 4 5 10 15 20

Count Disease Duration (Years)

Wolfe F, et al. Arthritis Rheum. 1998;41:1571-1582. Joint-space narrowing count Erosion count Deformity count

• Joint-space narrowing

and erosion are seen in up to two-thirds of patients within the first 2 to 5 years of disease

• Irreversible damage

can develop within months of RA onset

9

Articular Manifestations of RA

• Swelling, tenderness, warmth, and painful motion
• Morning stiffness

‒ May also appear after brief periods of inactivity

• Inflammation of synovial joints
• Joint and periarticular tissue destruction
• Joints most often involved:

‒ Proximal interphalangeal (PIP) ‒ Metacarpophalangeal (MCP) ‒ Wrists, elbows, shoulders, knees, ankles, and subtalar and metatarsophalangeal (MTP) joints

PIP Swelling

Haudenschild DR, et al. In: Kelley’s Textbook of Rheumatology, 9th ed. 2012. Image from: Ostendorf B, et al. Ann Rheum Dis. 2005;64:501-502.

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Early RA in a Young Woman

Image courtesy of Lester Miller, MD.

• Symmetrical joint swelling in

the hands

• Swelling prominent in the PIP

joints and in the left thumb interphalangeal (IP) joint

11

Early RA in a Young Woman

Image courtesy of Lester Miller, MD.

• Swelling is particularly

prominent in the MTP joints, especially the 1st and 5th MTPs

12

Case Study: Tara, a 42-year old woman

• Presents with a 3-month history of pain and stiffness in hands and right knee, as well as

chronic fatigue

• Complains of morning stiffness >30 minutes and increased pain at work as a post office

mail sorter

• 2 MCP joints (left hand) and 1 PIP joint (right hand) are visibly swollen
• Height: 5 ft 2 in; weight: 150 lb; BMI: 27.4 kg/m2; BP: 123/82 mm Hg
• Previous clinician had diagnosed OA, prescribed NSAIDs, and suggested diet and exercise

to lose weight

• Mother had RA
• Smoking status: 1/2 pack per day
• Alcohol consumption: drinks socially

NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis.

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Squeeze Test Assessment

• Squeeze test allows for

quick clinical evaluation

• f MTP/MCP joints
• Tenderness identified

by gentle palpation of the joints

Emery P, et al. Ann Rheum Dis. 2002;61:290-297.

\

14

Common Disorders to Consider in the Differential Diagnosis of Arthritides

RA OA PsA Gout Peripheral disease Symmetric Asymmetric Asymmetric — Axial joint/spondylitis No No Yes Less often Stiffness Morning/ immobility With activity Morning/ immobility Yes Enthesitis No No Yes Yes Nail lesions No No Yes No Psoriasis Uncommon Uncommon Yes Uncommon Female:male ratio 3:1 Hand/knee > in women 1:1 —

PsA = psoriatic arthritis. Gottlieb A, et al. J Am Acad Dermatol. 2008;58:851-864; Mease PJ, Armstrong AW. Drugs. 2014;74:423-441. 15

Progression of Joint Damage in Subgroups

• f Early RA

Radiographic Joint Damage Score Time (Years)

Anti-CCP– Anti-CCP+

Key Biomarker in RA: Anti-CCP

Van der Helm-van Mil AH, et al. Arthritis Res Ther. 2005;7:R949-R958. 2 4 10 20 30 40

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Case Study: Tara’s Lab and Imaging Results

ANA = antinuclear antibodies; ESR = erythrocyte sedimentation rate.

• ANA: 1:60 (positive)
• Anti-CCP: >250 u/mL (positive)
• CRP: 20.5 (positive)
• ESR: 48 mm/hr (positive)
• RF: 87 U/mL (positive)
• Uric acid: 4.5 mg/dL (normal)
• X-rays of hands and feet: normal

17

Case Study: Next Steps

• Based on the history, physical exam, lab tests, and x-rays, you suspect an

inflammatory arthritis, most likely RA

• You refer Tara to a rheumatology specialist for confirmation and

management

• Specialist performs a full workup and concludes that Tara has early,

moderately active RA

• Specialist discusses with Tara the advantages of treating RA aggressively

to achieve clinical remission (or at least low disease activity [LDA])

18

Treatment Strategy for RA: Treat-to-Target Task Force Algorithm

Active RA Clinical remission (eg, DAS) Clinical sustained remission LDA Sustained LDA MAIN TARGET ALTERNATIVE TARGET

• Measure disease

activity every 1-3 months

• Adapt therapy

accordingly

• Measure disease

activity ~3-6 months

• Adapt therapy if

state is lost

DAS = disease activity score. Task Force definitions: active RA = DAS44 score >2.4; remission = absence of signs and symptoms of significant inflammatory disease activity; sustained remission = remission sustained for 3-6 months; LDA = DAS44 score ≥1.6 to ≤2.4; sustained LDA = LDA sustained for 3-6 months. Adapted from: Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637. Grigor C, et al. Lancet. 2004;364:263-269.

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Criteria for Clinical Remission

*Patient Global Assessment = patient self-reporting questionnaire. ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; SDAI = Simplified Disease Activity Index; SJC = swollen joint count; TJC = total joint count. Felson DT, et al. Ann Rheum Dis. 2011;70:404-413.

• Definition: absence of signs and

symptoms of significant inflammatory disease activity

• According to ACR and EULAR,

remission is achieved when: ‒ TJC, SJC, CRP level (in mg/L) and Patient Global Assessment* (on a scale of 0-10 cm) are all ≤1; or ‒ SDAI score is ≤3.3

20

• MTX is the anchor drug

for treatment of RA

The ACR Guideline for Early RA: How it Applies to Tara

Combination traditional DMARDs or TNFi +/- MTX or non-TNF biologic +/- MTX See established RA algorithm

Treat to target

Moderate or high disease activity Low disease activity DMARD monotherapy DMARD monotherapy Moderate or high disease activity Moderate or high disease activity Strong recommendation Conditional recommendation

Tara

DMARD-naïve early RA

MTX = methotrexate; TNFi = tumor necrosis factor inhibitor. Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25. 21

Case Study: Tara’s Management Plan

• Tara is prescribed MTX (20 mg/week orally) and folic acid
• She is counseled on:

‒ Need for reliable contraception ‒ No alcohol within 24 hours of MTX dose ‒ Smoking cessation ‒ Diet and exercise to reduce weight

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Case Study: 3-month Follow-up

• Tara complains that she’s had only minimal improvement in symptoms

and that she has some nausea, vomiting, and hair loss from the MTX

• Other findings

‒ Has reduced alcohol intake as instructed ‒ Has lost 5 lbs ‒ Hasn’t stopped smoking ‒ Still has 2 swollen MCP joints and knee pain

23

• MTX is the anchor drug

for treatment of RA

Where Tara Is Now in the ACR Guideline for Early RA

Strong recommendation Conditional recommendation

Tara

Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25. Combination traditional DMARDs or TNFi +/- MTX or non-TNF biologic +/- MTX See established RA algorithm

Treat to target

Moderate or high disease activity Low disease activity DMARD monotherapy DMARD monotherapy Moderate or high disease activity Moderate or high disease activity DMARD-naïve early RA

24 *Contraindicated prior to and during pregnancy and breastfeeding, as well as in patients with active bacterial infection, active herpes zoster virus infection, active or latent tuberculosis, or acute or chronic hepatitis B or C. AE = adverse event. Hydroxychloroquine [prescribing information]. Sanofi-Aventis; 2019; Minocycline [prescribing information]. Medicis; 2011; Rigby WF, et al. Int J Rheumatol. 2017:9614241; Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639; Singh JA, et al. Arthritis Care Res. 2016;68:1-25; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531-541.

Conventional Synthetic DMARDs for RA

Agent Risks and AEs Routine Laboratory Monitoring Hydroxychloroquine Nausea, vomiting, diarrhea, rash/hyperpigmentation, cytopenia, myopathy, cardiac dysrhythmias, retinopathy None Leflunomide* Hypertension, hepatotoxicity, myelotoxicity, severe diarrhea Complete blood count, liver transaminase levels, and serum creatinine levels Methotrexate* Hepatotoxicity, fibrosing alveolitis, myelotoxicity,

• pportunistic infection, teratogenicity, nausea, vomiting

Minocycline Nausea, vomiting, diarrhea, dyspepsia, dizziness, skin rash, teratogenicity Sulfasalazine Hepatotoxicity, hypersensitivity reactions, myelotoxicity, reversible male infertility

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aContraindicated in patients with active bacterial infection, active herpes zoster virus infection, active or latent tuberculosis, or acute or chronic hepatitis B or C. bLive vaccines should be avoided in patients currently taking immunosuppressive agents or likely to start immunosuppressive therapy within 6-12 weeks.

ABA = abatacept; ADA = adalimumab; CTZ = certolizumab pegol; ETN = etanercept; GLM = golimumab; IFX = infliximab; RTX = rituximab. Furst DE, et al. Ann Rheum Dis. 2012;71(Suppl 2):i2-i45; Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531-541.

Class (Agent)a,b Risks and AEs Routine Laboratory Monitoring TNF blockade Adalimumab Certolizumab pegol Etanercept Golimumab Infliximab Injection site reactions, infections, demyelinating disease exacerbation or new onset, heart failure worsening or new onset, lymphoma, melanoma ADA: None CTZ: None ETN: None GLM and IFX: Liver enzymes, neutrophils and/or platelets, and serum creatinine T-cell costimulation blockade Abatacept Infusion reactions, infections ABA: None B-cell depletion Rituximab Infusion reactions, infections RTX: Liver enzymes, neutrophils and/or platelets, and serum creatinine

Biologic and Targeted Synthetic DMARDs for RA

26

aContraindicated in patients with active bacterial infection, active herpes zoster virus infection, active or latent tuberculosis, or acute or chronic hepatitis B or C. bLive vaccines should be avoided in patients currently taking immunosuppressive agents or likely to start immunosuppressive therapy within 6 to12 weeks.

BCB = baricitinib; IL = interleukin; JAK = Janus kinase; SRB = sarilumab; TCZ = tocilizumab; TOF = tofacitinib; UPA = upadacitinib; URI = upper respiratory infection. Baricitinib [prescribing information]. Lilly USA; 2019; Furst DE, et al. Ann Rheum Dis. 2012;71(Suppl 2):i2-i45; Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Sarilumab [prescribing information]. Sanofi-Aventis; 2018; Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639; Upadacitinib [prescribing information]. AbbVie Ireland NL B.V; 2019; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531-541.

Class (Agent)a,b Risks and AEs Routine Laboratory Monitoring IL-6 receptor blockade Sarilumab Tocilizumab Infusion reactions, infections, neutropenia, reduced platelet counts, elevated liver enzymes, elevated lipids, GI tract perforation SRB: Liver enzymes, neutrophils and/or platelets; infection, tuberculosis TCZ: Lipids, liver enzymes, neutrophils and/or platelets JAK inhibition Baricitinib Tofacitinib Upadacitinib URIs, shingles, headache, diarrhea, nasopharyngitis, lymphoma, nonmelanoma skin cancer, GI tract perforation, lipid abnormalities BCB: Infection, tuberculosis, hepatitis B TOF: Lipids, liver enzymes, neutrophils and/or platelets UPA: Lipids, liver enzymes, neutrophils, hemoglobin, lymphocytes IL-1 receptor blockade Anakinra Injection site reactions, infections, neutropenia None

Biologic and Targeted Synthetic DMARDs for RA (cont’d)

27

After 6 Months, Tara’s RA Remains Moderately Active

• After Tara’s last visit, the specialist

⎻ Switched her from oral to SC MTX to address her nausea and vomiting ⎻ Added the TNF inhibitor adalimumab ⎻ Continued folic acid; added folinic acid weekly

• Tara is still unsuccessful in attempts to quit smoking
• She continues to work toward losing weight with diet and exercise
• However, after 3 months of MTX + adalimumab therapy, Tara still:

⎻ Has morning stiffness and pain that impair her ability to work ⎻ Feels fatigued ⎻ Has problems tolerating MTX, even in SC form

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Case Study: Adjusting Treatment

• To reach the target of clinical remission for Tara, the specialist:

‒ Discontinues adalimumab and MTX ‒ Switches her to the IL-6 inhibitor sarilumab

29

Adjusting Treatment to Achieve the Therapeutic Target

Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625-639; Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637; Smolen JS, et al. Ann Rheum Dis. 2017;76:960-977.

• Frequent disease activity

assessments (1-3 months for active disease) recommended to assess treatment response

• If no improvement by 3 months or

target has not been reached by 6 months, treatment adjustment is warranted

Active RA Clinical remission (eg, DAS) Clinical sustained remission LDA Sustained LDA MAIN TARGET ALTERNATIVE TARGET

• Measure disease

activity every 1-3 months

• Adapt therapy

accordingly

• Measure disease

activity ~3-6 months

• Adapt therapy if

state is lost 30

Biologic Monotherapy for RA: Sarilumab vs Adalimumab

*Difference: -1.08 (95% CI: -1.36 to -0.79) LS = least squares. Burmester GR, et al. Ann Rheum Dis. 2017;76:840-847.

• Phase 3 study examined

sarilumab vs adalimumab as monotherapy in patients with RA

• Primary endpoint was change

from baseline in DAS28-ESR at week 24

• Sarilumab demonstrated

‒ 49% greater improvement in DAS28-ESR ‒ Reductions in disease activity and signs and symptoms of RA

• 2.2
• 3.28
• 5
• 4
• 3
• 2
• 1

12 24

LS mean change from baseline Week

Change in DAS28-ESR

Adalimumab, 40 mg q2w (n = 185) Sarilumab, 200 mg q2w (n = 184) P <0.0001 *

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JAK Inhibitors (Targeted Synthetic DMARDs) in Treatment of Moderate to Severe RA

• Tofacitinib

‒ For patients with inadequate response to MTX ‒ Do not use with biologic DMARDs or potent immunosuppressants

• Baricitinib

‒ For patients with inadequate response to ≥1 TNF inhibitor(s) ‒ Do not use with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants (eg, azathioprine, cyclosporine)

• Upadacitinib (most recently approved DMARD for RA)

‒ For patients with inadequate response to or intolerance of MTX ‒ Do not use with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants

Xeljanz [prescribing information].Pfizer; 2019; Olumiant [prescribing information]. Lilly USA; 2019; Rinvoq [prescribing information]. AbbVie: 2019. 32 ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03025308?term=filgotinib&cond=Rheumatoid+Arthritis&draw=2&rank=2. Accessed June 1, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02308163?term=Peficitinib&cond=Rheumatoid+Arthritis&draw=2&rank=2. Accessed May 27, 2020.

Emerging Treatments in Moderate to Severe RA

Filgotinib (Phase 3)

• JAK1 selective inhibitor

Peficitinib (Phase 3)

• Pan-JAK inhibitor, moderately selective for JAK3

33

Observations from the Epidemiological Investigation of RA and the Swedish Rheumatology Register Cohorts

Overall Cohort N = 994 MTX n = 626 No DMARD n = 109 TNF Inhibitors n = 301 Good Responders (%) 45 40 35 30 25 20 15 10 5 P = .05 P = .95 P = .42 P = .01 P = .07 P = .03 P = .52 P = .04

Smoking Status: Never Past Current

Smoking Blunts RA Treatment

Response in overall cohort and in subgroups receiving MTX or clinical care without a DMARD at baseline, as well as in those receiving subsequent TNF inhibitors. Saevarsdottir S, et al. Arthritis Rheum. 2011;63:26-36.

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Responsibilities of Primary Care Clinicians as Part of a Multidisciplinary Team in RA

• Symptom management
• Monitor for comorbidities and

extra-articular manifestations

• AE monitoring
• Smoking cessation counseling
• Nutrition and weight management
• Referrals as needed to

– Rheumatology – Cardiology – Pulmonary – Occupational therapy – Physical therapy – Psychiatry

• Pregnancy counseling

Hill J, et al. Musculoskeletal Care. 2003;1:5-20; Hooker RS, et al. Health Soc Care Community. 2012;20:20-31; Solomon DH, et al. Arthritis Care Res (Hoboken). 2014;66:1108-1113. 35

Don’t Neglect CVD Risk in Patients With RA

Agca R, et al. Ann Rheum Disease. 2017;76:17-28; Chodara AM, Curr Rheumatol Rep. 2017;19:16; Peters MJ, et al. Ann Rheum Dis. 2010;69:325-331.

• RA is an independent risk factor for CVD
• Patients with RA have an increased risk of CVD and a 50% to 70% greater risk
• f heart disease compared to the general population
• EULAR recommendations for CVD risk management in RA

‒ Assess CVD risk regularly ‒ Include total cholesterol and high-density lipoprotein cholesterol as part of risk assessment ‒ Measure lipids when disease activity is stable or in remission ‒ Consider screening for asymptomatic atherosclerotic plaques with carotid ultrasound

36

Extra-Articular Manifestations and Common Comorbidities in RA

• Extra-articular manifestations include:

‒ CVD ‒ Pulmonary disease ‒ Ocular inflammation ‒ Nodules ‒ Neuropathies ‒ Myopathies

Atzeni F, et al. Autoimmun Rev. 2013;12:575-579; Avina-Zubieta JA, et al. Arthritis Rheum. 2008;59:1690-1697; Cutolo M, et al. Semin Arthritis

• Rheum. 2014;43:479-488; Furst DE, et al. Ann Rheum Dis. 2012;71(Suppl 2):i2-i45; Makol A, et al. Rheum Dis Clin North Am. 2012;38:771-793;

Primdahl J, et al. Ann Rheum Dis. 2013;72:1771-1776; Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25; Young A, Koduri G. Best Pract Res Clin Rheumatol. 2007;21:907-927; Klodzinski T, et al. Reumatologia. 2018;56:288-233.

• Comorbidities include:

‒ Cardiovascular, lung, and kidney diseases ‒ GI disorders ‒ Infections ‒ Malignancies ‒ Osteoporosis ‒ Depression

• RA is a systemic disease with sequelae beyond joint damage

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• Older male patient with moderately

severe interstitial lung disease (ILD), primarily involving the mid and lower lung fields

• Most common form of ILD in RA is

interstitial pneumonitis

Rheumatoid Lung in an Elderly Man

Image courtesy of Lester Miller, MD. 38

• Scleritis in an older woman with

long-standing RA

• Inflammation in the sclera becomes

thinner and translucent

• Result is the sclera having a bluish

hue from the underlying choroid layer of the eye

Ocular Scleritis in RA

Image courtesy of Lester Miller, MD. 39

Vaccine Considerations in RA

Live vaccines to be avoided when using biologics

• Herpes zoster (shingles) [Zostavax only]*
• Live attenuated viral/intranasal spray for influenza
• Adenovirus
• Cholera
• Measles, mumps, rubella
• Measles, mumps, rubella, varicella
• Rotavirus
• Typhoid (live attenuated bacterial oral)
• Varicella
• Vaccinia (smallpox)
• Yellow fever

Important points to remember

• Inactivated influenza and pneumococcal

vaccines are strongly recommended and are safe, but therapeutic response may be reduced

• If a live vaccine is indicated, administer 4 weeks

before starting therapy

• Routine immunizations should be up to date

before travel

*Shingrix is an inactivated recombinant, adjuvanted (non-live) vaccine for herpes zoster. Centers for Disease Control and Prevention. www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/appdx-full-b.pdf. Accessed May 27, 2020; Wine-Lee L, et al. J Am Acad Dermatol. 2013;69:1003-1013.

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Coordinating Multidisciplinary Treatment Teams

Taal E, et al. Clin Rheumatol. 2006;25:189-197.

• Develop relationships with at least

1 to 2 rheumatology specialists to facilitate timely referrals

• Multidisciplinary teams do not have

to practice together in the same building or setting RA PATIENT

Rheumatology Specialty Care

Primary Care MD, PA, NP Cardiology Pulmonology Physical Therapy Psychology Orthopedics Social Work

41

ACR: RA Treatment Recommendations in the Context of COVID-19

AZA = azathioprine; CSA = cyclosporine; CQ = chloroquine; HCQ = hydroxychloroquine; LEF = leflunomide; MMF = mycophenolate mofetil; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SSZ = sulfasalazine. Mikuls TR, et al. Arthritis Rheum. 2020:[Epub ahead of print].

• Patients exposed to SARS-CoV-2

‒ Continue HCQ/CQ, SSZ, NSAIDs ‒ Temporarily halt immunosuppressants pending a negative test for COVID-19 or 2 weeks of symptom-free observation:

• Tacrolimus, CSA, MMF, AZA
• Non-IL-6 biologics
• JAK inhibitors

‒ IL-6 inhibitors may be continued in select circumstances, as part of a shared decision-making process

• Patients with documented or presumptive

COVID-19 ‒ Regardless of COVID-19 severity, HCQ/CQ may be continued, but SSZ, MTX, LEF, immunosuppressants, non-IL-6 biologics, and JAK inhibitors should be stopped or held ‒ In patients with severe respiratory symptoms, NSAIDs should be stopped ‒ IL-6 inhibitors may be continued in select circumstances, as part of a shared decision-making process

42

IL-6 Agents in Clinical Trials for COVID-19

ClinicalTrials.gov. clinicaltrials.gov/ct2/results?cond=COVID&term=sarilumab&cntry=&state=&city=&dist=. Accessed May 27, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/results?cond=COVID&term=Tocilizumab&cntry=&state=&city=&dist=. Accessed May 27, 2020.

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Case Conclusion

• Tara is given a PCR test for COVID-19; result was negative, and she did

not develop symptoms

• She achieves clinical remission 3 months after switching to sarilumab

monotherapy

• She is finally able to quit smoking
• Loses 15 lb by increasing exercise and following a low-fat diet with

anti-inflammatory benefits

• Multidisciplinary team will continue to monitor her RA disease activity and

quality of life, assess for any radiologic changes, and follow for AEs, extra-articular manifestations, and comorbidities

PCR = polymerase chain reaction. 44

PCE Action Plan

 Discuss with patients that the goal is to achieve clinical remission  Adjust treatment if the therapeutic target has not been achieved in 6 months  Consider RA as an independent risk factor for CVD  Identify members of your expanded care team and promote collaborative care PCE Promotes Practice Change

43 44