Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
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Learning Objectives
• Screen patients for insomnia according to current diagnostic criteria • Identify the cause of insomnia, including psychosocial and lifestyle issues and comorbidities, to determine treatment and reduce risk factors • Individualize treatment with approved insomnia medications, including dual orexin receptor antagonists
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Insomnia: Definition and Types
Desired • Patient report of difficulty: wake time Sleep-maintenance ‒ Initiating sleep insomnia ‒ Maintaining sleep • Adequate opportunity and circumstances for sleep Sleep-onset • Daytime impairment insomnia
Bedtime
Sateia MJ. Chest. 2014;146:1387-1394; Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349. 3 3 2020 PCE Symposia Series 3 1 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Epidemiology of Insomnia
Prevalence of Insomnia Symptoms* in the US Proportion of Patients With Insomnia† Who Discuss Symptoms with HCP 2%
5% Never Never discuss 19% Rarely 33% Mention during discussion 26% of a different problem A few nights per month Specifically seek evaluation 69% A few nights per week 25% for insomnia Every night or almost 21% every night
*Insomnia symptoms defined as trouble falling asleep, waking frequently at night, †Insomnia defined as having any history of difficulty sleeping waking too early and unable to fall back asleep, or waking feeling unrefreshed
Ancoli-Israel S, et al. Sleep. 1999;22(suppl 2):S347-S353; Bailes S, et al. Fam Pract. 2009;26:294-300; National Sleep Foundation. www.sleepfoundation.org/professionals/sleep-america-polls/2005-adult-sleep-habits-and-styles. Accessed October 19, 2020. 4 4
Pathophysiology of Insomnia
Increased brain & body metabolism
Cognitive arousal Hyperarousal EEG arousal
Sympathetic nervous HPA axis activation system activation
Insomnia
EEG = electroencephalogram; HPA = hypothalamic-pituitary-adrenal axis. Bonnet MH, et al. Sleep Med Rev. 2010;14:9-15; Buysse D. JAMA. 2013;309:706-716. 5 5
Case Study: Kylie, a 58-Year-Old Business Manager
• Primary reason for telehealth visit: wakes up around 3 AM every night and rarely gets back to sleep ‒ Symptoms began 6 months ago along with stress about working from home and maintaining company productivity due to quarantine measures • Works at small construction firm ‒ Worries about not being able to function during accepted work hours ‒ Falls asleep at computer most afternoons despite drinking coffee ‒ Complains of more time sitting, less exercise; has gained 7 pounds ‒ 1 to 2 alcoholic drinks nightly at home with partner—an increase from pre-pandemic days • Wants something to help her sleep through the night
6 6 6 2020 PCE Symposia Series 3 2 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Case Study (cont’d): Kylie’s History and Physical Findings
• Medical history • Physical exam at her last visit ‒ Generally healthy; last in-person visit ‒ Blood pressure: 140/80 mm Hg was February 2020 ‒ Heart rate: 83 beats/min ‒ Nonsmoker ‒ Respiration rate: 16 breaths/min ‒ Postmenopausal ‒ 5 ft 9 in; 145 lb (BMI: 21.4 kg/m2) ‒ Hypertension (controlled with • Testing at last visit amlodipine) ‒ CBC, CMP, TFT: all within normal • Anxious affect apparent during telehealth ranges consult
7 CBC = complete blood count; CMP = complete metabolic panel; TFT = thyroid function test. 7 7
Risk Factors for Insomnia
• Age ≥65 years • Female • Shift work • Stressors (eg, unemployment, divorce) • Lower socioeconomic status • Comorbid conditions
Matheson E, et al. Am Fam Physician. 2017;96:29-35; Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504. 8 8
What To Ask About When Taking a Thorough Insomnia History
Include history from bed partners or caregivers whenever possible • Frequency and quality of snoring • Activities before bed • Trouble falling sleep (eg, time to fall asleep) • Bedroom environment • Awakenings (eg, number, duration) • Daytime symptoms and activities (fatigue, naps, • Quality of sleep (poor or unrefreshing) work, quality of life) • When symptoms first started • Disturbance in mood or cognitive function • Frequency and severity of symptoms • Associated symptoms and behaviors surrounding and during sleep • Duration of sleep • Contributing comorbid conditions, medications, • Contributing and perpetuating factors and substances • Prior treatments and responses
Riemann D, et al. J Sleep Res. 2017;26:675-700; Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504. 9 9 2020 PCE Symposia Series 3 3 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Effects of COVID-19 Measures on Sleep
• Higher rates of insomnia, depression, anxiety reported in essential workers and general population • Disruption of regular schedules contributes to sleep disorders ‒ Effects of confinement/social isolation and limited outdoor activity ‒ Loss of sleep-wake cues due to atypical work, social, and exercise schedules • Depression and/or anxiety related to finances, social isolation, worries about childcare or infection • Changes in work schedules add to concerns about exposure and family time
Altena E, et al. J Sleep Res. 2020;29:e13052; Morin CM, et al. Can J Public Health. 2020;July 22:1-4. 10 10
Impact of Insomnia
• Impaired daytime functioning • Risk factor for: – Drowsy driving and fatal crashes – Coronary artery disease – Injuries and accidents – Depression – Decreased quality of life – Hypertension – Increased presenteeism and – Diabetes absenteeism – Obesity – Stroke – Suicide attempts – Overall mortality
Daley M, et al. Sleep. 2009;32:55-64; Liu Y, et al. MMWR. 2016;65:137-141; National Center for Statistics and Analysis. crashstats.nhtsa.dot.gov/Api/Public/ViewPublication/812446. Accessed October 19, 2020; Winkelman JW. N Engl J Med. 2015;373:1437-1444. 11 11
Increased Prevalence of Medical Disorders in People With Insomnia
100 90 No Insomnia (n = 401) P <.001 80 Insomnia (n = 137) 70 60 P <.001 50 P <.001 40 P <.001
Patients (%) Patients 30 P <.01 P <.05 P <.01 20 P <.05 10 0 Heart Cancer Hyper- Neurologic Breathing Urinary Diabetes Chronic GI Any Disease tension Disease Problems Problems Pain Problems Medical Problems
Taylor DJ, et al. Sleep. 2007;30:213-218. 12 12 2020 PCE Symposia Series 3 4 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Contributing Medications and Substances
Category Medications or Substances Stimulants Caffeine, amphetamines, methylphenidate, ephedrine, cocaine Antidepressants SSRIs (eg, sertraline, citalopram), duloxetine, venlafaxine, MAOIs Decongestants Pseudoephedrine, phenylephrine, phenylpropanolamine Opioids Codeine, oxycodone, propoxyphene, hydrocodone, meperidine, morphine, heroin Cardiovascular Diuretics Corticosteroids Hydrocortisone, cortisone, prednisolone, prednisone, methylprednisolone, dexamethasone (oral, IV, IM)
Pulmonary Albuterol, theophylline Alcohol Alcohol
MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor. Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504; Serdarevic M, et al. Sleep Health. 2017;3:368-372; Warrington TP, et al. Mayo Clin Proc. 2006;81:1361-1367. 13 13
Multiple Factors Contribute to Insomnia
• Sleep history provides clues to patient’s symptoms and environment • Medical history can identify comorbidities that may contribute to, or result from, insomnia • Medications, foods, alcohol, and recreational substances often contribute to insomnia • Identify modifiable triggers as a first step in management
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Case Study (cont’d): Kylie’s Sleep History
• Goes to bed by midnight and falls asleep quickly (confirmed by partner) • Wakes up around 3:00 AM every night, followed by no or fitful sleep until final awakening at 7:00 AM (desired wake-up time) • Partner confirms no snoring, breathing pauses, or limb movements during sleep • Forgetful, fatigued, slower than normal at work tasks despite six cups of coffee daily • Feels that symptoms are worsening over time (confirmed by partner)
15 15 2020 PCE Symposia Series 3 5 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
DSM-5 Diagnostic Criteria for Insomnia
A. Dissatisfaction with sleep quantity or quality with one or more of the following: 1. Difficulty initiating sleep 2. Difficulty maintaining sleep • Poor sleep maintenance 3. Early morning awakening with inability to return to sleep is the most prevalent B. Significant distress or impairment in social, occupational, educational, academic, symptom, reported by behavioral, or other important areas of function 50% to 70% of adults C. ≥3 nights per week with insomnia
D. ≥3 months • However, multiple sleep E. Adequate opportunity for sleep symptoms are more
F. Not better explained by or solely due to another sleep-wake disorder common than single symptoms G. Not attributable to medication or substance use
H. Not adequately explained by comorbid medical or mental disorders
16 Buysse D. JAMA. 2013;309:706-716; Center for Behavioral Health Statistics and Quality. www.ncbi.nlm.nih.gov/books/NBK519704/table/ch3.t36/. Accessed October 19, 2020. 16 16
Assessing Severity of Symptoms
• Sleep diary ‒ Helps identify patterns or behaviors that contribute to insomnia • Insomnia Severity Index (ISI) ‒ 7-item ISI is a validated, patient-completed tool ‒ Helps identify sleep onset from sleep maintenance insomnia • Other useful instruments ‒ Epworth Sleepiness Scale (ESS): Assesses daytime sleepiness ‒ Sleep Hygiene Self Test (SHST): Assesses behaviors contributing to insomnia ‒ Simple screening tests for depression or anxiety
American Academy of Sleep Medicine. yoursleep.aasmnet.org/pdf/sleepdiary.pdf. Accessed September 9, 2020; Bastien CH, et al. Sleep Med. 2001;2:297-307; Buysse DJ. JAMA. 2013;309:706-716; Doghramji P. In: Insomnia in Primary Care: Overcoming Diagnostic and Treatment Barriers. 2004:14-22; Riemann D, et al. J Sleep Res. 2017;26:675-700. 17 17
Kylie’s Sleep Diary
Day of Type of Date week day Noon 1 PM 2 3 4 5 6 PM 7 8 9 10 11PM Midnight 1 AM 2 3 4 5 6 AM 7 8 9 10 11 AM 9/15 Tuesday Work C C C A ↓ ↑ C ME C
9/16 Wednesday Work C C C ↓ ↑ C M C 9/17 Thursday Work C C C C ↓ ↑ CCME C 9/18 Friday Work C C C A ↓ M C C
Week 1 Week ↑ 9/19 Saturday ½ Work C C A ↓ ↑ M E C 9/20Sunday Off C C E ↓ ↑ M C C 9/21 Monday Work C C C C ↓ ↑ C M C
A = alcohol; C = caffeine; E = exercise; M = medication; ↓ = Going to bed; ↑ = Out of bed. = naps and nighttime sleep.
18 American Academy of Sleep Medicine. yoursleep.aasmnet.org/pdf/sleepdiary.pdf. Accessed October 19, 2020. 18 18 2020 PCE Symposia Series 3 6 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Kylie’s Results on the 7-Item ISI
Question Points 0 1 2 3 4 SEVERITY of insomnia symptoms 1. Difficulty falling asleep None Mild Moderate Severe Very 2. Difficulty staying asleep None Mild Moderate Severe Very 3. Problem waking up too early None Mild Moderate Severe Very 4. SATISFIED with current sleep pattern? Very Much Somewhat A little Not at all 5. Symptoms INTERFERE with daily function? Not at all A little Somewhat Much Very much 6. NOTICEABLE to others? Not at all Barely Somewhat Much Very much 7. WORRIED about your sleep problem? Not at all A little Somewhat Much Very much
Kylie’s Score = 21
No Insomnia Subthreshold Insomnia Moderate Insomnia Severe Insomnia 0 to 7 8 to 14 15 to 21 22 to 28
19 Bastien CH, et al. Sleep Med. 2001;2:297-307. 19 19
Consider Using the 3-Item ISI to Screen for Insomnia Disorder
Question Points 0 1 2 3 4 1. SATISFIED with current sleep pattern? Very Much Somewhat A little Not at all
2. Symptoms INTERFERE with daily function? Not at all A little Somewhat Much Very much
3. WORRIED about your sleep problem? Not at all A little Somewhat Much Very much
Kylie’s score would have been 10 if you had used this as a screening tool before she actually presented with insomnia
• Score ≥7 suggests clinically significant insomnia • If a patient scores ≥7 on the 3-item ISI, follow up with the 7-item ISI
20 Thakral M, et al. Sleep Med. 2020:[epub ahead of print] 20 20
Diagnostic Testing To Consider in Insomnia
• Order testing only if a comorbid medical disorder or another sleep disorder is suspected • Diagnostic testing for suspected medical disorders – Bloodwork: CMP, CBC, TFT, ferritin, vitamin B12, CRP ‒ Other testing: EEG, ECG, CT, MRI • Diagnostic testing for other suspected sleep disorders ‒ Polysomnography (eg, OSA, periodic limb movement disorder) ‒ Actigraphy (eg, circadian rhythm disorder)
CRP = C-reactive protein; OSA = obstructive sleep apnea. Riemann D, et al. J Sleep Res. 2017;26:675-700. 21 21 2020 PCE Symposia Series 3 7 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Differential Diagnosis of Insomnia
• Insomnia associated with other sleep disorders ‒ Movement disorders (eg, restless legs syndrome, periodic limb movement disorder) ‒ Sleep-related breathing disorders (eg, OSA) ‒ Circadian rhythm sleep disorders (eg, delayed sleep disorder, shift work disorder) • Shift work, jet lag, total blindness • Very early or very late sleep/wake times • Sleep-wake disturbance • Daytime impairment • Comorbid insomnia associated with medical or psychiatric disorders, medications, or substance use
Sack RL, et al. Sleep. 2007;30:1460-1483; Sack RL, et al. Sleep. 2007;30:1484-1501; Sateia MJ. Chest. 2014;146:1387-1394; Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504. 22 22
Case Study (cont’d)
• You ask Kylie to complete depression and anxiety rating scales, both of which are in the normal range • Although she reports feeling anxious, her anxiety appears to be entirely related to worry about her ability to sleep adequately • You rule out other comorbid conditions
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Sleep Hygiene: Necessary But Not Necessarily Sufficient
Patient should… Patient should avoid… • Awaken at same time every morning • Napping (unless shift worker) • Increase exposure to bright light during the day • Alcohol • Establish daily activity routine • Caffeine, nicotine, other stimulants • Exercise regularly in morning and/or afternoon • Bright light during the night (eg, TV, smartphone) • Set aside a “worry time” • Exercise within 3 hours of bedtime • Establish comfortable sleep environment • Heavy meals or drinking within 3 hours of bedtime • Do something relaxing before bed • Noise • Consider a warm bath before bed • Excessive heat/cold in bedroom • Using bed for other than sleep or sex • Watching the clock • Trying too hard to fall asleep
24 American Academy of Sleep Medicine. sleepeducation.org/essentials-in-sleep/healthy-sleep-habits. Accessed October 19, 2020; Ancoli-Israel S, et al. Postgrad Med. 2004;116(6 Suppl Insomnia):23-32; Doghramji K, Doghramji PP. Clinical Management of Insomnia. 2015. 24 24 2020 PCE Symposia Series 3 8 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
CBT-I: First-Line Treatment for Insomnia
Component Purpose Recommendations Stimulus control • Reduce arousal in sleep Go to bed when sleepy; get out of bed when awake environment or anxious; do not worry or plan in bed; use bed • Associate bed with sleep only for sleep or sexual activity Sleep restriction • Increase sleep drive Reduce amount of time in bed (no less than 5-6 • Stabilize circadian rhythm hours); gradually increase time in bed as sleep symptoms improve Sleep hygiene • Minimize behaviors that disrupt Avoid napping; limit caffeine (after noon) and sleep drive or increase arousal alcohol; regular exercise (but not close to bedtime); keep bedroom cool, dark, and quiet Cognitive therapy • Restructure maladaptive beliefs Identify and challenge dysfunctional beliefs about about sleep that may perpetuate sleep and consequences of insomnia; manage insomnia expectations about sleep Relaxation therapy • Reduce arousal (physical, Practice breathing exercises, meditation, physiologic) in sleep progressive muscle relaxation environment
Boland E, et al. Sleep Med Clin. 2019;14:291-299; Winkelman JW. N Engl J Med. 2015;373:1437-1444. 25 25
CBT-I Is an Effective Tool That Can Be Individualized to Patient Needs and Circumstances
• CBT-I administered by a trained provider • Effective in multiple formats for (usually for 6-8 sessions) is highly individuals or groups effective (~80% efficacy rate) ‒ In-person sessions ‒ Improves time to sleep onset ‒ Telephone/telehealth review of ‒ Decreases time awake after sleep questionnaires, sleep logs onset ‒ Internet-based CBT-I ‒ Provides benefit for 6 to 12 months after treatment is complete
American Academy of Sleep Medicine. aasm.org/covid-19-resources/considerations-practice-sleep-medicine/. Accessed October 19, 2020; Boland E, et al. Sleep Med Clin. 2019;14:291-299; Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504; Winkelman JW. N Engl J Med. 2015;373:1437-1444. 26 26
Adapting CBT-I for Insomnia Associated With COVID-19
• Maintain regular sleep/wake schedules to bring structure to the day (including for children) • Get natural daylight exposure as much as possible; minimize bright light in evening • Avoid between-meal eating and stress eating; avoid meals within 2 hours of bedtime • Schedule time to reflect on stressors to avoid these thoughts at bedtime • Choose relaxing diversions (yoga, reading a book – not Kindle or iPad) before bed • Reach out to friends or family to avoid feelings of isolation • Avoid using the bedroom (and especially bed) for work, eating, or TV
Altena E, et al. J Sleep Res. 2020;29:e13052. 27 27 2020 PCE Symposia Series 3 9 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Case Study (cont’d)
• You counsel Kylie on sleep hygiene and refer her to a certified CBT-I provider • At 2-month follow up, Kylie reports: ‒ CBT-I sessions on Zoom have been “surprisingly” helpful ‒ Has been sleeping through the night about 3 nights a week ‒ Daytime anxiety has improved ‒ Still anxious at bedtime and after waking up at night; now concerned about reopening the business office ‒ Still “slow” and “dragging” during work hours ‒ Symptoms improved, but have plateaued over the last 2 weeks
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Pharmacologic Treatment: Factors to Consider When Selecting an Agent for Insomnia
• Symptom pattern • Adverse effect profile • Response to prior therapies • Patient preference • Comorbid conditions • Risk for dependency • Mechanism of action • Cost • Potential medication interactions
Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349; Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504. 29 29
Pharmacologic Treatment for Insomnia: FDA Indications and AASM Recommendations on Approved Agents
Drug Class Agent FDA Indication AASM Recommendation Schedule IV Dose Range Benzodiazepine Triazolam Insomnia Onset 0.125–0.25 mg Temazepam Insomnia Onset, maintenance 7.5–30 mg Benzodiazepine receptor Eszopiclone Onset, maintenance Onset, maintenance 1–3 mg agonist Zaleplon Onset Onset 5–10 mg Zolpidem Onset Onset, maintenance 5–10 mg Zolpidem ER Onset, maintenance Onset, maintenance 6.25–12.5 mg Zolpidem SL MOTN awakening None 1.75–3.5 mg Melatonin agonist Ramelteon Onset Onset 8 mg Selective H1 antagonist Doxepin Maintenance Maintenance 3–6 mg Dual orexin receptor Lemborexant Onset, maintenance Not available 5–10 mg antagonist (DORA) Suvorexant Onset, maintenance Maintenance 5–20 mg
AASM = American Academy of Sleep Medicine; ER = extended release; H1 = histamine 1 receptor; MOTN = middle of the night. Doxepin [prescribing information]. Somaxon Pharmaceuticals; 2010; Eszopiclone [prescribing information]. Sunovion Pharmaceuticals; 2019; Lemborexant [prescribing information]. Eisai; 2020; Matheson E, et al. Am Fam Physician. 2017;96:29-35; Ramelteon [prescribing information]. Takeda Pharmaceuticals; 2018; Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349; Suvorexant [prescribing information]. Merck & Co; 2020; Temazepam [prescribing information]. Mallinckrodt Pharmaceuticals; 2019; Triazolam [prescribing information]. Pfizer Inc; 2016; Zaleplon [prescribing information]. Pfizer Inc;2019; Zolpidem [prescribing information]. Sanofi-aventis; 2019; Zolpidem ER [prescribing information]. Sanofi-aventis; 2019; Zolpidem SL [prescribing information]. Sanofi-aventis; 2019. 30 30 2020 PCE Symposia Series 3 10 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Pharmacologic Treatment for Insomnia: AASM Recommendations
• No specific recommendation due to inadequate evidence: ‒ Other benzodiazepines approved for insomnia (ie, estazolam, flurazepam, quazepam) ‒ Agents used off-label for insomnia: oxazepam, quetiapine, gabapentin, paroxetine • AASM does NOT recommend for insomnia: ‒ Dietary supplements (ie, melatonin, L-tryptophan, valerian) ‒ OTC diphenhydramine (although FDA-approved as a sleep aid) ‒ Trazodone (off-label use) ‒ Tiagabine (off-label use) • Lemborexant was not available when AASM recommendations were developed
Diphenhydramine [prescribing information]. BD Simplist; 2018; Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349. 31 31
Orexin (Hypocretin) Neuropeptides
Awake state Sleep state • Different names by different discovering groups Limbic system SCN Orexin ‒ Orexin-A and -B: promote feeding (orexis) Orexin Energy balance neurons neurons ‒ Hypocretin-1 and -2: similar to incretins, Sleep-active Wake-active produced in hypothalamus neurons neurons • Physiologic roles POA POA Wake-active Sleep-active ‒ Sleep and wakefulness neurons neurons Sleep Wake ‒ Feeding and appetite
Wake Sleep ‒ Reward pathways • Narcolepsy: absence of orexin neurons Excitatory Inhibitory • Two dual orexin receptor antagonists currently approved for treatment of insomnia
SCN = suprachiasmatic nucleus; POA = preoptic anterior. Scammell TE, et al. Annu Rev Pharmacol Toxicol. 2011;51:243-266; Tsujino N, et al. Front Behav Neurosci. 2013;7:28. 32 32
Suvorexant: Phase 3 Efficacy Data in Sleep Maintenance
Wakefulness After Persistent Sleep Onset (WASO) • WASO ‒ Coprimary endpoint for 40/30 mg Trial 1 Suvorexant 40/30 mg (n = 383) Suvorexant 20/15 (n = 254) Placebo (n = 384) ‒ Secondary/exploratory endpoint for 0 20/15 mg ‒ Significantly improved vs placebo -20 (both doses) • Significantly shortened sleep latency in -40 Trials 1 and 2
-60 • In separate trial vs placebo, improved total P <0.001 vs placebo Baseline (minutes) Baseline sleep time among patients with insomnia -80 and mild to moderate probable Baseline
Adjusted Mean With Change From Change With Mean Adjusted Alzheimer’s disease Night 1 Month 1 Month 3
Herring WJ, et al. Biol Psychiatry. 2016;79:136-148; Herring WJ, et al. Alzheimer’s Dement. 2020;16:541-551; Shrivastava D, et al. J Community Hosp Intern Med Perspect. 2014;4:24983. 33 33 2020 PCE Symposia Series 3 11 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Lemborexant: Phase 3 Efficacy Data in Sleep Maintenance
WASO2H in SUNRISE 1 Subjective WASO in SUNRISE 2
0 0 aP <0.001 vs placebo; bP ≤0.001 vs zolpidem ER; *P <0.0001; †P <0.001; ‡P <0.01; §P <0.05. cP <0.01 vs zolpidem ER. -10 -10
a -20 -20 a ** a, c -30 a. c -30 a, b a, b -40 ‡ Placebo LSM Change (min) Change LSM -40 ‡§ Zolpidem ER Placebo (n = 318) †‡ -50 ‡‡ Lemborexant 5 mg From Change (SE) LSM Lemborexant 5 mg (n = 316) † § aeiefrsAO(min) sWASO for Baseline Lemborexant 10 mg (n = 315) -50 Lemborexant 10 mg -60 BL 1/2 29/30 BLFirst 7 123 4 5 6 Nights nights Month
LSM = least squares mean; sWASO = subjective WASO; WASO = wake after sleep onset; WASO2H = WASO in the second half of the night. Rosenberg R, et al. JAMA Network Open. 2019;2:e1918254; Kärppä M, et al. Sleep. 2020;43;zssa123. 34 34
Pharmacologic Options Can Further Improve Sleep Maintenance
• Different medical treatments are recommended for managing sleep onset and sleep maintenance • Know these differences and use agents indicated for the insomnia type of the individual patient • Consider efficacy, dosing, and abuse potential when choosing agents to manage insomnia ‒ Most sleep medicines have abuse potential, which must be addressed with patients ‒ Newer agents are generally better tolerated and may be more effective
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DORAs: Dosing and Administration
Lemborexant Suvorexant Recommended starting dose • 5 mg once daily • 10 mg once daily Maximum daily dose • 10 mg once daily • 20 mg once daily Timing • Immediately before bed • Within 30 minutes of bed • Ensure ≥7 hours before planned awakening Ensure ≥7 hours before planned awakening
Taking with or immediately after • May prolong time to effect • May prolong time to effect a meal
Hepatic impairment • Mild-moderate: dose adjustment • Mild-moderate: no dose adjustment • Severe: not recommended • Severe: not recommended
CYP3A4 inhibitors • Moderate or strong: avoid concomitant use • Strong: not recommended • Weak: 5 mg maximum dose • Moderate: 5 mg recommended
CYP3A4 inducers • Moderate or strong: avoid concomitant use • Strong: may reduce efficacy Alcohol use • Increases lemborexant exposure • Increases psychomotor impairment
Lemborexant [prescribing information]. Eisai; 2020; Suvorexant [prescribing information]. Merck & Co; 2020. 36 36 2020 PCE Symposia Series 3 12 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
DORAs: Adverse Effects and Precautions
• Most frequent adverse event: • Use with caution in patients with dose-dependent somnolence moderate to severe OSA or COPD • Avoid next-day driving or activities • Worsening depression/suicidal requiring complete alertness while ideation: Risk increases with using maximum dose or after less increasing dose of suvorexant; than full night’s sleep prescribe lowest possible number of • Sleep paralysis, cataplexy, tablets to avoid intentional overdose hypnagogic/hypnopompic of lemborexant hallucinations may occur • Evaluate for comorbid diagnosis if • Complex sleep behaviors (eg, sleep insomnia persists after 7 to 10 days walking, sleep driving): Discontinue • Contraindicated: Narcolepsy immediately • Boxed warnings: None
Lemborexant [prescribing information]. Eisai; 2020; Suvorexant [prescribing information]. Merck & Co; 2020. 37 37
DORAs: Special Studies
• Patients aged ≥65 years from clinical trials ‒ Lemborexant (N = 413): Similarly effective and well tolerated as overall patient cohort at 1 month ‒ Suvorexant: (N = 202 receiving 15 mg): Generally effective and well tolerated over 3 months • Morning-after effects on driving (~9 hours after administration) ‒ Lemborexant (N = 48): No effect on driving performance vs placebo with any dose or any age ‒ Suvorexant (N = 52): Clinically meaningful impairment vs placebo with 20-mg dose in non-elderly subjects • Safety when awakened in the middle of the night: Dose-dependent potential for postural instability with both and with memory/recall impairment with lemborexant • Rebound insomnia/withdrawal effects: No evidence of either with suvorexant or lemborexant
Ardeljian AD, et al. www.ncbi.nlm.nih.gov/books/NBK559070/. Accessed October 19, 2020; Herring WJ, et al. Am J Geriatr Psychiatry. 2017;25:795- 782; Lemborexant [prescribing information]. Eisai; 2020; Moline M, et al. Neurology. 2020;94(15 Suppl):1860; Suvorexant [prescribing information]. Merck & Co; 2020; Vermeeren A, et al. Sleep J. 2019;42:zsy260. 38 38
Other Pharmacologic Therapies for Insomnia: Adverse Reactions
Drug Class Agent Boxed Warning Adverse Reactions†
Benzodiazepine* Triazolam Use with opioids: respiratory Drowsiness, headache, dizziness, daytime anxiety depression, coma, death Temazepam Drowsiness, headache, fatigue, nervousness, lethargy, dizziness
Benzodiazepine receptor Eszopiclone Complex sleep behaviors: Unpleasant taste, headache, somnolence, respiratory infection agonist* sleep walking, sleep driving, Zaleplonor other activities while not Headache, dizziness, nausea, asthenia, somnolence, abdominal pain fully awake Zolpidem Drowsiness, dizziness, lethargy, drugged feeling, diarrhea
Zolpidem ER Headache, somnolence, dizziness, hallucination, back pain, myalgia
Zolpidem SL Headache, nausea, fatigue
Melatonin agonist Ramelteon N/A Somnolence, dizziness, fatigue, nausea, worsening of insomnia
Selective H1 antagonist Doxepin N/A Somnolence/sedation, nausea, upper respiratory tract infection
*Avoid use in elderly and in patients with untreated sleep apnea or chronic nocturnal hypoxia; †All hypnotics carry risk for complex sleep-related behaviors (eg, sleep driving). N/A = not applicable. Doxepin [prescribing information]. Somaxon Pharmaceuticals; 2010; Eszopiclone [prescribing information]. Sunovion Pharmaceuticals; 2019; Matheson E, et al. Am Fam Physician. 2017;96:29-35; Ramelteon [prescribing information]. Takeda Pharmaceuticals; 2018; Temazepam [prescribing information]. Mallinckrodt Pharmaceuticals; 2019; Triazolam [prescribing information]. Pfizer Inc; 2016; Zaleplon [prescribing information]. Sanofi-aventis; 2019; Zolpidem [prescribing information]. Sanofi-aventis; 2019; Zolpidem ER [prescribing information.] Sanofi-aventis; 2019; Zolpidem SL [prescribing information]. Sanofi-aventis; 2019. 39 39 2020 PCE Symposia Series 3 13 Beyond Counting Sheep: New Strategies for Sleep Maintenance Insomnia
Case Conclusion
• Four weeks later, Kylie began a dual orexin receptor antagonist at the recommended starting dosage while continuing CBT-I practices • Falls asleep easily and stays asleep through the night most nights; has wakened at night only 5 times in the past 3 weeks • Experienced moderate morning somnolence when going to bed at midnight or later ‒ Tried going to bed around 11:00 PM; with this adjustment, feels mostly refreshed when getting out of bed around 7:30 AM • No trouble with morning exercise or driving • Discontinued dual orexin receptor antagonist after 3 months and was subsequently able to sleep without difficulty most nights
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PCE Action Plan
Review sleep history, medical history, and substances that may contribute to insomnia to identify possible triggers Use the sleep diary and 7-Item ISI to help characterize a patient’s insomnia and guide management Refer patients and offer support for CBT-I as first-line treatment for insomnia disorder Consider comorbidities and respect patient preferences when starting prescription treatment Discuss pharmacologic options with patients who need additional help with sleep maintenance
PCE Promotes Practice Change
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2020 PCE Symposia Series 3 14 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
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Learning Objectives
• Assess patients for symptoms and signs of rheumatoid arthritis (RA) • Identify standard and novel therapies for RA and their appropriate use in clinical practice • Apply strategies to evaluate patients with RA for extra-articular manifestations and comorbidities
2 2
Prevalence of RA
• 1.5 MILLION ADULTS in the United States have RA • 3x more women than men
= 10,000 people
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. 3 3
2020 PCE Symposia Series 3 1 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Environmental and Genetic Risk Factors for RA
• RA is thought to be associated with: ‒ Genetics ‒ Female sex
Environmental factors (eg, smoking, periodontitis, pollution, gut microbiota*, others)
Genetic Preclinical Clinical Outcomes (disability, background (autoimmunity) (inflammation) joint surgery)
Asymptomatic Intermittent mono- or oligo- Persistent symmetric arthritis polyarthritis
*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. 4 4
Pathogenesis of RA
Genetic factors and Environmental triggers
Synovial inflammation Cytokines
Anti-CCP = cyclic 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. 5 5
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 disease progression is linked to early treatment with DMARDs • Once bone and cartilage are damaged, they never return to normal
Disease • Severe functional decline onset Established End Stage • Radiographic damage
Early • Work disability • Premature death
Optimal window of opportunity
Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637; Smolen JS, et al. Ann Rheum Dis. 2017;76:960-977. 6 6
2020 PCE Symposia Series 3 2 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Radiographic Progression of RA
1987 2007
Images courtesy of Brian Peck, MD and Rick Pope MPAS, PA-C. 7 7
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: ‒ PIP ‒ Metacarpophalangeal (MCP) ‒ Wrists, elbows, shoulders, knees, ankles, and subtalar and metatarsophalangeal (MTP) PIP Swelling joints
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. 8 8
Early RA in a Young Woman
• Symmetrical joint swelling in the hands • Swelling prominent in the PIP joints and in the left thumb interphalangeal (IP) joint
Image courtesy of Lester Miller, MD. 9 9
2020 PCE Symposia Series 3 3 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Early RA in a Young Woman
• Swelling is particularly prominent in the MTP joints, especially the 1st and 5th MTPs
Image courtesy of Lester Miller, MD. 10 10
Case Study: Cameron, a 35-Year-Old Woman
• 3-month history of pain and stiffness in hands and right knee, as well as chronic fatigue • Morning stiffness >30 minutes and increased pain at work as a mail sorter at the post office • 2 MCP joints (left hand) and 1 PIP joint (right hand) are visibly swollen • Height: 5 ft 2 in; weight: 150 lbs; BMI: 27.4 kg/m2; BP: 123/82 mm Hg • Primary care clinician had diagnosed OA, prescribed an NSAID, and suggested diet and exercise to lose weight • Mother had “bad arthritis” • Smoking status: 1/2 pack per day • Alcohol consumption: drinks socially
NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis. 11 11
Squeeze Test Assessment
• Squeeze test allows for quick clinical evaluation of MTP/MCP joints • Tenderness identified \ by gentle palpation of the joints
Emery P, et al. Ann Rheum Dis. 2002;61:290-297. 12 12
2020 PCE Symposia Series 3 4 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Common Disorders to Consider in the Differential Diagnosis of Arthritides
RA OA PsA Gout Peripheral disease Symmetric Asymmetric Asymmetric Asymmetric (monoarticular) Axial joint/spondylitis No No Yes Infrequent Stiffness Morning/ Withactivity Morning/ Yes immobility immobility Enthesitis No No Yes Yes Nail lesions No No Yes No Psoriasis Uncommon Uncommon Yes Uncommon Female:maleratio 3:1 Hand/knee > in women 1:1 1:3 to 1:4
Gottlieb A, et al. J Am Acad Dermatol. 2008;58:851-864; Jin HJ, et al. Front Med (Lausanne). 2020;7:339-346; Mease PJ, Armstrong AW. Drugs. 2014;74:423-441; Wallace KL, et al. J Rheumatol. 2004;31:1582-1587. 13 13
Key Biomarker in RA: Anti-CCP
40 Progression of Joint Damage in Subgroups of Early RA
30
Anti-CCP+ 20
10 Anti-CCP– Radiographic Joint Damage ScoreDamageJoint Radiographic
0 0 2 4 Time (Years)
Van der Helm-van Mil AH, et al. Arthritis Res Ther. 2005;7:R949-R958. 14 14
Case Study (cont’d): Cameron’s Lab and Imaging Results
• ANA: 1:60 (positive) • Anti-CCP: >250 U/mL (positive) • CRP: 20.5 mg/L (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
ANA = antinuclear antibodies; ESR = erythrocyte sedimentation rate. 15 15
2020 PCE Symposia Series 3 5 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Case Study (cont’d): Next Steps
• Rheumatologist performs a full workup and concludes that Cameron has early, moderately active RA • Rheumatologist discusses with Cameron the advantages of treating RA aggressively to achieve clinical remission (or at least low disease activity [LDA])
16 16
Treatment Strategy for RA: Treat-to-Target Task Force Algorithm
Active Clinical Clinical MAIN TARGET remission sustained RA (eg, DAS) remission • Measure disease • Measure disease activity about activity about every 1-3 months every 3-6 months • Adapt therapy • Adapt therapy if accordingly state is lost Sustained LDA ALTERNATIVE TARGET LDA
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. 17 17
Criteria for Clinical Remission
• Definition: absence of signs and symptoms of significant inflammatory disease activity • According to ACR and EULAR, remission is achieved when: ‒ Tender joint count, swollen joint count, 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
*Patient Global Assessment = patient self-reporting questionnaire. ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; SDAI = Simplified Disease Activity Index. Felson DT, et al. Ann Rheum Dis. 2011;70:404-413. 18 18
2020 PCE Symposia Series 3 6 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
ACR Guideline for Early RA: How it Applies to Cameron
DMARD-naïve early RA
Moderate or high Low disease activity disease activity Cameron
DMARD monotherapy DMARD monotherapy
Treat to target Moderate or high disease activity • MTX is the anchor drug Combination traditional DMARDs or TNFi +/- MTX or for treatment of RA non-TNF biologic +/- MTX Strong recommendation Moderate or high disease activity Conditional recommendation See established RA algorithm
MTX = methotrexate; TNFi = tumor necrosis factor inhibitor. Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25. 19 19
Case Study (cont’d): Cameron’s Management Plan
• Cameron 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
20 20
Case Study (cont’d): 3-month Follow-up
• Cameron 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
21 21
2020 PCE Symposia Series 3 7 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
ACR Guideline for Early RA: Where Cameron Is Now
DMARD-naïve early RA • MTX is the anchor drug for treatment of RA Moderate or high Low disease activity disease activity Strong recommendation
DMARD monotherapy DMARD monotherapy Conditional recommendation
Treat to target Moderate or high disease activity
Combination traditional DMARDs or TNFi +/- MTX or Cameron non-TNF biologic +/- MTX
Moderate or high disease activity
See established RA algorithm
Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68:1-25. 22 22
Conventional Synthetic DMARDs for RA
Agent Risks and AEs Routine Laboratory Monitoring Nausea, vomiting, diarrhea, rash/hyperpigmentation, Hydroxychloroquine None cytopenia, myopathy, cardiac dysrhythmias, retinopathy
Leflunomide* Hypertension, hepatotoxicity, myelotoxicity, severe diarrhea
Methotrexate* Hepatotoxicity, fibrosing alveolitis, myelotoxicity, opportunistic infection, teratogenicity, nausea, vomiting Complete blood count, liver transaminase levels, serum Nausea, vomiting, diarrhea, dyspepsia, dizziness, skin rash, Minocycline creatinine teratogenicity Hepatotoxicity, hypersensitivity reactions, myelotoxicity, Sulfasalazine reversible male infertility
*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. 23 23
Biologic and Targeted Synthetic DMARDs for RA
Agenta,b Risks and AEs Routine Laboratory Monitoring TNF blockade Injection site reactions, infections, ADA: None Adalimumab exacerbation or new onset demyelinating CTZ: None disease, worsening or new onset heart failure, Certolizumab pegol lymphoma, melanoma ETN: None Etanercept GLM and IFX: Liver enzymes, neutrophils Golimumab and/or platelets, serum creatinine Infliximab T-cell costimulation Infusion reactions, infections ABA: None blockade Abatacept B-cell depletion Infusion reactions, infections RTX: Liver enzymes, neutrophils and/or Rituximab platelets, serum creatinine
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 to 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. 24 24
2020 PCE Symposia Series 3 8 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Biologic and Targeted Synthetic DMARDs for RA (cont’d)
Agenta,b Risks and AEs Routine Laboratory Monitoring IL-6 receptor blockade Infusion reactions, infections, SRB: Liver enzymes, neutrophils and/or Sarilumab neutropenia, reduced platelet counts, platelets; infection, tuberculosis elevated liver enzymes, elevated lipids, Tocilizumab TCZ: Lipids, liver enzymes, neutrophils and/or GI tract perforation platelets JAK inhibition URIs, shingles, headache, diarrhea, BCB: Infection, tuberculosis, hepatitis B Baricitinib nasopharyngitis, lymphoma, TOF: Lipids, liver enzymes, neutrophils and/or nonmelanoma skin cancer, GI tract platelets Tofacitinib perforation, lipid abnormalities Upadacitinib UPA: Lipids, liver enzymes, neutrophils, hemoglobin, lymphocytes IL-1 receptor blockade Injection site reactions, infections, None Anakinra neutropenia
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; 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 BV; 2019; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531-541. 25 25
Case Study (cont’d): After 6 Months, Cameron’s RA Remains Moderately Active
• At Cameron’s last visit to the rheumatologist, the rheumatologist: ⎻ 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 • Cameron still hasn’t quit smoking • Continues to work on losing weight with diet and exercise • Now, after 3 months of SC MTX + adalimumab therapy, Cameron: ⎻ Has morning stiffness and pain that impair her ability to work ⎻ Feels fatigued ⎻ Has problems tolerating MTX, even in SC form
26 26
Case Study (cont’d): Adjusting Treatment
• To reach the target of clinical remission for Cameron, the rheumatologist: ‒ Discontinues adalimumab and MTX ‒ Switches her to the IL-6 inhibitor sarilumab
27 27
2020 PCE Symposia Series 3 9 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Adjusting Treatment to Achieve the Therapeutic Target
Clinical Clinical • Frequent disease activity Active MAIN TARGET remission sustained RA assessments (1-3 months for (eg, DAS) remission • Measure disease • Measure disease active disease) recommended to activity about activity about assess treatment response every 1-3 months every 3-6 months • Adapt therapy • Adapt therapy if • If no improvement by 3 months or accordingly state is lost Sustained target has not been reached by 6 ALTERNATIVE TARGET LDA LDA months, treatment adjustment is warranted
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. 28 28
JAK Inhibitors (Targeted Synthetic DMARDs) in Treatment of Moderate to Severe RA
• Tofacitinib ‒ For patients with an 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
Olumiant [prescribing information]. Lilly USA; 2019; Rinvoq [prescribing information]. AbbVie: 2019; Xeljanz [prescribing information].Pfizer; 2019. 29 29
Some Emerging Treatments for Moderate to Severe RA
• Filgotinib (phase 3) ‒ JAK1 selective inhibitor • Otilimab (phase 3) ‒ Granulocyte-macrophage colony stimulating factor (GM-CSF) inhibitor
ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03025308?term=NCT03025308&draw=2&rank=1. Accessed October 19, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT04333147?term=otilimab&draw=2&rank=2. Accessed October 19, 2020. 30 30
2020 PCE Symposia Series 3 10 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Responsibilities of Primary Care Clinicians as Part of a Multidisciplinary Team in RA
• Symptom management • Referrals as needed to: • Monitor for comorbidities and – Rheumatology extra-articular manifestations – Cardiology • AE monitoring – Occupational therapy • Smoking cessation counseling – Physical therapy • Nutrition and weight management – Psychiatry – Pulmonary • 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. 31 31
Don’t Neglect CVD Risk in Patients With RA
• RA is an independent risk factor for CVD • Patients with RA have an increased risk of CVD and a 50% to 70% greater risk of 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
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. 32 32
Extra-Articular Manifestations and Common Comorbidities in RA
• RA is a systemic disease with sequelae • Comorbidities include: beyond joint damage ‒ CV, lung, and kidney diseases • Extra-articular manifestations include: ‒ Depression ‒ CVD ‒ GI disorders ‒ Myopathies ‒ Infections ‒ Neuropathies ‒ Malignancies ‒ Nodules ‒ Ocular inflammation ‒ Osteopenia/osteoporosis ‒ Pulmonary disease
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; Klodzinski T, et al. Reumatologia. 2018;56:288-233; 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. 33 33
2020 PCE Symposia Series 3 11 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Rheumatoid Lung in an Elderly Man
• 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
Image courtesy of Lester Miller, MD. 34 34
Ocular Scleritis in RA
• Scleritis in an older woman with long-standing RA • Inflammation causes the sclera to become thinner and translucent • Result is the sclera having a bluish hue from the underlying choroid layer of the eye
Image courtesy of Lester Miller, MD. 35 35
Vaccine Considerations in RA
Live vaccines to be avoided when using biologics Important points to remember • Herpes zoster (shingles) [Zostavax only]* • Inactivated influenza and pneumococcal • Live attenuated viral/intranasal spray for influenza vaccines are strongly recommended and • Adenovirus are safe, but therapeutic response may be reduced • Cholera • If a live vaccine is indicated, administer 4 • Measles, mumps, rubella weeks before starting therapy • Measles, mumps, rubella, varicella • Routine immunizations should be up to • Rotavirus date before travel • Typhoid (live attenuated bacterial oral) • Varicella • Vaccinia (smallpox) • Yellow fever
*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 October 19, 2020; Wine-Lee L, et al. J Am Acad Dermatol. 2013;69:1003-1013. 36 36
2020 PCE Symposia Series 3 12 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
Coordinating Multidisciplinary Treatment Teams
• Develop relationships with at least Primary Care 1 or 2 rheumatologists to facilitate Clinician timely referrals Social Work Cardiology • Multidisciplinary teams do not have to practice together in the same
building or setting RA PATIENT Rheumatology Specialty Care Orthopedics Pulmonology
Physical Psychology Therapy
Taal E, et al. Clin Rheumatol. 2006;25:189-197. 37 37
ACR: RA Treatment Recommendations in the Context of COVID-19
• Patients exposed to SARS-CoV-2 • Patients with documented or presumptive ‒ HCQ/CQ, SSZ, NSAIDs may be continued COVID-19 ‒ Temporarily halt pending negative test for ‒ Regardless of COVID-19 severity, COVID-19 or 2 weeks of symptom-free HCQ/CQ may be continued observation: ‒ SSZ, MTX, LEF, biologics, and JAK • Biologics inhibitors should be stopped – TNFi’s, abatacept, anakinra, ‒ If severe respiratory symptoms, NSAIDs rituximab should be stopped • JAK inhibitors ‒ IL-6 inhibitors may be continued in select circumstances, as part of a shared ‒ IL-6 inhibitors may be continued in select decision-making process circumstances, as part of a shared decision-making process
CQ = chloroquine; HCQ = hydroxychloroquine; LEF = leflunomide; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SSZ = sulfasalazine. Mikuls TR, et al. Arthritis Rheum. 2020;72:e1-e12. 38 38
Case Conclusion
• Cameron’s PCR test for COVID-19 was negative, and she did not develop symptoms • She achieved clinical remission 3 months after switching to sarilumab monotherapy • She finally quit smoking • Lost 15 lbs by increasing exercise and reducing calorie intake • 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. 39 39
2020 PCE Symposia Series 3 13 Early Identification and Management of Rheumatoid Arthritis: The Critical Role of Primary Care
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
40 40
2020 PCE Symposia Series 3 14 COVID-19: Updates for NPs and PAs
COVID-19: Update for NPs and PAs
1
Learning Objectives
• Describe what is currently known about COVID-19 epidemiology and transmission • Assess current COVID-19 diagnostic strategies • Discuss evolving therapeutic approaches to COVID-19
2 2
Epidemiology and Transmission
3 2020 PCE Symposia Series 3 1 COVID-19: Updates for NPs and PAs
Global Incidence (11/12/20)
Johns Hopkins University & Medicine. gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6. Accessed Nov 12, 2020. 4 4
US Average Daily Cases/100,000 in the Past 7 Days (11/12/20)
The New York Times. www.nytimes.com/interactive/2020/us/coronavirus-us-cases.html?action=click&auth=login- email&login=email&module=Top%20Stories&pgtype=Homepage#map. Accessed Nov 12, 2020. 5 5
Percent of New Tests That Are Positive, State by State (11/12/20)
Johns Hopkins University & Medicine. coronavirus.jhu.edu/testing/tracker/map/percent-positive. Accessed Nov 12, 2020. 6 6 2020 PCE Symposia Series 3 2 COVID-19: Updates for NPs and PAs
Transmission and Contagiousness
• Why rapid and global spread? • Third wave in the US—worries about this winter’s respiratory season? ‒ Asymptomatic shedding High-risk environments? • Estimates 25% to 79% of infected? ‒ Mass gatherings • Role of asymptomatic cases affecting ‒ Family gatherings/holidays models/forecasts ‒ Universities, schools ‒ Bars, restaurants ‒ Travel
Centers for Disease Control and Prevention. www.cdc.gov/coronavirus/2019-ncov/travelers/travel-during-covid19.html. Accessed Oct 29, 2020. 7 7
When Are You Most Infectious?
Most 10 Symptomatic Respiratory tract viral load with time >33 cycle threshold (generally not infectious)
15 Infectiousness
20
25
30 Cycle Cycle Threshold
35 Period of 40 infectiousness Least –5 –4–3–2–1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days Relative to Symptom Onset
Meyerowitz EA et al. Ann Intern Med. 2020;M20-5008: online ahead of print. 8 8
The Physics of Transmission
• Human sneeze or cough: 0.1 to 1000 microns • Respiratory droplets: Mostly 5 to 10 microns • Some aerosols: <5.0 microns • Silent shedders as main drivers ‒ Estimates up to 79% ‒ lnfectious up to 6 days before symptoms • 6 ft doesn’t account for particles ≤1 micron ‒ May be insufficient if indoors with poor circulation • Uncovered intense coughs: ≥20 ft • Universal masking as best weapon ‒ Surgical masks reduce transmission
9 9 2020 PCE Symposia Series 3 3 COVID-19: Updates for NPs and PAs
Who Transmits?—The Superspreaders
• Superspreaders – Biologically yield more droplets or aerosol – Loud speaking/singing • Estimates 10% to 20% of infected 80% of cases • High viral load likely important
Meyerowitz EA et al. Ann Intern Med. 2020;M20-5008: online ahead of print. 10 10
What About in a Household?
• Meta-analysis of 40 studies ‒ Secondary attack rate 18.8% (95% CI, 15.4% to 22.2%) • Higher for spouse/partner • Lower for other household members • Variable, depending on environmental factors • Rates only lower if mask wearing and social distancing in household ‒ Strongly suggested for high-risk people
Madewell ZJ, et al. medRxiv. 2020:preprint. 11 11
Preventing Transmission: The 3 Best Things You Can Do
aOR = adjusted odds ratio. Chu DK, et al. Lancet. 2020;395(10242):1973-1987. 12 12 2020 PCE Symposia Series 3 4 COVID-19: Updates for NPs and PAs
Range of COronaVIrus Disease-2019
Paul G. Auwaerter, personal communication. 13 13
Age and Gender Mortality Risks
Mallapaty S. Nature. 2020;585:16-17. 14 14
Diagnosis
15 2020 PCE Symposia Series 3 5 COVID-19: Updates for NPs and PAs
Test Sensitivity Varies With Time Since Symptom Onset
Image created with biorender.com. 16 16
COVID-19 Diagnostic Test Through RT-PCR
PCR = polymerase chain reaction; RNA =ribonucleic acid ; RT-PCR = reverse transcription PCR; qPCR = quantitative PCR. Image created with biorender.com. 17 17
PCR “Turkey Talk”
• False negatives ‒ Range 2% to 37% ‒ Depends on stage of illness, technique acquiring sample ‒ May need to repeat test if clinically suspicious • Pooled testing ‒ May reduce costs by batching ‒ Positive pool = all in that pool need individual testing delay ‒ Not widely used ‒ Most useful if community rates are declining and low
18 18 2020 PCE Symposia Series 3 6 COVID-19: Updates for NPs and PAs
Saliva-Based Tests: Is Drool Good?
• Emerging • Likely less sensitive than nasopharyngeal swab ‒ Detects only ~90% • No tests widely available • Decreases barrier to testing ‒ Who is most contagious?
A woman spits into a tube so that her saliva can be tested for the presence of novel coronavirus. UNIVERSITY OF ILLINOIS, URBANA-CHAMPAIGN.
Service RF. www.sciencemag.org/news/2020/08/new-drool-based-tests-are-replacing-dreaded-coronavirus-nasal-swab. Accessed Oct 30, 2020. 19 19
Antigen Testing
Adapted from Campbell IM. commons.wikimedia.org/wiki/File:Diagnostic_Medical_Dipstick.png. Accessed Oct 29, 2020. 20 20
Rapid Testing
21 21 2020 PCE Symposia Series 3 7 COVID-19: Updates for NPs and PAs
Molecular vs Antigen Tests
Factor RT-PCR Tests Antigen Tests • Antigen tests Intended use Detect current infection Detect current infection ‒ For early diagnosis in Analyte detected Viral RNA Viral antigens symptomatic patients Specimen type(s) Nasal swab, sputum, Nasal swab ‒ Not for screening saliva (clinical studies in Sensitivity High Moderate progress) Specificity High High ‒ Negative result should Test complexity Varies Relatively easy be followed up with a Authorized for Most not Yes molecular assay point of care Turnaround time 15 min to >2 days ~15 min
Cost Moderate Low
Centers for Disease Control and Prevention. www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html#table2. Accessed Oct 29, 2020. 22 22
Can the Role of Antigen Tests Be Widened?
Date: Mon 19 Oct 2020 17:01 • Uncertain From: Salerno, Reynolds (CDC/DDPHSS/CSELS/DLS) • Tests hard to obtain (most purchased by <…@cdc.gov> the government) We are working on a number of studies with • FDA EUA: only for symptomatic patients different partners to evaluate the performance of all of the widely available antigen tests on • Low sensitivity asymptomatic persons. The FDA authorizations for ‒ If repeated, increased false positive these tests are limited to their use on tests symptomatic persons. We will share data as soon as ‒ Asymptomatic screening—likely with we are able. lower sensitivity as pretest probability lower Ren Salerno CDC Atlanta, GA (POSTED TO EIN NETWORK)
EUA = Emergency Use Authorization. 23 23
SARS-CoV-Antibody Testing
• Positive test may reflect exposure to other coronaviruses • Positive test should not be taken as evidence of immunity • Positive test does not mean a COVID-19 diagnosis
ACE-2 = angiotensin-converting enzyme 2. Image created with biorender.com. 24 24 2020 PCE Symposia Series 3 8 COVID-19: Updates for NPs and PAs
Therapeutics
25
Remdesivir: Results From the ACTT-1 Trial—Now FDA Approved
• IV; only for hospitalized patients • 31% faster recovery vs placebo (P <0.001, 10 days vs 15 days) • Appears safe • Mechanically ventilated or ECMO patients don’t appear to benefit • Oxygen-requiring (largest group) had most benefit • FDA-approved Oct 2020 for ≥12 years of age • New EUA for children <12 years of age
ACTT-1 = stage 1 of Adaptive Covid-19 Treatment Trial. Beigel JH, et al. N Engl J Med. 2020:NEJMoa2007764. doi:10.1056/NEJMoa2007764. [Epub ahead of print.]. 26 26
Dexamethasone: Results From the RECOVERY Trial
• Target: hyperinflammatory state, trial halted • UK trial ‒ 2104 vs 4321 controls • NNT to avoid 1 death ‒ Ventilated patients: 8 • Mortality rate 40% 28% ‒ On oxygen: 25 • Mortality rate 25% 20% ‒ No benefit if not on oxygen, trend toward worsening
19
NNT = number needed to treat; RECOVERY = Randomized Evaluation of Covid-19 Therapy. Horby P, et al. N Engl J Med. 2020:NEJMoa2021436.doi:10.1056/NEJMoa2021436. [Epub ahead of print.]. 27 27 2020 PCE Symposia Series 3 9 COVID-19: Updates for NPs and PAs
LYCoV555 (Bamlanivimab): Results From the BLAZE-1 Trial
Symptom Score Hospitalization* Change From Baseline
BLAZE-1 = Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies Chen P et al. N Engl J Med. 2020. DOI: 10.1056/NEJMoa2029849. 28 28
Convalescent Plasma
• No RCTs support use (early terminations or Phase II) ‒ Li et al; Gharbharan et al; Agarwal et al (PLACID, n = 464)
RCT = randomized controlled trial. US Food & Drug Administration. www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma- potential-promising-covid-19-treatment. Accessed Oct 29, 2020. 29 29
Preliminary Data from Convalescent Plasma Expanded Access Program Adjusted Mortality—Graded Dose Effect (High vs Low Titer)
• 76 patients • High titer vs low titer • 7-day mortality if… – 7-day mortality ‒ ≤3 hospital days • 8.9% (6.8%, 11.7%) vs 13.7% (11.1%, 16.8%), P = 0.048 • 8.7% (95% CI 8.3%-9.2%) • 30-day mortality ‒ ≥4 hospital days – High titer, pooled 0.77 (0.63-0.94) • 11.9% (11.4%-12.2%) , P < 0.001 for 30 days • 30-day mortality ‒ 21.6% vs 26.7%, P <0.0001
Joyner JM, et al. medRxiv. 2020:doi:10.1101/2020.08.12.20169359. Preprint. 30 30 2020 PCE Symposia Series 3 10 COVID-19: Updates for NPs and PAs
Vaccines
31
The COVID-19 Vaccine Race (11/12/20)
• >300 candidate vaccines • Vaccines in Phase 3 trials ‒ BioNTech/Pfizer (mRNA) ‒ Moderna (mRNA) ‒ Murdoch (BCG vaccine) ‒ J&J (Ad26) ‒ Novavax (protein based) ‒ Oxford/AstraZeneca (ChAdOx1) ‒ CanSinoBio (Ad5)* ‒ Gamaleya (Ad5/Ad26)* ‒ Sinovac (inactivated)* All require two injections except: ‒ Sinopharm (inactivated)* • J&J and CanSinoBio (single injection) ‒ Wuhan Inst/Sinopharm (inactivated)* *Approved for early or limited use in China, Russia, or United Arab Emirates Corum J, et al. www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html?action=click&module=RelatedLinks&pgtype=Article. Accessed Nov 12, 2020. 32 32
Who Have Built the Biggest Vaccine Portfolios?
Gross A, Bott I. www.ft.com/content/e5012891-58da-4a4f-8a05-182adf3ba0e2. Accessed Oct 29, 2020. 33 33 2020 PCE Symposia Series 3 11 COVID-19: Updates for NPs and PAs
Summary
• Global effect • Worries for this winter • Likely only US hope = vaccines (Spring 2021) • WEAR MASKS
34 34
Be Sure to Visit PCE’s COVID Resource Center
Visit PCE.is/covid OR
Click the link at the top of the PCE homepage
35 35
2020 PCE Symposia Series 3 12 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
1
Learning Objectives
• Identify patients at high risk for complications 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
2 2
Epidemiology and Burden of Seasonal Influenza in the US
Annual Estimates by the CDC From 10 Influenza • Rates of serious illness and death Seasons (2010-2011 through 2019-2020)* from seasonal influenza are highest in persons >65 years, in 9.3 to 45 million illnesses children <2 years, and in anyone with medical conditions at increased risk for complications 14.2 to 21 million outpatient medical visits • During the 2017-2018 flu season, influenza is estimated to have 140,000 to 810,000 hospitalizations killed 61,000 people in the United States, more than any other year since 2010 12,000 to 61,000 deaths
*Data for 2017-2018, 2018-2019, 2019-2020 are preliminary estimates. Centers for Disease Control and Prevention. cdc.gov/flu/about/burden/index.html. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. gis.cdc.gov/GRASP/Fluview/FluHospRates.html. Accessed Nov 2, 2020; Rolfes MA, et al. Influenza Other Respir Viruses. 2018;12:132-137. 3 3
2020 PCE Symposia Series 3 1 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Pneumonia, Influenza, and COVID-19 Mortality: 2017-2020
28 Number of influenza coded deaths 18,000 26 Number of COVID-19 coded deaths 16,000 24 % of deaths due to PIC 22 14,000 Seasonal baseline 20 Epidemic threshold 12,000 18
16 10,000 14 12 Epidemic Threshold 8000 10 6000
8 Deaths of Number 6 4000 4 % of of to % PIC Due Deaths All 2000 2 Seasonal baseline 0 0 40 50 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 10 20 30 40 2017 2018 2019 2020 MMWR Week COVID-19 = Coronavirus disease 2019; PIC = pneumonia, influenza, or COVID-19. Centers for Disease Control and Prevention. www.cdc.gov/flu/weekly/overview.htm#anchor_1539281356004. Accessed Nov 2, 2020. 4 4
Pandemics: Influenza and COVID-19
Common Name Year Virus Estimated No. of Deaths 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 2020 SARS-CoV-2 2,342,648* (by Jan 1, 2021)
*Projected as of Oct 2, 2020. Dawood FS, et al. Lancet Infect Dis. 2012;12:687-695; Johns Hopkins University & Medicine. coronavirus.jhu.edu/map.html. Accessed Nov 2, 2020; Johnson NP, et al. Bull Hist Med. 2002;76:105-115; Saunders-Hastings PR, et al. Pathogens. 2016;5:66; Simonsen L, et al. PLoS Med. 2013;10:e1001558; Taubenberger JK, et al. Emerg Infect Dis. 2006;12:15-22; University of Washington Institute for Health Metrics and Evaluations. covid19.healthdata.org/global?view=total-deaths&tab=trend. Accessed Nov 2, 2020. 5 5
Influenza Virus
• The family Orthomyxoviridae has 3 genera, or types, Hemagglutinin NANA that infect humans: influenza viruses A, B, and C NS 2 • Influenza A virus subtypes are based on specific HA and NA glycoproteins that they express − 18 HAs (H1-H18) − 11 NAs (N1-N11) Lipid bilayer − Potential for 144 HA and NA combinations (some HAs and NAs cannot work together) Ion • Birds are reservoir for 16 HA and 9 NA subtypes channel
Matrix protein
Negative-sense HA = hemagglutinin; NA = neuraminidase; NS = nonstructural protein; RNA = ribonucleic acid; ss = single stranded. ssRNA Clancy S. Nature Education. 2008;1:83; Vemula SV, et al. Viruses. 2016;8:96. 6 6
2020 PCE Symposia Series 3 2 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Case Study: Victor, a 55-Year-Old Male of Hispanic and Native-American Descent
• Victor visits your primary care practice in November for an annual checkup • Height: 5 ft 8 in • Weight: 265 lb (BMI = 40.3 kg/m2) • Blood pressure: 132/79 mm Hg (controlled with medication) • Unvaccinated against influenza and skeptical about the vaccine ⎻ He received the vaccine last year and “got the flu” the day after • You recommend influenza vaccination, but he refuses
7 7 7
Focus on Patients at Higher Risk for Influenza Complications
Demographic factors Chronic Medical Conditions • Adults aged ≥65 years • Asthma • Children <5 years (highest risk in children • Neurologic and neurodevelopmental conditions <2 years, especially if <6 months) • Blood disorders (eg, sickle cell disease) • Pregnant women and women up to 2 • Certain types of cancer (lymphoma and leukemia) and cancer weeks postpartum survivors • American Indians/Alaska Natives • Chronic lung disease (eg, COPD, cystic fibrosis) • Residents of nursing homes and other • Diabetes long-term care facilities • Kidney disorders • Liver disorders • Morbid obesity (BMI ≥40 kg/m2) • <19 years of age and on long-term aspirin- or salicylate-containing medications • Compromised immune system or on immunosuppressive therapies
Centers for Disease Control and Prevention. cdc.gov/flu/highrisk/index.htm. Accessed Nov 2, 2020. 8 8
Influenza Vaccines: 2020-2021 Influenza Season
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* IIV4 high dose Egg based† ≥65 years IM Prefilled syringe IIV4 standard dose with Egg based† ≥65 years IM Prefilled syringe MF59 adjuvant IIV3 standard dose with Egg based† ≥65 years IM Prefilled syringe MF59 adjuvant RIV4 Recombinant HA ≥18 years IM Prefilled syringe LAIV4‡ Egg based† 2 to 49 years Intranasal Single-use intranasal spray
*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. 2020;69:1-24. 9 9
2020 PCE Symposia Series 3 3 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Vaccine Composition: 2020-2021 Influenza Season
Egg-based influenza vaccines (ie, vaccines Cell culture-based inactivated (ccIIV4) and other than ccIIV4 and RIV4) will contain HA recombinant (RIV4) influenza vaccines will derived from: contain HA derived from:
Influenza A/Guangdong-Maonan/SWL1536/2019 Influenza A/Hawaii/70/2019 (H1N1)pdm09-like (H1N1)pdm09-like virus virus
Influenza A/Hong Kong/2671/2019 (H3N2)-like Influenza A/Hong Kong/45/2019 (H3N2)-like virus virus
Influenza B/Washington/02/2019 (Victoria Influenza B/Washington/02/2019 (Victoria lineage)-like virus lineage)-like virus
Influenza B/Phuket/3073/2013 (Yamagata Influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus (for quadrivalent vaccines only) lineage)-like virus
ACIP = Advisory Committee on Immunization Practices. Grohskopf LA, et al. MMWR Recomm Rep. 2020;69:1-24. 10 10
Case Study (cont’d): Victor
• Returns to your office in early December after sudden onset of symptoms the previous morning ⎻ Fever (101.8°F), chills, body aches, intense headache, extreme fatigue, cough • Missed work today and yesterday • Several coworkers have been sick with flu-like illness • Influenza and COVID-19 are highly prevalent in the community • 3 days earlier, Victor babysat his 4-year-old grandson who was having some head congestion and coughing • Wife, aged 57 years, has not been vaccinated
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Influenza Symptoms and Clinical Course
• Classic flu • Complications – Abrupt onset of fever, chills, myalgia, – Sinusitis, otitis media headache, fatigue, nonproductive cough, – Pneumonia—primary viral or secondary bacterial sore throat, rhinitis – Coinfections with other bacterial/viral pathogens – Some people may have GI symptoms – Exacerbation of underlying medical conditions (eg, nausea, diarrhea) (eg, COPD, asthma, cystic fibrosis, diabetes) – Typically resolves within 3 to 7 days – Associations with cardiovascular events (eg, MI, – Cough, malaise can persist for >2 weeks stroke), parotitis • Mild illness without fever may also occur • Atypical presentations may occur in elderly, immunocompromised hosts, infants
MI = myocardial infarction. Centers for Disease Control and Prevention. cdc.gov/flu/symptoms/symptoms.htm. Accessed Nov 2, 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. 12 12
2020 PCE Symposia Series 3 4 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Differential Diagnosis of URIs, Influenza, and COVID-19
Symptom Acute URI (common cold) Influenza COVID-19 Itchy, watery eyes Uncommon Uncommon Uncommon Nasal discharge Very common Common Common Nasal congestion Very common Common Common Sore throat Very common Sometimes Common Cough Common Common Common Headache Sometimes Common Common Fever/chills Rare (adults) possible (children) Common Common Fatigue, weakness Sometimes Very common Common Shortness of breath Rare Common Common Myalgia Rare Very common Uncommon Loss of taste or smell Uncommon Uncommon Common Symptom start, duration 3 to 14 days 3 to 10 days; several weeks cough, fatigue 5 to 14 days
URI = upper respiratory tract infection. Centers for Disease Control and Prevention. www.cdc.gov/flu/index.htm. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. www.cdc.gov/flu/symptoms/flu-vs-covid19.htm. Accessed Nov 2, 2020; National Institutes of Health. newsinhealth.nih.gov/2014/10/cold-flu-or-allergy. Accessed Nov 2, 2020. 13 13
Influenza vs COVID-19: Differentiation Considerations
Influenza COVID-19 Transmission: Respiratory droplet, contaminated Transmission: Respiratory droplet, contaminated surfaces surfaces, and contributions of aerosolization Incubation: 2 days (mean), range 1-4 days Incubation: 6.4 days (mean), range 2-12 days Age range for high risk of illness: ≤5 and ≥ 65 Age range for high risk of illness: >50 (risk increases with advancing age) Hospitalization rate: 2% Hospitalization rate: Age 20-29 = 1.1%; age 80+ = 18.4% Fatality rate: approximately 0.1% Estimated fatality rate: Approximately 6- to 12-fold greater than influenza; preliminary data range = 0.66% to >4%, with an increasing age gradient
Auwaerter PG. www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540747/all/Coronavirus_COVID_19__SARS_CoV_2_. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. www.cdc.gov/flu/about/disease/spread.htm. Accessed Nov 2, 2020; Johns Hopkins University & Medicine. coronavirus.jhu.edu/map.html. Accessed Nov 2, 2020; Verity R, et al. Lancet Infect Dis. 2020;20:669-677. 14 14
Respiratory Syncytial Virus Infection (RSV)
• Common cause of childhood illness but causes annual outbreaks of respiratory illness in all age groups • Clinical symptoms nonspecific; can overlap with other viral respiratory infections • Symptoms include: ‒ Nasal congestion or rhinorrhea ‒ Dry cough ‒ Low-grade fever ‒ Sore throat ‒ Mild headache • May cause severe disease in infants and young children, as well as older adults • In severe cases, RSV infection can cause pneumonia or bronchiolitis
Centers for Disease Control and Prevention. www.cdc.gov/rsv/clinical/index.html. Accessed Nov 2, 2020; Mayo Clinic. www.mayoclinic.org/diseases-conditions/respiratory-syncytial-virus/symptoms-causes/syc-20353098 Accessed Nov 2, 2020. 15 15
2020 PCE Symposia Series 3 5 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Multiplex PCR: A New Testing Option
• A number of molecular multiplex panels are approved or seeking approval to include the novel coronavirus • For example, Cepheid received Emergency Use Authorization (EUA) from the FDA for its GeneXpert combination test for: ‒ SARS-CoV-2 ‒ Influenza A ‒ Influenza B ‒ RSV • Provides rapid detection of COVID-19 within 30 minutes • Provides results for all four pathogens within 45 minutes
US Food and Drug Administration. Press Release. 2020. https://www.fda.gov/media/142438/download 16 16
Laboratory Diagnostic Methods to Confirm 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 Nucleic acid amplification 1 to 8 hours High High RT-PCR Multiplex molecular assays Nucleic acid amplification 1 to 2 hours High High
Rapid cell culture (shell vials, Virus isolation 1 to 3 days High High cell mixtures) 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. RT-PCR = reverse transcription polymerase chain reaction. Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Nov 2, 2020; Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902. 17 17
Interpreting Influenza Testing Results
• Use information on local influenza activity (eg, from health Cannot rule out flu, department), patient history and travel, clinical signs/symptoms, Negative especially if test does and physical examination to decide if treatment is indicated result not have high sensitivity • Initiate antiviral treatment if flu is suspected and patient is at high or if specimen was risk for complications or is being admitted to the hospital collected >4 days after • Consider additional diagnostic testing for other pathogens illness onset
• Initiate antiviral treatment if indicated Positive result Influenza virus • Implement infection prevention and control measures (A or B) infection likely • Consider additional influenza testing if subtype info is desired
Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/algorithm-results-circulating.htm. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Nov 2, 2020. 18 18
2020 PCE Symposia Series 3 6 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
When to Treat Influenza: Complicated vs Uncomplicated
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 otherwise at high risk • Consider antiviral treatment for outpatients without known risk factors for severe illness if treatment can be initiated within 48 hours of onset
Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902. 19 19
Why Is It Important to Treat Early?
• 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)
RCT = randomized controlled trial. 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 Infect 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. 20 20
Influenza Antivirals: Mechanisms of Action
Adsorption Packaging and budding Release Receptor containing sialic acid
M2 inhibition Antibodies (adamantanes)
Endocytosis mRNA NA inhibitors and fusion Cap snatching (oseltamivir, Uncoating RNA (+/-) (baloxavir, peramivir, pimodivir) zanamivir) RNA polymerase inhibition (favipiravir)
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. 21 21
2020 PCE Symposia Series 3 7 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
FDA-approved Antiviral Agents for Influenza Treatment
• NAs: 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
Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Nov 2, 2020; Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21; Wester A, et al. Infect Drug Resist. 2016;9:201-214. 22 22
Antivirals for Influenza: Dosing Considerations
Age Route of Antiviral Dosage Indication Administration Precautions Baloxavir Single oral dose ≥12 years Tablets Do not take with: • 40 mg for patients 40 to 80 kg • Dairy products or calcium-fortified • 80 mg for patients ≥80 kg beverages • Polyvalent cation-containing laxatives Oseltamivir Twice daily for 5 days ≥2 weeks Capsule or oral • 75 mg (≥13 years) suspension — • Weight based (1-12 years) • 3 mg/kg (2 weeks-1 year) 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
Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Nov 2, 2020; Rapivab [prescribing information]. BioCryst Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018; Tamiflu [prescribing information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019. 23 23
Antivirals for Influenza: Adverse Events (AEs)
Antiviral 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, 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*
*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 Nov 2, 2020; Rapivab 24 [prescribing information], BioCryst Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018; Tamiflu [prescribing information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019. 24 24
2020 PCE Symposia Series 3 8 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
CAPSTONE-1: Time to Alleviation of Symptoms With Baloxavir vs Placebo
100 ++ • Phase 3 study + + + ‒ 1436 otherwise healthy patients 80 + + Placebo ‒ 12 to 64 years of age 60 ‒ Symptomatic uncomplicated flu
40 Baloxavir + • Time to alleviation of symptoms + + ‒ Baloxavir group: 53.7 hours 20 + + ++ + ypo leito (%) AlleviationSymptom + + ++++ ‒ Placebo group: 80.2 hours (P <.001) Patients Who Did Not Have Not Did Who Patients 0 0 30 60 90 120 150 180 210 240 270 300 330 • Baloxavir generally well tolerated Hours From Start of Trial Regimen ‒ Diarrhea most common AE, but less frequent than with placebo
Hayden FG, et al. N Engl J Med. 2018;379:913-923. 25 25
CAPSTONE-2: Baloxavir vs Placebo or Oseltamivir in Patients at High Risk for Influenza Complications
• 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
P Value P Value Measure* Baloxavir Placebo Oseltamivir (Baloxavir vs Placebo) (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 .014 68.2 NS
Influenza B TTIIS 74.6 h 100.6 h .014 101.6 h .025
Time to cessation of viral 48 h 96 h <.0001 96 h <.0001 shedding**
*All reported values are medians; **As determined by virus titer. NS = not significant; TTIIS = Median time to improvement of influenza symptoms. ClinicalTrials.gov. clinicaltrials.gov/ct2/show/results/NCT02949011. Accessed Nov 2, 2020; Ison MG, et al. Lancet Infect Dis. 2020;20:1204-1214. 26 26
Case Conclusion
• Swab test for COVID-19 was negative • You prescribe baloxavir for Victor, advising him 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) • He feels better within a few days; 12 days later he feels almost completely better, except for a slight lingering cough • He has urged his wife and family to get vaccinated and is committed to getting vaccinated himself early in the season each year
27 27
2020 PCE Symposia Series 3 9 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Case Study: Allie, an 11-Year-Old Student
• Has mild, intermittent asthma, which is treated with albuterol PRN • Sudden onset of headache, pharyngitis, fever, chills, nasal congestion yesterday; symptoms worse today and now include dry cough, fatigue, weakness • OTC meds providing limited relief • Flu prevalent at school and in 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: slight wheezing • Rapid strep test: negative • Oral salivary test for COVID-19 sent out for laboratory analysis
28 28
Case Study (cont’d): Allie
• Given Allie’s symptoms and underlying asthma, which puts her at high risk for influenza complications, as well as 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 Allie and her mother
29 29
Case Conclusion
• You prescribe Allie oseltamivir, 75 mg twice daily for 5 days, because it is approved for children of Allie’s age and has more than 20 years of clinical use • Her symptoms start to resolve over the next few days and by the weekend she is feeling much better • You recommend she get vaccinated early in the next flu season
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2020 PCE Symposia Series 3 10 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
MINISTONE-2: Baloxavir vs Oseltamivir in Pediatric Patients With Influenza-like Symptoms
• Phase 3 multicenter study in patients 1 to <12 years of age with confirmed influenza • 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 AEs, deaths, AEs of special interest, or new safety signals observed
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 138.1 h (116.6 to 163.2) 150.0 h (115.0 to 165.7) symptoms (95% CI)
CI = confidence interval. *Determined via virus titer. Baker J, et al. Pediatr Infect Dis J. 2020;39:700-705. 31 31
BLOCKSTONE: Baloxavir Prophylaxis vs Placebo in Subjects Living With Someone With Confirmed Influenza
• Phase 3 randomized study assessing Percentage of household contacts infected post-exposure prophylaxis in after treatment with baloxavir or placebo unvaccinated household contacts of influenza-infected patients (influenza 30 P <0.001 confirmed by RIDT) 25
• Household contacts randomized to 20 single-dose baloxavir vs placebo 15 13.6 • Primary endpoint: Proportion of participants testing positive for 10 influenza (RT-PCR positive, with 5 InfluenzaPositive (%)* fever and ≥1 symptom[s]) during 1.9 0 10-day assessment period BaloxavirCategory 1 Placebo
• Serious AEs not observed *Influenza positive = Baloxavirbaloxavir 7 of Placebo374 [1.9%] vs placebo 51 of 375 [13.6%]; adjusted risk ratio, 0.14; 95% CI, 0.06 to 0.30.
Ikematsu H, et al. N Engl J Med. 2020;383:309-320. 32 32
Considerations Regarding Baloxavir
• 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 • Resistance to baloxavir among circulating influenza viruses is currently low • Quicker reduction of influenza B symptoms than oseltamivir • Faster clearance of virus than oseltamivir • CDC does not recommend use of baloxavir in pregnant women, breastfeeding mothers, outpatients with complicated or progressive illness, severely immunosuppressed people, or hospitalized patients because of lack of data in these groups
Centers for Disease Control and Prevention. www.cdc.gov/flu/treatment/baloxavir-marboxil.htm. Accessed Nov 2, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02949011. Accessed Nov 2, 2020; Hayden FG, et al. N Engl J Med. 2018;379:913-923; Ison MG, et al. IDSA Week. 2018. Abstract LB16; Xofluza [prescribing information]. Genentech; 2019. 33 33
2020 PCE Symposia Series 3 11 Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
PCE Action Plan
Be aware of the potential for influenza complications, especially in higher risk patients Confirm influenza using rapid molecular assay if available; RIDT 2nd choice Despite COVID-19, consider a clinical influenza diagnosis without diagnostic lab testing for stable outpatients 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 outcomes Treat influenza A and B with an NA inhibitor or baloxavir
PCE Promotes Practice Change
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2020 PCE Symposia Series 3 12 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
1
Learning Objectives
• Discuss the benefits of weight loss with persons who are candidates for medical management of obesity • Discuss weight loss goals and treatment options with people who are candidates for medical management of obesity • Describe the indications, administration, and potential adverse events associated with anti-obesity medications • Examine approaches for addressing obstacles and adjusting therapy in the long-term management of obesity
2 2
Obesity Is a Chronic Medical Condition Associated With a Number of Comorbidities
US FDA:1 “…a chronic relapsing health risk defined by excess body fat.”
Metabolic2-5: • Prediabetes, T2DM, asthma, gallstones, infertility, fatty liver • Cancers: endometrial, kidney, ovarian, breast, colorectal • Cardiovascular diseases: stroke, dyslipidemia, hypertension, coronary artery disease, heart failure
Mechanical2,3,6: Incontinence, osteoarthritis, sleep apnea, chronic back pain
Mental health2,7,8: Depression, anxiety, bipolar disorder, agoraphobia
FDA = US Food and Drug Administration. 1. US FDA. www.fda.gov/media/71252/download; 2. Sharma AM. Obes Rev. 2010;11:808-809; 3. Guh DP, et al. BMC Public Health. 2009;9:88; 4. Church TS, et al. Gastroenterology. 2006;130:2023-2030; 5. Hosler AS. Prev Chronic Dis. 2009;6:A48; 6. Li C, et al. Prev Med. 2010;51:18-23; 7. Luppino FS, et al. Arch Gen Psychiatry. 2010;67:220-229; 8. Simon GE, et al. Arch Gen Psychiatry. 2006;63:824-830. 3 3
2020 PCE Symposia Series 3 1 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
A Diagnosis of Obesity Improves Outcomes for the Patient
Obesity is underdiagnosed in the US1,2 A diagnosis of obesity or discussion about weight by an HCP is associated with2-4: “I can help you” Weight loss advice from Increased likelihood of weight loss providers increases a patient’s attempts (OR, 2.42)3 weight loss efforts by 3.5 to 3.8 times5,6 Increased likelihood of actual weight loss (OR, 2.70)3
HCP = healthcare provider; OR = odds ratio. 1. Kaplan LM, et al. Obesity. 2018;26:61-69; 2. Post RE, et al. JAMA Int Med. 2011;171:316-321; 3. Singh S, et al. Am Heart J. 2011;160:934-942; 4. Pool AC, et al. Obes Res Clin Pract. 2014;8:e131-e139; 5. Jackson SE, et al. BMJ Open. 2013;3:e003693; 6. Rose SA, et al. Int J Obes (Lond). 2013;37:118-128. 4 4
Case Study: Introducing Tasha
• Tasha has recently moved to the city and is attending your clinic following a health check-up that raised some worrying results • Current status ‒ Height: 156 cm (61.4 in) ‒ Weight: 68.9 kg (152 lb) ‒ BMI: 28.7 kg/m2 Age: 26 ‒ WC: 92.5 cm (36.4’’) Ethnicity: ‒ BP: 156/94 mm Hg African American ‒ A1C: 6.1% ‒ FPG: 102.7 mg/dL (5.7 mmol/L)
FPG = fasting plasma glucose; WC = waist circumference. 5 5
Motivational Interviewing (5As)1,2: Start With Asking the Patient Permission to Discuss Weight
“Would you be open to discussing your weight today?”
Weight and obesity are personal If the patient makes it clear that they and sensitive topics; discussing do not want to have a discussion them could be difficult for the today, respect the choice and table patient and cause feelings of the conversation for a later date1,3 embarrassment or fear1,3
Seeking permission to discuss weight encourages a nonjudgmental conversation1
1. Vallis M, et al. Can Fam Physician. 2013;5:27-31; 2. Bays HE, et al. Obesity Algorithm 2020. https://obesitymedicine.org/obesity-algorithm/; 3. STOP Obesity Alliance. whyweightguide.org/tool-content.php. 6 6
2020 PCE Symposia Series 3 2 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
Motivational Interviewing: Assess the Stage and Class of the Obesity
BMI classification1 kg/m2 Stage 4: End stage Underweight ≤18.5 Stage 3: End-organ Normal weight 18.6-24.9 damage Stage 2: Established Overweight 25.0-29.0 comorbidity Obesity class I 30.0-34.9 Stage 1: Preclinical risk factors Obesity class II 35.0-39.9 Stage 0: No apparent Obesity class III ≥40 risk factors
WHO = World Health Organization. 1. WHO. www.who.int/dietphysicalactivity/childhood_what/en/; 2. EOSS Staging tool. www.drsharma.ca/wp-content/uploads/edmonton-obesity- staging-system-staging-tool.pdf. 7 7
Motivational Interviewing: Assess the Stage and Class of the Obesity
BMI classification1 kg/m2 Stage 4: End stage Underweight ≤18.5 Stage 3: End-organ Normal weight 18.6-24.9 damage Stage 2: Established Overweight 25.0-29.0 comorbidity
TashaObesity is overweight class I according to the 30.0-34.9 WHO classification system, Stage 1: Preclinical risk 2 factors Obesity class IIwith a BMI of 28.3 35.0-39.9 kg/m Stage 0: No apparent However, she has stage 2 obesity per the Edmonton Obesity risk factors ObesityStaging classSystem III because she has ≥40 established hypertension
WHO = World Health Organization. 1. WHO. www.who.int/dietphysicalactivity/childhood_what/en/; 2. EOSS Staging tool. www.drsharma.ca/wp-content/uploads/edmonton-obesity- staging-system-staging-tool.pdf. 8 8
Motivational Interviewing: Assess Drivers, Complications and Barriers, and Readiness for Change
“Have you experienced problems in any of the following “Are you interested in taking some domains, which could contribute to weight management?” steps to lose weight?”
Mental Health Mechanical If the patient is ready to make a change: Feels low/isolated None reported following move to new • Ask about previous weight loss efforts and what has worked in the past city; husband frequently Metabolic away for work, leaving her • Determine the level of support the to care for young child Hypertension patient desires from you Reports eating out of Prediabetes boredom during Missed periods If the patient is not ready to make a change: evenings/weekends Reports concern about her • Work to address barriers to readiness, Recently started a newly diagnosed health such as existing health conditions stressful new office job problems • Invite the patient to let you know when Monetary: Well educated; insurance will cover medical they are ready therapy for obesity if needed
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2020 PCE Symposia Series 3 3 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
Motivational Interviewing: Advise That Small Amounts of Weight Loss Can Lead to Meaningful Health Improvements
• Weight loss required for therapeutic benefits (%)1,2
0 5 10 15 Diabetes (prevention) 3 to 10% 10 to 15% Diabetes (remission) 5 to >15% Hypertension 3% to >15% Dyslipidemia 3% to >15% Hyperglycemia 10% 5% to 10% NAFLD 10% weight loss can Sleep apnea 10% improve quality of Osteoarthritis 5% to 10% life, and this Stress incontinence 5% to 10% improvement is GERD (males) 10% maintained even if GERD (females) 5% to 10% some weight is 3 PCOS 5% to 15% regained GERD = gastroesophageal reflux disease; NAFLD = nonalcoholic fatty liver disease; PCOS = polycystic ovary syndrome. 1. Cefalu WT, et al. Diabetes Care. 2015;38:1567-1582; 2. Lean MJ, et al. Lancet. 2018;391:541-551; 3. Blissmer B, et al. Health Qual Life Outcomes. 2006;4:43. 10 10
Why Is Modest Weight Loss Beneficial?
10% weight loss = 30% VAT Loss Increased Risk Lowered Risk Deterioration Lipid profile Improvement VAT VAT Impaired Insulin sensitivity Improved
After Abdominal Blood insulin weight obesity, loss, increased Blood glucose reduced WC WC Risk markers for thrombosis Inflammatory markers Impaired Endothelial function Improved SCAT = subcutaneous adipose tissue; VAT = visceral adipose tissue. Adapted from: Després J, et al. Br Med J. 2001;322:716-720. 11 11
Motivational Interviewing: Agree on a Weight Loss Target and Approach
• Weight loss goals1-4 6 ─ Good initial goal: 5% to 10% within 6 months Think Beyond the Scale! ─ Complications? More aggressive approach? Health improvement (eg, BP), ability to do more, less pain, ─ Reassess therapy when health goal is met better sleep, better diet, etc ─ Greater losses yield greater benefits
• Goal-setting tips5 ─ SMART (Specific, Measurable, Attainable, Relevant to you, Time limited) ─ Short and long term ─ Expect setbacks ─ Reassess and adjust 1. Garvey WT, et al. Endocr Pract. 2016;22:842-884; 2. Apovian CM, et al. J Clin Endocrinol Metab. 2015;100:342-362; 3. Jensen MD, et al. Obesity. 2014;22(suppl 2):S1-S410; 4. Bays HE, et al. Obesity Algorithm 2020. https://obesitymedicine.org/obesity-algorithm/; 5. Mayo Clinic. https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/weight-loss/art-20048224; 6. Dietitians Association of Australia. https://daa.asn.au/smart-eating-for-you/smart-eating-fast-facts/weight-management/weight-loss-goals-other-than-the-scales/. 12 12
2020 PCE Symposia Series 3 4 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
Motivational Interviewing: Assist the Patient by Recommending Weight Management Interventions
• Nutrition, physical activity, and behavioral interventions are core components of weight management1-4
─ Many types of diet will work (eg, meal replacements, keto, low-carbohydrate, low-fat, Mediterranean, commercial), but aim for a caloric deficit of 500 to 750 kcal/day ─ Consider patient needs, limitations, preferences ─ A supervised very-low-calorie diet is an option for select patients ─ Aim for regular physical activity and a reduction in sedentary behavior ─ Aerobic (>150 min/week; 3-5 days/week) ─ Resistance (major muscle groups, 2-3 times/week)
─ Behavioral interventions: self-monitoring, goal setting, education, problem solving, stimulus control, contracting, stress reduction, psychological treatment, cognitive restructuring, motivational interviewing, social support
1. Garvey WT, et al. Endocr Pract. 2016;22:842-884; 2. Wharton S, et al. CMAJ. 2020;192:E875-E891; 3. Durrer Scuhtz D, et al. Obesity Facts. 2019;12:40-66; 4. Bays HE, et al. Obesity Algorithm 2020. obesitymedicine.org/obesity-algorithm/. 13 13
Pharmacotherapy and Surgery Can Be Used as Adjunctive Therapies
• More severe disease—based on anthropometric measurements and complication status—warrants more intensive therapy
Complication Status Pharmacotherapy Bariatric Surgery No obesity-related complications Pharmacotherapy Consider if lifestyle is not Consider if lifestyle not should be offered effective and BMI ≥302,3,a effective and BMI ≥40b to patients with obesity–when ≥1 mild to moderate obesity-related potential benefits Consider if BMI ≥272,3 Consider if BMI ≥35a complication outweigh the risks–for the chronic treatment ≥1 severe obesity-related of their disease1 Add if BMI ≥272,3 Consider if BMI ≥35a complication
a American Association of Clinical Endocrinologists recommendations, ≥27; b European Union guidelines: bariatric surgery should be considered for individuals with BMI ≥30 if lifestyle is not effective and comorbidities are present or if the patient has a BMI ≥30 and T2DM in the absence of previous lifestyle changes. 1. Garvey WT, et al. Endocr Pract. 2016;22:s3; 2. Wharton S, et al. CMAJ. 2020;192:E875-E891; 3. Durrer Scuhtz D, et al. Obesity Facts. 2019;12:40-66. 14 14
Importance of Personalized Care
All interventions take into account Tasha’s personal circumstances
• Patient-centered care is a key concept in the treatment of multiple chronic diseases, including diabetes, dyslipidemia, and cardiovascular diseases Group aspect addresses Tasha’s need for companionship after moving to a new city and help • Attend a twice-weekly weight loss support group address eating from boredom • Walk to work 3 times/week Introduction of “lifestyle activity” • Interest in taking weight loss pharmacotherapy reduces amount of time spent on • Begin taking ramipril 5 mg/day for hypertension sedentary activities
Control comorbidities separately Fastenau J, et al. Clin Obes. 2019;9:e12309. 15 15
2020 PCE Symposia Series 3 5 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
The Addition of Pharmacotherapy to Lifestyle Intervention Can Improve Long-Term Weight Loss Outcomes
Long-Term Use of Combined therapy Pharmacotherapy Aids in Weight Maintenance • Can help maintain weight and Lifestyle modification alone support additional weight loss following dietary intervention2-4 a • Weight regain is likely if a 5,6 Medication alone medications are stopped • Effective as adjunct to bariatric surgery for inadequate weight -14 -12 -10 -8 -6 -4 -2 0 loss or weight regain4,5,7,8 Weight Loss Over 52 Weeks, kg1
aSibutramine 15 mg daily. 1. Wadden TA, et al. N Engl J Med. 2005;353:2111-2020; 2. Wadden T, et al. Int J Obes. 2013;37:1443-1451; 3. Hill JO, et al. Am J Clin Nutr. 1999;69:1108-1116; 4. Richelsen B, et al. Diabetes Care. 2007;30:27-32; 5. Smith SR, et al. N Engl J Med. 2010;363:245-256; 6. Sjostrom L, et al. Lancet. 1998;352:167-172; 7. Standford FC, et al. Obes Relat Dis. 2017;13:491-500; 8. Wharton S, et al. Clin Obes. 2019; 9:e12323. 16 16
Approved Obesity Agents Target Different Obesity Mechanisms
Agent1 Dosage form; frequency1 Mechanism of action1 GI lipase inhibitor Orlistat Oral tablet; 3× daily Promotes fat excretion (GI) Phentermine/topiramate ER Oral tablet; 1× dailya Sympathomimetic/antiepileptic (schedule IV) (titrate to final dose) Regulates appetite (CNS) 2 oral tablets; 2× daily Opioid antagonist/antidepressant Naltrexone ER/bupropion ER (titrate to final dose) Regulates appetite (CNS)
1 SC injection; 1× daily GLP-1 RA Liraglutide 3.0 mg (titrate to final dose) Regulates appetite (CNS)
Diethylpropion, phendimetrazine, benzphetamine, and phentermine: sympathomimetic amines that increase satiety; approved for short-term use1-4 Clinical data support administration of phentermine for longer than 12 weeks4
CNS = central nervous system; ER = extended release; GLP-1 RA = glucagon-like peptide-1 receptor agonist; SC = subcutaneous. a15-mg/92-mg dose for use only if 7.5-mg/46-mg dose is not effective. 1. Drugs at FDA. www.accessdata.fda.gov/Scripts/cder/DrugsatFDA; 2. Garvey WT, et al. Endocr Pract. 2016;22:842-884; 3. Apovian CM, et al. J Clin Endocrinol Metab. 2015;100:342-362; 4. Obesity Medicine Association. www.obesityalgorithm.org. 17 17
Decisions Surrounding Weight Loss Drugs Should Take Into Account a Variety of Factors
Contraindications Patient-centered Insurance discussion coverage/accessibility/ Efficacy of individual agents cost
Potential for adverse events
Lifestyle
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2020 PCE Symposia Series 3 6 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
Counsel Patients on the Efficacy of Different Weight Management Pharmacotherapies
Medications approved for long-term weight management: 1-year efficacy in clinical trials1,a Future agents may 0 provide additional -1.6 -1.8 weight loss options: -5 -4.3 -3.5 2-4,b Δ BW, % Semaglutide -10 -8.1 (phase 3): -8.8 -9.6 -9.2 -15 Control Naltrexone ER/bupropion Orlistat 360 mg/day ER 32/360 mg/day Exenatide QW + dapagliflozin5 Liraglutide 3.0 mg/day Phentermine/topiramate (phase 2a): ER 7.5/46 mg/day
aData not from head-to-head studies; key clinical trials of ≥1 year in duration that included data for recommended doses; participants had a baseline BW of ≈100 kg and average BMIs in the range of 35 to 39.9 kg/m2; bPreliminary results. BW = body weight; QW = once weekly. 1. Garvey WT, et al. Endocr Pract. 2016;22:842-884; 2. GlobeNewswire. www.globenewswire.com/news-release/2020/06/04/2043954/0/en/Novo-Nordisk-reports-weight-loss-of- 14-9-16-9-if-taken-as-intended-in-STEP-1-trial.html; 3. GlobeNewswire. https://www.globenewswire.com/newsrelease/2020/06/12/2047467/0/en/Semaglutide-2-4-mg-shows- superior-weight-loss-versus-placebo-in-the-phase-3-trials-STEP-2-and-STEP-3-thereby-successfully-completing-the-programme.html; 4. FiercePharma. www.fiercepharma.com/pharma/novo-nordisk-s-all-powerful-semaglutide-hits-first-mark-obesity; 5. Lundkvist P, et al. Diabetes Obes Metab. 2019;19:1276-1288. 19 19
Consider Contraindications, and Counsel Patients on AE Profiles of Different Weight Management Pharmacotherapies
Agent Contraindications1,a AE Profile1,2,d Orlistat Chronic malabsorption syndrome; cholestasis; pregnancy Abdominal pain/discomfort; oily spotting/stool; fecal urgency Phentermine/ Glaucoma; hyperthyroidism; during/within 14 days of MAOI Paresthesia; dizziness; distorted taste; topiramate ER use; pregnancy (risk of fetal malformation) insomnia; constipation; dry mouth (schedule IV) Naltrexone ER/ Chronic opioid use; uncontrolled hypertension; seizure GI AEs (nausea, vomiting); headache bupropion ER disorders; anorexia nervosa; bulimia; use of other bupropion-containing products; during/within 14 days of MAOI use; discontinuation of some drugsb
Liraglutide 3.0 mg MEN2; personal/family history of MTC (potential risk of GI AEs (nausea, diarrhea); headache thyroid C-cell tumors); pregnancyc
MAOI = monoamine oxidase inhibitor; MEN2 = multiple endocrine neoplasia type II; MTC = medullary thyroid cancer. a For all agents: known hypersensitivity to agent or any component, not recommended during breastfeeding, caution on use of reliable contraception; b Alcohol, benzodiazepines, barbiturates, antiepileptic drugs; c From rat data; risk not determined in humans; d Selected common AEs, generally with incidence >10%, are noted; please refer to medication package inserts and cited references for complete information. 1. Garvey WT, et al. Endocr Pract. 2016;22:842-884; 2. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. 20 20
Case Study (cont’d): 3-Month Follow-Up With Tasha
Initial status Current status Height, cm/in 156/61 156/61 Weight loss: Weight, kg/lb 68.9/152 65.7/145 3.17 kg/7 lb/4.6% BMI, kg/m2 28.7 27.4 WC, cm/in 92.5/36.4 81.3/32 BMI reduction: 1.3 kg/m2/4.5% BP, mm Hg 156/94 110/70 A1C, % 6.1 5.7 FPG, mg/dL 102.7 88.3
21 21
2020 PCE Symposia Series 3 7 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
Monitor Pharmacotherapy to Assess Need for Adjustment or Discontinuation1,2
Initiate
Initiate therapy with dose Monitor escalation based on efficacy and tolerability; do not exceed the Monitor for efficacy, safety, and Adjust highest approved dose tolerability monthly for first 3 months and then every 3 months • If effective continuea Tasha started taking • If ineffective, discontinue: consider alternative naltrexone/bupropion Tasha lost 3.2 kg/7 lb/4.6% over medications, treatmentsb 12 weeks ago; the dose was 12 weeks • Discontinue if there are safety or tolerability titrated from initial dose of Attendance records show Tasha issues 8/90 mg daily to a final dose of has attended 22 of 24 weight 32/360 mg by week 4 Tasha’s weight loss was not >5% at 3 months loss group sessions; she despite adequate engagement with lifestyle reports following advice from interventions. Therefore, she should be these sessions during her switched to an alternative medication; Tasha day-to-day life is switched to liraglutide 3.0 mg/day
aWeight loss ≥5% at 3 months, except ≥4% at 16 weeks with liraglutide 3.0 mg; bWeight loss <5% at 3 months, except <4% at 16 weeks with liraglutide 3.0 mg. 1. Drugs@FDA. www.accessdata.fda.gov/Scripts/cder/DrugsatFDA; 2. Apovian CM, et al. J Clin Endocrinol Metab. 2015;100:342-362. 22 22
Communication Tips for Follow-Up Consultations
• Congratulate the patient for their achievements so far, including small amounts of weight loss • If the patient has not lost weight, do not blame the patient; react with empathy • Review the causes of and barriers to weight loss; how have these changed since you last saw the patient?
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Case Conclusion: Status at 6-Month Follow-Up
Weight loss: BMI reduction: BP controlled with Blood sugars 6.3 kg/14 lb 2.7 kg/m2 medication stabilized 9.21% 9.41%
A1C: Weight: BP: 5.5% BMI: 62.6 kg/ 110/70 FPG: 26 kg/m2 138 lb mm Hg 86.5 mg/dL
• Tasha is very pleased with her weight loss and resolution of health conditions • She reports wanting to continue with lifestyle interventions, because she has enjoyed them— particularly her exercise classes • Liraglutide 3.0 mg can be continued for weight loss and weight maintenance long term
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2020 PCE Symposia Series 3 8 Traversing the Chasm: Overcoming the Challenges of Obesity Management in Primary Care
PCE Action Plan
Before beginning any discussion surrounding weight, ask the patient whether they are comfortable discussing their weight on this occasion Focus conversations around the health-related and quality of life benefits of small amounts of weight loss Develop a personalized, patient-centric, weight management plan that respects the patient’s preferences, values, and needs and sets achievable goals Review weight loss medications every 3 months; if weight loss is inadequate, discontinue the medication and consider alternatives
PCE Promotes Practice Change
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2020 PCE Symposia Series 3 9 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
1
Learning Objectives
• Assess patients for symptoms and signs of early multiple sclerosis (MS) in order to facilitate appropriate diagnosis and treatment • Differentiate relapse from pseudorelapse so that a patient may be treated effectively • Implement patient-centered strategies to promote adherence to therapy and long-term management of MS
2 2
MS: A Progressive Disease of the CNS
• Affects ~1,000,000 people in the United States • Age of onset: between 20 and 50 years • Risk increases in first-degree relatives • Marked disease variability • 2x to 3x more common in women than men • Higher rate in white patients; increasing in blacks and Latinos • Indirect and direct costs: ~$28 billion annually
CNS = central nervous system. National Multiple Sclerosis Society. www.nationalmssociety.org/About-the-Society/MS-Prevalence. Accessed Oct 28, 2020; National Multiple Sclerosis Society. www.nationalmssociety.org/What-is-MS/Who-Gets-MS. Accessed Oct 28, 2020; National Multiple Sclerosis Society. www.nationalmssociety.org/What-is-MS/Who-Gets-MS/African-American-Resources. Accessed Oct 28, 2020; National Multiple Sclerosis Society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Documents/Health-Policy-Fact-Sheet-2-Costs.pdf. Accessed Oct 28, 2020; National Multiple Sclerosis Society. www.nationalmssociety.org/What-is-MS/Who-Gets-MS/Hispanic-Latino-Resources. Accessed Oct 28, 2020; Saguil A, et al. Am Fam Physician. 2014;90:644-652. 3 3
2020 PCE Symposia Series 3 1 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Impact of MS on Patients
Motor Symptoms Nonmotor Symptoms (eg, muscle spasticity, (eg, cognitive changes, weakness, impaired bladder/bowel mobility) dysfunction)
Risk of Clinical Reduced Productivity Relapse; Worsening (eg, employment, on Neurologic Exam functional abilities)
Decreased Quality of Life
Gelfand JM. Handb Clin Neurol. 2014;122:269-290; Newsome SD, et al. Int J MS Care. 2016;18:314-323; Newsome SD, et al. Int J MS Care. 2017;19:42-56. 4 4
Impact of MS: The Patient’s Perspective…
Video courtesy of the Multiple Sclerosis Association of America. Multiple Sclerosis Association of America. mymsaa.org/journey/just-starting-out/. Accessed Oct 28, 2020.
5
Rationale for Early MS Diagnosis and Treatment
• Preserve brain volume and function • Prevent axonal damage • Reduce risks and severity of clinical and subclinical attacks • Delay disability process • Delay disease progression • Decrease autoimmune attack on CNS
Giovannoni G, et al. Mult Scler Relat Disord. 2016;9(Suppl 1):S5-S48; Kuhlmann T, et al. Brain. 2002;125(Pt 10):2202-2212; Saguil A, et al. Am Fam Physician. 2014;90:644-652. 6 6
2020 PCE Symposia Series 3 2 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Disease Courses in MS
• RRMS, SPMS, and PPMS may be part of a spectrum of disease progression with different initial clinical presentations
PPMS
RIS CIS RRMS SPMS Neuroaxonal loss Inflammation Subclinical disease First clinical attack Disease Severity Disease Relapses MRI Events First MRI lesion Time (years)
RIS = radiologically isolated syndrome, CIS = clinically isolated syndrome RRMS = relapsing remitting multiple sclerosis, PPMS = primary progressive multiple sclerosis; SPMS = secondary progressive multiple sclerosis. Lublin FD, et al. Neurology. 2014;83:278-286. 7 7
Case Study: Anissa
• African American woman, married, 36 years old, generally healthy • Gave birth to second child 3 years ago; works as a phlebotomist • Diagnosed with Hashimoto’s thyroiditis 6 years ago; managed with levothyroxine 125 mcg per day • Mononucleosis at age 28 • Alcohol: drinks socially • Blood pressure and BMI: normal
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Case Study (cont’d): Anissa’s Initial Visit
• Anissa is seeing you today in follow up for her Hashimoto’s thyroiditis • You ask her how she’s been feeling since her last visit • She says she’s trying to get in shape, but… ‒ She feels very fatigued, and her right leg has been consistently “numb” and “tingly” for the last month or two ‒ She wonders if her levothyroxine dosage needs adjustment
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2020 PCE Symposia Series 3 3 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Case Study (cont’d): Anissa’s Initial Visit
• Anissa also complains that: ‒ She feels pain behind her left eye when she moves her eyes ‒ Vision in her left eye has gotten worse • You perform an eye exam and find: ‒ Decreased visual acuity in left eye ‒ Relative afferent pupillary defect in left eye (Marcus Gunn pupil) ‒ Color desaturation (red) ‒ Normal fundoscopic findings • During further examination, you note hyperreactive reflexes in right leg • CBC, thyroid, lipid, metabolic panels normal; Lyme serology normal
CBC = complete blood count. 10 10
Initial Workup for MS in Primary Care
Assess: • Eyes ‒ Movement, pupillary response, acuity, visual fields, color saturation, fundoscopy • Muscle strength • Coordination • Sensory disturbances • Reflexes • Lhermitte sign
Saguil A, et al. Am Fam Physician. 2014;90:644-652; Waubant E. Prim Care Companion CNS Disord. 2012;14:PCC.11016co2cc. 11 11
MS: Common Signs and Symptoms
Sign/Symptom Type Examples Sensory Tingling, numbness, pain
Motor Spasticity, weakness Cerebellar Impaired coordination, tremor, unsteady gait, vertigo, changes in speech tone/cadence Constitutional Fatigue, heat sensitivity Autonomic Bladder, bowel, sexual dysfunction Visual Diplopia, decreased vision, color distortion Cognitive Difficulties with attention, concentration, memory, processing information
National Institutes of Health. www.ninds.nih.gov/disorders/all-disorders/multiple-sclerosis-information-page. Accessed Oct 28, 2020; Newsome SD, et al. Int J MS Care. 2017;19:42-56. 12 12
2020 PCE Symposia Series 3 4 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Case Study (cont’d): MRI Findings
• You order brain and orbital MRIs ‒ Brain MRI reveals: • 2 ovoid lesions in corpus callosum, radiating from lateral ventricles • Asymptomatic enhancing lesion next to ventricle ‒ Orbital MRI reveals: • Increased T2 signal with gadolinium enhancement in optic nerve of left eye • You refer Anissa to a neurologist
Images courtesy of Claire S. Riley, MD. 13 13
Potential Elements of the MS Laboratory and Imaging Workup
Blood Tests Imaging CSF Other CSF and Differentials Evoked Potentials
• B12, D3, and folate • Brain MRI • Oligoclonal banding • Cell count • Visual • ANA, ESR, RF • Orbital MRI • IgG index • Cells (lymphocytes and monocytes) • Somatosensory • Lyme disease, HIV, • Spinal MRI • Total protein HTLV-1 titers • Glucose ratio (CSF/plasma) • Thyroid function • Cytology • Anticardiolipin, • Others antiphospholipid antibodies • Angiotensin-converting enzyme • NMO-IgG • Anti-MOG antibody
ANA = antinuclear antibody; CSF = cerebrospinal fluid; ESR = erythrocyte sedimentation rate; HTLV = human T-lymphotropic virus; IgG = immunoglobulin G; MOG = myelin oligodendrocyte glycoprotein; NMO = neuromyelitis optica; RF = rheumatoid factor. National Multiple Sclerosis Society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Diagnosis_DiagnosticWorkupTestingOptions.pdf. Accessed Oct 28, 2020. 14 14
2017 McDonald Criteria for Diagnosis of MS: Establishing Dissemination in Space (DIS) and Dissemination in Time (DIT)
Lesions With Objective Clinical Attacks Clinical Evidence Additional Data Needed to Make the Diagnosis ≥2 ≥2 None ≥2 1* None ≥2 1 DIS (shown by additional clinical attack implicating different CNS site or by MRI) 1 ≥2 DIT (shown by additional clinical attack or by MRI)**
1 1 DIS and DIT***
*Plus clear historical evidence of a previous attack involving a lesion in a distinct anatomic location; **Or by demonstration of CSF-specific oligoclonal bands; ***DIS shown by additional clinical attack implicating a different CNS site or by MRI; DIT shown by additional clinical attack or by MRI or by demonstration of CSF-specific oligoclonal bands. Thompson AJ, et al. Lancet Neurol. 2018;17:162-173. 15 15
2020 PCE Symposia Series 3 5 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Case Study (cont’d): Neurologist’s Assessment
• Clinical, laboratory, and imaging findings consistent with diagnosis of relapsing-remitting MS (RRMS) • Patient has: ‒ Had one multifocal attack (leg paresthesias + optic neuritis) ‒ Periventricular and optic nerve lesions demonstrated by MRI, with evidence of: • Dissemination in time by the asymptomatic enhancing lesion • Dissemination in space by location of lesions
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Case Study (cont’d): Neurologist’s Plan
• Methylprednisolone 1 g/day x 5 days, then taper, for optic neuritis • Order pre-DMT workup (eg, CBC with differential, lymphocytes, HIV, Quantiferon Gold, hepatitis B and C, JC virus antibody) • Initiate DMT ‒ Patient prefers agent with long safety record and is concerned about infectious AEs, so injectable agent is chosen • Refer patient to ophthalmologist • Follow-up brain, cervical, and thoracic MRIs in 6 months
AE = adverse event. 17 17
Overview of DMTs for MS
• Disease modifying, not curative • Decrease the relapse rate • Slow the accumulation of brain lesions on MRI • Reduce disability progression • Lower the long-term risk of disease progression
Olek MJ, Mowry E. www.uptodate.com/contents/disease-modifying-treatment-of-relapsing-remitting-multiple-sclerosis-in-adults. Accessed Oct 28, 2020. 18 18
2020 PCE Symposia Series 3 6 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
DMTs by Mode of Administration
Injection Oral Infusion Glatiramer acetate (SC) Cladribine Alemtuzumab (IV) IFN β-1a (IM or SC) Dimethyl fumarate Natalizumab (IV) IFN β-1b (SC) Diroximel fumarate Ocrelizumab (IV) Ofatumumab (SC) Fingolimod Mitoxantrone (IV)* Peginterferon β-1a (SC) Ozanimod Siponimod Teriflunomide
*An anthracenedione that is rarely, if ever, used in the United States. IFN = interferon; IM = intramuscular; SC = subcutaneous. National Multiple Sclerosis Society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-The-MS-Disease- Modifying-Medications.pdf. Accessed Oct 28, 2020. 19 19
Injectables: Safety Considerations
Agent Examples of AEs Warnings and Precautions IFN β-1a (IM) Flu-like symptoms; ↑ hepatic transaminases Depression and suicide; hepatic injury; anaphylaxis and other allergic reactions; low peripheral or white blood cell counts; seizures; thrombotic microangiopathy IFN β-1a (SC) Injection-site reactions; flu-like symptoms; ↑ hepatic transaminases
IFN β-1b (SC) Flu-like symptoms; injection-site reactions; ↑ hepatic transaminases
Peginterferon β-1a (SC) Flu-like symptoms; injection-site reactions; ↑ hepatic transaminases
Glatiramer acetate (SC) Injection-site reactions; lipoatrophy Immediate postinjection reaction (harmless)
Ofatumumab (SC) URI; headache; injection-related reactions; Increased risk of infection; injection-related reactions; local injection site reactions decreased immunoglobulin levels; fetal risk
URI = upper respiratory tract infection MS Coalition. www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed Oct 28, 2020; Ofatumumab [prescribing information]. Novartis; 2020. 20 20
Orals: Safety Considerations
Agent Examples of AEs Warnings and Precautions Cladribine URI; headache; lymphopenia; nausea; back Malignancies; risk of teratogenicity; lymphopenia; infections; pain; arthralgia and arthritis; insomnia hematologic toxicity; graft-versus-host disease with blood transfusion; liver injury; hypersensitivity; cardiac failure; PML
Dimethyl fumarate Flushing; GI symptoms (abdominal pain, Anaphylaxis and angioedema; PML; lymphopenia; liver injury diarrhea, nausea); pruritus, rash, erythema
Diroximel fumarate Redness; itching; rash; nausea, vomiting, Allergic reactions; PML; serious infections; leukopenia; herpes diarrhea; stomach pain; indigestion zoster and other opportunistic infections; liver problems
Fingolimod Headache; influenza; diarrhea; back pain; Bradyarrhythmia and/or AV block after first dose; cryptococcal ↑ hepatic enzymes; lymphopenia; bronchitis; meningitis and disseminated cryptococcal infections; macular pneumonia edema; PML; PRES; hepatic injury; ↑ BP; basal cell carcinoma; fetal risk; severe increase in disability after stopping treatment
AV = atrioventricular; PML = progressive multifocal leukoencephalopathy; PRES = posterior reversible encephalopathy syndrome. Fingolimod [prescribing information]. Novartis; 2019; MS Coalition. www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_ Consensus_MS_Coalition_color. Accessed Oct 28, 2020; National Multiple Sclerosis Society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-The-MS-Disease-Modifying-Medications.pdf. Accessed Oct 28, 2020. 21 21
2020 PCE Symposia Series 3 7 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Orals: Safety Considerations (cont’d)
Agent Examples of AEs Warnings and Precautions Ozanimod URI; ↑ hepatic enzymes; orthostatic Risk of infections; bradyarrhythmia and AV conduction delays; BP; hypotension; urinary tract infection; decline pulmonary function; macular edema back pain; hypertension
Siponimod Headache; hypertension; ALT Risk of infections; macular edema; bradyarrhythmia and AV elevation; falls; edema; nausea; conduction delays; respiratory effects, liver injury; BP; fetal risk; dizziness; diarrhea; bradycardia; pain PRES; disease rebound after stopping treatment in extremity
Teriflunomide ALT elevation; hair thinning; diarrhea; Hepatotoxicity; risk of teratogenicity; reactivated TB; decrease in influenza; nausea; paresthesia neutrophils, lymphocytes, platelets; rare peripheral neuropathy; single case of toxic epidermal necrolysis; BP; rare potassium/renal issues; increased risk of malignancy; interstitial lung disease; acute renal failure
ALT = alanine aminotransferase. Mavenclad [prescribing information]. EMD Serono; 2020; Mayzent [prescribing information]. Novartis; 2020; MS Coalition. www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed Oct 28, 2020; Zeposia [prescribing information]. Bristol Myers Squibb; 2020. 22 22
Infused mAbs: Safety Considerations
Agent Examples of AEs Warnings and Precautions Alemtuzumab (IV) Infusion reactions; rash; fever; headache; Autoimmunity; serious infections; malignancies; muscle aches pneumonitis; myocardial infarction; stroke; arterial dissection
Natalizumab (IV) Headache; fatigue; urinary tract infection; PML; hepatic injury; herpes encephalitis and meningitis; lower respiratory tract infection acute retinal necrosis; hypersensitivities
Ocrelizumab (IV) Infusion-related reactions (itchy skin, rash, Infections; malignancies; hepatitis B reactivation throat irritation, flushed face or fever, headache)
mAb = monoclonal antibody. Hauser SL, et al. N Engl J Med. 2017;376:221-234; Montalban X, et al. N Engl J Med. 2017;376:209-220; MS Coalition. www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed Oct 28, 2020. 23 23
Examples of MS Agents in Late-Stage Development
Agent Administration Route Indication Status
Masitinib Oral PPMS, SPMS Phase 3 completed
Ponesimod Oral RRMS Pending approval
Ublituximab Oral RRMS Phase 3 active, not recruiting
ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT01433497. Accessed Oct 28, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/results?term=ofatumumab&cond=multiple+sclerosis&age_v=&gndr=&type=&rslt=&phase=2&phase=3&Search=Apply. Accessed Oct 28, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/results?term=ponesimod&cond=multiple+sclerosis&age_v=&gndr=&type=&rslt= &phase=2&phase=3&Search=Apply. Accessed Oct 28, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03277261. Accessed Oct 28, 2020. 24 24
2020 PCE Symposia Series 3 8 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Choosing Initial Therapy for RRMS
RRMS
“Safety: tried and true” approach “Convenience” “Efficacy” approach approach
Injection therapy Oral therapy Infusion therapy
Olek MJ, Mowry E. www.uptodate.com/contents/disease-modifying-treatment-of-relapsing-remitting-multiple-sclerosis-in-adults. Accessed Oct 28, 2020. 25 25
Case Study (cont’d): Partnering With Anissa on Her MS Management Journey
• After seeing the neurologist, Anissa comes to see you • You discuss: ‒ Importance of DMTs, possible barriers to adherence and how to overcome them ‒ Continuing her exercise regimen ‒ Joining an MS support group ‒ Referral to mental health professional if needed ‒ Need to see an ophthalmologist every 6 months for her optic neuritis • You give her educational materials and a list of resources, including NMSS and MSSA
MSAA = Multiple Sclerosis Association of America; NMSS = National Multiple Sclerosis Society. Remington G, et al. Int J MS Care. 2013;15:36-45. 26 26
Interdisciplinary Management of MS Requires Patient-Centered Coordinated Care
Nursing Neurologist Primary Care Pharmacy Clinician
Vocational/ Ophthalmologist/ Physical Patient Urologist Therapist Financial Planning/ Legal Assistance Services Mental Health Other Medical Professional Social Worker Specialists
National Multiple Sclerosis Society. www.nationalmssociety.org/For-Professionals/Clinical-Care/Managing-MS/Comprehensive-Care. Accessed Oct 28, 2020; Newsome SD, et al. Int J MS Care. 2016;18:314-323; Noyes K, Weinstock-Guttman B. Am J Manag Care. 2013;19(17 Suppl):s321-s331. 27 27
2020 PCE Symposia Series 3 9 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Reasons for Nonadherence in MS
Intolerance/ Forgot to Administer Nonadherance Adverse Effects
Lack of Perceived Dosing Schedule Efficacy
Mood Lack of Support Disorders/Depression
Needle Phobia and Did Not Refill Prescription Anxiety
Ben-Zacharia A, et al. Int J MS Care. 2018;20:287-297. 28 28
Shared Decision-Making Improves Adherence in MS
• Patients who are well informed about MS and risk-benefit trade-offs of therapies are more likely to be adherent • Active, dynamic discussion may reduce gaps between clinician’s and patient’s expectations and goals • Taking patient’s preferences into account (eg, route of administration, tolerance, work, lifestyle) may optimize DMT selection and adherence • Provides opportunities for healthcare team to correct misconceptions about MS and therapies available on the internet and in social media
Ben-Zacharia A, et al. Int J MS Care. 2018;20:287-297. 29 29
Optimizing Treatment Outcomes
• DMTs should be started as soon as possible and continued as long as possible • Explain purpose of DMTs to patients, family, caregivers • Set realistic expectations to help improve adherence • Instruct/reinforce proper use of medications (eg, injection techniques/rotation) • Identify suboptimal response • Monitor disease activity; refer back to neurologist for new neurologic symptoms • Monitor for AEs and provide management strategies • Monitor safety and laboratory parameters
MS Coalition. www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed Oct 28, 2020; National Multiple Sclerosis Society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-The-MS- Disease-Modifying-Medications.pdf. Accessed Oct 28, 2020; Remington G, et al. Int J MS Care. 2013;15:36-45. 30 30
2020 PCE Symposia Series 3 10 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Monitoring Patients With MS
• Provide regular preventive screenings, vaccinations, and treatments ‒ Vaccinations considered safe for patients with MS • Inactivated vaccines generally preferred • Live attenuated vaccines (eg, MMR, chickenpox) not recommended • Manage hypertension, hyperlipidemia, diabetes, and other vascular comorbidities, as they may worsen the course of MS • Offer continuing communication with care team to support patient, monitor and evaluate MS treatments, monitor for and address MS-associated comorbidities
MMR = measles-mumps-rubella. Hersh CM, Fox RJ. www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/. Accessed Oct 28, 2020; Saguil A, et al. Am Fam Physician. 2014;90:644-652; The Consortium of Multiple Sclerosis Centers. www.mscare.org/page/MRI_protocol. Accessed Oct 28, 2020. 31 31
Monitoring Patients With MS (cont’d)
• Laboratory parameters Examples of DMTs ‒ Baseline and follow-up tests Abnormal Result That Can Cause Elevated liver enzymes Interferons, teriflunomide • Different requirements with different therapies Elevated peripheral Interferons, natalizumab • Some treatments may cause abnormal WBC count results (see examples in table) High or low TSH Alemtuzumab, interferon β-1b • Follow-up MRIs Lymphopenia Oral DMTs, alemtuzumab, ‒ Surveillance MRI every 6 months to 2 years interferons for patients with relapsing MS ‒ New baseline MRI if modifying therapy
TSH = thyroid stimulating hormone; WBC = white blood cell. Alemtuzumab [prescribing information]. Genzyme Corporation; 2019; Bridel C, et al. Neurol Neuroimmunol Neuroinflamm. 2015;2:e123; ; Dimethyl fumarate [prescribing information]. Biogen; 2020; Fingolimod [prescribing information]. Novartis; 2019; Hersh CM, Fox RJ. www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis. Accessed Oct 28, 2020; Ocrelizumab [prescribing information]. Genentech; 2020; The Consortium of Multiple Sclerosis Centers. www.mscare.org/page/MRI_protocol. Accessed Oct 28, 2020. 32 32
Managing Nonmotor Symptoms of MS
Symptom Examples of Treatment
Fatigue Exercise, rest periods, physical therapy, cooling (if heat sensitive), assistive devices, rehabilitation, amantadine, modafinil
Pain Stretching, exercise, massage, appropriate medications
Bladder dysfunction Inability to store: fluid management, frequent bathroom breaks, protective pads, oxybutynin, tolterodine, solifenacin, mirabegron Inability to void: fluid management, pelvic floor exercises, scheduled bathroom breaks, intermittent or continuous catheterization, tamsulosin, doxazosin Bowel dysfunction Constipation: high fiber diets, fluid intake, exercise, laxatives, stool softeners Fecal incontinence: timed bowel movements
Newsome SD, et al. Int J MS Care. 2017;19:42-56. 33 33
2020 PCE Symposia Series 3 11 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Managing Nonmotor Symptoms of MS (cont’d)
Symptom Examples of Treatment
Sexual dysfunction Lifestyle changes, positioning, lubricants, assistive devices, bupropion, flibanserin, sildenafil, tadalafil
Cognitive impairment Rehabilitation, compensatory strategies, exercise, attention- enhancing medications (modafinil, armodafinil, stimulants)
Depression Counseling, psychotherapy, support groups, antidepressants, anti-anxiety medications
Pseudobulbar affect* Dextromethorphan hydrobromide/quinidine sulfate
*Characterized by sudden laughter or crying without an identifiable trigger. Newsome SD, et al. Int J MS Care. 2017;19:42-56. 34 34
Case Study (cont’d): 6-Month Follow-up
• Anissa’s MS is clinically stable • She has successfully adhered to her treatment regimen • MRI findings ‒ Contrast enhancement seen previously has resolved; no new lesions observed • She has joined a local support group • She has improved her diet and modified her exercise program • She and her husband are considering having more children and wants to know what her options are
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DMT Use and Pregnancy
• No DMT approved for use during pregnancy or breastfeeding • Generally, discontinue DMTs for 5 maximal half-lives (~2-6 weeks) prior to conception; exceptions: ‒ 2 months for fingolimod ‒ 3 months for natalizumab and ozanimod ‒ Teriflunomide: wash-out period of 11 days with cholestyramine; measure levels prior to conception; males taking teriflunomide should avoid getting partners pregnant ‒ Cladribine has specific recommendations in men and women planning to conceive • Evidence suggests that glatiramer acetate and IFN-β may be continued safely during conception and pregnancy in patients with very active MS • Risks and benefits of continuing DMTs during pregnancy, and for postponing resumption of treatment to allow breastfeeding, require careful discussion
MS Coalition. www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed Oct 28, 2020. Zeposia [prescribing information]. Bristol Myers Squibb; 2020. 36 36
2020 PCE Symposia Series 3 12 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Case Study (cont’d): Long-term Follow-up
• Anissa is stable and free from clinical events for the next year ‒ She has decided to postpone trying to have another baby for the time being • After a stressful event at work she suddenly experiences numbness and tingling in her right leg • Her family takes her to the ED ‒ Neurologist consulted ‒ No new enhancing lesions on spinal MRI
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Differentiating Relapse From “Pseudorelapse”
Relapse Pseudorelapse • Onset of a new neurologic • Sudden onset of new or worsened symptoms symptom or worsening of a • Triggered by a specific situation: neurologic symptom that had ‒ Heat exposure, overexertion, infections (eg, urinary previously been stable for at tract, upper respiratory), or psychological stress least 30 days, lasting more • Generally transient, resolving as the triggering situation than 24 hours, and unrelated resolves to any active infection • Treated based on clinical observation • Symptoms arise over hours to ‒ If fever is present, evaluate for possible infection days, and worsen over several weeks, then generally subside ‒ Acetaminophen, NSAIDs over weeks or months ‒ Physical therapy to return to baseline functionality
NSAID = nonsteroidal anti-inflammatory drug. Burns MN, et al. Psychosom Med. 2013:75:76-82; Galea I, et al. BMJ. 2015;350:h1765; Fox RJ.; Ontaneda D, et al. Ann Indian Acad Neurol. 2009;12:264-272; Hersh CM, Fox, RJ. www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis. Accessed Oct 30, 2020; Thrower BW. Neurologist. 2009;15:1-5. 38 38
Managing Relapse and Breakthrough Disease in MS
• Relapse ‒ Should be documented to determine if change in treatment might be necessary ‒ Emergence of new neurologic symptoms—including sphincter dysfunction and mood disorders—may be a sign of relapse ‒ Usually treated with high-dose corticosteroids ‒ Alternatives are corticotropin injection gel and plasmapheresis • Breakthrough disease ‒ Generally defined as continued clinical relapses or new or active MRI lesions despite DMT ‒ DMT with alternative mechanism of action may be considered
Personal communication, Boyd AL. 2019; Hersh CM, Fox RJ. www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/ multiple_sclerosis. Accessed Oct 28, 2020; Kalincik T. Neuroepidemiology. 2015;44:199-214. 39 39
2020 PCE Symposia Series 3 13 Collaborative Care in the Management of Multiple Sclerosis: Where Does Primary Care Fit?
Case Conclusion
• Anissa sees you a day after receiving her MRI results; by this time, she has started regaining normal sensation in her right leg • You counsel her on pseudorelapse and explain the triggers to be aware of, including fluctuations in temperature, infection, and stress • Long-term follow-up ‒ Neurologist • Devise plan for surveillance of immunotherapy/monitoring • Provide education about signs and symptoms of relapse vs pseudorelapse ‒ Primary care • Health maintenance with special consideration to immunomodulation • Consult neurologist regarding infections, any general medical changes
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PCE Action Plan
Query patients about symptom onset, duration, precipitating factors, and previous symptoms; perform neurologic exam Use a collaborative multidisciplinary approach to coordinate all aspects of MS treatment Explain the purpose of DMTs to patients, family, and caregivers, and set realistic expectations to help improve adherence Proactively inquire about and address the comorbidities associated with MS to help improve your patients’ quality of life
PCE Promotes Practice Change
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