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© 2019 PRIME® Education, LLC. All Rights Reserved.
TREATMENT OF EARLY RA: CONVENTIONAL DMARDS
AND STEROIDS
Rebecca L Manno, MD, MHS
This activity is provided by PRIME Education and is supported by an educational grant from Gilead Sciences, Inc. There is no fee to participate in this activity.
© 2019 PRIME® Education, LLC. All Rights Reserved.
This module is part of a video library featuring 3 additional segments.
(2 of 4)
Please note that to claim credit, participants must complete
all four modules.
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© 2019 PRIME® Education, LLC. All Rights Reserved.
Accreditation
In support of improving patient care, PRIME® is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.
This activity was planned by and for the healthcare team, and learners will receive 2.0 Interprofessional Continuing Education (IPCE) credits for learning and change.
Physician Credit Designation StatementPRIME Education, LLC (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.PRIME® designates this Enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only credit commensurate with the extent of their participation in the activity.
Physician Assistant Credit Designation StatementPRIME® has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credits for activities planned in accordance with AAPA CME Criteria. This activity is designated for 2.0 AAPA Category 1 CME credits. PAs should only claim credit commensurate with the extent of their participation.
Nurse Practitioner Credit Designation StatementPRIME® is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 060815. This activity is approved for 1.5 contact hours of continuing education (which includes 0.5 hours of pharmacology).
Pharmacist Credit Designation StatementThis Application-based activity has been approved for 2.0 contact hours (0.2 CEUs) by PRIME® for pharmacists. The Universal Activity Number for this activity is JA0007144-0000-19-095-H01-P. Pharmacy CE credits can be electronically submitted to the NABP upon successful completion of the activity. Pharmacists with questions can contact NABP customer service ([email protected]).
Nurse Credit Designation StatementPRIME Education, LLC (PRIME®) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. PRIME® designates this activity for 2.0 contact hours.
© 2019 PRIME® Education, LLC. All Rights Reserved.
Disclosure Policy
PRIME Education, LLC (PRIME®) endorses the standards of the ACCME, as well as those of the AANP, ANCC, and ACPE, which require everyone in a position of controlling the content of a CME/CE activity to disclose all financial relationships with commercial interests related to the activity content. CME/CE activities must be balanced, independent of commercial bias, anddesigned to improve quality in health care. All recommendations involving clinical medicine must be based on evidence accepted within the medical profession. A conflict of interest is created when individuals in a position of controlling the content of CME/CE activities have a relevantfinancial relationship with a commercial interest which therefore may bias his/her opinion and teaching. This may include receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, stocks, or other financial benefits. PRIME® will identify, review, and resolve all conflicts of interest that speakers, authors, course directors, planners, peer reviewers, or relevant staff disclose prior to an educational activity being delivered to learners. Disclosure of a relationship is not intended to suggest or condone bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. Disclosure information for speakers, authors, course directors, planners, peer reviewers, and/or relevant staff is provided with this activity.Presentations that provide information in whole or in part related to non-FDA-approved uses of drugs and/or devices will disclose the unlabeled indications or the investigational nature of their proposed uses to the audience. Participants should refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. The opinions expressed in the educational activity are those of the presenting faculty and do not necessarily represent the views of PRIME®, ACCME, AANP, ACPE, ANCC, or other relevant accreditation bodies.
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© 2019 PRIME® Education, LLC. All Rights Reserved.
Faculty Disclosures
The following individuals have identified relevant financial relationships with commercial interests to disclose:• William FC Rigby, MD (Speaker)
Advisory Board/Panel – Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, RocheConsultant – Bristol-Myers Squibb, Pfizer, RochePrincipal Investigator of Research Grant – PfizerSpeaker's Bureau Promotional Education – Bristol-Myers Squibb
The following individuals have no relevant financial relationships with commercial interests to disclose:• Sandeep K Agarwal, MD, PhD (Lead Faculty, Speaker)• Rebecca L Manno, MD, MHS (Speaker)• Kristi Kay Orbaugh, RN, MSN, RNP, AOCN (Planner/Reviewer)
All PRIME staff participating in planning and content development have no relevant financial relationships with commercial interests to disclose.
© 2019 PRIME® Education, LLC. All Rights Reserved.
Learning Objectives
• Incorporate strategies for assessing and monitoring disease activity, prognostic factors, and patient-reported outcomes to guide clinical decisions
• Assess new research findings on the pathogenesis of RA, focusing on the TNF-α, JAK/STAT, and interleukin-6 inflammatory pathways
• Differentiate the latest evidence on the efficacy and safety of new and emerging small-molecule and biologic therapies for moderately to severely active RA
• Apply treat-to-target approaches and evidence on switching mechanism of action for patients with inadequate therapy responses
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© 2019 PRIME® Education, LLC. All Rights Reserved.
2015 ACR RA Guideline Recommendations: Initial Treatment
“Use glucocorticoids at the lowest dose possible and for the shortest duration possible”
Singh JA, et al. Arthritis Rheumatol. 2016;68:1–26.
Treat to Target#
DMARD Monotherapy†
Combination Traditional DMARDs*† or TNFi +/- MTX*† or
Non-TNF Biologic +/- MTX*† orTofacitinib +/- MTX
Low Disease Activity
Moderate or High Disease
Activity
Moderate or High Disease
Activity*†
DMARD Monotherapy†
DMARD-Naïve
Early RA
Strong Recommendations
Conditional Recommendations
Disease Activity
Treatment Options or Strategy
Algorithm Pathway for Most Patients Disease or Prior Treatment State
© 2019 PRIME® Education, LLC. All Rights Reserved. 8
Treat-to-Target in RA
Treat to desired goal: REMISSION
• Remission: TJC≤1, SJC≤1, CRP≤1mg/dL, PGA≤1
• For long-standing disease, goal may be low disease activity
Measure disease activity
• High/moderate disease activity: monthly
• Remission/low disease activity: x6 months
Adjust therapy
• At least x3 months until target is reached
Personalize treatment strategy
• Consider all factors (comorbidities and other patient factors)
*2010 T2T recommendations updated in 2014 to reflect better supportive evidence.TJC = tender joint count; SJC = swollen joint count; PGA = physician global assessmentSmolen JS, et al. Ann Rheum Dis. 2010;69(4):631-637; Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1-26; Singh JA, et al. Arthritis Care Res. 2016;68(1):1-25; Smolen JS, et al. Ann Rheum Dis. 2017;0:1-18.
Use a treat-to-target strategy in all patients regardless of disease activity level
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© 2019 PRIME® Education, LLC. All Rights Reserved. 9
Conventional DMARDs for RA
Route Generic Name Dosing Frequency Safety Precautions
InjectionMethotrexate Once a week
• Contraindicated in pregnancy and during breastfeeding• Can also cause liver damage, best to avoid if you drink alcohol• May cause fatigue or pneumonitis
Oral
Methotrexate Once a week • Same as above – more GI issues• Always give with folic acid to reduce side effects
Hydroxychloroquine Once a day • Taking high doses for many years may cause eye/vision problems• Make sure to tell your doctor if you have kidney disease
Leflunomide Once a day • Contraindicated in pregnancy • Can cause or worsen liver damage
Sulfasalazine 1 or 3 times a day
• Can upset stomach and cause sensitivity to sunlight • Not recommended to take with certain therapies• Talk with your doctor if you have known allergic reactions to sulfa• Decreased sperm count in men
© 2019 PRIME® Education, LLC. All Rights Reserved. 10
Initial Treatment With MTX: Oral or SC
Results for 39,440 RA patients starting MTX treatment in the United States
• Oral MTX has variable dose-dependent bioavailability Limited bioavailability is a result of saturable
transport out of the intestinal lumen Greater variability and reduced absorptions at
higher doses required to achieve RA outcomes May drop off by as much as 30% when
increasing from 7.5 to 15 mg or more
• Switching to parenteral administration can be highly effective Greatly improves bioavailability
• Splitting the dose also works
SC = subcutaneousMedac, Pharma, Inc. Data on file. 2015; Hamilton HR, Kremer JM. Br J Rheum. 1997;36:86-90.
9.6%
90.4%
SC MTX
Oral MTX
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© 2019 PRIME® Education, LLC. All Rights Reserved.
Recommendations for Patients with MTX Contraindication/Intolerance
AE = adverse eventSmolen JS, et al. Ann Rheum Dis. 2017;0:1-18; Bello AE, et al. Open Access Rheumatol. 2017;9:67-79; Hider SL, et al. Ann Rheum Dis. 2006;65(11):1449-55; Alam MK, et al. 2012. Mymensingh Med J. 2012;21(3):391-398.
EULAR guidelines:“In patients with a contraindication to MTX (or early intolerance), leflunomide or
sulfasalazine should be considered as part of the (first) treatment strategy”
Potential approaches for managing AEs/intolerance with oral MTX:• Switch to sc MTX
• Change MTX dose or apply an alternative dosing regimen
• Add folic or folinic acid• Switch to other csDMARDs
• Switch to a biologic agent
© 2019 PRIME® Education, LLC. All Rights Reserved.
• Osteoporosis• Cushing’s syndrome• Fat tissue accumulation• Hyperglycemia• Bacterial, fungal, viral infections• Decreased wound healing• Bone metabolism • Cataracts• Glaucoma
Corticosteroids: Wonderful and Wicked
Poetker DM, et al. Otolaryngol Clin North Am. 2010;43(4):753-768; Judd LL, et al. Am J Psychiatry. 2014;171:1045-1051.
• Skin changes• Peptic ulceration• Adrenal suppression• Muscle atrophy • Increased blood pressure • Myocardial infarction • Mood changes • Insomnia • Anxiety• Depression
The long term/recurrent use of steroids has been associated with significant side effects
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© 2019 PRIME® Education, LLC. All Rights Reserved. 13
Corticosteroid Utilization:AEs, Health Care Utilization, and Costs
Incidence Rates (per 100 Patient Years) of Adverse Conditions in Corticosteroid Users vs Non-Users
49.84
16.9
33.65
19.77
28.77
21.37
30.06
17.7
7.5
41.99
13.23
24.01
13.9
18.9
17.51
23.58
14.5
6.66
0 10 20 30 40 50
Cardiovascular
Gastrointestinal
Infections
Skin
Lipodystrophy
Metabolic
Neuropsychiatric
Ophthalmologic
Osteoporotic Fracture
Corticosteroid Users Non-Users
Annualized Mean Health CareUtilization and Costs
$735.91
$1,661.88 $1,970.63
$3,988.08
$10,344.63
$573.89
$1,072.92 $1,462.53
$2,639.90
$7,578.95
$0.00
$2,000.00
$4,000.00
$6,000.00
$8,000.00
$10,000.00
$12,000.00
Physician VisitCosts
HospitalizationCosts
MedicationCosts
OtherOutpatient
Costs
Total HealthCare Costs
Spivey CA, et al. Rheumatol Ther. 2018;5:255-270.
© 2019 PRIME® Education, LLC. All Rights Reserved.
• What is the goal of steroid therapy? Quickly and effectively control symptoms to help induce remission
• ACR recommendation for steroids: Suitable for patients with symptomatic early RA If disease activity remains moderate or high despite DMARD or biologic therapies, add low-dose
glucocorticoids (<10 mg/day*) If disease flares, add short-term glucocorticoids at the lowest possible dose and for the shortest possible
duration (<3 months) Glucocorticoid therapy is effective as a short-term therapy to “bridge” patients until the benefits of
DMARDs takes effect
Use and Management of Steroids in RA
*Prednisone or equivalent Smolen JS, et al. Ann Rheum Dis. 2017;76(6):960-977; Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68(1):1-25.
High dose*>7.5 mg/day (EULAR)
>10 mg/day (ACR)
GoalSteroid-Free Remission
3 months
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© 2019 PRIME® Education, LLC. All Rights Reserved. 15
TICORA Study: Treatment Strategy of Tight Control for RA
Grigor C et al. Lancet. 2004;1(9430):263-269.
Single-blind, randomized controlled trial in 111 patients allocated toeither intensive management or routine care
A strategy of intensive outpatient management of RA substantially improves disease activity, radiographic disease progression,physical function, and quality of life at no additional cost
Sulfasalazine, increasing every week to target
dose of 40 mg/kg per day
• Sulfasalazine• MTX• Folic acid• Hydroxychloroquine
Triple therapy with monthly increments of methotrexate followed
by weekly increments of sulfasalazine
Addition of prednisolone
Change triple therapy to:• Ciclosporin• MTX• Folic acid
Change to alternative DMARD (leflunomide or sodium aurothionalate)
0
1
2
3
4
5
6
0 3 4 5 12 15 18Month
Dis
ease
act
ivity
sco
re
Intensive Routine
© 2019 PRIME® Education, LLC. All Rights Reserved.
16
64
18 16
91
7165
0
20
40
60
80
100
ACR20 ACR70 Remission
Patie
nts
(%)
Routine Care (n = 55) Intensive Management‡ (n = 55)
TICORA Study: Combination of Non-Biologic DMARDs
*With protocol-based escalation of DMARDs: SSZ, MTX, hydroxychloroquine; †P <0.0001; ‡P = 0.02.SSZ = sulfasalazine; TSS = total sharp score.
Grigor C et al. Lancet. 2004;1(9430):263-269.
Single-blind, randomized controlled trial in 111 patients allocated toeither intensive management or routine care
Disease Activity Score Radiographic Progression
†
†
†
8.5
4.5
0
1
2
3
4
5
6
7
8
9
Incr
ease
in M
edia
n TS
S Fr
om
Base
line
Routine Care (n = 55) Intensive Management‡ (n = 55)
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© 2019 PRIME® Education, LLC. All Rights Reserved.
Treatment Options After DMARD Monotherapy Failure in Patients with Established RA and Poor Prognostic Factors
Singh JA, et al. Arthritis Rheumatol. 2016;68(1): 1-26; Singh JA, et al. Arthritis Care Res. 2016;68(1): 1-25; Smolen JS, et al. Ann Rheum Dis. 2017;0:1-18.
*According to the 2015 ACR RA treatment recommendations, combination therapy with MTX is recommended, when possible, due to superior efficacy of this combination over biologic monotherapy (no particular order or preference of treatment options).
**Current practice would be to start with a bDMARD (in combination with MTX or another csDMARD) because of the long-term experience and registry data compared with tsDMARDS.
ⱡIn patients who cannot use csDMARDs as comedication, IL-6 and tsDMARDs may have some advantages over other bDMARDs.
Treatment Options ACR 2015 EULAR 2016**
csDMARD Combination of csDMARDs Recommended in the absence of prognostically unfavorable factors
TNF Inhibitor +/- MTX* + MTX or another csDMARDⱡ
Non-TNF inhibitor +/- MTX* + MTX or another csDMARDⱡ
tsDMARD +/- MTX* + MTX or another csDMARDⱡ
© 2019 PRIME® Education, LLC. All Rights Reserved.
SWEFOT Study: Triple Therapy vs MTX/TNFi
DAS = disease activity score; CSA = cyclosporine.van Vollenhoven RF, et al. Lancet. 2009;374(9688):459-466; van Vollenhoven RF, et al. ACR/ARHP 2009; Philadelphia, PA. Abstract 1010.
• Early RA; symptoms <1 year; no other DMARD, DAS28 >3.2N = 487
• Mean age 52; symptom duration 6.3 months; 67% RF+; DAS28 5.95
MTX monotherapy(up to 20 mg/week)
3–4 months
MTX + SSZ + HCQ ( CsA); n = 130
MTX + IFX ( ETN); n = 128
Screening 3 monthsrandomization of
patients not in LDA (DAS28 >3.2)
12 monthsPrimary endpoint:
patients with EULARgood response (%)
24 months Re-randomization of
patients in LDAor remission
Patient Disposition• Randomized, not blinded
27 (5.5%)9 (1.8%)
48 (9.9%)
130(26.7%)
144(29.8%)
128(26.3%)
Arm BArm AOther
Other DiseaseMTX IntoleranceMTX Responders
A
B
Conclusion: 30% patients responded to initial 3- to 4-month MTX monotherapy (16% in remission)
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© 2019 PRIME® Education, LLC. All Rights Reserved.
IMPORTANT: NON-PHARMACOLOGIC MANAGEMENT OF RA
• Nutrition – You are what you eat! Food journaling Pro / anti inflammatory foods Vegan / vegetarianism
• Exercise Monitored program vs self driven Appropriate for damage
• Sleep• Stress• Self-management of RA and community