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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.


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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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.


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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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.


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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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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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


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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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


• 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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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.


• 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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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


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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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


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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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

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