a cme-certified supplement to rheumatology news · 2020-02-10 · a cme-certified supplement to...

A CME-CERTIFIED SUPPLEMENT TO

Rheumatology News®

Early and Aggressive Approaches to RA Management to Minimize Disease Progression and Improve Quality of Life

Supported by an independent educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals

Jointly provided by

Original Release Date: May 1, 2018Expiration Date: May 1, 2019

Estimated Time to Complete Activity: 1.5 hours

FACULTY

Marc D. Cohen, MDEmeritus Professor of Medicine, Mayo ClinicRochester, MinnesotaAdjunct Professor of MedicineDivision of Rheumatology, National Jewish HealthDenver, Colorado

Jeffrey R. Curtis, MDProfessor of MedicineThe William J. Koopman Endowed Professor in Rheumatology and ImmunologyDirector, Arthritis Clinical Intervention ProgramUniversity of Alabama at BirminghamBirmingham, Alabama

Iain B. McInnes, PhD, FRCP, FRSE, FMedSciMuirhead Chair of MedicineDirector of the Institute of Infection, Immunity, and InflammationUniversity of GlasgowGlasgow, Scotland

Page

3 Introduction: Current Issues in RA Management

3 The Importance of Early Diagnosis and DMARD Treatment

6 Optimal Early Management10 Special Section: Treatment Update

Update on IL-6 Receptor Inhibitors and JAK Inhibitors

12 Adverse Events14 Nonpharmacologic Therapy14 Key Teaching Points16 Post-Test and Evaluation Form

This continuing education supplement is the final activity in a three-part CME curriculum. The supplement content was developed from interviews with the faculty and the key teaching points of the two previous online activities, The Impact of Earlier Diagnosis and Timelier Treatment of Rheumatoid Arthritis on Patient Outcomes and Heathcare Systems and Effective Practice Strategies to Achieve Earlier RA Diagnosis and Faster Initiation of Care, which may be found at: https://www.globalacademycme.com/specialties/rheumatology/cme?promote=All. The faculty acknowledge the editorial assistance of Global Academy for Medical Education, LLC, in the development of this supplement. Neither the editors of Rheumatology News nor the Editorial Advisory Board nor the reporting staff contributed to its content. The ideas and opinions expressed are those of the faculty and do not necessarily reflect the views of the supporters, Global Academy for Medical Education, Postgraduate Institute for Medicine, or the Publisher.

Copyright © 2018 by Global Academy for Medical Education, LLC, Frontline Medical Communications Inc., and its Licensors. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Global Academy for Medical Education, LLC, Frontline Medical Communications, and Postgraduate Institute for Medicine will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.

A CME-CERTIFIED SUPPLEMENT TO

Rheumatology News®Early and Aggressive Approaches to RA Management to

Minimize Disease Progression and Improve Quality of LifeOriginal Release Date: May 1, 2018Expiration Date: May 1, 2019Estimated Time to Complete Activity: 1.5 hours

Method of Participation Participants should read the activity information, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail or you may print it out at that time. The online post-test and evaluation can be accessed at: https://tinyurl.com/RAEarly18S. Inquiries may be directed to Global Academy for Medical Education at [email protected] or (973) 290-8225 or the Postgraduate Institute for Medicine at (720) 895-5357.

Joint Accreditation StatementIn support of improving patient care, this activity has been planned and imple-mented by Postgraduate Institute for

Medicine and Global Academy for Medical Education. Postgraduate Institute for Medicine 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 health care team.

Physician Continuing Medical EducationPostgraduate Institute for Medicine designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participa-tion in the activity.

Target Audience This enduring activity is intended for rheumatologists, internal medicine physicians with a secondary specialty in rheumatology, physician assistants, and other clini-cians who treat patients with rheumatic diseases.

Educational NeedsClinical studies on patients with rheumatoid arthritis have consistently found that patients are more likely to respond and more likely to reach remission if they are treated with disease-modifying antirheumatic drugs (DMARDs) within 3 to 6 months of symptom onset. But studies of patients in clinical practice find that diagnosis is often delayed, and typically treatment begins a year or more after symptom onset. Clinicians need informa-tion on strategies to enable earlier treatment. Guidelines also recommend a treat-to-target approach with a goal of sustained remission. This approach requires ongoing monitoring and treatment changes to meet patient needs. New medications have been approved recently, adding to the rheumatologist’s armamentarium for treating rheumatoid arthritis.

Learning ObjectivesAt the conclusion of this program, participants should be better able to:• Design appropriate strategies to increase the timeli-

ness of rheumatoid arthritis diagnosis and subsequent linkage to evidence-based care

• Design appropriate strategies to relieve articular and systemic symptoms of rheumatoid arthritis

• Design strategies for using the most appropriate therapies based on the safety and efficacy data of the emerging classes of therapies for rheumatoid arthritis, including anti-interleukin (IL)-6/IL-6R agents, tumor necrosis factor (TNF) inhibitors, and other biologic disease-modifying antirheumatic drugs (DMARDs)

• Design treatment strategies for rheumatoid arthritis that take into consideration recommendations from current guidelines and emerging data from clinical trials

• Describe the data presented at national and global scientific conferences that may help clinicians achieve the treatment goals for rheumatoid arthritis

Disclosure of Conflicts of InterestPostgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COIs are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME/CE activities and related materials that promote improvements or quality in health care and not a specific proprietary business interest of a commercial interest.The faculty reported the following financial relation-ships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity.Marc D. Cohen, MD, has nothing to disclose.Jeffrey R. Curtis, MD, Consultant: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo Bioscience, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, and UCB. Grant/Research Support: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo Bioscience, Ortho-McNeil-Janssen Pharmaceuticals, Roche/Genentech, Pfizer, and UCB.Iain B. McInnes, PhD, FRCP, FRSE, FMedSci, Consultant: AbbVie, Galapagos, Lilly, and Pfizer. Grant/Research Support: Bristol-Myers Squibb, Janssen, Pfizer, and UCB.The planning staff and content managers hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.Global Academy for Medical Education Staff: Mike LoPresti; Shirley V. Jones, MBA; and Margaret McLauglin, PhD, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Postgraduate Institute for Medicine: planners and managers have nothing to disclose.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contra-indications, and warnings.

DisclaimerParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The informa-tion presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' condi-tions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

2 Early and Aggressive Approaches to RA Management to Minimize Disease Progression and Improve Quality of Life

Early and Aggressive Approaches to RA Management to Minimize Disease Progression and Improve Quality of Life • globalacademycme.com/rheumatology 3

R esearch over several decades has shown that patients who receive early treatment with DMARDs have better outcomes than patients whose treatment is delayed (see Evidence of the

Benefits of Early Treatment, page 4). Over time, with more data, the definition of what constitutes “early” treatment has narrowed, from 2 or 3 years after symptom onset to its current 3 to 6 months. The American College of Rheumatology (ACR) guideline recom-mends treatment within 6 months of symptom onset.3 The recent recommendations from the European League Against Rheumatism (EULAR)4 indicate that patients at risk for persistent arthritis should receive DMARD treatment “ideally within 3 months” of symptom onset, even if they do not meet the formal criteria for rheumatoid arthritis. The guideline notes that a 3-month standard may be difficult to meet in clinical practice.4,5 Given that joint damage is irreversible, every effort should be made to begin treatment promptly.

Studies on early treatment of rheumatoid arthritis have suggested a “window of opportunity” may exist in the months immediately following symptom onset, during which patients are more responsive to treatment and more likely to achieve remission (see Window of Opportunity, page 5).

The Rheumatoid Arthritis Classification Criteria,5 developed by a joint working group of the ACR and EULAR, was designed in part to iden-tify newly presenting patients who would benefit from early intervention with DMARDs (Table 1).5 Unlike an earlier classification system with more focus on characteristics of later rheumatoid arthritis,6 the current classification criteria include factors apparent in early disease that can discriminate between those who are and those who are not at high risk for persistent and/or erosive disease. Identification of these patients early in the course of the disease should allow for earlier treatment, before the development of erosions that can be observed on radiographs. 5

Are Patients Receiving Early Treatment in Clinical Practice?Although rheumatologists may be aware of the importance of prompt treatment for patients with rheumatoid arthritis, patients and primary care clinicians may be unfamiliar with this. One study7 specifically examined the consequences of delays in referral and treatment initiation for patients with arthritis who were later diagnosed with rheumatoid arthritis. For each of the 598 patients in a clinic cohort, researchers determined the time from symptom onset to assessment in primary care, as well as the time from that initial assessment to the assessment at the arthritis clinic. • The median total time to treatment was 18.4 weeks, mostly accounted

for by the time for referral from the primary care setting to the arthritis clinic

• Only 31% of the patients were assessed at the arthritis clinic within 12 weeks of symptom onset

• Of the patients who were assessed and treated after 12 weeks, 69% had greater disease progression over 6 years of follow-up, according to radiographs of hands and feet

Introduction: Current Issues in RA Management

The Importance of Early Diagnosis and DMARD Treatment

T he past 2 decades have seen dramatic changes in the treatment of rheumatoid arthritis (RA), resulting in significant improvements in health, functional status, and quality of life for many patients.

These changes have been partly driven by the availability of new classes of disease-modifying antirheumatic drugs (DMARDs). In contrast to the earlier conventional synthetic DMARDs (csDMARDs), whose mechanisms of action are still poorly understood, the new medica-tions were designed to target specific immunologic processes. Biologic DMARDs (bDMARDs) include inhibitors of tumor necrosis factor (TNF)-alpha, as well as therapies that antagonize other proinflam-matory cytokines, inhibit T-cell costimulatory activation, and deplete CD20-positive B cells. The most recent additions to the armamen-tarium are targeted synthetic DMARDs (tsDMARDs), small-molecule inhibitors of Janus kinases. Rheumatologists have a far greater selection of therapies today, with probably more to come.1

New treatment strategies have also contributed to better patient outcomes. Treatment with DMARDs early in the course of illness, preferably as soon as rheumatoid arthritis has been diagnosed, has been shown to slow disease progression and increase the probability of remis-sion. An aggressive, treat-to-target approach with the goal of remission aims to keep inflammation in check and prevent joint erosion.1

Despite these advances, in practice many patients are not receiving guideline-concordant care.2 Continued delays in assessment and treat-ment initiation, as well as less than aggressive treatment, contribute to reduced chances of remission and increases in disease progression and functional disability.

In this supplement, we will consider the evidence for early treatment and discuss the use of csDMARDs, bDMARDs, and tsDMARDs in the initial treatment of rheumatoid arthritis.

“Early treatment gives us better responses and longer duration of response, as well as higher likelihood of remission.”

Iain B. McInnes, PhD, FRCP, FRSE, FMedSci

“Rheumatologists need to be willing to change their schedules to see patients with rheumatoid arthritis earlier.”

Marc D. Cohen, MD

• The patients with delayed treatment had a 1.3-fold higher rate of joint destruction over 6 years. Fewer of these patients achieved DMARD-free remission, 10.5% vs 18.5%, which was associated with a hazard ratio of 1.87

• In this study, a majority of patients experienced a delay between symptom onset and treatment initiation, resulting in greater long-term joint destruction. Earlier referral to a rheumatologist has a significant positive impact on patient outcomesMore detailed studies of treatment delays have found that delays in

treatment are typical. Delays may occur at any step: from symptom onset to assessment in primary care, from primary care to assessment by a rheumatologist, from assessment to diagnosis, and from assessment to treatment initiation.

A 2010 study of 10 centers in Europe13 found that the median time from symptom onset to assessment by a rheumatologist was 24 weeks. An important contributor to the overall delay was the time for the referral to a rheumatologist.

A recent meta-analysis of 55 studies published between 1993 and 201614 examined the length of time reported for each step in seeking treatment. The total time from symptom onset to DMARD treatment in this study was 11.79 months (Table 2),14 with lag times rather evenly spread among all steps in the process.

These studies suggest that the time from symptom onset to treatment initiation is much longer than the 3 months4 and 6 months3 recom-mended by guidelines.

Causes of Treatment DelaysA variety of factors contribute to the delay in treatment initiation for patients with rheumatoid arthritis. • Some factors are attributable to the patients themselves. Patients may

assume their pain and fatigue are due to an injury, stress, or aging, or they may self-medicate instead of seeking medical care. Patient delay is more common when symptoms develop gradually. There may be a natural tendency to assume “self-resolution of symptoms”

• Delays in referral to a rheumatologist may contribute significantly to the overall delay in initiating treatment; one study found it was a major cause of delayed treatment.13 In primary care, rheuma-toid arthritis may be overlooked because it is much less common than other chronic illnesses to which clinicians must devote their limited time and attention. In addition, when clinicians see patients with inflammatory arthritis, they may be uncertain about the diagnosis and may decide on an approach of watchful waiting. Instead, they need to know that timely referral and treatment is critical for these patients14,15

• Other delays are related to the health care system. In some countries or regions, patients have limited access to primary or specialty care14,15

• In some geographic areas, few rheumatologists are available to meet patient needs. A 2015 workforce study by the ACR found that in some regions of the United States, an adult would have to travel more than 200 miles to see a rheumatologist. Among surveyed adult patients, 27% reported having to wait more than 4 months to see a rheumatologist. These circumstances may interfere with a treat-to-target strategy, which requires frequent patient visits and the use of composite rheumatoid arthritis disease activity measures that typically include joint examinations16

Figure 1. Effects of Early DMARD Treatment

Evidence of the Benefits of Early TreatmentAlthough evidence of the benefits of early treatment has been accumu-lating for decades, four recent studies have demonstrated that initiating DMARD treatment within 3 months of symptom onset results in better outcomes (remission, response to treatment, Health Assessment Questionnaire [HAQ] disability score, or radiographic progression).8-11

For example, in a study by Bosello and colleagues,8 121 consec-utive patients with disease duration of less than 12 months were treated with methotrexate (up to 20 mg weekly). Those who did not achieve a 44-joint Disease Activity Score (DAS44) ≤2.4 at 3 months also received adalimumab 40 mg/every 2 weeks or etanercept 50 mg/week. At 12 months, patients were evaluated for remission by the EULAR and ACR criteria.12 • The only independent predictor of remission by ACR criteria was

treatment within 12 weeks of symptom onset • Patients were also examined for the presence of new erosions.

Again, early treatment was the only predictor of the absence of new erosions. This finding suggests that treatment within 12 weeks results in better patient outcomes In another study,9 711 patients diagnosed with rheumatoid arthritis

were treated in three tertiary referral centers within 12 months of symptom onset. Remission, defined by the Disease Activity Score in 28 joints (DAS28 <2.6) and by the ACR criteria, was assessed at 12 months in 481 patients who had moderate-high disease activity (DAS28 >3.2) at baseline. Patients were treated with methotrexate (15 to 25 mg/week); if predefined targets were not met, a combination of conventional synthetic DMARDs (csDMARDs) was used or a biologic anti-tumor necrosis factor-alpha (anti-TNFα) was added to the regimen. • Remission was achieved in 34% (DAS28 criteria) and 15% (ACR

criteria) of the 481 patients • Importantly, of those patients beginning treatment within 12 weeks

of symptom onset (22%), 90% were treated with csDMARDs only, compared with 74% of the other patients (Figure 1)9

• Patients receiving treatment before 12 weeks were also more likely to achieve an HAQ score indicating no disability at 12 months, compared with the other patients (63% vs 41%)

• In the cohort of 481 patients with moderate-high disease activity, the only predictors of achieving DAS28 remission were treatment within 12 weeks of symptom onset and being on a DMARD within 3 months of symptom onset

• Again, because patients treated within 12 weeks were more likely to reach remission, more likely to receive treatment with csDMARDs only, and more likely to have an HAQ score indicating no disability, early treatment appears to have advantages over later treatment These and other studies have consistently found that early initiation

of rheumatoid arthritis treatment was a predictor of remission and better response to treatment. The timing of treatment initiation of rheumatoid arthritis is a modifiable risk factor, dependent on prompt patient presenta-tion, prompt referral to a rheumatologist, and prompt treatment.

0

10

20

30

40

50

60

70

Patients on csDMARDOnly at 12 Months

Patients With No Disability at 12 Months (HAQ)

Treatment initiation <12 weeks

Treatment initiation >12 weeks

Patie

nts,

%“As soon as you have some reasonable expectation that this is rheumatoid arthritis, you should initiate therapy.”

Jeffrey R. Curtis, MD

4 globalacademycme.com/rheumatology • Early and Aggressive Approaches to RA Management to Minimize Disease Progression and Improve Quality of Life

csDMARD=conventional synthetic disease-modifying antirheumatic drug; HAQ=Health Assessment Questionnaire. Patients with early treatment initiation were less likely to need treatment beyond a csDMARD (left). Patients with early treatment initiation were more likely to have no disability at 12 months as determined using the HAQ. Source: Gremese E, et al.9


Table 1. The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis

Target population (Who should be tested?): Patients1) who have at least 1 joint with definite clinical synovitis (swelling)a

2) with the synovitis not better explained by another diseaseb

Classification criteria for RA (score-based algorithm: add score of categories A–D; a score of ≥6/10 is needed for classification of a patient as having definite RA)c

ScoreA. Joint involvementd

1. 1 large jointe 02. 2-10 large joints 13. 1-3 small joints (with or without involvement of large joints)f 24. 4-10 small joints (with or without involvement of large joints) 35. >10 joints (at least 1 small joint)g 5

B. Serology (at least one test result is needed for classification)h

Negative RF and negative ACPA 0Low-positive RF or low-positive ACPA 2High-positive RF or high-positive ACPA 3

C. Acute-phase reactants (at least one test result is needed for classification)i

Normal CRP and normal ESR Abnormal CRP or abnormal ESR 1

D. Duration of symptomsj

<6 weeks 0≥6 weeks 1ACPA=anti-citrullinated protein antibody; CRP=C-reactive protein; ESR=erythrocyte sedimentation rate; RA=rheumatoid arthritis; RF=rheumatoid factor.a The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis with a history compatible with prior fulfillment of the 2010 criteria should be classified as having rheumatoid arthritis. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having rheumatoid arthritis.

b Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.

c Although patients with a score of <6/10 are not classifiable as having rheumatoid arthritis, their status can be reassessed and the criteria might be fulfilled cumulatively over time.

d Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classi-fied according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement.

e “Large joints” refers to shoulders, elbows, hips, knees, and ankles.f “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.

g In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large and additional small joints, as well as other joints not specifically listed elsewhere (eg, temporomandibular, acromioclavicular, sternoclavicular, etc.).

h Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; low-positive refers to IU values that are higher than the ULN but ≤3 times the ULN for the laboratory and assay; high-positive refers to IU values that are >3 times the ULN for the laboratory and assay. Where RF information is only available as positive or negative, a positive result should be scored as low-positive for RF.

i Normal/abnormal is determined by local laboratory standards. j Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (eg, pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.

Source: Aletaha D, et al.5 Used with permission.

Table 2. Summary of Lag Times

Number of Studies

Median Lag Time, months(range)

From onset of symptoms to the first physician consultation 12 3.41

(0–5.7)

From first consult to assessment by a rheumatologist

13 2.13(0.5–6.6)

From a rheumatology assessment to diagnosis 3 2.91

(0–5) Source: Barhamain AS, et al.14

Strategies for Increasing the Likelihood of Early TreatmentFor rheumatologists, some future steps to address these challenges are clear. It is important to make system changes that will allow patients with suspected rheumatoid arthritis to be seen promptly. Patients with suspected rheumatoid arthritis should not wait months for appointments. In some early arthritis clinics in Europe, it is standard practice to see such patients within 48 hours. Once a patient has been assessed and has been found to be a candidate for treatment, that treatment should begin without delay.

Rheumatologists should also consider taking the lead in educating primary care clinicians about the ACR/EULAR classification criteria and differential diagnosis of rheumatoid arthritis, so they will better understand when referral is necessary. It would also be useful to educate the primary care community about the tests that should be ordered before referring a patient for a rheumatologist’s assessment.

The rheumatology community might also be engaged in the educa-tion of the undiagnosed population. Questionnaires for primary care patients could help identify undiagnosed patients with possible rheu-matoid arthritis. In Europe, EULAR has begun various educational activities such as “Don’t Delay, Connect Today,” engaging patient orga-nizations, health professional associations, and scientific communities to raise awareness of the importance of early diagnosis of rheumatic and musculoskeletal diseases among the general public.20

To increase the chance of every patient reaching DMARD-free remission, actions will need to be taken to decrease the delays in every step of the process, from symptom onset to initial treatment.

Is There a Window of Opportunity for Optimal Treatment Initiation?

Studies on early treatment of rheumatoid arthritis have suggested a “window of opportunity” may exist shortly after symptom onset, during which treatment leads to significantly better outcomes.17,18 The timing of this window has been much debated over the years, as more recent studies and expert opinion have suggested earlier windows.19 A study by van Nies and colleagues19 sought to distinguish between two possible scenarios. First, is there a linear relationship between earlier treatment and better outcomes such that treatment should be provided “the earlier the better”? Or could it be that there is a defined period of time— a window of opportunity—during which the disease is more suscep-tible to treatment? • Using data from two patient cohorts, they determined that the

relationship between symptom duration before treatment and DMARD-free sustained remission was not linear, suggesting that a window of opportunity exists

• Their analysis found that the symptom duration with the best discrimination between patients with DMARD-free sustained remission and patients with persistent disease for one patient cohort was at treatment initiation at 14.9 weeks, and for the other cohort at 19.1 weeks

• When the patients were stratified by the presence or absence of anti-citrullinated peptide antibody (ACPA), the difference between remission and persistent disease was at treatment initiation at 11.4 weeks for the ACPA-positive group and at 15.0 weeks for the ACPA-negative group

• Nonlinear curves were also observed for radiographic progression and sustained remissionThe study had limitations but, in general, the data suggest that a

window of opportunity during which the disease is more susceptible to treatment does exist. It suggested that this window was on the order of 3 to 5 months.19


I nflammation is the main cause of the joint swelling and stiffness of rheumatoid arthritis, and in the longer term, the cause of cartilage and bone destruction, disability, comorbidity, and mortality. Hence the

immediate goal of treatment is rapid reduction or elimination of inflam-mation, with the ultimate goal of disease remission or low disease activity. If tight control of inflammation can be maintained, disease progression can be slowed or halted.1

Rheumatologists should also be alert to the development of comorbid disorders common in patients with rheumatoid arthritis (Table 3) and work with other health care providers to ensure that these are recognized, evaluated, and treated.21,22 A team approach to care may be appropriate, depending on the health care setting.

Assessing and Monitoring Disease Activity Scales commonly used to monitor disease activity and response to treatment include: • Health Assessment Questionnaire (HAQ) or Multidimensional

Health Assessment Questionnaire (MDHAQ)23

• Routine Assessment of Patient Index Data 3 (RAPID3), which is part of the MDHAQ24

• Clinical Disease Activity Index (CDAI)25

• Simplified Disease Activity Index (SDAI)26

• Disease Activity Score 28 (DAS28/DAS28-C-reactive protein [CRP]/DAS28-erythrocyte sedimentation rate [ESR])27

• Patient Activity Scale (PAS) or PASII28

The ACR has endorsed six rheumatoid arthritis disease activity measures: CDAI, DAS28-CRP/DAS28-ESR, PAS, PASII, RAPID3, AND SDAI.29 EULAR recommends using composite measures that include joint counts, such as the CDAI, DAS28, and SDAI.30

These measures characterize the level of disease activity as high, moderate, low, or in remission; these levels correlate with joint damage and disease progression. In clinical practice, the use of measures of disease activity in patients with rheumatoid arthritis has been increasing, as shown by a series of surveys of US rheumatologists conducted in 2005, 2008, and 2014.31 The patient-rated scales HAQ and RAPID3, which

do not include joint counts, were most frequently used in 2014 (35.5% and 27.1%, respectively). These measures require patient input only and can be completed quickly. Clinicians who used any of the measure-ment tools reported that the tools facilitated care (76.1%) and medical decision-making (62.7%), while being simple and useful (48.2%). However, about a third of the sample, 35.3%, reported using none of these measures, primarily because they were believed to be time- consuming (62.5%) or unavailable electronically (34.8%).

Treat-to-Target StrategyGuidelines recommend a treat-to-target strategy, with assessment at baseline and regular monitoring of disease activity, adverse events, and comorbid disorders. Treatment adjustments based on those find-ings should continue until the target is reached.3,4,32-34 The target for patients with early rheumatoid arthritis is remission, the absence of active disease. For patients with longstanding disease, low disease activity may be a more reasonable goal.3,30 Low disease activity can be defined as an SDAI score of 11 or lower or a CDAI score of 10 or lower. Patients who achieve low disease activity have low mean progression of joint damage.35 Low disease activity may also be a reasonable target for a patient with comorbid disorders. Clinical judgment must therefore be applied along with the algorithmic guideline adherence.

The ACR and EULAR have jointly developed remission criteria based on two approaches, a Boolean approach and an index approach.36

Remission by the Boolean-based definition requires each of these factors to be ≤1:• Swollen joint count • Tender joint count • C-reactive protein (mg/dL)• Patient global assessment score (on a 0-10 scale)

The index approach is based on the SDAI definition, which is a composite index of rheumatoid arthritis activity, including: • Swollen joint count • Tender joint count • C-reactive protein (mg/dL)• Patient global Visual Analogue Scale (VAS) score• Physician global VAS score

The score is the simple sum of the measurements. Remission is defined as ≤3.3 (based on 28 joints).

Remission is closely associated with positive outcomes. For example, in a study of older patients with rheumatoid arthritis participating in a large registry, remission was associated with significantly lower rates of hospitalization, emergency department visits, mortality, and medical costs.37 Even when compared with patients with low disease activity, patients in remission demonstrate better function, health-related quality of life, and productivity.38

Optimal Early Management

Table 3. Disorders Comorbid With Rheumatoid Arthritis

• Cardiovascular disease • Pulmonary disease

• Cancer • Serious infections

• Stroke • Diabetes

• Hypertension • Depression and anxiety

• Peptic ulcer • Osteoporosis

Source: England BR, et al.21


Table 4. Disease-Modifying Antirheumatic Drugs and Recommended Doses

Conv

entio

nal s

ynth

etic

DM

ARDs Methotrexate

Mol

ecul

ar ty

peSmall chemical

Usua

l dos

ea

25 mg once weeklya

Sulfasalazine Small chemical 3 g/daya

Leflunomide Small chemical 20 mg/day

Hydroxychloroquine Small chemical 400 mg/day

Biol

ogic

al D

MAR

Ds

TNF

inhi

bito

rs

Adalimumab Human monoclonal antibody 40 mg every 2 weeks subcutaneously

Certolizumab pegol F(ab′) fragment of a humanized monoclonal antibody 200 mg every 2 weeks subcutaneously

Etanercept IgG-Fc receptor construct (fusion protein) 50 mg/week subcutaneously

Golimumab Human monoclonal antibody 50 mg/week subcutaneously

Infliximab Chimeric monoclonal antibody 3-10 mg/kg intravenously every 4-8 weeks

Anti-

B-ce

ll

Rituximab Chimeric monoclonal antibody 1,000 mg intravenously every 6 months

Anti-

T-cel

l co

-stim

ulat

ion

Abatacept IgG-Fc receptor construct (fusion protein) 125 mg/week subcutaneously

Anti-

IL6R Sarilumab Human monoclonal antibody 200 mg/2 weeks subcutaneously

Tocilizumab Human monoclonal antibody 162-166 mg/week subcutaneously

Targ

eted

syn

thet

ic D

MAR

Ds

Janu

s kin

ase

inhi

bito

rs

Baricitinib Small chemical 4 mg once daily

Tofacitinib Small chemical 5 mg twice daily

DMARDs=disease-modifying antirheumatic drugs; FDA=Food and Drug Administration; IgG=immunoglobulin G; IL6R=interleukin 6 receptor; JAK=Janus kinase; TNF=tumor necrosis factor.aContraindicated or dose reduction needed with renal or hepatic impairment.Source: Modified from Smolen JS, et al.1

Treatment: Beginning Therapy in Treatment-Naïve Patients With Early Rheumatoid ArthritisAccording to guidelines,3,4,30 patients diagnosed with rheumatoid arthritis and patients with arthritis who are at high risk for persistent and/or erosive disease should be treated promptly with a csDMARD (Figure 2 on page 8).39 DMARD monotherapy, typically methotrexate, is preferred over double or triple combinations of csDMARDs. But

more than one-third of patients are intolerant to methotrexate.40 If methotrexate cannot be used, another csDMARD—leflunomide, sulfasalazine, and (for very mild disease) hydroxychloroquine—can be substituted and the dose optimized (Table 4).1 Glucocorticoids are usually added to csDMARDs as a short-term bridging therapy and then tapered and discontinued. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used instead of glucocorticoids but are also unsuitable for long-term use.

Methotrexate

1988 1998

Infliximab

1999 2002

Abatacept

2005 2006

Certolizumab

2008

Tocilizumab

2010 2012

Biosimilars of several biologic DMARDs

2015 2017

Leflunomide

Etanercept

Adalimumab Rituximab Tofacitinib

Sarilumab

BaricitinibaGolimumab

2009

csDMARDs Biologic DMARDs tsDMARDs

Trials directly comparing methotrexate with other csDMARDs have found that methotrexate has a faster onset of action, comparable or greater efficacy, better long-term tolerance, and results in improved survival.41,42 Head-to-head trials comparing methotrexate with TNF inhibitor monotherapy have shown that they have similar clinical benefit.43,44 Patients with an inadequate response to methotrexate can be quickly identified and treated prior to the development of irre-versible joint erosion. Side effects of csDMARDs are well known and generally treatable. Adverse effects of methotrexate, leflunomide, and sulfasalazine include serious infection, neutropenia, and elevated liver enzymes. The only notable side effect of hydroxychloroquine is anemia.

Patients with active disease should be monitored regularly, every 1 to 3 months. If, after 3 months of treatment, an assessment reveals that disease activity is low or an 80% improvement is seen in SDAI or CDAI, it is highly likely that the target will be reached at the 6-month point.25 If improvement is small or nonexistent after 3 months of treatment, changes to the drug regimen should be made. Similarly, if the target has not been reached at 6 months, further changes should be considered.3,4,30

In clinical trials in which patients with early rheumatoid arthritis received a dose of methotrexate that was rapidly increased to 20 mg/week and which was continued for at least 3 months, approximately 30% of the patients reached a state of low disease activity within 3 to 6 months.45,46 Unfortunately, a majority of patients treated with metho-trexate monotherapy do not have an adequate response and will require additional treatment.

Inadequate Response to Initial TreatmentGuidelines differ somewhat on the next step to take after failure to reach the target using the first csDMARD. In general, treatments are added to methotrexate, which has attained the status of the “anchor drug” that optimizes the efficacy of biological DMARDs.3,30

According to the ACR guideline, for a patient with symptomatic early rheumatoid arthritis (<6 months from symptom onset), if disease activity is moderate or high despite csDMARD monotherapy (with or without glucocorticoids), any one the following therapies are recom-mended, in no particular order, with or without methotrexate.3

• Combination csDMARDs• TNF inhibitors• Non–TNF-inhibitor biologics

The use of combinations of csDMARDs has become somewhat controversial. The most recent trials found no significant clinical advantage of double or triple csDMARD treatment over methotrexate

monotherapy and disadvantages may exist in the form of more adverse events and discontinuations.47,48 The ACR guidelines note, however, that some patients may prefer triple therapy because of its rapid short-term benefit if they are willing to assume additional risk.3

The EULAR recommendations take a slightly different approach to treatment after an inadequate response to initial csDMARD therapy, based on the presence or absence of poor prognostic factors (Table 5).30 For patients without poor prognostic factors, the EULAR recommen-dations suggest switching to another csDMARD. For patients with poor prognostic factors, a bDMARD or a tsDMARD should be added, with the note that current practice would be to start a bDMARD.30

Biosimilar DMARDs may also be used because their efficacy and safety are indeed similar to their respective original bDMARDs and they may be less expensive.30

The ACR and EULAR recommendations note that all approved bDMARDs may be used, and because of their similar efficacy, no bDMARD is preferred over the others. In an earlier version of the EULAR recommendations,49 TNF inhibitors were preferred over other biologics due to the availability of long-term registry data, but that is not the case in the most recent recommendations. All bDMARDs are preferred over tsDMARDs ( JAK inhibitors), again due to better availability of long-term data.3,30

If treatment with a bDMARD (with or without a csDMARD) does not result in reaching the target of remission or low disease activity, another bDMARD or tsDMARD should be substituted. If the first bDMARD was a TNF inhibitor, using a different TNF inhibitor seems to be as efficacious as switching to a bDMARD with a different mechanism of action.50-52

Biologic DMARDsBiologic DMARDs are efficacious in treating rheumatoid arthritis, improving symptoms, and slowing the progression of structural damage.53,54 These benefits, in turn, lead to decreases in disability and the cost of care for patients with rheumatoid arthritis.55

Biologic DMARDs for rheumatoid arthritis that are currently in use have four mechanisms of action: • TNF inhibition: infliximab, adalimumab, certolizumab pegol,

etanercept, golimumab• Interleukin (IL)-6 receptor inhibition: tocilizumab, sarilumab• T-cell co-stimulation blockade: abatacept• B-cell depletion: rituximab

A biologic with a fifth mechanism, anakinra, an IL-1 inhibitor, is rarely used for patients with rheumatoid arthritis because it is less efficacious than other bDMARDs.56


Figure 2. Recent Development of Drugs for Rheumatoid Arthritis

csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; tsDMARDs=targeted synthetic disease-modifying antirheumatic drugs. aBaricitinib has been approved in the EU, but not yet in the US. Source: Modified from Burmester GR, et al.39


The TNF inhibitors include infliximab for intravenous use, and four drugs—adalimumab, certolizumab pegol, etanercept, and golimumab—delivered subcutaneously. Infliximab, adalimumab, and golimumab are monoclonal antibodies, and certolizumab is a fragment of a monoclonal antibody. Etanercept is a fusion protein, an immunoglobulin G (IgG)-Fc receptor construct.

Tocilizumab and sarilumab are medications for rheumatoid arthritis that block the IL-6 receptor. IL-6 is a cytokine that plays a key role in inflammatory, immune-stimulatory processes and modula-tion of bone metabolism.57,58 Patients with rheumatoid arthritis have elevated levels of IL-6 in serum and synovial fluid, which correlate with inflammation and disease activity.58-60 Sarilumab was approved in the United States and Europe in 2017. For tocilizumab, recent data from the U-Act-Early trial suggest that it may eventually have a role as initial monotherapy in rheumatoid arthritis (see Special Section, Treatment Update, page 10).

Abatacept is a T-cell co-stimulation inhibitor, but it may have an addi-tional effect on the immune system. Recent studies in mice have found that abatacept also causes a sustained inhibition of T-cell activation that results in reduced functionality of antigen-presenting cells.61

Rituximab is a chimeric mouse/human monoclonal antibody that targets CD20, a molecule found on the surface of B cells during their development. This action leads to depletion of B-cell precursors and mature B cells. It is the only B-cell–directed monoclonal antibody approved for the treatment of rheumatoid arthritis.

Biosimilars equivalent to several bDMARDs are available in the United States and Europe. The US Food and Drug Administration (FDA) has approved biosimilars that may be used in place of adalimumab, inflix-imab, and etanercept.62 The European Medicines Agency has approved biosimilars for adalimumab, infliximab, etanercept, and rituximab.63

Efficacy of bDMARDs Used With MethotrexateAlthough the different classes of bDMARDs have different mecha-nisms of action, they all seem to have roughly similar efficacy. Used in combination with methotrexate, the ACR70 response rates (low disease activity) are approximately 30% to 40%, compared with 20% to 25% for those receiving methotrexate alone.1 Similarly, approxi-mately 60% to 70% of patients who start treatment with a bDMARD plus methotrexate will achieve an ACR50 response, compared with approximately 40% who start treatment with methotrexate alone.64 For patients with an inadequate response to initial methotrexate monotherapy, the addition of a bDMARD will help achieve an ACR50 response in 50% to 56% of the patients.65

Head-to-head trials directly comparing bDMARD/methotrexate combinations with other bDMARDs are few, but the available studies find similar response rates for bDMARDs.

• In the AMPLE study, abatacept was compared with adalimumab in patients with an incomplete response to methotrexate mono-therapy. Response rates, measured as ACR20, were similar in the two groups: 64.8% in the abatacept group and 63.4% in the adali-mumab group. Inhibition of radiographic progression was also similar in the two groups66

• The EXXELERATE trial compared adalimumab and certolizumab pegol in patients with an incomplete response to methotrexate. It showed that the efficacy of certolizumab pegol and adalimimuab, both in combination with methotrexate, were not significantly different (ACR20 response rates of 65% for certolizumab pegol and 67% for adalimumab)67

• Indirect comparisons also suggest similar efficacy within all bDMARDs when used in combination with methotrexate53

Clinical trials have also explored the combination of two bDMARDs with different modes of action. However, trials comparing the combi-nation of abatacept plus TNF inhibitors,68 an IL-1 receptor antagonist plus TNF inhibitors,69 and rituximab plus TNF inhibitors70 found that combination treatment had no added benefit. The first two of these combination treatments also found significantly increased rates of adverse events, including serious infections. The lack of additional benefit with combination therapies also suggests that perhaps drugs for rheumatoid arthritis with different mechanisms of action may actually exert their effects through a common downstream pathway.1

Targeted Synthetic DMARDsTargeted synthetic DMARDs are small molecules developed to modulate a specific immunologic process. Currently, tsDMARDs are limited to a single class, the Janus kinase ( JAK) inhibitors, which includes tofacitinib (approved in Europe and the United States) and baricitinib (approved in Europe, but not yet in the United States). The tsDMARDs are oral medications.

The efficacy of tofacitinib appears to be similar to that of bDMARDs (see Special Section, Treatment Update, page 10). In trials as mono-therapy or in combination with csDMARDs, tofacitinib was effective in reducing signs and symptoms of disease and improving health- related quality of life in a range of patient populations, including methotrexate-naïve patients and those with inadequate response to csDMARD/bDMARD combination treatment or TNF inhibitors.71 Unlike most bDMARDs, tofacitinib monotherapy has been shown to be superior to methotrexate.72

In clinical trials in patients with rheumatoid arthritis, baricitinib appeared to have efficacy similar to that of tofacitinib and bDMARDs.73

Rheumatology Practice SnapshotIn December 2017, the first two activities in this educational series began educating clinicians about early diagnosis and treatment of RA: • The Impact of Earlier Diagnosis and Timelier Treatment of

Rheumatoid Arthritis on Patient Outcomes and Healthcare Systems• Effective Practice Strategies to Achieve Earlier RA Diagnosis and

Faster Initiation of CareData collected from learners were used, in part, to shape the focus

of this educational supplement. Learner gaps in knowledge and compe-tence were assessed, and specific deficiencies received extra emphasis in this activity. Please take a moment to review the data of your peers and consider how they compare to your knowledge levels and opinions.

In a series of questions, clinicians demonstrated that they knew that early treatment of RA was important, but they were not familiar with the supporting data and did not seem to follow through in practice.

continued on page 13

Table 5. Poor Prognostic Factors

• Moderate to high disease activity according to composite measures (after csDMARD therapy)

• High acute phase reactant levels

• High swollen joint counts

• Presence of RF and/or ACPA, especially at high levels

• Combinations of the above

• Presence of early erosions

• Failure of two or more csDMARDs

ACPA=anti-citrullinated protein antibody; csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; RF=rheumatoid factor.Source: Smolen JS, et al.30


Special Section: Treatment Update Update on IL-6 Receptor Inhibitors and JAK InhibitorsTocilizumab: U-Act-Early TrialTocilizumab, like other bDMARDs, is indicated for the treatment of patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more DMARDs. As recommended in the guidelines, it is added to a csDMARD, usually methotrexate. In the U-Act-Early trial,74 the standard approach to treatment was compared with using tocilizumab as an initial treatment. In this study, the efficacy of tocilizumab, as monotherapy and in combination with methotrexate, was examined in patients who had been diagnosed with rheumatoid arthritis for ≤1 year who were DMARD-naïve.

Patients were randomized to tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm, n=106), or tocilizumab plus placebo-methotrexate (the tocilizumab arm, n=103), or methotrexate plus placebo-tocilizumab (the methotrexate arm, n=108). Using a study design similar to the treat-to-target approach recommended for clinical practice, patients who did not achieve remission on their initial regimen were switched from placebo to active treatments; patients in the tocili-zumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumor necrosis factor inhib-itor). The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2.6 with a swollen joint count ≤4, persisting for at least 24 weeks) on the initial regimen and during the entire study duration. When sustained remission was achieved, treatments were tapered and stopped.

Similar proportions of patients in the three treatment arms completed the study. The number of serious adverse events was also similar among the groups.

Patients treated with tocilizumab as initial treatment achieved high rates of sustained remission (Table 6).74 In this patient population, initial treatment with tocilizumab, with or without methotrexate, was more effective in achieving sustained remission compared with the current recommendation of initial treatment with methotrexate.

Another analysis from the U-Act-Early trial evaluated the effect of the three treatment strategies on radiographic joint damage.75 Erosions and joint space narrowing in feet and hands were scored at baseline and after 52 and 104 weeks. No differences among the treatment groups were observed in joint space narrowing. The progression in erosions, however, was significantly lower at week 104 in both tocilizumab arms compared with the methotrexate arm (P≤0.023). Progression of erosions in the feet at week 104 was lower in the tocilizumab groups, but erosions in the hands were not significantly different among the groups. The proportion of patients with no progression in erosions was higher in the tocilizumab arms compared with the methotrexate arm at weeks 52 and 104. The data suggest that initial treatment with tocilizumab inhibits the progression of erosions.

Patient-reported outcomes were also improved with tocilizumab treatment compared with methotrexate in this trial, particularly in the first 24 weeks.76 Significant improvements were observed in the 36-Item Short Form Health Survey (SF-36) physical component score and the 5-dimensional EuroQol score in the tocilizumab groups.

These three studies found that initial treatment with tocilizumab in patients starting treatment less than 1 year after diagnosis resulted in a higher proportion of patients achieving sustained remission, with lower progression of erosions and improved patient-reported outcomes. Tocilizumab may become a useful first-line treatment in newly diagnosed patients.

Sarilumab, an IL-6 Receptor InhibitorSarilumab, approved in 2017 in the United States and Europe, is the second IL-6 receptor inhibitor available for the treatment of rheuma-toid arthritis. Its safety and efficacy were demonstrated in four trials.77-80

A dose-ranging study77 established sarilumab 150 mg every 2 weeks and 200 mg every 2 weeks as doses for phase 3 trials. The first of the phase 3 trials78 was conducted in 1,197 patients on methotrexate with an inad-equate response to treatment. Patients remained on methotrexate and were randomized to receive sarilumab 150 mg every 2 weeks (n=400), 200 mg every 2 weeks (n=399), and placebo (n=398). Both sarilumab groups (150 mg and 200 mg) showed a higher rate of ACR20 response compared with the placebo group at week 24 (58.0 vs 66.4% vs 33.4%, respectively; P<0.0001 vs placebo plus methotrexate). Radiographic progression at week 52 was significantly reduced with sarilumab 150 mg and 200 mg sarilumab compared with placebo (0.9 and 0.25 vs 2.78, respectively; P<0.0001).

An additional phase 3 study79 was conducted in patients with moderate-to-severe rheumatoid arthritis and an inadequate response or intolerance to anti-TNF treatment. Patients taking a csDMARD were randomized to sarilumab 150 mg every 2 weeks (n=181), sarilumab 200 mg every 2 weeks (n=184), or placebo (n=181). The proportion of patients with ACR20 response at 24 weeks was significantly greater in the sarilumab groups (55.8% in the 150 mg sarilumab group, 60.9% in the 200 mg sarilumab group, and 33.7% in the placebo group, P<0.0001).

Another trial80 was a 24-week, head-to-head comparison of sarilumab monotherapy vs adalimumab monotherapy in bDMARD-naïve patients with moderate-to-severe active disease who were intolerant to or inade-quate responders to methotrexate. In this trial, patients were randomized to receive sarilumab 200 mg every 2 weeks (n=184) or adalimumab 40 mg every 2 weeks (n=185). The primary endpoint, change from baseline in DAS28-ESR at week 24, was greater in the sarilumab group than the adalimumab group (-3.28 vs -2.20, respectively; P<0.0001). The ACR20, 50, and 70 response rates were also greater in the sarilumab group, as was the change from baseline in HAQ-Disability Index (DI) at week 24. In this trial, sarilumab treatment also resulted in greater and clinically meaningful improvements in many patient-reported outcomes, including patient-reported disease activity, pain, physical function, morning stiffness, productivity, health-related quality of life, and health status.81 The most common adverse events associated with sarilumab in these trials included injection site reaction, neutropenia not related to infection, and increased cholesterol levels.

Table 6. Efficacy of Tocilizumab in the U-Act-Early Trial

Patients Achieving Sustained Remission on the Initial Regimen

Patients Achieving Sustained Remission Over the 2-Year Study

Tocilizumab plus methotrexate

91/106 (86%)P<0.0001

91/106(86%)

Tocilizumab 86/103 (83%)P<0.0001

91/103 (88%)

Methotrexate 48/108 (44%) 83/108(77%)

Source: Bijlsma JWJ, et al.74


In these studies, sarilumab was safe and efficacious in patients with an inadequate response to methotrexate and TNF inhibitors. It is not yet known if it will, like tocilizumab, be more efficacious than methotrexate in DMARD-naïve patients with early rheumatoid arthritis. That study remains to be done. Currently, sarilumab is a safe and efficacious addi-tion to the armamentarium of medications for rheumatoid arthritis.

Update on Janus Kinase Inhibitors: Tofacitinib and BaricitinibTofacitinib, a JAK inhibitor, is a small-molecule kinase inhibitor approved for use in the United States in 2012 and Europe in 2017 for the treatment of rheumatoid arthritis. A second JAK inhibitor, barici-tinib, was approved in Europe in 2017; it is in FDA review for possible US approval in 2018.

Several clinical trials have demonstrated the safety and efficacy of tofacitinib in various patient populations. The first, the ORAL Solo trial,82 randomized 611 patients with active disease who failed previous treatment with ≥1 csDMARD or bDMARD. The treatment groups received tofacitinib 5 mg or 10 mg twice daily for 6 months, whereas the other groups received placebo for 3 months followed by tofacitinib 5 mg or 10 mg twice daily for 3 months. A greater proportion of the tofacitinib groups achieved ACR20, 50, and 70 responses compared with the placebo groups after 3 months. There were no differences among the groups in the patients achieving DAS28-ESR remission at 3 months. At the 6-month point, the patients who transitioned from placebo to tofacitinib had a response similar to the 3-month response of the patients who began the trial with tofacitinib.

A second trial, the ORAL Standard study,83 found that patients treated with either tofacitinib/methotrexate or adalimumab/methotrexate were more likely than those treated with methotrexate monotherapy to achieve an ACR20 response at 6 months. They were also more likely to show improvement in HAQ-DI scores and reach clinical remission. An open-label extension of this trial demonstrated that use of tofacitinib after adalimumab was safe and effective.84

An additional trial examined the use of tofacitinib as initial treat-ment in DMARD-naïve patients.72 Patients with a diagnosis of active rheumatoid arthritis were randomized to tofacitinib 5 mg or 10 mg daily, or methotrexate titrated to a dose of 20 mg over 8 weeks. After 6 months, patients in both tofacitinib groups were more likely to achieve ACR70 responses compared with methotrexate and to achieve a greater reduction in the progression of structural joint damage. These improvements were maintained over 2 years. A further analysis showed that improvements in function and health-related quality of life with tofacitinib monotherapy were sustained over 2 years.85 Additional trials have confirmed the efficacy and safety of tofacitinib,86-89 including one demonstrating efficacy and safety in patients with an inadequate response to TNF inhibitors.86

The risk of developing herpes zoster is increased in patients with rheu-matoid arthritis who take tofacitinib.90 Vaccination is recommended for patients aged ≥50 years prior to starting treatment with tofacitinib. The effect of tofacitinib on the immune response and safety of live zoster vaccine was evaluated in a 14-week, placebo-controlled trial.90 Patients with active rheumatoid arthritis being treated with methotrexate were vaccinated and randomized to tofacitinib 5 mg twice daily or placebo 2 to 3 weeks postvaccination. Humoral response was evaluated by determining the varicella zoster virus–specific IgG level and cell-mediated response by varicella zoster virus–specific T-cell enumeration. Patients treated with tofacitinib had similar or even numerically higher VZV-specific humoral and cell-mediated immune responses to the vaccine compared with placebo-treated patients. One patient who had no preexisting VZV immunity developed cutaneous vaccine dissemination 2 days after starting tofacitinib, which resolved after tofacitinib discontinuation and antiviral treatment. The results suggest that live zoster vaccine was safe in patients with prior exposure to varicella zoster virus.

Baricitinib safety and efficacy in different patient populations has been evaluated in four clinical trials.91-94

Guidelines recommend that tsDMARDs be used when csDMARDs and bDMARDs have failed. One trial tested baricitinib treatment in this population.91 The trial enrolled 527 patients with moderate to severe rheumatoid arthritis who had not responded to one or more bDMARDs or who experienced intolerable side effects. Patients continued on csDMARDs and were randomized to baricitinib 2 mg or 4 mg daily, or placebo. At 3 months, greater proportions of patients in the baricitinib groups compared with the placebo group achieved an ACR20 response, had a ≥0.3-point improvement in HAQ-DI score, and achieved either clinical remission or low disease activity. The higher dose of baricitinib was associated with greater improvement.

Another clinical trial92 was a head-to-head comparison of baricitinib vs adalimumab in patients with an inadequate response to methotrexate. Patients continued on methotrexate and were randomized to barici-tinib 4 mg daily, adalimumab 40 mg every 2 weeks, or placebo. Patients treated with baricitinib or adalimumab, compared with placebo, were more likely to achieve ACR20, 50, and 70 responses at week 12, as well as to reach DAS28-CRP remission. Interestingly, patients treated with baricitinib were more likely to achieve ACR20, 50, and 70 responses, as well as achieve more DAS28-CRP improvement, than were patients in the adalimumab arm. Baricitinib was shown to be superior to adali-mumab in helping patients achieve an ACR20 response at month 3.

Baricitinib was evaluated in a third patient population in a trial that enrolled patients who had had an incomplete response to ≥1 csDMARDs but who were bDMARD-naïve.93 Patients continued their csDMARD and were randomized to baricitinib 2 mg or 4 mg daily, or placebo. A greater proportion of patients in the baricitinib groups achieved an ACR20 response at week 12. The baricitinib groups also had greater improvements in DAS28, SDAI remission, the HAQ-DI, and morning joint stiffness, with better results in the higher-dose group.

An analysis95 of results from two studies92,93 evaluated the safety and efficacy of baricitinib in elderly patients (aged ≥65 years) compared with patients aged <50 and ≥50 to <65 years, from pooled data of two studies of patients with inadequate response to csDMARDs. Baricitinib had similar efficacy in elderly and younger patients and incidence of serious adverse events or withdrawal due to adverse events in baricitinib-treated patients that were similar to age-matched, placebo-treated patients.

Finally, baricitinib safety and efficacy were evaluated in treat-ment-naïve patients.94 Patients were randomized to methotrexate monotherapy, baricitinib 4 mg daily, or combination baricitinib and methotrexate for 52 weeks. Baricitinib monotherapy was superior to methotrexate monotherapy at week 24 with a higher ACR20 response rate (77% vs 62%, respectively; P≤0.01). Similar results were seen with combination therapy. Patients in both baricitinib groups also reported greater improvement in (P≤0.01) in HAQ-DI, Patient’s Global Assessment of Disease Activity, pain, fatigue, worst joint pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52.96

The JAK inhibitors are the newest class of treatments for rheumatoid arthritis. Less information is available about their safety, especially in clinical practice, compared with other rheumatoid arthritis medica-tions. For this reason, the most recent ACR and EULAR guidelines recommend using bDMARDs first.3,30 Increasing data indicate that that JAK inhibitors, when used as monotherapy or in combination with methotrexate, have at least equivalent efficacy to bDMARDs, with a slightly higher incidence of herpes zoster infection. They are also avail-able in oral formulations, which patients may prefer.


The safety profile of bDMARDs is well understood. Biologic DMARDs are associated with neutropenia, anemia, and elevated liver enzymes. Of greater concern is a higher risk of infection.

Compared with csDMARDs, bDMARDs increase the risk of serious infection by approximately 30%. A meta-analysis of 106 trials of 42,330 patients with rheumatoid arthritis receiving bDMARDs found that the increased risk was dose-dependent. Standard-dose bDMARDs (odds ratio [OR], 1.31; 95% credible interval [CrI], 1.09-1.58) and high-dose bDMARDs (OR, 1.90; Crl, 1.50-2.39) were associated with an increased risk of serious infections, but low-dose bDMARDs were not. The absolute risk of serious infections for patients taking standard-dose bDMARDs is 6 per 1,000 per year, and for those taking high-dose bDMARDs, 17 per 1,000 per year.97

A systematic literature review of 26 observational studies confirmed the risk of serious infections in studies of patients taking bDMARDs.98 This review also found an increased risk of reacti-vation of latent tuberculosis with TNF inhibitors, but for other bDMARDs this risk is unknown. In this review, the bDMARDs were not associated with an increased risk of herpes zoster, but TNF inhibitors have been associated with herpes zoster in other meta-analyses.99,100 No increased risk of malignancy was seen, with the possible exception of melanoma.98 Population-based studies of TNF inhibitors suggest that they do not increase the risk of solid or lymphoproliferative malignancy in patients with rheumatoid arthritis.101,102 Rituximab may possibly be associated with a small risk of progressive multifocal leukoencephalopathy.103

Like bDMARDs, tsDMARDs are associated with serious infection, neutropenia, anemia, and elevated liver enzymes. Overall, the risk of serious infections seems to be similar to that of bDMARDs, with a few notable exceptions. Risk of tuberculosis appears to increase with the dose of tofacitinib; as observed with TNF inhibitors, the abso-lute risk depends on the background rate in the region. In tofacitinib extension trials, a few cases of cytomegalovirus infection have also been reported.104

Of additional concern, the risk of herpes zoster is 1.5 to 2 times higher in patients with rheumatoid arthritis compared with the general popu-lation, and treatment with tofacitinib or baricitinib increases that risk an additional 1.5- to 2-fold. Rates of herpes zoster are higher in patients receiving concomitant methotrexate or glucocorticoids.90 The ACR recommends vaccination before treatment initiation with bDMARDs or tofacitinib.3 In a clinical trial, patients received tofacitinib or placebo 3 weeks after vaccination with the live zoster vaccine. Immune responses were similar in the two groups.105

ACR-Recommended VaccinesThe guideline recommends vaccination for patients with rheumatoid arthritis, based on age and risk, with killed vaccines for pneumococcal disease, influenza (intramuscular), and hepatitis B (if hepatitis B risk factors are present); also recommended is the recombinant vaccine for human papillomavirus. These vaccines are recommended for patients initiating or already on csDMARDs or bDMARDs.

The live, attenuated herpes zoster vaccine is recommended for patients aged ≥50 years before initiating or while taking csDMARDs. The vaccine is recommended for patients aged ≥50 years before initiating treatment with bDMARDs or tofacitinib, with a 2-week waiting period between vaccination and treatment initiation. Patients receiving bDMARDs should not receive the live, attenuated herpes zoster vaccine.3

A new herpes zoster vaccine (RZV), combining recombinant glycoprotein E with a novel adjuvant (AS01B), has been approved for use in the United States and Europe. The US Centers for Disease Control Advisory Committee on Immunization Practices (ACIP) has written that “adults with chronic medical conditions (eg, chronic renal failure, diabetes mellitus, rheumatoid arthritis, and chronic pulmonary disease) should receive RZV.”106 However, the ACIP only recommends RZV in persons taking low-dose immunosuppressive therapy (eg, <20 mg/day of prednisone or equivalent or using inhaled or topical steroids). Individuals on moderate to high doses of immu-nosuppressive therapy were excluded from the clinical trials, so the ACIP is not making any recommendations about this population until more research becomes available.106

Selecting Treatment in Clinical PracticeOne of the four overarching principles of the EULAR recommendations states that treatment decisions are based on disease activity and other patient factors, such as progression of structural damage, comorbidities, and safety issues.30 In practice, there are additional factors to consider:• Regulatory and payor restrictions • Physician experience and familiarity with specific medications• National or international practice guidelines • Comorbid disorders • Patient preferences

Regulatory authorities and payors may restrict the choice of medi-cations. Unless there are dramatic differences in efficacy, safety, or cost-effectiveness among treatments, payors often require trials of older, less expensive drugs before the use of newer medications. For example, etanercept and adalimumab have been preferred by insurers and govern-ment agencies over other TNF inhibitors as initial treatment.

Physicians tend to prescribe drugs they have prior experience with. They know how patients in their own practice typically respond and which safety issues tend to arise. Again, this tends to favor older drugs over newly approved drugs. Practice patterns may also become entrenched due to recommendations in previous versions of national or international guidelines. Current rheumatoid arthritis guidelines may recommend that any bDMARD be added to methotrexate after an inadequate response to methotrexate monotherapy, but previous guide-lines suggested the use of a TNF inhibitor as the first bDMARD. Using a TNF inhibitor as the first bDMARD is common practice, although guidelines no longer specify it. A survey of US rheumatologists found that 86% would add a TNF inhibitor if the response to methotrexate were inadequate.107

Adverse Events


According to the ACR guidelines, certain drugs should be avoided in patients with high-risk comorbid disorders.3 The evidence base for these recommendations is not strong.• Patients with congestive heart failure should not use TNF inhibitors

because of reports of worsening of congestive heart failure with TNF inhibitor treatment

• Patients with hepatitis C who have received or are receiving antiviral treatment can be treated like patients without hepatitis C. Patients with hepatitis C who have not been treated should receive csDMARDs rather than TNF inhibitors

• Patients with previous skin cancer (melanoma or nonmelanoma) should receive csDMARDs rather than bDMARDs or tofacitinib

• Patients with previous lymphoproliferative disorders should receive rituximab rather than a TNF inhibitor because rituximab is an approved treatment for some of these disorders. These patients could also be treated with combination csDMARDs, or abatacept, or tocilizumab rather than a TNF inhibitor, but the evidence for this recommendation is weak

• Patients with previous serious infection should be treated with combination csDMARDs or abatacept rather than a TNF inhibitorPatient preference is also an important consideration in treatment

selection. Patients may express strong preferences about particular attributes of their medications. In one study, the greatest concern of patients was out-of-pocket costs, followed by adverse events, frequency of administration, efficacy, and route of administration.108 Research suggests that such factors as dosing frequency, delivery type, pH levels, and needle size may influence a patient’s decision to discontinue medi-cation.109 Incorporating these patient concerns into treatment decisions requires full discussion of the attributes of bDMARDs and the conse-quences of different choices. Surveys of rheumatologists and patients find some discrepancies in their reports. In one study, nearly all of the rheumatologists surveyed reported discussing the intravenous (95.1%) or subcutaneous (99.0%) experience with their patients. A patient survey found that only about one-third (30.9% and 34.2%, respectively) reported discussions on these topics.110

Presented with a hypothetical case of a 53-year-old woman presenting with potential symptoms of RA, 43% of learners (n=316) incorrectly selected that her RA diagnosis was incomplete or unconfirmed, suggesting that they are unnecessarily delaying diagnosis and therefore not initiating early RA treatment.

A 53-year-old woman presents with right wrist tenderness and impres-sive synovitis and subtle synovitis of the right 2nd MCP joint. She feels fatigued with generalized stiffness in the mornings. She reports that her symptoms began about 2 months ago. She has been taking various over-the-counter NSAIDs, which have helped relieve her pain, but her symptoms have been worsening. She has no other symptoms or abnormal findings on exam. One year earlier, when she lived in another city, she had seen her primary care physician because she had had 2 months of pain and swelling in her right wrist. She had been treated with prednisone at that time.

Which of the following is the next appropriate step to take in the care of this patient?

Rheumatology Practice Snapshot (continued)

The Impact of Earlier Diagnosis and Timelier Treatment of Rheumatoid Arthritis on Patient Outcomes and Healthcare Systems

Many clinicians, 38% of learners (n=316), were not familiar with the results of a key study on early treatment of RA, that “treatment within 12 weeks of symptom onset” was the only independent predictor of remission by ACR criteria.

In a study by Bosello and colleagues of RA patients with disease duration of <12 months who were treated with methotrexate, and, if necessary, adalimumab or etanercept, what was the only independent predictor of remission by ACR criteria?

6216

145 3

Treatment within 12 weeks of symptom onset

Treatment with methotrexate and adalimumab

BMI <30

Female sex

Erythrocyte sedimentation rate >35 mm/h

Two-thirds (66%) of learners (n=316) were not aware that there is a specifically identified “window of opportunity” ending at approximately 15-20 weeks after symptom onset during which RA disease is more susceptible to treatment.

True or False? According to a study by van Nies and colleagues, the relationship between the time of treatment initiation and better outcomes in RA is linear, suggesting that treatment should be provided “the earlier the better,” and there is no specific “window of opportunity” during which the disease is more susceptible to treatment.

66

34

True

False

5717

16

10The diagnosis of RA is established, begin patient on methotrexate 15 mg/week

The diagnosis of RA is clinically suspected but not confirmed, begin patient on hydroxychloroquine 200 mg twice daily

The diagnosis of RA is incomplete, order additional lab testing (eg, CRP) and re-evaluate patient in 3 months

The diagnosis of RA is incomplete, begin patient on nonsteroidal anti-inflammatory drugs (NSAIDs)

Laboratory findings:• CBC=normal Hb and WBC, but increased platelets=523,000• Chemistry panel=normal; ESR=48 mm/hr• Anti-CCP=81; RF=negative• Radiograph of right wrist shows an erosion at the ulnar styloid

and juxta-articular osteoporosis of the 2-5 MCP joints

continued on page 14


Key Teaching Points

T he treatment strategies and medications introduced over the last 2 decades have improved outcomes for patients with rheu-matoid arthritis. Strategies critical for preventing or slowing

damage to joints, disease progression, and subsequent functional impairment include:• Early diagnosis• Prompt initiation of csDMARD therapy with short-term glucocorticoids• Using a treat-to-target strategy with the goal of remission or low

disease activity within 6 months of treatment initiation• Regular assessment of disease activity with composite disease activity

measures (especially joint counts)• Promptly adjusting treatment, adding bDMARDs or tsDMARDs as

needed to reach the target

Careful attention to these strategies increases the likelihood of remis-sion, and for some patients, sustained remission with no further disease progression and the maintenance of a high quality of life. Remission and low disease activity are also associated with lower risk of the comorbid disorders typically observed in patients with rheumatoid arthritis, particularly cardiovascular disease. Drug-free sustained remission, an endpoint unimaginable 20 years ago, is becoming an attainable goal for a subset of patients.113,114

Unfortunately, some patients do not respond sufficiently to currently available agents. Rheumatoid arthritis still imposes a substantial burden on patients, not only because of joint erosion and its effects on physical function, but also because it affects pain, mental function, and fatigue. There is still a need for a better understanding of disease processes and additional pharmacotherapies to improve outcomes for all patients.115,116

A recent systematic review considered the efficacy of occupational therapy–related interventions for adults with rheumatoid arthritis. Strong evidence was found to support the use of aerobic exercise,

resistive exercise, and aquatic therapy. More limited data supported the benefits of dynamic exercise, tai chi, and yoga. Among psychoeducational interventions, strong evidence supports the use of patient education,

self-management, cognitive-behavioral approaches, multidisciplinary approaches, and joint protection.111 Few trials have been conducted specifically with patients with early rheumatoid arthritis. Evidence exists to support the efficacy of dynamic exercise and cognitive behavioral interventions, and to a lesser degree, joint protection programs and foot orthoses in patients with early rheumatoid arthritis.112

Nonpharmacologic Therapy

Rheumatology Practice Snapshot (continued)

Effective Practice Strategies to Achieve Earlier RA Diagnosis and Faster Initiation of CareFew clinicians, only 7% of learners (n=224), knew that the 2015 ACR treat-ment guideline identified that RA is established when symptoms have been present for ≥2 weeks. Almost half of respondents selected ≥6 months, suggesting they are waiting too long to confirm an RA diagnosis.

Considering that the “window of opportunity” identified by van Nies and colleagues ends at 15-20 weeks (approximately 4 to 5 months after symptom onset), this means that many patients may not be receiving therapy during the period in which RA is most susceptible to treatment

Rheumatoid arthritis is considered to be established when symptoms have been present for:

Most learners (n=316) recognized that there is evidence that delay in referral from a primary care physician to a rheumatologist may negatively affect patient outcomes.

True or False? There is evidence that delay in referral from a primary care physician to a rheumatologist may negatively affect patient outcomes.

46

31

16

7

≥3 months

≥1 month

≥6 months

≥2 weeks

93

7 True

False

However, 20% of learners said they typically take more than a month to see a patient referred from primary care with suspected RA.

DistributionWithin 1 day 8%Within 2 days 10%Within 1 week 39%Within 1 month 23%>1 month 20%


References1. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):

2023-2038. doi: 10.1016/S0140-6736(16)30173-82. Harrold LR, Reed GW, Kremer JM, et al. Identifying factors associated with concordance with

the American College of Rheumatology rheumatoid arthritis treatment recommendations. Arthritis Res Ther. 2016;18:94. doi: 10.1186/s13075-016-0992-3

3. Singh JA, Saag, KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25. doi: 10.1002/acr.22783

4. Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis. 2017;76(6):948-959. doi: 10.1136/annrheumdis-2016-210602

5. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. doi: 10.1002/art.27584

6. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315-324. doi: 10.1002/art.1780310302

7. van der Linden MP, le Cessie S, Raza K, et al. Long-term impact of delay in assessment of patients with early arthritis. Arthritis Rheum. 2010;62(12):3537-3546. doi: 10.1002/art.27692

8. Bosello S, Fedele AL, Peluso G, Gremese E, Tolusso B, Ferraccioli G. Very early rheumatoid arthritis is the major predictor of major outcomes: clinical ACR remission and radiographic non-progression. Ann Rheum Dis. 2011;70(7):1292-1295. doi: 10.1136/ard.2010.142729

9. Gremese E, Salaffi F, Bosello SL, et al. Very early rheumatoid arthritis as a predictor of remission: a multicentre real life prospective study. Ann Rheum Dis. 2013;72(6):858-862. doi: 10.1136/annrheumdis-2012-201456

10. Lukas C, Combe B, Ravaud P, Sibilia J, Landew R, van der Heijde D. Favorable effect of very early disease-modifying antirheumatic drug treatment on radiographic progression in early inflammatory arthritis: data from the Étude et Suivi des polyarthrites indifférenciées récentes (study and followup of early undifferentiated polyarthritis). Arthritis Rheum. 2011;63(7):1804-1811. doi: 10.1002/art.30371

11. Söderlin MK, Bergman S, BARFOT Study Group. Absent “Window of Opportunity” in smokers with short disease duration. Data from BARFOT, a multicenter study of early rheu-matoid arthritis. J Rheumatol. 2011;38(10):2160-2168. doi: 10.3899/jrheum.100991

12. Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum. 1981;24(10):1308-1315. doi: 10.1002/art.1780241012.

13. Raza K, Stack R, Kumar K, et al. Delays in assessment of patients with rheumatoid arthritis: variations across Europe. Ann Rheum Dis. 2011;70(10):1822-1825. doi: 10.1136/ard.2011.151902

14. Barhamain AS, Magliah RF, Shaheen MH, et al. The journey of rheumatoid arthritis patients: a review of reported lag times from the onset of symptoms. Open Access Rheumatol. 2017;9:139-150. doi: 10.2147/OARRR.S138830

15. Villeneuve E, Nam JL, Bell MJ, et al. A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of inflammatory arthritis. Ann Rheum Dis. 2013;72(1):13-22. doi: 10.1136/annrheumdis-2011-201063

16. American College of Rheumatology. 2015 Workforce Study of Rheumatology Specialists in the United States. https://www.rheumatology.org/Learning-Center/Statistics/Workforce-Study.

17. O'Dell JR. Treating rheumatoid arthritis early: a window of opportunity? Arthritis Rheum. 2002;46(2):283-285. doi: 10.1002/art.10092

18. van Nies JA, Krabben A, Schoones JW, Huizinga TW, Kloppenburg M, van der Helm-van Mil AH. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis. 2014;73(5):861-870. doi: 10.1136/annrheumdis-2012-203130

19. van Nies JA, Tsonaka R, Gaujoux-Viala C, Fautrel B, van der Helm-van Mil AH. Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts. Ann Rheum Dis. 2015;74(5):806-812. doi: 10.1136/annrheumdis-2014-206047

20. European League Against Rheumatism. Don’t Delay, Connect Today. https://www.eular.org/what_we_do_dont_delay_connect_today_2018.cfm. Accessed April 12, 2018.

21. England BR, Sayles H, Mikuls TR, Johnson DS, Michaud K. Validation of the rheumatic disease comorbidity index. Arthritis Care Res (Hoboken). 2015;67(6):865-872. doi: 10.1002/acr.22456

22. Roubille C, Richer V, Starnino T, et al. Evidence-based recommendations for the manage-ment of comorbidities in rheumatoid arthritis, psoriasis, and psoriatic arthritis: expert opinion of the Canadian Dermatology-Rheumatology Comorbidity Initiative. J Rheumatol. 2015;42(10):1767-1780. doi: 10.3899/jrheum.141112

23. Pincus T. A multidimensional health assessment questionnaire (MDHAQ) for all patients with rheumatic diseases to complete at all visits in standard clinical care. Bull NYU Hosp Jt Dis. 2007;65(2):150-160.

24. Pincus T, Swearingen CJ, Bergman M, Yazici Y. RAPID3 (Routine Assessment of Patient Index Data 3), a rheumatoid arthritis index without formal joint counts for routine care: proposed severity categories compared to disease activity score and clinical disease activity index catego-ries. J Rheumatol. 2008;35(11):2136-2147.

25. Aletaha D, Alasti F, Smolen JS. Optimisation of a treat-to-target approach in rheumatoid arthritis: strategies for the 3-month time point. Ann Rheum Dis. 2016;75(8):1479-1485. doi: 10.1136/annrheumdis-2015-208324

26. Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford). 2003;42(2):244-257. doi: 10.1093/rheumatology/keg072

27. Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44-48. doi: 10.1002/art.1780380107

28. Parekh K, Taylor WJ. The patient activity scale-II is a generic indicator of active disease in patients with rheumatic disorders. J Rheumatol. 2010;37(9):1932-1934. doi: 10.3899/jrheum.100008

29. American College of Rheumatology. Disease Activity and Functional Status Assessments. https://www.rheumatology.org/Practice-Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-Assessments.

30. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977. doi: 10.1136/annrheumdis-2016-210715

31. Curtis JR, Chen L, Danila MI, Saag KG, Parham KL, Cush JJ. Routine use of quantitative disease activity measurements among US rheumatologists: implications for treat-to-target management strategies in rheumatoid arthritis. J Rheumatol. 2018;45(1):40-44. doi: 10.3899/jrheum.170548

32. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheu-matoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430):263-269. doi: 10.1016/S0140-6736(04)16676-2

33. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146(6):406-415. doi: 10.7326/0003-4819-146-6-200703200-00005

34. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3-15. doi: 10.1136/annrheumdis-2015-207524

35. Smolen JS, Aletaha D. Monitoring rheumatoid arthritis. Curr Opin Rheumatol. 2011;23(3):252-258. doi: 10.1097/BOR.0b013e328345743a

36. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573-586. doi: 10.1002/art.30129.

37. Curtis JR, Chen L, Greenberg JD, et al. The clinical status and economic savings associated with remission among patients with rheumatoid arthritis: leveraging linked registry and claims data for synergistic insights. Pharmacoepidemiol Drug Saf. 2017;26(3):310-319. doi: 10.1002/pds.4126

38. Radner H, Smolen JS, Aletaha D. Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs. Arthritis Res Ther. 2014;16(1):R56. doi: 10.1186/ar4491

39. Burmester GR, Bijlsma JWJ, Cutolo M, McInnes IB. Managing rheumatic and musculoskeletal diseases – past, present and future. Nat Rev Rheumatol. 2017;13(7):443-448. doi: 10.1038/nrrheum.2017.95

40. Nikiphorou E, Negoescu A, Fitzpatrick JD, et al. Indispensable or intolerable? Methotrexate in patients with rheumatoid and psoriatic arthritis: a retrospective review of discontinua-tion rates from a large UK cohort. Clin Rheumatol. 2014;33(5):609-614. doi: 10.1007/s10067-014-2546-x

41. Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C. Meta-analysis of treat-ment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. Rheumatology (Oxford). 2000;39(9):975-981. doi: 10.1093/rheumatology/39.9.975

42. Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359(9313):1173-1177. doi: 10.1016/S0140-6736(02)08213-2

43. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000; 343(22):1586-1593. doi: 10.1056/NEJM200011303432201

44. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggres-sive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1):26-37. doi: 10.1002/art.21519

45. Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combi-nation of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008; 372(9636):375-382. doi: 10.1016/S0140-6736(08)61000-4

46. Moreland LW, O'Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824-2835. doi: 10.1002/art.34498

47. de Jong PH, Hazes JM, Han HK, et al. Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial. Ann Rheum Dis. 2014;73(7):1331-1339. doi: 10.1136/annrheumdis-2013-204788

48. Verschueren P, De Cock D, Corluy L, et al. Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial. Ann Rheum Dis. 2015;74(1):27-34. doi: 10.1136/annrheumdis-2014-205489

49. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509. doi: 10.1136/annrheumdis-2013-204573

50. Smolen JS, Kay J, Matteson EL, et al. Insights into the efficacy of golimumab plus methotrexate in patients with active rheumatoid arthritis who discontinued prior anti-tumour necrosis factor therapy: post-hoc analyses from the GO-AFTER study. Ann Rheum Dis. 2014;73(10):1811-1818. doi: 10.1136/annrheumdis-2013-203435

51. Schoels M, Aletaha D, Smolen JS, Wong JB. Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis. Ann Rheum Dis. 2012;71(8):1303-1308. doi: 10.1136/annrheumdis-2011-200490

52. Manders SH, Kievit W, Adang E, et al. Cost-effectiveness of abatacept, rituximab, and TNFi treatment after previous failure with TNFi treatment in rheumatoid arthritis: a pragmatic multi-entre randomised trial. Arthritis Res Ther. 2015;17:134. doi: 10.1186/s13075-015-0630-5

53. Nam JL, Ramiro S, Gaujoux-Viala C, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2014;73(3):516-528. doi: 10.1136/annrheumdis-2013-204577

54. Iannone F, Lopalco G, Cantarini L, Galeazzi M, Lapadula G. Efficacy and safety of combination therapy for preventing bone damage in rheumatoid arthritis. Clin Rheumatol. 2016;35(1):19-23. doi: 10.1007/s10067-015-3120-x

55. Jansen JP, Incerti D, Mutebi A, et al. Cost-effectiveness of sequenced treatment of rheu-matoid arthritis with targeted immune modulators. J Med Econ. 2017;20(7):703-714. doi: 10.1080/13696998.2017.1307205

56. Mertens M, Singh JA. Anakinra for rheumatoid arthritis. Cochrane Database Syst Rev. 2009;(1):CD005121. doi: 10.1002/14651858.CD005121.pub3

57. Choy EH, Kavanaugh AF, Jones SA. The problem of choice: current biologic agents and future prospects in RA. Nat Rev Rheumatol. 2013;9(3):154-163. doi: 10.1038/nrrheum.2013.8

58. Srirangan S, Choy EH. The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2010;2(5):247-256. doi: 10.1177/1759720X10378372

59. Sugiyama E, Kuroda A, Hori F, et al. Serum interleukin-6 level is a sensitive parameter of disease activity in rheumatoid arthritis. J Clin Rheumatol. 1995;1(2):93-98.

60. Matsumoto T, Tsurumoto T, Shindo H. Interleukin-6 levels in synovial fluids of patients with rheumatoid arthritis correlated with the infiltration of inflammatory cells in synovial membrane. Rheumatol Int. 2006;26(12):1096-1100. doi: 10.1007/s00296-006-0143-2

61. Patakas A, Ji RR, Weir W, et al. Abatacept inhibition of T cell priming in mice by induction of a unique transcriptional profile that reduces their ability to activate antigen-presenting cells. Arthritis Rheumatol. 2016;68(3):627-638. doi: 10.1002/art.39470

62. US Food and Drug Administration. Biosimilar Product Information. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580432.htm Accessed March 21, 2018.

63. European Medicines Agency. European public assessment reports. Biosimilars. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125. Accessed March 21, 2018.

64. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. BMJ. 2016;353:i1777. doi: 10.1136/bmj.i1777

65. Buckley F, Finckh A, Huizinga TW, Dejonckheere F, Jansen JP. Comparative efficacy of novel DMARDs as monotherapy and in combination with rheumatoid arthritis patients with inade-quate response to conventional DMARDs: a network meta-analysis. J Manag Care Spec Pharm. 2015;21(5):409-423. doi: 10.18553/jmcp.2015.21.5.409

66. Weinblatt ME, Schiff M, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study. Arthritis Rheum. 2013;65(1):28-38. doi: 10.1002/art.37711

67. Smolen JS, Burmester GR, Combe B, et al. Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study. Lancet. 2016;388(10061):2763-2774. doi: 10.1016/S0140-6736(16)31651-8

68. Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety of the selec-tive costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: a one-year randomized, placebo-controlled study. Arthritis Rheum. 2006;54(9):2807-2816. doi: 10.1002/art.22070

69. Genovese MC, Cohen S, Moreland L, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004;50(5):1412-1419. doi: 10.1002/art.20221

70. Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum. 2011;63(3):622-632. doi: 10.1002/art.30194

71. Rein P, Mueller RB. Treatment with biologicals in rheumatoid arthritis: an overview. Rheumatol Ther. 2017;4(2):247-261. doi: 10.1007/s40744-017-0073-3

72. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377-2386. doi: 10.1056/NEJMoa1310476

73. Richez C, Truchetet ME, Kostine M, Schaeverbeke T, Bannwarth B. Efficacy of baricitinib in the treatment of rheumatoid arthritis. Expert Opin Pharmacother. 2017;18(13):1399-1407. doi: 10.1080/14656566.2017.1359256

74. Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343-355. doi: 10.1016/S0140-6736(16)30363-4

75. Teitsma XM, Jacobs JWG, Welsing PMJ, et al. Radiographic joint damage in early rheumatoid arthritis patients: comparing tocilizumab- and methotrexate-based treat-to-target strategies. Rheumatology (Oxford). 2018;57(2):309-317. doi: 10.1093/rheumatology/kex386

76. Teitsma XM, Jacobs JWG, Welsing PMJ, et al. Patient-reported outcomes in newly diagnosed early rheumatoid arthritis patients treated to target with a tocilizumab- or methotrexate-based strategy. Rheumatology (Oxford). 2017;56(12):2179-2189. doi: 10.1093/rheumatology/kex319

77. Huizinga TW, Fleischmann RM, Jasson M, et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part

A trial. Ann Rheum Dis. 2014;73(9):1626-1634. doi: 10.1136/annrheumdis-2013-20440578. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with

active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67(6):1424-1437. doi: 10.1002/art.39093

79. Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2017;69(2):277-290. doi: 10.1002/art.39944

80. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847. doi: 10.1136/annrheumdis-2016-210310

81. Strand V, Gossec L, Proudfoot C, et al. Patient reported benefits of sarilumab monotherapy versus adalimumab monotherapy in adult patients with active rheumatoid arthritis. Ann Rheum Dis. 2017;76(suppl 2):94. doi: 10.1136/annrheumdis-2017-eular.2955

82. Fleischmann R, Kremer J, Cush J, et al; ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507. doi: 10.1056/NEJMoa1109071

83. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508-519. doi: 10.1056/NEJMoa1112072

84. Genovese MC, van Vollenhoven RF, Wilkinson B, et al. Switching from adalimumab to tofaci-tinib in the treatment of patients with rheumatoid arthritis. Arthritis Res Ther. 2016;18:145. doi: 10.1186/s13075-016-1049-3

85. Strand V, Lee EB, Fleischmann R, et al. Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial. RMD Open. 2016;2(2):e000308. doi: 10.1136/rmdopen-2016-000308

86. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combina-tion with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381(9865):451-460. doi: 10.1016/S0140-6736(12)61424-X

87. Strand V, Kremer JM, Gruben D, Krishnaswami S, Zwillich SH, Wallenstein GV. Tofacitinib in combination with conventional disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: patient-reported outcomes from a phase III randomized controlled trial. Arthritis Care Res (Hoboken). 2017;69(4):592-598. doi: 10.1002/acr.23004

88. Fleischmann R, Mease PJ, Schwartzman S, et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group. Clin Rheumatol. 2017;36(1):15-24. doi: 10.1007/s10067-016-3436-1

89. Fleischmann R, Mysler E, Hall S, et al. Tofacitinib with and without methotrexate versus adalimumab with methotrexate for the treatment of rheumatoid arthritis: results from ORAL Strategy, a phase 3b/4 randomised trial. Ann Rheum Dis. 2017;76(suppl 2):149. doi: 10.1136/annrheumdis-2017-eular.7113

90. Winthrop KL, Curtis JR, Lindsey S, et al. Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol. 2017;69(10):1960-1968. doi: 10.1002/art.40189

91. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. New Engl J Med. 2016;374(13):1243-1252. doi: 10.1056/NEJMoa1507247.

92. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. doi: 10.1056/NEJMoa1608345

93. Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(1):88-95. doi: 10.1136/annrheumdis-2016-210094

94. Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. doi: 10.1002/art.39953

95. Fleischmann R, Alam J, Arora V, et al. Safety and efficacy of baricitinib in elderly patients with rheumatoid arthritis. RMD Open. 2017;3(2):e000546. doi: 10.1136/rmdopen-2017-000546

96. Schiff M, Takeuchi T, Fleischmann R, et al. Patient-reported outcomes of baricitinib in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treat-ment. Arthritis Res Ther. 2017;19(1):208. doi: 10.1186/s13075-017-1410-1

97. Singh JA, Cameron C, Noorbaloochi S, et al. Risk of serious infection in biological treat-ment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015;386(9990):258-265. doi: 10.1016/S0140-6736(14)61704-9

98. Ramiro S, Sepriano A, Chatzidionysiou K, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1101-1136. doi: 10.1136/annrheumdis-2016-210708

99. Galloway JB, Hyrich KL, Mercer LK, et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford). 2011;50(1):124-131. doi: 10.1093/rheumatology/keq242

100. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301(7):737-744. doi: 10.1001/jama.2009.146

101. de La Forest Divonne M, Gottenberg JE, Salliot C. Safety of biologic DMARDs in RA patients in real life: a systematic literature review and meta-analyses of biologic registers. Joint Bone Spine. 2017;84(2):133-140. doi: 10.1016/j.jbspin.2016.02.028

102. Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf. 2011;20(2):119-130. doi: 10.1002/pds.2046

103. Cohen MD, Keystone E. Rituximab for rheumatoid arthritis. Rheumatol Ther. 2015;2(2):99-111. doi: 10.1007/s40744-015-0016-9

104. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13(4):234-243. doi: 10.1038/nrrheum.2017.23

105. Winthrop KL, Wouters AG, Choy EH, et al. The safety and immunogenicity of live zoster vaccination in patients with rheumatoid arthritis before starting tofacitinib: a randomized phase II trial. Arthritis Rheumatol. 2017;69(10):1969-1977. doi: 10.1002/art.40187

106. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67(3):103-108. doi: 10.15585/mmwr.mm6703a5

107. Glauser TA, Ruderman EM, Kummerle D, Kelly S. Current practice patterns and educational needs of rheumatologists who manage patients with rheumatoid arthritis. Rheumatol Ther. 2014;1(1):31-44. doi: 10.1007/s40744-014-0004-5

108. Augustovski F, Beratarrechea A, Irazola V, et al. Patient preferences for biologic agents in rheumatoid arthritis: a discrete-choice experiment. Value Health. 2013;16(2):385-393. doi: 10.1016/j.jval.2012.11.007

109. Bolge SC, Goren A, Tandon N. Reasons for discontinuation of subcutaneous biologic therapy in the treatment of rheumatoid arthritis: a patient perspective. Patient Prefer Adherence. 2015;9:121-131. doi: 10.2147/PPA.S70834

110. Bolge SC, Goren A, Brown D, Ginsberg S, Allen I. Openness to and preference for attributes of biologic therapy prior to initiation among patients with rheumatoid arthritis: patient and rheumatologist perspectives and implications for decision making. Patient Prefer Adherence. 2016;10:1079-1090. doi: 10.2147/PPA.S107790

111. Siegel P, Tencza M, Apodaca B, Poole JL. Effectiveness of occupational therapy inter-ventions for adults with rheumatoid arthritis: a systematic review. Am J Occup Ther. 2017;71(1):7101180050p1-7101180050p11. doi: 10.5014/ajot.2017.023176

112. Vliet Vlieland TP, Pattison D. Non-drug therapies in early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2009;23(1):103-116. doi: 10.1016/j.berh.2008.08.004

113. Ajeganova S, Huizinga T. Sustained remission in rheumatoid arthritis: latest evidence and clinical considerations. Ther Adv Musculoskeletal Dis. 2017;9(10):249-262. doi: 10.1177/1759720X17720366

114. Akdemir G, Heimans L, Bergstra SA, et al. Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study. Ann Rheum Dis. 2018;77(1):111-118. doi: 10.1136/annrheumdis-2017-211375.

115. Cheung TT, McInnes IB. Future therapeutic targets in rheumatoid arthritis? Semin Immunopathol. 2017;39(4):487-500. doi: 10.1007/s00281-017-0623-3

116. Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol Int. 2016;36(5):685-695. doi: 10.1007/s00296-015-3415-x

EVALUATION FORM Please indicate your profession/background: (check one) MD/DO MSN/BSN/RN PA APN/NP PharmD/RPh Resident/Fellow Researcher Administrator Student Other; specify ___________________________________

If you do not feel confident that you can achieve the above objectives to some extent, please describe why not.________________________________________________________________________________

Based on the content of this activity, what will you do differently in the care of your patients/regard-ing your professional responsibilities? (check one)

Implement a change in my practice/workplace. Seek additional information on this topic.Do nothing differently. Current practice/job responsibilities reflect activity recommendations.Do nothing differently as the content was not convincing. Do nothing differently. System barriers prevent me from changing my practice/workplace.

If you anticipate changing one or more aspects of your practice/professional responsibilities as a result of your participation in this activity, please briefly describe how you plan to do so.________________________________________________________________________________

If you plan to change your practice/workplace, may we contact you in 2 months to see how you are progressing?

Yes. E-mail address: ___________________________________________No. I don’t plan to make a change.

If you are not able to effectively implement what you learned in this activity, please tell us what the system barriers are (eg, institutional systems, lack of resources, etc)?________________________________________________________________________________

What topics do you want to hear more about, and what issue(s) regarding your practice/professional responsibilities will they address?_________________________________________________________________________________

Please provide additional comments pertaining to this activity and any suggestions for improvement._________________________________________________________________________________

OVERALL EVALUATION Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

The information presented increased my awareness/understanding of the subject. 5 4 3 2 1

The information presented will influence how I practice/do my job. 5 4 3 2 1

The information presented will help me improve patient care/my job performance. 5 4 3 2 1

The program was educationally sound and scientifically balanced. 5 4 3 2 1

Overall, the program met my expectations. 5 4 3 2 1

I would recommend this program to my colleagues. 5 4 3 2 1

Marc D. Cohen, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1

Author was organized in the written materials. 5 4 3 2 1

Jeffrey R. Curtis, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Iain B. McInnes, PhD, FRCP, FRSE, FMedSciAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


© 2018 Global Academy for Medical Education. All Rights Reserved.

Postgraduate Institute for Medicine and Global Academy for Medical Education thank you for your participation in this CME activity. All information provided improves the scope and purpose of our programs and your patients’ care.

LEARNING OBJECTIVES: Having completed this activity, you are better able to: Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

Design appropriate strategies to increase the timeliness of rheumatoid arthritis diagnosis and subsequent linkage to evidence-based care 5 4 3 2 1

Design appropriate strategies to relieve articular and systemic symptoms of rheumatoid arthritis 5 4 3 2 1

Design strategies for using the most appropriate therapies based on the safety and efficacy data of the emerging classes of therapies for rheumatoid arthritis, including anti-interleukin (IL)-6/IL-6R agents, tumor necrosis factor (TNF) inhibitors, and other biologic disease-modifying antirheumatic drugs (DMARDs)

5 4 3 2 1

Design treatment strategies for rheumatoid arthritis that take into consideration recommendations from current guidelines and emerging data from clinical trials 5 4 3 2 1

Describe the data presented at national and global scientific conferences that may help clinicians achieve the treatment goals for rheumatoid arthritis 5 4 3 2 1

POST-TEST CME QUESTIONS1. When should DMARD treatment begin in a new

patient who is at high risk for developing persistent and erosive disease, according to the ACR/EULAR Classification Criteria?A. Within 3 to 6 months of symptom onsetB. Within 1 year of symptom onsetC. Within 2 years of symptom onsetD. Within 3 years of symptom onset

2. In a recent global study by Barhamain et al, what was the median time from symptom onset to DMARD treatment initiation?A. 3 monthsB. 6 monthsC. 12 monthsD. 18 months

3. EULAR recommends monitoring disease activity using composite measures that include which of the following features?A. CRP (mg/dL)B. Joint countsC. Patient pain assessmentD. Patient global assessment of disease activity

4. The ACR and EULAR have jointly developed two methods of measuring remission. Which of these standard measures of disease activity have they recommended as one method?A. Clinical Disease Activity Index (CDAI)B. Multidimensional Health Assessment

Questionnaire (MDHAQ)C. Routine Assessment of Patient Index Data 3

(RAPID3)D. Simplified Disease Activity Index (SDAI)

5. Which csDMARD should only be prescribed for patients with mild disease?A. HydroxychloroquineB. LeflunomideC. MethotrexateD. Sulfasalazine

6. A 63-year-old man who met ACR/EULAR Classification Criteria began treatment with methotrexate 4 months after symptom onset. After 6 months on methotrexate, his symptoms improved, but he still had moderate disease activity according to the SDAI. According to the ACR guideline, which of these should NOT be added to this patient’s methotrexate regimen?A. AbataceptB. LeflunomideC. Tocilizumab D. Tofacitinib

7. A 70-year-old woman who met ACR/EULAR Classification Criteria began treatment with methotrexate 4 months after symptom onset. After 6 months on methotrexate, her symptoms improved, but she still had moderate disease activity according to the SDAI. According to the EULAR recommendations, which of these medications should NOT be added to this patient’s

methotrexate regimen?A. AbataceptB. AdalimumabC. LeflunomideD. Sarilumab

8. Tocilizumab monotherapy was compared with methotrexate monotherapy and tocilizumab-methotrexate combination treatment in a head-to-head clinical trial (U-Act-Early). What was found in this study?A. The efficacy of methotrexate was noninferior to

tocilizumab monotherapyB. Tocilizumab was better than methotrexate in joint

space narrowingC. No differences were observed between the groups

in progression of erosions in hands and feetD. Tocilizumab was better than methotrexate in rates

of sustained remission

9. Which of these is associated with TNF inhibitor treatment?A. Myocardial infarctionB. Progressive multifocal leukoencephalopathyC. Reactivation of latent tuberculosis D. Solid tumors

10. Which adverse event is associated with tofacitinib?A. Herpes zosterB. Lymphoproliferative malignancy C. Non-Hodgkin lymphoma D. Progressive multifocal leukoencephalopathy

Early and Aggressive Approaches to RA Management to Minimize Disease Progression and Improve Quality of Life Post-Test and Evaluation FormOriginal Release Date: May 1, 2018 • Expiration Date: May 1, 2019 • Estimated Time to Complete Activity: 1.5 hoursTo get instant CME credits online, go to https://tinyurl.com/RAEarly18S. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail. If you have any questions or difficulties, please contact: Global Academy for Medical Education at [email protected] or (973) 290-8225.

FOR REVIEW PURPOSES ONLY. MUST BE COMPLETED ONLINE.

a cme-certified supplement to rheumatology news · 2020-02-10 · a cme-certified supplement to...

Documents