aplar rheumatoid arthritis treatment recommendations

SPECIAL EDITORIAL REVIEW

APLAR rheumatoid arthritis treatment recommendations

Chak Sing LAU,1 Faith CHIA,2 Andrew HARRISON,3 Tsu-Yi HSIEH,4 Rahul JAIN,5

Seung Min JUNG,6 Mitsumasa KISHIMOTO,7 Ashok KUMAR,8 Khai Pang LEONG,2

Zhanguo LI,9 Juan Javier LICHAUCO,10 Worawit LOUTHRENOO,11 Shue-Fen LUO,12 Peter

NASH,13 Chin Teck NG,14 Sung-Hwan PARK,6 Bagus Putu Putra SURYANA,15

Parawee SUWANNALAI,16 Linda Kurniaty WIJAYA,17 Kazuhiko YAMAMOTO,18 Yue YANG9

and Swan Sim YEAP19

1Division of Rheumatology and Clinical Immunology, Queen Mary Hospital, University of Hong Kong, Hong Kong, 2Department ofRheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore City, Singapore, 3Department of Medicine, University ofOtago Wellington, Wellington South, New Zealand, 4Section of Allergy, Immunology and Rheumatology, and Section of ClinicalSkills Training, Taichung Veterans General Hospital, Taichung, Taiwan, 5Narayana Hospital, Jaipur, India, 6Division ofRheumatology, Department of Internal Medicine, The Catholic University of Korea, St. Mary’s Hospital, Seoul, South Korea,7Immuno-Rheumatology Center, St Luke’s International Hospital, Tokyo, Japan, 8Department of Rheumatology, Fortis Flt. Lt RajanDhall Hospital, New Delhi, India, 9Department of Rheumatology, Peking University People’s Hospital, Beijing, China,10St. Luke’s Medical Center, Quezon City, Philippines, 11Division of Rheumatology, Department of Internal Medicine, Faculty ofMedicine, Chiang Mai University, Chiang Mai, Thailand, 12Department of Rheumatology, Allergy and Immunology, Chang GungMemorial Hospital and Chang Gung University, Tao-Yuan, Taiwan, 13Department of Medicine, University of Queensland, Brisbane,Queensland, Australia, 14Department of Rheumatology and Immunology, Singapore General Hospital, Singapore City, Singapore,15Rheumatology Division, Department of Internal Medicine, Brawijaya University, Saiful Anwar General Hospital, Malang,Indonesia, 16Allergy, Immunology and Rheumatology Division, Internal Medicine Department, Faculty of Medicine, RamathibodiHospital, Mahidol University, Bangkok, Thailand, 17Division of Rheumatology, Department of Internal Medicine, University ofIndonesia, Jakarta, Indonesia, 18Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo,Tokyo, Japan, and 19Subang Jaya Medical Centre, Selangor, Malaysia

AbstractAims: Rheumatoid arthritis is a chronic inflammatory condition that affects approximately 1% of the world’s

population. There are a wide number of guidelines and recommendations available to support the treatment of

rheumatoid arthritis; however, the evidence used for these guidelines is predominantly based on studies in Cau-

casian subjects and may not be relevant for rheumatoid arthritis patients in the Asia-Pacific region. Therefore,

the Asia Pacific League of Associations for Rheumatology established a Steering Committee in 2013 to address

this issue.

Materials and methods: The AGREE II instrument and the ADAPTE Collaboration framework were applied to

systematically identify, appraise, synthesize, and adapt international rheumatoid arthritis guidelines for use in

the Asia-Pacific region.

Results: Forty rheumatoid arthritis treatment recommendations, based on evidence and expert opinion, were

drafted and are presented in this report.

Correspondence: Professor Chak Sing Lau, Division of Rheuma-tology and Clinical Immunology, Queen Mary Hospital,University of Hong Kong, Hong Kong, Hong Kong.Email: [email protected]

© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

International Journal of Rheumatic Diseases 2015; 18: 685–713

Conclusion: The Asia Pacific of Associations for Rheumatology rheumatoid arthritis treatment recommenda-

tions are intended to serve as a reference for best practice management of rheumatoid arthritis in Asia-Pacific,

focusing on local issues to ensure the delivery of basic care for these patients, and to improve their outcomes. In

addition, the document will serve as a reference for national rheumatology associations in Asia-Pacific for devel-

oping guidelines in their respective countries.

Key words: drug treatment, rheumatoid arthritis.

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic inflammatory

autoimmune disease of unknown etiology that affects

approximately 1% of the global population.1–3 The dis-

ease is characterized by inflammation, pain, stiffness

and progressive joint destruction leading to high rates of

morbidity and mortality in the affected individuals.1–3

Furthermore, RA is associated with productivity losses

and increased financial burden, increased psychological

distress, depression and, consequently, significantly

decreased health-related quality of life.4–6

Disease-modifying antirheumatic drugs (DMARDs)

form the cornerstone of RA treatment. These agents

have the capacity to modify the disease process by

reducing or reversing signs and symptoms, disability,

impairment of quality of life, inability to work, and

progression of joint damage.7 Early and aggressive treat-

ment with DMARDs has been shown to be effective in

altering the clinical course of RA, and slowing or stop-

ping the radiographic progression. DMARDs are

broadly classified into conventional DMARDs

(cDMARDs) including synthetic chemical agents such

as methotrexate, sulfasalazine and leflunomide, and

biological DMARDs (bDMARDs), including: tumor

necrosis factor (TNF) inhibitors (adalimumab, cer-

tolizumab pegol, etanercept, golimumab and inflix-

imab); the T-cell costimulation inhibitor, abatacept; the

anti-B cell agent, rituximab; the interleukin (IL)-6 recep-

tor (IL-6R)-blocking monoclonal antibody, tocilizu-

mab; as well as the IL-1 inhibitor, anakinra. Recently,

tofacitinib, a Janus kinase (JAK) inhibitor, has also been

shown to have disease-modifying effects in RA.

NEED FOR RA RECOMMENDATIONS INTHE ASIA-PACIFIC (AP) REGION

As the evidence used in most international RA treatment

guidelines is obtained predominantly from studies in

Caucasian subjects, these guidelines may not be relevant

for RA patients in the AP countries. Data show that

there is an increased prevalence of certain infections

(e.g., tuberculosis [TB], hepatitis B and C infection,

Epstein–Barr virus infection)8,9 and malignancies (e.g.,

T-cell and natural killer-cell lymphomas,10 stomach

cancer11) in the AP region. Thus, a Steering Committee

under the auspice of the Asia Pacific League of Associa-

tions for Rheumatology (APLAR) was formed in 2013

to formulate AP region-specific treatment recommenda-

tions for RA that address AP-specific issues.

However, the AP region has vast intra-regional diver-

sity in terms of ethnicities, socioeconomic structures

and health resources; these characteristics also differ

from those in Western countries. Furthermore, the

availability and dosage of medications vary across AP

countries. Thus, it is difficult to develop RA treatment

recommendations that will be appropriate for all AP

countries. Owing to a shortage of rheumatologists, RA

patients in the region are also often managed by general

practitioners and allied health practitioners. Conse-

quently, the treatment practices are not standardized

and vary widely, even within countries. Furthermore,

there are limited data from the AP region to endorse

evidence-based recommendations that may be consid-

ered more appropriate in some countries in the region.

Nevertheless, this Steering Committee aimed to develop

recommendations that will be as evidence-based as pos-

sible and define the best practices for managing RA in

the AP region.

In addition, the Steering Committee also made rec-

ommendations based on expert opinion and consensus

so that countries with limited resources may be able to

achieve the minimum essential standard of care for

their RA patients.

TARGET AUDIENCE AND CONTENTS

The intended target audience for this document includes

rheumatologists and all practitioners who manage RA. It

focuses predominantly on recommendations for the

pharmacological treatment of RA. The document

includes 40 recommendations across the following RA

treatment domains: general RA treatment strategies; role

of non-steroidal anti-inflammatory drugs (NSAIDs),

including: cyclooxygenase-2 (COX-2) inhibitors; role of

corticosteroids; role of conventional DMARDs

686 International Journal of Rheumatic Diseases 2015; 18: 685–713

C. S. Lau et al.

(cDMARDS); and role of bDMARD agents. Specific key

questions across these key domains were identified and

recommendation statements developed accordingly

(Table 1).

This document does not include recommendations

for the diagnosis of RA, patient referral policies or

Table 1 Key questions regarding the treatment of RA in the

AP region

A. General RA treatment strategies

i. What are the goals of treatment?

ii. What are the clinical, laboratory and radiological fea-

tures and prognostic features that will guide treatment

decisions?

iii. Overall treatment strategies

1. How is treatment initiated and the goal of treatment

discussed with patients?

2. How are adjustments made based on clinical, bio-

chemical and radiological findings?

a. What are the response criteria and what should

be the frequency of monitoring?

b. What precautions are necessary for ensuring the

safety of patients on RA treatment?

3. How long should patients be maintained on

DMARD and non-DMARD treatments?

B. Role of NSAIDs including COX-2 inhibitors

i. What is the optimum dosage of NSAIDs and COX-2 inhi-

bitors?

ii. What are the side effects of NSAIDs and COX-2 inhibi-

tors?

iii. What are the associated gastrointestinal and cardiovas-

cular risks?

iv. What are the adverse events in patients with comorbidi-

ties?

v. Do NSAIDs have disease-modifying activity?

C. Role of cDMARDs

i. When are cDMARDS prescribed?

ii. Which cDMARDs should be used?

iii. What investigations are required before starting

cDMARD treatment?

iv. What is the optimal dosing for cDMARDs?

v. Which cDMARD combinations are preferred?

vi. What are the precautions when using cDMARDs?

vii. How to monitor patients on cDMARDs and what is the

frequency of assessment?

viii. How is treatment failure defined with cDMARDs?

ix. Is dose reduction or cessation possible with cDMARDs

when disease is deemed to be in remission?

D. Role of corticosteroid agents

i. What is the difference in opinions between AP and Euro-

pean/US practitioners about corticosteroid use?

ii. When should corticosteroids be prescribed?

iii. How should corticosteroids be administered?

iv. What is the optimal dosing regimen for corticosteroids?

v. When should treatment with corticosteroids be tapered

and stopped?

vi. What precautions are necessary when treating with cor-

ticosteroids?

vii. How should patients on corticosteroids be monitored?

E. Role of bDMARD agents

i. When should bDMARDs be prescribed?

1. What is the definition of inadequate response to

cDMARDs?

2. Which prognostic factors should be assessed when

prescribing bDMARDs?

ii. Which class of drugs should be used?

1. Need to discuss individual agents or class?

2. What is the algorithm for initiating and switching

treatment with bDMARDs?

iii. Should methotrexate or other cDMARDs be co-pre-

scribed with bDMARDs?

iv. Which investigations should be performed before pre-

scribing bDMARDs?

v. What is the optimal dosing strategy for different

bDMARDs?

vi. What is the therapeutic strategy for combination ther-

apy of bDMARDs with non-biologic DMARDs?

vii. What precautions should be taken when prescribing

bDMARDs?

viii. How should treatment with bDMARDs be monitored

and what should be the frequency of assessment?

ix. What are the definitions of primary and secondary treat-

ment failure with bDMARDs?

x. What is the therapeutic strategy for dose reduction or

cessation with bDMARDs when RA is deemed to be in

remission?

xi. What is the therapeutic strategy for bDMARDs in the

following special situations:

1. Infectious complications

a. TB

b. Hepatitis

c. Others

2. Autoimmunity

3. Malignancies

4. Surgery

5. Pregnancy/lactation

6. Vaccination policies

F. What is the role of complementary/unproven therapies in

the treatment of RA?

AP, Asia Pacific; bDMARD, biological DMARD; cDMARD, conven-tional DMARD; COX-2 inhibitors, cyclooxygenase-2 inhibitors;DMARD, disease-modifying antirheumatic drug; NSAID, non-steroidalanti-inflammatory drug; RA, rheumatoid arthritis; TB, tuberculosis.

Table 1 (continued)

International Journal of Rheumatic Diseases 2015; 18: 685–713 687

APLAR RA recommendations

management of comorbid conditions. Furthermore,

costs were not embedded in the discussion of the rec-

ommendations, as formal cost-effectiveness analyses

were not performed.

FUNDING AND CONFLICT OF INTEREST

The process of developing the APLAR RA treatment rec-

ommendations was funded by APLAR and was also

supported by unrestricted educational grants from the

following pharmaceutical companies: AbbVie, Janssen,

Pfizer, Roche and UCB. Relevant disclosures for the

Steering Committee members, including industry fund-

ing, consultancies and commercial interests, are

included at the end of this article.

OBJECTIVES

The primary objective was to develop a document that

would serve as a reference for best RA management

practices in the AP region, focusing on local issues in

the region. In addition, the document would also serve

as a reference for national rheumatology associations in

the region for developing RA guidelines in respective

countries.

MATERIALS AND METHODS

The ADAPTE framework was used to systematically

identify, appraise, synthesize, and adapt international

RA guidelines for use in the AP region. This was done

by following the steps outlined in the ADAPTE manual

and toolkit, and helped to expedite the process of rec-

ommendation development.12,13

Assembly of the APLAR RA RecommendationsSteering CommitteeA Steering Committee was formed by inviting 22 mem-

bers of APLAR representing 12 countries from the AP

region, as well as one RA patient for developing this set

of recommendations. The APLAR members were

rheumatology experts who had served on numerous RA

research projects and decision-making panels both

internationally and in their respective countries. All

members of the Steering Committee attended the meet-

ings, contributed to discussions and were actively

involved in every phase of recommendation develop-

ment. No representative of pharmaceutical companies

was involved in any part of recommendation

development.

Scope of the recommendationsMembers of the Steering Committee developed key

questions pertaining to RA treatment in the AP region.

These questions, developed during a face-to-face meet-

ing, addressed various domains of RA treatment, as

described earlier (Table 1).

Search criteriaThe studies included were clinical practice guidelines

and consensus statements with recommendations for

adult RA populations, and published in English

between January 2000 and December 2013. Studies

that provided evidence from the AP region to support

recommendation of RA treatment practices specific to

the region were also included. Non-English articles

were considered, provided a member of the Steering

Committee could translate them into English. Articles

were excluded if they did not address the key ques-

tions or were deemed to be of poor methodological

quality by a validated guidelines quality appraisal

instrument.14,15

Search strategyA systematic search was performed according to the

inclusion–exclusion criteria described above in Med-

line, EMBASE, Google Scholar and SCOPUS. The search

terms included RA, specific drug names for cDMARDs

and bDAMRDs, NSAIDs, corticosteroids, AP, guideli-

nes, consensus statements and recommendations. All

search results were reviewed by two independent mem-

bers. The steps involved in the systematic search are

shown in Figure 1.

Appraisal of guideline qualityThe quality of each guideline was assessed using a vali-

dated questionnaire, the Appraisal of Guidelines,

Research and Evaluation (AGREE) instrument.15 This

instrument includes 23 questions that are organized

into six domains: (i) scope and purpose; (ii) stake-

holder involvement; (iii) rigor of development; (iv)

clarity of presentation; (v) applicability; and (vi) edito-

rial independence. Each of the 23 items targets various

aspects of practice guideline quality. Each guideline was

independently assessed by two reviewers to formulate a

single-item overall assessment as ‘Recommend’, ‘Rec-

ommend with modifications’ or ‘Not recommend’.

Grading evidenceEach guideline had a different system for grading evi-

dence. To reconcile these differences, we translated each


C. S. Lau et al.

guideline’s evidence grading system into a simplified

system as suggested by the Scottish Intercollegiate

Guideline Network (SIGN) to assign a level of evidence

and strength of recommendation for each recommen-

dation.16

Evidence synthesisWe prepared a table of included guidelines containing

descriptive characteristics, including guideline devel-

oper, country, year, summary of recommendations and

AGREE assessment, for each subsection of the guideline.

This was followed by development of evidence tables

for each question; these included guideline characteris-

tics, recommendations, summary of guideline assess-

ment (AGREE assessment) and supporting evidence

(Table 2).

Development of recommendationsMembers of the Steering Committee summarized rec-

ommendations and supporting evidence from inter-

national guidelines to address each key question. A

recommendation for the AP region was developed

by adapting and rewording the existing recommen-

dation. An emphasis was placed on recent guidelines

with strong methodological quality. Supporting evi-

dence from randomized controlled trials (RCTs) and

observational studies referenced by the guideline was

reviewed by members in detail. All members partici-

pated in developing the wording of recommenda-

tions. Consensus was achieved by using the Delphi

technique whereby members had an opportunity to

cast a vote anonymously, without getting swayed by

opinions of fellow members; disagreements were

resolved through discussions and multiple rounds of

voting. Statements were included as recommenda-

tions provided more than 80% of the members par-

ticipated in the polling and more than 50% of the

members voted in favor of the outcome. Setting the

acceptance margin to 70% resulted in exclusion of

many questions considered important during meet-

ing discussions. Thus, for the purpose of this recom-

mendation document, a majority was determined by

more than 50% of votes.

Extended reviewDraft recommendations developed by the group were

sent to Josef Smolen and Vibeke Strand for review and

comments. The draft recommendations were also pre-

sented in an open forum during the 2014 APLAR Con-

gress to seek opinions and suggestions from

participants. Feedback from the respondents was used

to finalize the recommendations and inform supporting

text. This document was developed in accordance with

the principles outlined by the AGREE II instrument and

the ADAPTE collaboration. The recommendations were

also sent for review and official endorsement by APLAR.

Figure 1 Steps in the systematic review of international guidelines and recommendations on the pharmacological managementof rheumatoid arthritis.



RESULTS

Each recommendation is presented with a level of evi-

dence and strength (Table 3) and accompanied with

supporting text which is structured as follows.

Supporting evidence

Description of the source guidelines used for adapta-

tion

Summary of evidence linked to recommendation statement

Summary of original evidence presented in source

guidelines.

Special comment/recommendation for the AP region

A special comment/expert opinion that is relevant for

the region.

RecommendationsA summary of the recommendations is presented in

Table 3. It should be noted that the recommendations

are stratified into different sections relevant to the dif-

ferent stages and groups of drugs used in the treatment

of RA. These sections may thus be referenced separately

and individually. An algorithm summarizing the rec-

ommendations for treatment of patients with RA in the

AP region is presented in Figure 2.

Section 1 – General RA treatment strategies

Recommendation 1. RA treatment should be aimed atmaintaining physical functioning and good qualityof life through achieving a state of sustained remis-sion, or low disease activity when remission may notbe an achievable target. (Level II; Strength B)

Supporting evidence

References 17–29.


It was noted that, in every patient, treatment should be

aimed at reaching a target of remission17–24 or low dis-

ease activity,17–20,24 as soon as possible25 and measur-

ing disease activity using objective parameters such as

Disease Activity Score (DAS), DAS28 (DAS of 28 joints),

Simplified Disease Activity Index (SDAI) and Clinical

Disease Activity Index (CDAI).26,27 Consequently, this

will halt joint damage, prevent disability and improve

quality of life.28,29 It should be noted that DAS28 < 2.6

is regarded by the Food and Drug Administration

(FDA) as a cut-off point for low disease activity,

whereas remission is probably better defined according

to the American College of Rheumatology–EuropeanLeague Against Rheumatism (ACR–EULAR) criteria

based on SDAI, CDAI or the Boolean criteria.30


In the AP region, there may be some situations in which

remission or even low disease activity may not be possi-

ble. For example, many AP patients first present to their

clinician with advanced disease and often severe joint

deformity. For these patients to achieve remission, the

use of bDMARDs is often required but these agents are

not affordable for most of these patients. Furthermore,

many patients are engaged in work involving physical

labor which may aggravate the signs and symptoms of

RA, rendering a low disease activity state non-achiev-

able. Thus, for many RA patients in the region, we rec-

ommend counselling to ensure compliance, and an

agreement on a treatment target, maintaining symptom

control and work ability, to be reached between the

clinician and the patient.

Recommendation 2. Treatment of RA is a shared deci-sion between the clinician and patient, and should bestarted once diagnosed. (Level I; Strength A)

Supporting evidence

References 17, 19–25, 27, 29, 31, 32 and 33.

Table 2 System used for assigning level of evidence and

strength of recommendation16

Levels of evidence Strength of recommendation

I. Meta-analyses, systematic

reviews of RCTs, or

individual RCT

A. Strong recommendation:

Direct level I evidence

II. Meta-analyses, systematic

reviews of observational

studies (cohort/case

control studies), or

individual observational

studies

OR

RCT subgroup/post-hoc

analyses

B. Moderate

recommendation:

Direct level II evidence or

extrapolated level I

evidence

III. Non-analytical studies, e.g.,

case reports, case series

C. Weak recommendation:

Direct level III evidence

or extrapolated level II

evidence

IV. Expert opinion

OR

Recommendations are not

linked to evidence

D. Consensus

recommendation:

Expert opinion based on

very limited evidence

RCT, randomized controlled trial.


C. S. Lau et al.

Table 3 APLAR treatment recommendations for the management of RA in the AP region

Recommendations Level Strength

Section 1 – General RA treatment strategies

1. RA treatment should be aimed at maintaining physical functioning and good quality of life through

achieving a state of sustained remission, or low disease activity when remission may not be an

achievable target.

II B

2. Treatment of RA is a shared decision between the clinician and patient, and should be started once

diagnosed.

I A

3. The choice of treatment is based on the findings of active disease and/or poor prognosis and

comorbidities.

II B

4. Poor prognostic factors include positivity for ACPA or RF, increased ESR or CRP, radiological evidence of

erosion or progression of erosions.

II B

5. All patients with recently diagnosed RA or active disease should be monitored for disease activity every 1

to 3 months.

I A

6. A suitable and practical standardized measure of disease activity should be routinely performed to assess

patients’ response to treatment.

I A

7. Safety monitoring while patients are on bDMARD therapy is likewise recommended. II B

8. All patients should be assessed clinically at presentation for extra-articular disease manifestations,

comorbidities, and infections such as TB and hepatitis (II). Information on vaccination status and

special situations such as pregnancy and lactation should be obtained (II).

II B

9. If patients show persistent remission for 6 months, treatment with corticosteroids and NSAIDs may be

tapered, with the aim of eventually stopping these treatments.

II B

10. If a patient is in sustained remission for more than 6 to 12 months after discontinuation of NSAIDs,

corticosteroids and bDMARDs, then a gradual reduction in cDMARDs can be attempted with caution, as

a shared decision between the patient and physician.

IV D

Section 2 – Role of NSAIDs (including COX-2 inhibitors)

11. NSAIDs and COX-2 inhibitors should be used at the lowest effective dose for the shortest possible period

of time.

IV D

Section 3 – Role of corticosteroids

12. Oral corticosteroid monotherapy is not recommended. IV D

13. Oral corticosteroids can be considered to control active RA in combination with cDMARDs. I A

14. In early RA, the addition of low-dose corticosteroids (prednisolone ≤ 7.5 mg/day) to cDMARDs leads to

a reduction in radiographic progression.

I A

15. Corticosteroids should be used in the lowest possible dose and tapered as rapidly as clinically feasible. IV D

Section 4 – Role of conventional DMARDs

16. Treatment with cDMARDs as monotherapy or in combination should be started as soon as the diagnosis

of RA is made.

I A

17. Methotrexate is the first-line cDMARD for RA patients, and is considered as the “anchor drug”. I A

18. Patients who cannot tolerate methotrexate may receive other cDMARDs such as leflunomide,

sulfasalazine and hydroxychloroquine as first-line treatments.

I A

Bucillamine, iguratimod, cyclosporin, azathioprine, IM gold or tacrolimus may also be considered in

some AP countries.

I B

19. Pretreatment investigations: complete blood count, liver function and renal function tests, viral hepatitis

serology and chest radiograph should be ordered prior to initiating methotrexate therapy.

II B

20. Combination cDMARD therapy should be considered in active RA patients, particularly those with poor

prognostic factors.

I B

21. Combination cDMARD therapy should include methotrexate as the anchor drug unless methotrexate is

contraindicated.

II B

22. Triple therapy with cDMARDs is an effective option in patients who show inadequate response to

methotrexate monotherapy.

II B

23. Patients should be assessed every 1 to 3 months after the initial treatment or change of regimen until

the disease is stabilized, in remission or in low disease activity state.

I A

24. Patients who have been stabilized or are in remission or low disease activity can be monitored every 3 to

6 months.

IV D




Successful management of patients with RA depends

upon empowering the patients with the knowledge

about the chronic and fluctuating course of the disease,

treatment goal31 and, particularly, about the possible

evolution and prognosis,24 including side effects, costs

of the drugs and the continuous need of physiother-

apy.22 Offering verbal and written information to

Table 3 (continued)

Recommendations Level Strength

25. Definition of treatment failure: Inadequate response with cDMARDs is defined as failure to achieve

remission or low disease activity after a therapeutic trial of at least two standard cDMARDs in

combination at optimal doses for 6 months (I). One of the failed cDMARDs must be methotrexate

unless methotrexate is contraindicated (I).

I A

Section 5 – Role of bDMARDs

26. A bDMARD can be prescribed in patients who have inadequate response or intolerance to cDMARDs. I A

27. Early bDMARD use can be considered in patients who have active disease with poor prognostic factors. IV D

28. Prior to starting treatment with bDMARDs, history regarding active or current infections, comorbidities

including tumors and malignancies, vaccinations, pregnancy, and possible contraindications should be

obtained in all patients.

I A

29. All patients should be screened for TB, and HBV and HCV infections before initiating bDMARD therapy. I A

30. Live vaccines should be given at least 4 weeks prior to bDMARD administration. III–IV C–D31. Monotherapy or combination with methotrexate/cDMARDs: bDMARDs are most effective when

combined with methotrexate.

I A

32. In patients with RA who are candidates for bDMARD therapy, the therapeutic options include TNF

antagonists, abatacept, rituximab and tocilizumab.

I A

33. Patients who fail to achieve remission or low disease activity after 6 months of bDMARD therapy are

recommended to switch to another bDMARD agent.

III C

34. Dose reduction

In patients who have achieved remission, a reduction in treatment should be considered. I A

If the patient remains in extended remission (> 12 months), tapering of bDMARDs can be considered. II B

35. Infectious complications: TB

Screening for TB is recommended prior to starting bDMARD therapy. II B

All patients with latent TB infection should receive prophylactic anti-TB therapy. II B

Patients with active TB infection need to be adequately treated before consideration of bDMARD

treatment.

III C

36. Infectious complications: hepatitis

Patients should be screened for HBV and HCV infections prior to the commencement of bDMARDs. IV D

bDMARDs should be avoided in patients with active or untreated chronic HBV infection and active

HCV infection.

III C

37. Active infections

Active infections are contraindications for bDMARDs. I A

When an infection is suspected, based on clinical judgement, the bDMARD agent should be stopped

and the patient must be treated appropriately.

IV D

38. Pregnancy and lactation while on bDMARDs should only be considered after thorough assessment of

benefits and risks.

IV D

39. Vaccination

Administration of all vaccines, if indicated, should, ideally, be undertaken at least 4 weeks before

starting a bDMARD.

III–IV C–D

Concurrent administration of live, attenuated vaccines is an absolute contraindication for patients

being treated with bDMARDs.

IV D

Section 6 – Role of tofacitinib

40. Tofacitinib may be considered if a bDMARD has failed II B

ACPA, anti-citrullinated peptide antibodies; AP, Asia-Pacific; bDMARD, biological DMARD; COX-2 inhibitors, cyclooxygenase-2 inhibitors;cDMARD, conventional DMARD; CRP, C-reactive protein; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate;HBV, hepatitis B virus; HCV, hepatitis C virus; IM, intramuscular; NSAID, non-steroidal anti-inflammatory drug; RA, rheumatoid arthritis; RF,rheumatoid factor; TB, tuberculosis; TNF, tumor necrosis factor.


C. S. Lau et al.

(a)

(b)

Figure 2 (a) Algorithm summarizing the recommendations for treatment of patients with RA in the AP region. *Poor prognosticmarkers include positivity for ACPA or RF, increased ESR or CRP, radiological evidence of erosion or progression of erosions.ACPA, anti-cyclic citrullinated peptide antibody; CRP, C-reactive protein; DMARD, disease-modifying antirheumatic drug; ESR,erythrocyte sedimentation rate; HCV, hepatitis C virus; LDA, low disease activity; MTX, methotrexate; RA, rheumatoid arthritis; RF,rheumatoid factor; TB, tuberculosis. (b) Algorithm summarizing the recommendations for treatment of patients with RA in the APregion (continued). DMARD, disease-modifying antirheumatic drug; LDA, low disease activity; MTX, methotrexate.



people with RA will improve their understanding of the

condition and its management, and counter any mis-

conceptions they may have.32

Early treatment could improve the outcome of RA.23,29

Treatment with traditional DMARDs with or without low

dose glucorticoids should be considered as soon as the

diagnosis of RA is made17,24,25,32 to increase clinical

response and decrease radiographic progression.


Early treatment of RA in this region may not be possible

in some countries with poor economic status due to an

inefficient referral system and a shortage of rheumatolo-

gists. The Steering Committee would, therefore, like to

reinforce that this recommendation is aimed not only

for rheumatologists but any clinicians who participate

in the care of patients with RA. For many countries in

the AP region, improving the knowledge of general clin-

icians of RA and its treatment is of utmost importance.

Recommendation 3. The choice of treatment is basedon the findings of active disease and/or poor progno-sis and comorbidities. (Level II; Strength B)

Supporting evidence

References 17, 18, 21–24 and 27–29.


The presence of poor prognostic features should be

assessed at baseline and considered when making treat-

ment decisions. These include high disease activity

state, (high number of swollen and tender joints, ele-

vated erythrocyte sedimentation rate [ESR] or C-reactive

protein [CRP]), rheumatoid factor (RF) positivity, anti-

cyclic citrullinated peptide antibody (ACPA) positivity,

and early presence of joint damage,17,18,21–24,28,29 extra-

articular features (e.g., presence of rheumatoid nodules,

vasculitis, Felty’s syndrome) and functional limitation

as measured by the Health Assessment Questionnaire

Disability Index (HAQ-DI).18,23,28


Most RA patients in the AP region present late with it

and many would have developed erosive disease. Bas-

ing radiological erosions solely as an indication for

aggressive treatment may lead to over-treatment for

some patients. Therefore, other markers of high dis-

ease activity and poor prognosis may be more appro-

priate indications for intensive DMARD treatment.

Recommendation 4. Poor prognostic factors includepositivity for ACPA or RF, increased ESR or CRP, radi-ological evidence of erosion or progression of ero-sions. (Level II; Strength B)

Supporting evidence

References 17, 18, 21–24, 28, 29 and 34.


Refer to Recommendation 3 above.


In addition to comments made under Recommenda-

tion 3 above, clinicians should be aware of the wide-

spread misuse of corticosteroid agents, many of which

may be purchased over the counter or from a quack in

the AP region, which may mask some of these poor

prognostic factors.

Recommendation 5. All patients with recently diag-nosed RA or active disease should be monitoredfor disease activity every 1 to 3 months. (Level I;Strength A)

Supporting evidence

References 18–20, 22, 24, 28, 32–37.


At the beginning of RA treatment, especially in patients

with high/moderate disease activity, the patient should

preferably be assessed every month.19,20,24 The fre-

quency of monitoring in patients with active RA should

be 1 to 3 months,22,28,32–37 aiming to achieve remis-

sion by 6 months33 when the interval for monitoring

may be between 3 to 6 months, depending on the

degree of disease activity.18


Lack of resources in many countries in the AP region is

a major obstacle for frequent monitoring of RA disease

activity and treatment. Rheumatologists may need the

assistance of general clinicians and allied health work-

ers in the monitoring process, as well as a patient self-

reporting system. The development of a good allied

health worker and patient education program is of

utmost importance in the overall management of

patients with RA in this region.

Recommendation 6. A suitable and practical standard-ized measure of disease activity should be routinely


C. S. Lau et al.

performed to assess patients response to treatment.(Level I; Strength A)

Supporting evidence

References 17–19, 21–24, 26–28, 32, 34–36 and 38–42.


Most guidelines recommend the use of a validated com-

posite score such as DAS28, SDAI and CDAI for mea-

suring disease activity before starting treatment, and for

monitoring disease activity and drug response after

starting treatment.17,18,21–24,26–28,32,35,36,38–42 In addi-

tion, some guidelines recommend using the Health

Assessment Questionnaire (HAQ) for evaluating the

functional impact of the disease.21,32,36,41 The French

guidelines also recommend anteroposterior X-rays of

the hands, wrist and forefeet to monitor the course of

RA; this may be done every 6 months until the end of

the first year, then once every year until end of the third

year, and thereafter every 2 to 4 years.42


Regular measurement of serum CRP may not be afford-

able in many AP countries. Rheumatologists from these

countries are recommended to use ESR instead; other-

wise, clinical activity measurement without ESR, for

example, CDAI, should be used in patient monitoring.

Recommendation 7. All patients should be assessedclinically at presentation for extra-articular diseasemanifestations, comorbidities and infections, such asTB and hepatitis (Level II; Strength B). Informationon vaccination status and special situations such aspregnancy and lactation should be obtained (Level II;Strength B)

Supporting evidence

References 18, 22–24, 29, 31, 33–35, 37, 38 and 43–59.


Given that RA is a systemic disease accompanied with

not only joint dysfunction but also other comorbidities

(such as cardiovascular disease and osteoporosis), extra-

articular manifestations (such as pericarditis, pleuritis

and vasculitis), and an increased risk of infections,32 it is

recommended to evaluate and screen patients for these

conditions before initiating treatment with DMARDs,

NSAIDs or corticosteroids.18,22–24,29,31,33–35,37,38,43–59

As most drugs used in the treatment of RA are con-

traindicated during pregnancy and breastfeeding, it is

recommended to rule out these situations before initiat-

ing treatment.24,31,33–35,37,38,48,52–54,58 Before starting

cDMARDs or bDMARDs, patients’ vaccination status

should be assessed and updated, and all killed, recom-

binant and live attenuated vaccinations under-

taken.18,24,31,33,37,38,46,53,54,56


No region-specific comments.

Recommendation 8. Safety monitoring while patientsare on bDMARD therapy is likewise recommended.(Level II; Strength B)

Supporting evidence

References 18, 22, 23, 32, 34, 35, 37, 43–47 and 60.


Treatment with bDMARDs, particularly TNF inhibitors,

is associated with an increased risk of certain infections,

including TB, as well as that of non-Hodgkin’s lym-

phoma and congestive heart failure.43,44 Thus, many

guidelines recommend screening for active and latent

TB before starting bDMARDs,18,22,23,34–37,43–47 and per-

forming baseline hepatitis serology as well as other

investigations, including a complete blood picture, liver

function tests, serum urea and creatinine levels and

antinuclear antibody status, and to rule out presence of

active and latent infections and other comorbidities.

Furthermore, continuous monitoring for these condi-

tions and side effects is also emphasized during

bDMARD therapy.18,22,23,32,34,35,37,43–47,60


It is especially important to monitor for the emergence

of infective complications. Clinicians should be on the

alert for not only TB and hepatitis infections but all

other opportunistic infections, including fungal and

parasitic infections.

Recommendation 9. Once the patient has improvedsymptomatically, treatment with corticosteroids andNSAIDs may be tapered, with the aim of eventuallystopping these treatments. (Level II; Strength B)

Supporting evidence

References 17, 21, 22, 24–26, 28, 29, 32, 55, 57, 61 and

62.


While NSAIDs in combination with DMARDs are

effective in controlling pain and inflammation in RA,



long-term use is not recommended as these drugs are

associated with significant gastrointestinal, cardiovascu-

lar and renal adverse effects.21,22,24,55,57,61 Furthermore,

these agents have not demonstrated any efficacy in

modifying the disease course.57 Corticosteroids, in

combination with DMARDs, are effective in limiting

disease progression, and are particularly effective in

decreasing inflammation in patients with flares and

improving symptom control in those with early dis-

ease.59 However, given the toxicity with long-term use,

it is recommended to taper therapy as symptoms

improve and discontinue completely once patients

achieve remission.17,21,22,24–26,28,29,32,55,57,61,62


Clinicians should be aware of over-the-counter and

quack-provided corticosteroid preparations, and their

use must be discouraged.

Recommendation 10. If a patient is in sustained remis-sion for more than 6 to 12 months after discontinua-tion of NSAIDs, corticosteroids and bDMARDs, thena gradual reduction in cDMARDs can be attemptedwith caution, as a shared decision between thepatient and physician. (Level IV; Strength D)

Supporting evidence

References 17, 21, 22, 25, 26, 28, 32 and 55.


Duration of remission is required for more than

1 year in the Indian 2008 guidelines,22 6–12 months

in the 2013 Brazilian guidelines26 and over

6 months in the German 2013 guidelines.25 The

suggested sequence of drug withdrawal is NSAID,

corticosteroid, bDMARD and then cDMARD.26,28 The

reduction in treatment should be performed cau-

tiously, gradually and in a stepwise manner. A

shared decision must be reached between the patient

and physician in this regard.17,25,28 According to the

BeST study, sustained remission was defined as

DAS < 1.6 for more than 6 months. According to

the Indian guidelines, a minimum maintenance dose

will be required for an indefinite period.22 The Bri-

tish Society for Rheumatology and British Health

Professionals in Rheumatology (BSR-BHPR) guideli-

nes warn about the frequent association of with-

drawal with flare and disease progression.55 The

2013 Brazilian guidelines describe withdrawal of

cDMARD in exceptional situations.26


Because of the poor affordability of bDMARDs for

most patients in this region, patients may rely more

on cDMARDs for disease control. Thus, we recom-

mend primarily cautious dose reduction but not

complete cessation of cDMARDs for the majority of

patients.

Section 2 – Role of NSAIDs (including cyclo-oxygenase-2

inhibitors)

Recommendation 11. NSAIDs and COX-2 inhibitorsshould be used at the lowest effective dose forthe shortest possible period of time. (Level IV;Strength D)

Supporting evidence

References 29, 32 and 55.

Summary of evidence linked to recommendation

The National Institute for Health and Care Excellence

(NICE) 2009 guidelines reviewed data from several

studies to show that NSAIDs and COX-2 inhibitors

were effective in treating the symptoms of RA and

recommended that oral NSAIDs/COX-2 inhibitors be

used in the lowest effective dose over the shortest

period of time; it is advisable to use NSAIDs as

needed.32 However, no optimum dose was proposed.

The BSR 2006 and 2009 guidelines emphasized that

long-term use of NSAIDs should be at the lowest

effective dose and are best avoided because of the

associated risks.29,55

NSAIDS and COX-2 inhibitors, undoubtedly, are effi-

cacious in controlling RA symptoms, but their gastroin-

testinal, cardiovascular and renal adverse effects are a

matter of serious concern. A balanced approach should

be undertaken whereby the benefits are weighed against

the possible adverse effects.


In the AP region, there is a general lack of awareness

among patients and clinicians of the adverse effects

associated with long-term NSAID use. Since NSAID use

can mask symptoms by reducing inflammation,32,61 it

can obscure RA progression and often delays referral

from general practitioners. Availability of NSAIDs over

the counter in many Asian countries also poses a signifi-

cant challenge. Clearly, therefore, educating the public

and allied healthcare workers is an important priority

concern in this region.


C. S. Lau et al.

Section 3 – Role of corticosteroids

Recommendation 12. Oral corticosteroid monotherapyis not recommended. (Level IV; Strength D)

Supporting evidence

References 17, 21, 22, 25, 28, 32, 57, 62 and 63.


Advice from a rheumatologist must be obtained before

treatment initiation with oral corticosteroids.62 The

Latin American guidelines do not recommend corticos-

teroids as a sole disease-modifying agent.57 The EULAR

2013 guidelines state that monotherapy is not specifi-

cally recommended and should only be used in excep-

tional cases when all other DMARDs are

contraindicated.17 Other guidelines advise corticos-

teroid usage in combination with DMARDs.25,62


The use of corticosteroids in Asia poses particular risks.

There is a widespread practice of self-medication as a

result of ineffective control of the sales of prescription

medications, leading to inappropriate use of corticos-

teroid agents.57 Misuse of corticosteroids among clini-

cians in some AP countries is also widespread. It is,

therefore, recommended that patients with suspected

RA be assessed by a practitioner experienced in dealing

with RA and not be put on corticosteroid monotherapy

without a firm indication.

Recommendation 13. Oral corticosteroids can be con-sidered to control active RA in combination withcDMARDs. (Level I; Strength A)

Supporting evidence

References 17, 21, 22, 25, 28, 32, 57, 62 and 63.


Low-dose corticosteroids can be considered as part of

the initial treatment strategy (in combination with

one or more cDMARDs) for up to 6 months, but

should be tapered as rapidly as clinically feasible.17

Short-term treatment with corticosteroids should be

offered for managing flares in patients with recent-

onset or established disease, to rapidly decrease

inflammation.28,32

For polyarticular flares, or at first presentation of the

disease, intramuscular/intra-articular, or short oral

courses of corticosteroids can decrease symptoms while

waiting for other slower-acting drugs to take effect; this

is described as “bridging therapy”.17,22,23,25,32,57,62,63

Intra-articular injections are extremely useful for treat-

ing a flare in one or only a few joints.22,28,32 Injection

into the same joint should not be repeated before

3 months, and it is advised that no more than three

injections be administered per joint per year.22

For severe extra-articular manifestations, intravenous

corticosteroids can save critical organs (e.g., eyes in scle-

ritis) or, occasionally, even life-threatening complica-

tions (e.g., severe serositis or vasculitis); however,

corticosteroids should be used in combination with

immunosuppressive agents such as cyclophos-

phamide.32

In people with established RA, only continue

long-term treatment with corticosteroids when: (a)

the long-term complications of corticosteroid therapy

have been fully discussed; and (b) all other treat-

ment options (including bDMARDs) have been

offered.32



Recommendation 14. In early RA, the addition of low-dose corticosteroids (prednisolone ≤ 7.5 mg/day) tocDMARDs leads to a reduction in radiographic pro-gression. (Level I; Strength A)

Supporting evidence

References 17, 21, 22, 25, 28, 32, 57, 62 and 63.


The EULAR 2010, Latin American and NICE guidelines

discuss the evidence that low-dose prednisolone

(< 7.5 mg daily) in patients with early RA does reduce

radiographic progression over 2 years.32,57,63 According

to the European Standing Committee for International

Clinical Studies Including Therapeutics (ESCISIT) 2007

guidelines, corticosteroids are “probably effective in

slowing radiographic progression in early and estab-

lished RA”.21



Recommendation 15. Corticosteroids should be usedin the lowest possible dose and tapered as rapidly asclinically feasible. (Level IV; Strength D)

Supporting evidence

References 17, 21, 22, 25, 28, 32, 57, 62 and 63.




It is recommended to keep the requirement for con-

tinuing corticosteroid treatment under constant

review, and titrate the dose against therapeutic

response, risk of under-treatment and development

of adverse events.17 However, the panel could not

recommend an optimal tapering strategy based on

the existing evidence. The Canadian 2012 and Ger-

man 2013 guidelines recommend that corticosteroids

should be used at the lowest possible dose and

tapered as rapidly as possible.25,28 In contrast, the

EULAR 2010 guidelines recommend slow tapering to

avoid clinical relapses.63

Special comment/recommendation for the Asia-Pacific region

This recommendation is particularly relevant in the AP

region due to the widespread misuse of corticosteroids

in some countries as stated above.

Section 4 – Role of cDMARDs

Recommendation 16. Treatment with cDMARDs asmonotherapy or in combination should be started assoon as the diagnosis of RA is made. (Level I;Strength A)

Supporting evidence

References 17, 18, 21–26, 28, 29 and 57.


Most of the guidelines recommend starting cDMARDs

as soon as possible once the diagnosis of RA is con-

firmed;17,23,25,28,29,57 treatment should not be delayed

by more than 3 months.23 The ACR–EULAR 2010 clas-

sification criteria should be used to confirm diagnosis

of RA and facilitate early introduction of effective ther-

apy in RA. In patients with undifferentiated arthritis,

the use of cDMARDs can be considered,26 but in

patients at risk of developing persistent and/or erosive

arthritis, treatment with cDMARDs should be started as

early as possible even if they do not fulfil the diagnostic

criteria.21 In patients with early RA, cDMARD

monotherapy is recommended in low and moderate

disease activity, or high disease activity without poor

prognostic markers.


Delay in initiating cDMARD treatment for patients with

RA in the AP region remains a major concern, primarily

due to delay in the diagnosis of the underlying condi-

tion. Much work is needed to enhance public and clini-

cian awareness of RA and its treatment.

Recommendation 17. Methotrexate is the first-linecDMARD for RA patients, and is considered as the an-chor drug. (Level I; Strength A)

Supporting evidence

References 17, 21–29 and 57.


Methotrexate is the preferred cDMARD with respect

to efficacy and safety and should be the first

cDMARD used in RA unless contraindicated;17,24–26,28

it is described as the “anchor drug”21,22,27 or “drug

of choice”.24,57 DMARD-naive patients should be

started on methotrexate monotherapy, and treatment

should be given for a duration of no less than

3 months at the maximally tolerated dose.23 Choice

of the first agent is based on the risk : benefit ratio

with hydroxychloroquine an option in disease per-

ceived as mild, and methotrexate or sulfasalazine in

diseases adjudged moderate-to-severe, or likely to

progress.29


Methotrexate used to be a taboo and thought to be

excessively hepatotoxic in many AP countries. However,

the efficacy and safety of this agent is now well estab-

lished and methotrexate should be used unless con-

traindicated or there is poor tolerance.

Recommendation 18. Patients who cannot toleratemethotrexate may receive other cDMARDs such asleflunomide, sulfasalazine and hydroxychloroquineas first-line treatment (Level I; Strength A). Bucil-lamine, iguratimod, cyclosporin, azathioprine, intra-muscular gold or tacrolimus may also be consideredin some AP countries. (Level I; Strength B)

Supporting evidence

References 17, 23–26, 57 and 64–68.


Patients without poor prognostic factors (i.e., with no

erosions, are RF-negative, with low CRP levels, or with

low disease activity) or those who cannot tolerate

methotrexate may receive other cDMARDs, such as

leflunomide, sulfasalazine, hydroxychloroquine or

injectable gold.23 The antimalarials hydroxychloro-

quine and chloroquine are less effective and should be


C. S. Lau et al.

reserved for mild disease forms and diseases with low

erosive potential.24


In many Asian countries, chloroquine may be recom-

mended and is preferred to hydroxychloroquine or

other cDMARDs due to its low treatment cost and high

availability. In some AP countries, cDMARDs such as

bucillamine and iguratimod, which are not available in

Western countries, are widely used. Though these drugs

have not been thoroughly evaluated outside their coun-

tries of origin, they have undergone rigorous testing

locally and may also be the cDMARDs of choice for RA

in the respective countries. For example, the efficacy of

bucillamine can be judged within 3 months in moder-

ately active RA patients either before or after methotrex-

ate treatment.64 Iguratimod is non-inferior in active RA

patients when compared to methotrexate65 or salazo-

sulfapyridine.66 Tacrolimus improves RA symptoms in

patients with RA inadequately controlled with at least

one prior cDMARD67 and is well tolerated.68

Recommendation 19. Pre-treatment investigations:complete blood count, liver function and renal func-tion tests, viral hepatitis serology and chest radio-graph should be ordered prior to initiatingmethotrexate therapy (Level II; Strength B).

Supporting evidence

References 22, 23 and 57.


Pre-treatment investigations prior to initiating

methotrexate should include complete blood count

(CBC), liver function test (LFT) and renal function test

(RFT), hepatitis B and C serology and chest X-

ray.22,23,57 Other guidelines also consider screening for

risk factors for cardiovascular diseases and osteoporo-

sis,23 and human immunodeficiency virus (HIV) in

high-risk patients.28 The pre-treatment investigations

for other cDMARDs are: eye examination (funduscopy

and perimetry) for antimalarials; and CBC, RFT and

LFT for leflunomide, sulfasalazine, cyclosporine, and

azathioprine. Blood pressure and serum creatinine

should also be measured prior to initiating leflunomide

and cyclosporine.22


The high prevalence of hepatitis and TB in the AP

region provides the rationale for recommending the

pre-treatment investigations described above before

starting methotrexate treatment.

Recommendation 20. Combination cDMARD therapyshould be considered in patients with active RA, par-ticularly those with poor prognostic factors. (Level I;Strength B)

Supporting evidence

References 17, 18, 23–25 and 28.


If, after 3 months of cDMARD monotherapy (in

patients without poor prognostic features), a patient

deteriorates from low to moderate/high disease activ-

ity, then methotrexate, hydroxychloroquine or

leflunomide should be added.18 A combination of

cDMARDs (including double or triple therapy) may

be considered in patients with very serious disease

and poor prognostic factors.17,18,23–25,28 Patients with

suboptimal treatment response should receive step-

up therapy with combination therapy of methotrex-

ate plus another agent (leflunomide, sulfasalazine,

hydroxychloroquine).23 Initial combination therapy

with cDMARDs may also be considered, particularly

in patients with poor prognostic features, moderate-

to-high disease activity, and patients with recent-on-

set disease.


Long-term treatment compliance with mono- or combi-

nation cDMARD therapy is a challenge in many AP

countries. This may be related to the cost of treatment,

anxiety about drug side effects and the need for regular

monitoring. Patients should be educated about the dis-

ease and the need for uninterrupted treatment. Clini-

cians should explore this possibility and patients

should also be reassured of the safety of the prescribed

drugs, and encouraged to have adequate trials of

cDMARD monotherapy before escalation to combina-

tion cDMARD therapy.

Recommendation 21. Combination cDMARD therapyshould include methotrexate as the anchor drugunless methotrexate is contraindicated. (Level II;Strength B)

Supporting evidence

References 17, 18, 21–26, 28, 32 and 57.




Most guidelines recommend methotrexate as the anchor

drug unless it is contraindicated.17,18,21–24,26,28,57

Although direct comparisons between different regimens

are lacking, combination cDMARD therapies, including

methotrexate, have been proven to be superior to

cDMARD monotherapy. Other combinations without

methotrexate are not sufficiently evaluated. On the basis

of guideline review, the panel recommends methotrexate

combination therapy in patients who have inadequate

response to methotrexate monotherapy.

The most commonly used cDMARDs in combina-

tion with methotrexate are hydroxychloroquine, sul-

fasalazine or their concurrent use. Leflunomide has

also been studied in association with methotrexate.

However, methotrexate combined with leflunomide

should be cautiously used because of higher toxic-

ity.69,70 Methotrexate-based combination therapies

with azathioprine, cyclosporine A and intramuscular

gold have been evaluated in at least one random-

ized controlled trial. The details of the regimens are

listed in the ACR 2008, NICE 2009 and EULAR

guidelines and a meta-analysis by Katchamart

et al.32,69,71–73


As described above, cDMARDs available for treatment

of RA extend to bucillamine, iguratimod and tacrolimus

in certain AP countries. However, the use of these drugs

combined with methotrexate or as an anchor drug in

combination regimens has not been extensively studied

and requires further evaluation.

Recommendation 22. Triple therapy with cDMARDs isan effective option in patients who show inadequateresponse to methotrexate monotherapy. (Level II;Strength B)

Supporting evidence

References 17, 18, 21–26, 28, 32 and 57.


All the reviewed guidelines recommend changing regi-

men in patients who fail methotrexate monother-

apy.17,18,21–26,28,32,57 The options include switching

among cDMARDs and switching from cDMARDs to

bDMARD agents. Combination cDMARD therapy can

be an effective alternative to bDMARD therapy. In

methotrexate-inadequate responders, methotrexate

combination with one or two kinds of other cDMARDs

was proven to be superior to methotrexate monother-

apy.73 More recent data showed that triple therapy with

cDMARDs had similar efficacy with bDMARD ther-

apy.74–76 Although most recommendations did not

specify the mandatory application of triple cDMARDs

after methotrexate failure, current evidence suggests that

triple therapy with cDMARDs may be able to substitute

for bDMARD therapy.

The TACIT trial, which was published since the cur-

rent consensus was reached, showed combination

methotrexate and leflunomide was an equally effective

regimen as methotrexate plus a TNF inhibitor.77 This

combination may also be considered as an alternative

for triple combination cDMARDs.


Because of the high cost and limited availability of

bDMARDs in many AP countries, the panel recom-

mends triple cDMARD therapy as an effective

option for patients with inadequate response to

methotrexate.

Recommendation 23. Patients should be assessedevery 1 to 3 months after the initial treatment orchange of regimen until the disease is stabilized, inremission or in low disease activity state. (Level I;Strength A)

Supporting evidence

References 17–19, 21, 24–26, 28, 32 and 72.


One systematic review of trials on strategy-driven

treatment approaches in RA concluded that intensive

steering (treatment target, follow up method) and

intensive medication strategies in early active RA pro-

duces a better clinical outcome, improved physical

function and less structural damage.78

Early-stage active RA can be monitored

monthly.19,24,26,31 Radiographs of joints are recom-

mended as frequently as every 6 to 12 months during

the first few years21,28 or annually19 to estimate poten-

tial progression of joint damage.


The shortage of rheumatologists in many AP coun-

tries represents a major hurdle to the frequent moni-

toring of RA patients. As indicated earlier, an

effective educational program for patients and other

healthcare providers, including general practitioners

and allied health workers, is urgently needed in

many AP countries.


C. S. Lau et al.

Recommendation 24. Patients who have been stabi-lized or are in remission or low disease activitycan be monitored every 3 to 6 months. (Level IV;Strength D)

Supporting evidence

References 17, 19, 24, 26, 28, 32 and 55.


Most guidelines agree that monitoring can be less fre-

quent once the treatment target has been stabilized.

However, the suggested monitoring intervals are vari-

able and may only represent the compromise of

expert opinion (IV, D). According to the Canadian

guidelines, patients in remission can be monitored at

longer intervals without further specification.28 The

Brazilian guidelines suggest monitoring every

3 months for controlled disease.25,26 The treat-to-tar-

get guidelines consider less frequent monitoring such

as every 3 to 6 months for patients in sustained, low

disease activity or remission.19 The EULAR 2013

guidelines propose monitoring every 6 to 12 months

once the treatment target has been stabilized.17 The

BSR-BHPR 2009 and NICE guidelines recommend

annual review.32,55



Recommendation 25. Definition of treatment failure:inadequate response with cDMARDs is defined asfailure to achieve remission or low disease activityafter a therapeutic trial of at least two standardcDMARDs in combination at optimal doses for6 months (Level I; Strength A). One of the failedcDMARDs must be methotrexate unless methotrex-ate is contraindicated. (Level I; Strength A)Supporting evidence

References 17, 18, 21–26, 28, 32, 34, 35, 52 and 57.


Six guidelines define treatment target as remission or

low disease activity; thus, any other status would be

inadequate response/treatment failure.18,24–26,28,57

Three guidelines define target as remission.17,21,23 The

required treatment usually includes at least methotrex-

ate monotherapy unless not tolerated;18,28,34,35 or in

combination with another cDMARD.17,18,22–

24,26,28,32,48,52 The treatment duration, at a standard tar-

get dose, may be at least 3 months18,23,28,34,35,48,57 or

6 months.17,22,23,26,31,52



Section 5 – Role of bDMARDs

Recommendation 26. A bDMARD can be prescribed inpatients who have inadequate response or intoler-ance to cDMARDs. (Level I; Strength A)

Supporting evidence

References 17, 18, 22, 23, 25, 26, 28, 31, 33–36, 38, 39,48–51, 53, 54, 56–58 and 79.


The BSR 2010 guidelines recommend starting a TNF

inhibitor in those who have active RA and have

inadequate response to cDMARDs.39 Inadequate

response is defined as DAS28 > 3.2 with ≥ 3 tender

and swollen joint counts, and being treated with at

least two cDMARDs (one should be methotrexate

unless contraindicated) in combination over a 6-

month period, and at a standard dose for at least

2 months, unless a significant toxicity occurs and

limits the dose and duration of treatment. Rituximab

(anti-CD20) should be prescribed in a patient who

has inadequate response or intolerance to at least

one TNF inhibitor,58 and still has active disease

defined by DAS28 ≥ 3.2 or SDAI > 11 or similar

indices. Tocilizumab (anti-IL-6) is recommended for

those who have moderate or severe disease activity,

according to a validated composite measure, and

have had inadequate response or intolerance to at

least one cDMARD or TNF inhibitor. Abatacept

(CTLA-4Ig) is recommended for those who have

moderate or severe disease activity, according to a

validated composite measure, and have had inade-

quate response or intolerance to at least one

cDMARD or TNF inhibitor.


As has been stated above, as a result of the high cost

and limited availability of bDMARDs in many AP coun-

tries, triple cDMARD combination therapy may be con-

sidered for patients in whom bDMARDs are indicated.

Recommendation 27. Early bDMARD use can be con-sidered in patients who have active disease with poorprognostic factors. (Level IV; Strength D)

Supporting evidence

Reference 18.




In 2012, the ACR suggested that TNF inhibitors,

with or without methotrexate, may be considered in

patients with early RA (duration < 6 months) and

high disease activity and poor prognostic features.

This recommendation is based on expert opinion as

the data on the use of TNF inhibitors in early RA

patients with active disease and poor prognostic fac-

tors are limited.18


Once again, for countries with poor socioeconomic

status and where the reimbursement system is inade-

quate, combination cDMARD therapies, including triple

therapy, may be considered for these patients instead.

Recommendation 28. Prior to starting treatment withbDMARDs, history regarding active or current infec-tions, comorbidities including tumors and malignan-cies, vaccinations, pregnancy, and possiblecontraindications should be obtained in all patients.(Level I; Strength A)

Supporting evidence

References 18, 21, 22, 24, 26, 31, 33, 35, 38, 46, 48–50,53, 54, 56 and 57.


Reports on the risk of serious infections and the devel-

opment of malignancies in RA patients receiving

bDMARD therapy, particularly TNF inhibitors, showed

conflicting results. A meta-analysis showed the use of

TNF inhibitors is associated with increased risk of seri-

ous infections,80,81 but another meta-analysis could not

confirm this finding.82

A meta-analysis of randomized controlled trials

found that the point estimate of malignancy risk was

higher in etanercept-treated patients than in controls,83

but two recent meta-analyses failed to confirm these

findings.84,85

Regarding pregnancy, data from the BSR Biologics

Register found that the incidence of spontaneous loss

among those who were prior exposed to TNF inhibitors

was higher than in controls (17% vs. 10%), but without

risk of significant congenital abnormalities. Neverthe-

less, they recommended that pregnancy be avoided dur-

ing anti-TNF therapy.86

A study on the effect of high-dose TNF inhibitor (in-

fliximab) showed a detrimental effect on congestive

heart failure;87 however, two recent studies could not

confirm this finding.88,89

Rituximab may be used in RA patients with lym-

phoma46 and should be avoided in those with

hypogammaglobulinemia or low CD4 counts.56 Tocili-

zumab should be avoided in those with a history of

bowel perforation.24,33,48


It is of particular importance that clinicians have a high

level of alertness of pre-existing infectious diseases,

including uncommon infections, and other comorbidi-

ties in AP patients receiving bDMARDs because of dif-

ferences in the pattern and frequency of occurrence of

these conditions in this region.

Recommendation 29. All patients should be screenedfor TB, and hepatitis B and C virus infections beforeinitiating bDMARD therapy. (Level I; Strength A)

Supporting evidence

References 18, 22–24, 28, 31, 33, 34, 38, 43, 46, 48–50,52–54 and 56–58.


Overall, 22 studies recommended screening for infec-

tions that included TB, HBV and HCV infections prior

to starting bDMARD therapy.18,22–24,28,31,33,34,38,43,46,

48–50,52–54,56–58 In Japan, testing for beta D-glucan is

also recommended prior to initiating TNF inhibitors

and tocilizumab (anti-IL-6).48,49


The AP region is endemic for TB. Therefore, active and

latent TB should be evaluated and treated properly,

according to each individual country guideline, prior to

commencement of bDMARDs.

Recommendation 30. Live vaccines should be given atleast 4 weeks prior to administration of bDMARDagents. (Level III–IV; Strength C–D)

Supporting Evidence

References 18, 22–24, 31, 33–35, 37, 38, 43, 46, 48, 52,55, 56 and 58.


Patients who are immunocompromised are at risk of

disseminated infection with live attenuated vaccines.

All guidelines reviewed emphasized that concurrent

administration of live attenuated vaccines was not rec-

ommended in patients receiving bDMARDs. Most

guidelines agree that live attenuated vaccines should be,

ideally, given 4 weeks prior to initiation of bDMARDs


C. S. Lau et al.

but the level of evidence for this remained low (Level

IV).

Patients already on bDMARDs who require live

vaccines should only receive it 6 months after the

last infusion of infliximab or 23 weeks after the last

dose of etanercept.22,46,52 There was no guidance on

how long to discontinue other bDMARD agents,

although the Canadian guidelines recommend that

the timing for withholding/restarting therapy should

be based on the pharmacokinetic properties of the

agent used.

In the rare event when a live vaccine may be required

urgently in a patient on bDMARDs (e.g., outbreak or

urgent travel), discussion about the risks and benefits

should be undertaken with the patient in consultation

with an infectious disease physician.



Recommendation 31. Monotherapy or combinationwith methotrexate/cDMARDs: bDMARDs are mosteffective when combined with methotrexate. (Level I;Strength A)

Supporting evidence

References 17–19, 21, 23–26, 28, 29, 31–33, 35, 36, 38,48, 51, 52, 56 and 57.


The guidelines reviewed recommend the use of

methotrexate in combination with bDMARD agents.

This combination is associated with significant ben-

efits in terms of control of disease activity,

improved function and quality of life as well as

retardation of radiographic progression.17,32

Methotrexate is also believed to reduce development

of human anti-chimeric antibody (HACA) in

patients receiving infliximab.51 In the CONCERTO

trial that enrolled early RA patients receiving adali-

mumab plus methotrexate, an increasing trend of

efficacy was observed with increased doses of

methotrexate. However, the efficacy of the 10 mg

weekly dose of methotrexate was equivalent to the

20 mg weekly dose.17

In cases where methotrexate is contraindicated, sev-

eral guidelines mention that alternative cDMARDs such

as leflunomide, sulfasalazine, azathioprine and cyclos-

porine can be combined with bDMARD agents.36,56 In

addition, adalimumab, etanercept and certolizumab

have been approved as monotherapy18,25,38,56 and toci-

lizumab has, likewise, been used as monotherapy for

patients with RA.17,23,25,33,48


Please refer to recommendations 18 and 21.

Recommendation 32. In patients with RA who are can-didates for bDMARD therapy, the therapeutic optionsinclude TNF inhibitors, abatacept, tocilizumab andrituximab. (Level I; Strength A)

Supporting evidence

References 17–19, 21, 23–26, 28, 29, 31–33, 35, 36, 38,48, 51, 52, 56 and 57.


In the ACR 2012 guidelines, TNF inhibitors may be

used as initial treatment for patients with early RA

(< 6 months’ duration) who present with high dis-

ease activity and poor prognostic factors).18 TNF

inhibitors provide the most robust efficacy and

safety among all bDMARD agents for RA. However,

recent data have shown other bDMARD agents such

as abatacept and tocilizumab have sufficient and

comparable efficacy and safety data and can be con-

sidered as first-line bDMARD agents.17,25 The use of

rituximab as first-line bDMARD therapy has been

described in certain circumstances, such as in

patients with history of lymphoma, demyelinating

disease or TB which precludes the use of other

bDMARD agents.17,56


Patient preference and cost of treatment should always

be considered when choosing a particular bDMARD.

Several countries may have problems in sustaining the

use of bDMARDs due to non-reimbursement.

Recommendation 33. Patients who fail to achieveremission or low disease activity after 6 months ofbDMARD therapy are recommended to switch toanother bDMARD agent. (Level III; Strength C)

Supporting evidence

References 17, 18, 23–25, 28, 29, 31, 33, 34, 36, 38, 44,52–54, 57 and 58.


In the era of treat-to-target in RA, a significant delay

should not be allowed before switching therapy in

patients who have not achieved an adequate response.

Most guidelines suggest a timeline of 12 weeks. The



ACR guidelines separated the duration of failure with a

TNF inhibitor (3 months) and a non-TNF inhibitor

bDMARD (6 months) as it was felt that the response to

treatment to non-TNF inhibitor bDMARDs may take

longer.18

Observational studies have suggested that switching

to a second TNF inhibitor after failure of the first

may be a feasible option. There are no controlled tri-

als to compare switching to a second TNF inhibitor

or a bDMARD agent of another mode of action, so

the choice should be based on a shared decision

between the patient and the physician based on

patient’s preferences and characteristics. The EULAR

recommendations emphasize that no preference is

stated.17

Two guidelines specifically looked at switching to

another bDMARD after failure of rituximab.31,58 Early

studies suggested a numerical but not statistically sig-

nificant increase in infections with the use of TNF

inhibitors after rituximab but further follow up

showed that there was no difference in incidence of

infection. Data from registries suggest that use of

abatacept after rituximab is also safe, but further data

are needed.


Biosimilars may be available in certain AP countries.

They may be considered because of their comparatively

lower cost. However, the use of these agents must also

be based on available evidence. This will be discussed

in a subsequent APLAR statement.

Recommendation 34. Dose reduction: in patients whohave achieved remission, a reduction in treatmentshould be considered. (Level I; Strength A). If thepatient remains in extended remission(> 12 months), tapering of bDMARDs can be consid-ered. (Level II; Strength B)

Supporting evidence

References 21, 28, 29, 34–37, 44 and 52.


Of the 10 guidelines which discussed tapering of treat-

ment in the case of sustained remission, several recom-

mend that corticosteroids and/or NSAIDs should be

tapered first.28,29,34–37,44,52 Some, but not all, recom-

mend tapering of bDMARDs in patients with sustained

remission.21,29,35,37,44,52 The issue of withdrawal after

remission is reached remains inadequately researched

and is stated as an item in the ‘research agenda’ in the

EULAR 2013 guidelines.17


As has been highlighted earlier, long-term bDMARDs

are not often affordable by most patients in the AP

region. They often request their clinician to taper or

even stop their treatment early. While awaiting further

data to become available, the Steering Committee rec-

ommends that tapering should only be considered if a

patient has remained in disease remission for at least

12 months.

Recommendation 35. Infectious complications: TBScreening for TB is recommended prior to startingbDMARD therapy. (Level II; Strength B) All patientswith latent TB infection (LTBI) should receive pro-phylactic anti-TB therapy. (Level II; Strength B)Patients with active TB infection need to be ade-quately treated before consideration of bDMARDtreatment. (Level III; Strength C)

Supporting evidence

References 18, 22–24, 28, 35, 37, 43, 45–47 and 48–52.


The most common criteria for “LTBI” included a

weal > 10 mm (different guidelines/consensus/recom-

mendations suggested different cut-off values for

tuberculin skin testing [TST]; the Hong Kong recom-

mendations used 10 mm induration for immuno-

competent patients and 5 mm for patients who are

significantly immunocompromised such as those

with HIV infection; the French 2003 TNFi and Latin

American 2006 guidelines also suggested 10 mm; the

Japanese 2007 guidelines suggested 20 mm; the

French 2007, Portuguese 2011 and Brazilian 2012

guidelines used 5 mm; the Philippine 2006 guideli-

nes suggested 8 mm) or a blister in response to a

TST done more than 10 years after the last Bacille-

Calmette Guerin (BCG) vaccination, with no history

of correct treatment for active TB, or residual radio-

graphic TB lesions > 1 cm in size with no

certainty.49

TNF inhibitors, particularly the monoclonal antibod-

ies, have been found to be associated with increased

incidence of TB.90 Prophylaxis with anti-TB drugs with

an accepted regimen, such as isoniazid 300 mg/day is

recommended at least 1 month prior to starting

TNF inhibitors and other bDMARD agents and be


C. S. Lau et al.

maintained for 9 months in RA patients with occult TB

infection.


The AP region has a high prevalence of active TB infec-

tions. Thus, the proportion of patients at risk for TB

infection and re-infection during bDMARD therapy is

higher when compared with Europe and North

America.

The high cost and limited availability of interferon-

gamma release assay (IGRA) and the lack of timely

access to infectious disease specialists may be barriers to

the accurate diagnosis of latent TB infection. Neverthe-

less, a chest X-ray and TST are the minimum require-

ments for screening for LTBI.

The common practice of administration of the BCG

vaccine across many AP countries may lead to a high

false-positive rate for TST. Thus, many AP countries

have set a higher cut-off value for LTBI screening pur-

poses. Clinicians are therefore recommended to refer to

their national guidelines for their respective criteria for

LTBI based on TST results. Where such guidelines are

unavailable, the committee recommends using the

development of a weal > 10 mm following TST as the

cut-off value for LTB1 warranting the use of prophylac-

tic anti-TB antibiotics prior to bDMARD treatment.

The issue of TB infections and RA treatment will be

dealt with in a subsequent APLAR recommendation

report.

Recommendation 36. Infectious complications: Hepati-tisPatients should be screened for HBV and HCV infec-

tions prior to the commencement of bDMARDs.(Level IV; Strength D) bDMARDs should be avoidedin patients with active or untreated chronic HBV infec-tion and active HCV infection. (Level III; Strength C)

Supporting evidence

References 18, 22–24, 31, 33, 35, 37, 43, 48, 51, 52, 56and 58 addressed the topic of hepatitis-related compli-

cations associated with bDMARD use, but no evidence

was identified to support this statement.


Although there was some evidence, most is in the form

of case reports, some of which are contradictory.


Patients with evidence of chronic viral hepatitis B infec-

tion, including serum positivity for hepatitis B surface

antigen or anti-hepatitis core antibodies, should be

given appropriate anti-viral treatment while on

bDMARD therapies. The cost of anti-viral treatment

plus the need for regular monitoring, including blood

hepatitis B DNA detection, will further lower the afford-

ability of bDMARDs for many RA patients in this

region. While appreciating the very high cost of anti-

HCV treatments, they should be considered in HCV-in-

fected patients prior to dDMARDs.

The timely access to infectious disease and hepa-

tology specialists is not always possible in many AP

countries. Rheumatologists need to stay vigilant of

these infections when starting bDMARDs for these

patients.

Recommendation 37. Active infections are contraindi-cations for bDMARDs. (Level I; Strength A) When aninfection is suspected, based on clinical judgement,the bDMARD agent should be stopped and thepatient must be treated appropriately. (Level IV;Strength D)

Supporting evidence

References 25, 26, 35, 37, 38, 43, 48–52 and 57.


Of the 48 RA management recommendation reports, 11

discussed non-TB, non-hepatitis infec-

tions.25,26,35,37,43,48–52,57 Active infections as contraindi-

cations for bDMARDs were discussed in four

recommendations.35,38,48 Besides, past history of seri-

ous infections in the last 6 months and history of pneu-

mocystis pneumonia (PCP) were identified as

contraindications for bDMARDs in four guidelines.48–50

Compared with the general population, patients with

RA have an increased risk of infection, which is nearly

twice as high as that observed in matched non-RA con-

trols.91,92 When considering serious infections, a trend

toward an increased frequency compared to cDMARDs

has been noted regarding monoclonal anti-TNF anti-

bodies,93–95 with a significant increase reported in two

previous studies with infliximab and adalimumab.96,97

These findings are consistent with the results of a meta-

analysis published in 2006 that included all random-

ized controlled trials performed with infliximab and

adalimumab.80


While there is no prevalence data from the AP region of

several transmissible diseases such as leprosy, malaria,

Chagas’ disease, schistosomiasis, yellow fever, dengue



fever, filariasis and helminthic infections, we recom-

mend physicians to remain alert regarding these condi-

tions so as to allow timely diagnosis and appropriate

treatment.

Recommendation 38. Pregnancy and lactation whileon bDMARDs should only be considered after thor-ough assessment of benefits and risks. (Level IV;Strength D)

Supporting evidence

References 22, 24, 31, 33, 37, 38, 43, 48, 51, 52, 57 and

58.


There is an inherent inadequacy of safety data on

bDMARD agents during pregnancy because pregnant

women as a group are excluded from the majority of

premarketing clinical trials and safety studies for ethi-

cal reasons. However, most recommendations stated

that pregnancy and lactation should be avoided while

on bDMARDs and effective contraception is strongly

recommended to prevent pregnancy in women with

childbearing potential until more safety data are

available.


Earlier, the Steering Committee suggested the consider-

ation of triple combination cDMARDs as an alternative

to bDMARDs because of cost and availability concerns.

It should be noted that cDMARDs are as potentially, or

more, toxic than bDMARDs.98

Recommendation 39. Vaccination: administration ofall vaccines, if indicated, should, ideally, be under-taken at least 4 weeks before starting a bDMARD.(Level III–IV; Strength C–D) Concurrent administra-tion of live, attenuated vaccines is an absolute con-traindication for patients being treated withbDMARDs. (Level IV; Strength D)

Supporting evidence

References 18, 22–24, 31, 33–35, 37, 38, 43, 46, 48, 52,55, 56, 58.

Table 4 Research agenda for some of the 40 treatment recommendations for RA patients in the AP region

I. General RA treatment strategies

Longitudinal studies of the socioeconomic cost of RA

Prevalence of use of complementary, over-the-counter and self-medications for RA

Setting a realistic treatment target for patients from countries with low resources

Evaluation of the role of non-rheumatologists and allied health workers in RA management

II. Role of NSAIDs

The use of NSAIDs and their short- and long-term side effects (much of this has already been carried out previously)

III. Role of corticosteroids

The prevalence of corticosteroid abuse

Evaluation of the effects of long-term low-dose corticosteroids

IV. Role of cDMARDs

Do Asian patients tolerate methotrexate less well?

Efficacy of combination cDMARDs involving agents such as bucillamine, iguratimod, intramuscular gold or tacrolimus

Effects of cDMARDs on TB reactivation and novel infections

Effects of cDMARDs on chronic viral hepatitis carriers

Comparison of the efficacy of triple cDMARD combination and biologic agents

V. Role of bDMARDs

Effects of bDMARDs on TB reactivation and novel infections

Effects of bDMARDs on chronic viral hepatitis carriers

The frequency and occurrence of infective complications, including opportunistic infections associated with bDMARD use

The frequency and occurrence of malignant conditions associated with bDMARD use

Dose titration of bDMARDs

VI. Role of tofacitinib

The efficacy and long- and short-term side-effect profile of tofacitinib

The efficacy of tofacitinib in bDMARD failure patients

The possible role of tofacitinib in bDMARD-na€ıve patients

bDMARD, biological DMARD; cDMARD, conventional DMARD; DMARD, disease-modifying antirheumatic drug; NSAID, non-steroidal anti-in-flammatory drug; RA, rheumatoid arthritis; TB, tuberculosis.


C. S. Lau et al.


Overall, there is a lack of data on the safety of vaccina-

tion during treatment with most bDMARDs. Further-

more, there are not many studies on the efficacy of

vaccines during treatment with bDMARDs; a study on

pneumococcal vaccination suggested that patients on

TNF inhibitors may not respond adequately to vaccina-

tion.99 Thus, the recommendation of the Steering Com-

mittee in this regard aligns with that of most guidelines

and is predominantly based on expert opinion.



Section 6 – Role of tofacitinib

Recommendation 40: Tofacitinib may be considered if abDMARD has failed. (Level II; Strength B).Supporting evidence

This recommendation is made not based on a review

of the treatment recommendations/guidelines that the

Steering Committee had initially identified. However,

the role of tofacitinib was included in the EULAR RA

treatment recommendations 2013 update.17


Tofacitinib, a JAK inhibitor, has been under investiga-

tion as a therapy for RA. It is not a bDMARD or a

cDMARD. In a number of placebo-controlled studies,

tofacitinib, used either as a monotherapy or in combi-

nation with a cDMARD, primarily methotrexate, was

associated with reductions in signs and symptoms of

RA and improvement in physical function in patients

with active disease despite previous treatment with

cDMARDs.100–102 In another study of active disease-pa-

tients receiving background methotrexate, tofacitinib

was found to be significantly superior to placebo and

was numerically similar to adalimumab in efficacy.103

Furthermore, in a 6-month, double-blind, parallel-

group phase 3 study involving 266 patients who were

TNF inhibitor refractory, tofacitinib use was associated

with meaningful improvements in signs and symptoms

of RA and physical function.104 However, the efficacy of

this agent in other bDMARD refractory RA patients has

not been reported.


While there is evidence that tofacitinib is useful in

active RA disease patients who have failed cDMARDs,

and probably those who are refractory to TNF inhibi-

tors, more data is needed to support its use as a first-

line DMARD or after a patient has failed a bDMARD,

specifically the non-TNF inhibitors. While we await

long-term data on the efficacy and side-effect profiles,

particularly infectious disease complications, of tofaci-

tinib, the Steering Committee felt it is not yet ready

to recommend its use in DMARD-na€ıve patients. The

other consideration is to do with the possible high

financial cost of tofacitinib which is significantly

higher than that of all cDMARDs. This is an impor-

tant consideration for many AP countries where there

are financial constraints in obtaining access to expen-

sive medications. Our decision to recommend its use

in patients who have failed a bDMARD is based on

an extrapolation of the data reported by Burmester

et al.104 The Steering Committee encourages national

societies to include tofacitinib in their national drug

formulary.

DISCUSSION

These are the first RA treatment recommendations

developed by APLAR. The AP region is unique in many

ways. It accounts for 61% of the world population with

diverse ethnic, cultural and socioeconomic varia-

tions.105 The prevalence, clinical manifestations,

response to treatment and outcome of RA patients in

many Asian countries have been suggested to differ

from those reported in the West. Importantly, rheuma-

tology is still a developing medical subspecialty in the

region with a severe shortage of trained rheumatologists

in many countries.106 Not only are many RA patients in

the AP region managed by non-rheumatologists, the

lack of resources also means RA clinical studies are

sparse and that a big gap exists in the evidence-based

management of RA in this region.

The primary aim of these treatment recommenda-

tions is to provide clinicians with an evidence-based

reference for the treatment of RA in the AP region.

The Steering Committee was comprised of rheumatol-

ogists from 12 AP countries representing a diverse

spectrum of cultures and ethnicities, health economic

statuses and practises of rheumatology in the region.

A patient with RA was also invited to join the Com-

mittee so as to include patients’ perspectives on the

treatment of their condition in the recommendations.

Because of the nature of the recommendation drafting

process which required members to communicate in

English, a patient from Hong Kong who was literate

in the language was invited to join the Committee.



The Steering Committee did not perform a system-

atic review of original articles to inform recommenda-

tions. Instead, the recommendations were developed

using the ADAPTE framework12,13 appraising all

international RA practice guidelines and recommen-

dations through to December 2013. The ADAPTE

Collaboration is an international collaboration of

researchers, guideline developers and guideline

implementers who aim to promote the development

and use of clinical practice guidelines through the

adaptation of existing guidelines. Having first estab-

lished the scope and purpose of the current RA

treatment recommendations, the Steering Committee

conducted a thorough search for guidelines and rele-

vant documentations that have been previously pub-

lished. Each of these articles was then assessed for

guideline quality, currency, content, consistency and

acceptability/applicability for the AP region using the

AGREE instrument.15 Selected previous guidelines

were rigorously and systematically reviewed and dis-

cussed by members of the Steering Committee

before they were customized to create the current

adapted recommendations. The generic adaptation

process of ADAPTE has been shown to be valid and

of high quality.12,13

Based on the key questions that the Steering Com-

mittee had identified regarding the treatment of RA

in the AP region, 40 recommendations concerning

the general RA treatment strategies, and the role of

NSAIDs, corticosteroids, cDMARDs, bDMARDs and

tofacitinib have been made. Specific issues relating to

the safety and monitoring of cDMARDs and

bDMARDs are not covered in the current report.

These include screening and prophylactic treatment

for latent TB, management of patients who are

chronic viral hepatitis B/C carriers and precautions

with other regional prevalent infectious diseases.

These will be covered separately in a later instalment

of the recommendations.

The role of tofacitinib, a JAK inhibitor, in RA was not

originally included as one of the key questions. How-

ever, midway through the development of these recom-

mendations, tofacitinib became available in a number

of AP countries and a recommendation on the use of

this agent was included in the EULAR RA treatment rec-

ommendations 2013 update. The Steering Committee

therefore felt it would be appropriate to include the role

of tofacitinib in RA treatment in the current recommen-

dations.

Realizing that many Asian countries are under-re-

sourced to allow them to adhere strictly to the recom-

mendations made in this report, the Steering

Committee added comments based on expert opinions

and consensus following each recommendation in the

hope that minimum care requirement is achieved for all

RA patients in these countries. In addition, it is hoped

that some of these region-specific comments, which

may lack full evidence, may form the basis of a research

agenda, which is by no means exhaustive, for clinicians

in the AP region (Table 4).

It should be noted that the current report does not

include recommendations for physical and occupa-

tional treatment, and alternative/complementary ther-

apies which are widely practised by many patients in

the AP region. This is partly because evidence on the

role of these treatment modalities is sparse. Further-

more, in many AP countries, the physical and occu-

pational therapy disciplines are poorly developed.

However, where physical and other non-pharmaco-

logical therapies are available, clinicians should

advise RA patients about their roles in protecting nor-

mal joint function. For example, the BSR 2005 guide-

lines mentioned that patients should be informed

about alternative techniques of effective pain manage-

ment, including transcutaneous nerve stimulation

(TENS) and behavioral approaches.60 Others have

also found that physical therapy and exercise are ben-

eficial in RA patients.57 Where resources are limited

and patients are unable to afford the cost of proce-

dures such as TENS, patients may be advised to exer-

cise at home, as leisure time physical activity has

also been shown to be beneficial and should be

encouraged.22

CONCLUSION

APLAR has developed a set of general recommenda-

tions for the best practise management of RA in the

AP region. We are also hopeful that some of these

recommendations, where evidence for this region

may be lacking, may stimulate clinicians to embark

on research studies to resolve them. Specific issues

such as the prevention of reactivation or novel TB

and viral hepatitis infections will be addressed in a

second instalment.

ACKNOWLEDGEMENTS

We would like to thank the Asia Pacific League of Asso-

ciations for Rheumatology (APLAR) for funding this

project, Ms King Chu Chan for serving as a patient rep-

resentative on the Steering Committee, Dr Josef Smolen


C. S. Lau et al.

and Dr Vibeke Strand for reviewing the recommenda-

tions, and Dr Pradnya Kulkarni and Mr Chris Facey of

MIMS (Hong Kong) Limited for providing medical writ-

ing support.

FUNDING

APLAR and unrestricted educational grants from the fol-

lowing pharmaceutical companies: AbbVie, Janssen, Pfi-

zer, Roche and UCB.

CONFLICT OF INTEREST

All authors have disclosed any conflicts of interest. The

individual declarations are summarized below. CSL has

received unrestricted educational grants from AbbVie,

Janssen-Cilag, Pfizer, Roche and UCB, and personal fees

from Abbvie, Bristol-Myers Squibb, Celltrion,

GlaxoSmithKline, Pfizer, Roche, Sanofi-Aventis and

UCB; AH has received grants from Roche, and personal

fees from Abbvie and Pfizer; MK has received personal

fees from AbbVie, Astellas, Bristol-Myers Squibb, Chu-

gai, Eisai, Janssen, Ono, Pfizer, Santen and Tanabe-Mit-

subishi; JJL has received personal fees from Janssen,

Pfizer and Roche; WL has received personal fees from

Janssen, Pfizer, Roche and Sanofi-Aventis, and investiga-

tor fees from Janssen, Pfizer and Roche; PN has received

research grants and personal fees from Pfizer; PS has

received research grants from Pfizer. All other authors

declare no conflict.

CONTRIBUTIONS

All authors were involved in performing the literature

search, appraisal of guideline quality, grading of evi-

dence, evidence synthesis, development of recommen-

dations, and writing and proofreading of recommen-

dations.

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