Arthritis Care & Research

Vol. 64, No. 5, May 2012, pp 625– 639
DOI 10.1002/acr.21641
© 2012, American College of Rheumatology
SPECIAL ARTICLE

2012 Update of the 2008 American College of
Rheumatology Recommendations for the Use of
Disease-Modifying Antirheumatic Drugs and
Biologic Agents in the Treatment of
Rheumatoid Arthritis
JASVINDER A. SINGH,1 DANIEL E. FURST,2 ASEEM BHARAT,1 JEFFREY R. CURTIS,1
ARTHUR F. KAVANAUGH,3 JOEL M. KREMER,4 LARRY W. MORELAND,5 JAMES O’DELL,6
KEVIN L. WINTHROP,7 TIMOTHY BEUKELMAN,1 S. LOUIS BRIDGES JR.,1 W. WINN CHATHAM,1
HAROLD E. PAULUS,2 MARIA SUAREZ-ALMAZOR,8 CLAIRE BOMBARDIER,9 MAXIME DOUGADOS,10
DINESH KHANNA,11 CHARLES M. KING,12 AMYE L. LEONG,13 ERIC L. MATTESON,14
JOHN T. SCHOUSBOE,15 EILEEN MOYNIHAN,16 KAREN S. KOLBA,17 ARCHANA JAIN,1
ELIZABETH R. VOLKMANN,2 HARSH AGRAWAL,2 SANGMEE BAE,2 AMY S. MUDANO,1
NIVEDITA M. PATKAR,1 AND KENNETH G. SAAG1

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are
intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient.
The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determi-
nation regarding their application to be made by the physician in light of each patient’s individual circumstances.
Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee
any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic
revision as warranted by the evolution of medical knowledge, technology, and practice.
The American College of Rheumatology is an independent, professional, medical and scientific society which does
not guarantee, warrant, or endorse any commercial product or service.

Introduction agents in the treatment of rheumatoid arthritis (RA) in
The American College of Rheumatology (ACR) most re- 2008 (1). These recommendations covered indications for
cently published recommendations for the use of disease- use, monitoring of side effects, assessment of the clinical
modifying antirheumatic drugs (DMARDs) and biologic response to DMARDs and biologic agents, screening for
tuberculosis (TB), and assessment of the roles of cost and
The views expressed in this article are those of the authors
and do not necessarily reflect the position or policy of the Pittsburgh, Pennsylvania; 6James O’Dell, MD: University of
Department of Veterans Affairs or the United States govern- Nebraska, Omaha; 7Kevin L. Winthrop, MD, MPH: Oregon
ment. Health and Science University, Portland; 8Maria Suarez-
Supported by a research grant from the American College Almazor, MD, MPH: University of Texas MD Anderson Can-
of Rheumatology. cer Center, Houston; 9Claire Bombardier, MD, MSc: Toronto
1
Jasvinder A. Singh, MBBS, MPH, Aseem Bharat, MBBS, General Research Institute, Toronto, Ontario, Canada;
10
MPH, Jeffrey R. Curtis, MD, MPH, Timothy Beukelman, MD, Maxime Dougados, MD: Hôpital Cochin, Paris, France;
11
MSCE, S. Louis Bridges Jr., MD, PhD, W. Winn Chatham, Dinesh Khanna, MD, MSc: University of Michigan, Ann
MD, Archana Jain, MD, Amy S. Mudano, MPH, Nivedita M. Arbor; 12Charles M. King, MD: North Mississippi Medical
Patkar, MD, MSPH, Kenneth G. Saag, MD, MSc: University Center, Tupelo; 13Amye L. Leong, MBA: Healthy Motivation,
of Alabama at Birmingham; 2Daniel E. Furst, MD, Harold E. Santa Barbara, California; 14Eric L. Matteson, MD, MPH:
Paulus, MD, Elizabeth R. Volkmann, MD, Harsh Agrawal, Mayo Clinic, Rochester, Minnesota; 15John T. Schousboe,
MD, Sangmee Bae, BS: University of California, Los Angeles; MD, PhD: University of Minnesota and Park Nicollet Clinic,
3
Arthur F. Kavanaugh, MD: University of California, San Di- Minneapolis; 16Eileen Moynihan, MD: Highmark Medicare
ego; 4Joel M. Kremer, MD: Albany Medical College, Albany, Services, Woodbury, New Jersey; 17Karen S. Kolba, MD:
New York; 5Larry W. Moreland, MD: University of Pittsburgh, Pacific Arthritis Center, Santa Maria, California.

625

Tupelo). MD (Hôpital Cochin. honoraria (more than $10. Centocor. and Novartis. and (more than $10.000 each) from Allergan. MPH (tuberculosis.. Pittsburgh. Faculty Office lion. MD.000) from and Genentech. Dr. MD (University of Pittsburgh. BMS.000) from Genentech. Pfizer (Wyeth). given their in the 2008 guidelines (1) to maintain consistency and to importance in RA patients receiving or starting allow cumulative evidence to inform this 2012 recommen- biologic agents. and Amgen. San Di- Gilead. and 5) vac- agents in patients with RA. (Schering). Singh. Actelion. each) from Abbott. Maxime Dougados.000 each) MSc (University of Toronto. Outcome Measures in Rheuma. TX). the ACR commissioned an update of the 2008 rec- Significance & Innovations ommendations in select topic areas. ● These 2012 recommendations update the 2008 The 2012 revision updates the 2008 ACR recommenda- American College of Rheumatology recommenda. Canada). and/or honoraria (less than $10. MD (North Mississippi Medical Center. evidence-based med- icine.md@gmail. Ontario. Members of the Task Force Panel: Claire Bombardier. and/or honoraria (less than $10. MD (Albany Medical Center. patient representatives. and Wyeth. GSK. Clinic. PA). Larry W. tology (OMERACT). Genentech. MBBS. MBA (Healthy Motivation. thur F. Biogen Idec. NIH. Dr. Singh. 2) switching between DMARD and (RA). NY). 4) screening for TB in patients modifying antirheumatic drugs and biologic starting or currently receiving biologic agents. UCB. Acte. Janssen (Merck). biologic therapies. Genentech/Roche. Dr. MSc (University of Michigan. and (more than $10. France). cor. MD. Jeffrey R. Winthrop has received consul.000 Moreland. Charles M. and 2) a (1). MSCE. 2011. speaking fees. and/or ma- We utilized the same methodology as described in detail lignancy in these recommendations. MD. UCB. MD (Pacific Arthritis and/or honoraria (less than $10. and/or honoraria (more than $10. Paris. Los Angeles). Karen S. MD. and/or Santa Barbara. PhD. MN). immunization. Joel M. Pfizer. Dougados has received consultant fees. speaking fees. the evidence patient preference in decision making for biologic agents synthesis. Ar- from Abbott. Saag. and URL. MD. speaking fees. Jasvinder A. [CHF]. MD. Dr. MD (infections. UCB. congestive heart failure. MD. Dr. MD. Omaha). Furst. These recommendations were developed by 2 expert panels: 1) a nonvoting working group and Core Expert Panel (CEP) of clinicians and methodologists re- sponsible for the selection of the relevant topic areas to be considered. Genentech. MD (Highmark Medicare Ser- gen. Roche. MPH (MD Anderson Cancer Center. and/or honoraria Address correspondence to Jasvinder A. Leong. tology Researchers of North America (CORRONA). CA). tions in the following areas: 1) indications for DMARDs tions for the treatment of rheumatoid arthritis and biologic agents. and (more than $10. speaking fees. MBBS. MPH (Mayo honoraria (less than $10. and patient preferences who were tasked with rating Dr. Ann Arbor). and methodolo- garding the safety and efficacy of existing and newer ther- gists with expertise in RA treatment. UCB.626 Singh et al apies. (less than $10. Centocor. and/or honoraria (less than $10. Kolba. MD. Amye L. Eric L. and Takeda. Daniel E.000 each) E-mail: Jasvinder. Michael Saag. Amgen. Genentech. Woodbury. University of Ala- from Pfizer. Moreland has received consultant fees (less than $10. James O’Dell. speaking fees. Pfizer. MD. Ted Chatham has served as a paid consultant with investment Mikuls. Singh has received consultant fees. Amgen. Kavanaugh. 510 20th Street South.000 each) from Abbott Interna. Merck Suarez-Almazor. MD. Harold E. Omaha). and creation of “clinical scenarios”. Saag has received consultant fees. congestive heart failure ● The recommendations cover the use of disease. MSc. Eileen Moynihan. Dr.000 each) Savient and Takeda. tional and Pfizer. and has received Houston. AstraZeneca. University of Nebraska. AL 35294. and/or honoraria (less than $10. Furst has received consultant fees. and Gilead. and Amgen. MD (University of Nebraska. from Centocor Ortho Biotech and GlaxoSmithKline. DMARDs or biologic agents (Table 1). Maria ada. Dr. speaking fees.000 each) from Nicollet Clinic and University of Minnesota. PhD (Park scendo. dations update. Horizon. Submitted for publication May 27. King. Tower 805B. vices. June 2010. Kremer has received consultant fees. MSPH (participated in meetings only prior to analysts on behalf of Gerson Lehrman and Leerink-Swann. Curtis. Minneapolis).000 each) from Pfizer. Biogen Idec. and is an executive member of an from Merck. Dr. W. 2012. and Roche. Pfizer. . and (more than $10. University of Alabama at Birmingham. John T. and Abbott. Cre. Dr. Savient. Abbott.com. received consultant fees. NIH. and is a member of the Consortium of Rheuma.000 Alabama at Birmingham). MD (University of California. Content-Specific Expert Advisors: Kevin L. Takeda. Kremer. vised form February 8. each) and/or served on the advisory board for Abbott Can. CA). Albany. BMS. Bombardier has received honoraria (less than $10. Winthrop. Oregon Health and Science University. Cur. Amgen. the systematic literature review. Matteson. Dr. S. Takeda. Dr. Louis Bridges Jr. ● We address screening for tuberculosis reactiva- tion.000 each) from Pfizer. Ardea. Toronto.000 each) from Genentech. tis has received consultant fees.000) from Amgen. Ms Leong has received consultant fees. Dinesh Khanna. Center. Dr. Novartis. Cellestis. Winn from Pfizer and is a member of the data safety monitoring Chatham. MPH. Recognizing the rapidly evolving knowledge in RA Task Force Panel (TFP) of 11 internationally recognized management and the accumulation of new evidence re- expert clinicians. CORRONA. MPH (University of tant fees. and Roche/ ego). BMS. NJ). speaking fees. MD. Lilly. Birmingham. and treatment of RA patients Materials and Methods with hepatitis. MD (University of California. has received an investigator-initiated grant from speaking fees. Members of the Core Expert Panel: Timothy Beukelman. MPH. Paulus. Kavanaugh has conducted clinical research for Cento. BMS. Khanna has bama at Birmingham). and/or honoraria (less than $10. UCB. 3) use of biologic agents in high-risk patients (those with hepatitis.000 each) Portland). Santa Maria. Schousboe.000) MD. and malignancy). Kenneth G. accepted in re- Kolba owns stock and/or stock options in Merck. including switching cination in patients starting or currently receiving between drugs. board for ChemoCentryx. BMS. and Am. speaking fees. Abbott. Novartis. Rochester. international organization.

Methotrexate 4. Literature searches for both DMARDs and bio. The methods library. congestive heart failure. Etanercept 4. for additional qualitative reviews related to TB screening. influenza.2012 ACR RA Treatment Recommendations 627 Table 1. influenza. Hydroxychloroquine 2. Infliximab 5. it was not included in the recommendations. but due to the lack of new data and/or infrequent use.1002/(ISSN)2151-4658). § Anakinra was included in the literature search. databases. and herpes agents zoster vaccines * DMARDs ! disease-modifying antirheumatic drugs. Minocycline 4. Minocycline 5. Abatacept 2. Golimumab Role of cost and patient preference in " See 2008 recommendations¶ decision making for biologic agents Switching between therapies Considered. receiving DMARDs or biologic vaccines human papillomavirus. hepatitis. Tocilizumab 3.wiley. but not addressed in detail " Monitoring of side effects of DMARDs " See 2008 recommendations¶ and biologic agents TB screening for patients starting/ " " receiving biologic agents Use of biologic agents in high-risk " " patients (those with hepatitis. Leflunomide 2. Rituximab Anti-TNF 3. controlled clinical trials. additional studies (5– 8) and further supplemented by quasi-experimental designs. ology). Overview comparison of topics and medications included in the 2008 and 2012 American College of Rheumatology rheumatoid arthritis recommendations* Topic area considered 2008 2012 Indications for starting or resuming " " DMARDs and biologic agents DMARDs included† 1. and case– control studies. we also reviewed the Cochrane sys- online version of this article at http://onlinelibrary. and hepatitis (similar to the 2008 method- with medical subject headings and relevant keywords sim. search that ended on February 14. 2010 domains. Adalimumab Anti-TNF 4. the Cochrane Database of Systematic Reviews to identify domized controlled trials (RCTs). Infliximab 7. The literature search end date for the 2012 update was February 26. available in the For biologic agents. Leflunomide 3. and malignancy) Vaccinations in patients starting/ Pneumococcal. when appropriate.wiley. but due to the lack of new data and/or infrequent use. Certolizumab pegol 8. 2007. logic agents relied predominantly on PubMed searches immunization. Studies published subsequent to that date were not ilar to those used for the 2008 ACR RA recommendations included. TB ! tuberculosis. the scenarios created using an ordinal scale specified in retrospective). when appropriate. are listed below and in Supplementary Appendix 3 (avail- ited formal input from this multidisciplinary TFP to make able in the online version of this article at http://online recommendations informed by the evidence. combination DMARD therapy with 2 or 3 DMARDs† DMARD therapy with 2 or 3 DMARDs‡ Biologic agents included§ Non-TNF Non-TNF 1. Abatacept 1. . combination And. with no restric- the RAND/University of California at Los Angeles (RAND/ tions on sample size. Methotrexate 3. Sulfasalazine 5. 2010 Systematic literature review: sources. Sulfasalazine And. Adalimumab 5. azathioprine. † Cyclosporine. tematic reviews and overviews (published and in press) in com/journal/10. ¶ No significant new data related to these topics.com/journal/10. cohort studies (prospective or hand checking the bibliographies of all included articles. and hepatitis Pneumococcal. Etanercept 6. This method solic. and for the efficacy and safety studies and September 22. and gold were included in the literature search. Hydroxychloroquine 1. More details about inclusion criteria UCLA) Appropriateness Method (2– 4). ‡ Triple therapy with methotrexate " hydroxychloroquine " sulfasalazine. used to develop the updated ACR recommendations are The 2008 recommendations were based on a literature described briefly below.1002/(ISSN)2151-4658). Rituximab 2. (see Supplementary Appendices 1 and 2. they were not included in scenarios and the recommendations. We included ran. non-TNF ! non–tumor necrosis factor.

systematic lu. mentary Appendix 3. TB.1002/(ISSN)2151-4658). studies. or the Food and Drug Ad. Full-text article review. Clinical scenarios and abstracts of the 2.497 potential articles from the were drafted by the investigators and the CEP. We used the same key determi- above selection method. moderate. and tocilizumab. available in the online version of this available in the online version of this article at http:// article at http://onlinelibrary. and the rest of the biologic criteria: 1) the report was a meeting abstract. 2010). Clinical scenarios were constructed that might have been overlooked. Following this tis) (see Supplementary Appendix 2. Two journal/10. We identified 149 orig. line version of this article at http://onlinelibrary. 128 unique original articles were established RA).84 (excellent) for a combination of certolizumab pegol. A list of all included articles is pro- we did not review any unpublished data from product vided in Supplementary Appendix 4 (available in the on- manufacturers. available in the online cess database that was developed and used for data version of this article at http://onlinelibrary. the CEP and TFP confirmed that the relevant lit.1002/(ISSN)2151- beyond chance) for independent selection of articles for 4658). regarding TB screening and vaccination in immunocom- inra was not included in the recommendations due to promised patients. tional studies (case– control or cohort) or intervention and evidence report generation. The full text of each ar- studies. recommendations and 14 on certolizumab pegol. The kappa coefficients (agreement http://onlinelibrary. and Inclusion and exclusion criteria for review of article 0. Details of the biblio- graphic search strategy are listed in Supplementary Ap- Agreement between reviewers for selection of studies pendix 1 (available in the online version of this article at for full-text retrieval. infliximab. reviewers were assigned to abstract data on DMARDs (SB. based on permutations in the particular therapeutic con- inal articles from the 3 searches for full-text retrieval. Studies were excluded if they met any of the following DEF).65 (very good) for the 6 biologic Literature search criteria and article selection. site (www. 3) related to the treatment of RA with DMARDs or ticle was reviewed. rituximab. based on the PubMed and Cochrane Library searches by applying the updated evidence report. leflunomide. psoriatic arthritis. articles focused on DMARDs and 112 on biologic agents available in the online version of this article at http:// (98 on the 6 biologic agents assessed in the 2008 RA onlinelibrary. and tocilizumab. Literature was searched for 8 DMARDs: azathioprine. Similar to 2008. 0. we included searches on Literature was searched for 9 biologic agents: abatacept.com/ abstraction for the 2008 ACR RA recommendations.cdc. hepatitis.1002/(ISSN)2151-4658). The lead points that were developed for the 2008 ACR RA treatment author also reviewed all titles and abstracts to identify any recommendations (1).com/journal/10. 2008 recommendations. We searched the literature for the 8 DMARDs and 9 Additional literature searches for articles reviewing TB biologic agents most commonly used for the treatment of screening. hepatitis. Entered data were pus erythematosus) or non–FDA-approved use in health further checked against raw data on biologic agents from conditions other than RA (e. metho. certolizumab pegol.wiley. and tocilizumab (9). azathioprine. or meta-analysis. the Cochrane systematic reviews (5– 8). of the literature were performed for these 3 topics (com- cyclosporine.. agents included in the 2008 ACR recommendations. 2) the study duration was less than 6 abstractions were similar. etanercept.wiley. plus inclusion of dis- on their infrequent use and lack of new data (Table 1).wiley. cyclosporine. ministration (FDA) Adverse Event Reporting System. non-RA conditions (e. . data abstraction and entry were per- biologic agents.1002/(ISSN)2151-4658). This included 16 high) (Tables 2 and 3 and Supplementary Appendix 5. To ensure that the error rates were low and cle. data abstraction.628 Singh et al Finally. ened to include case reports and case series of any size.. infrequent use and lack of new data. the Centers for Disease Control and Prevention (CDC) web adalimumab. com/journal/10. literature searches were broad- fasalazine. 2) observa. (ISSN)2151-4658). hydroxychloroquine.gov) for past and current recommendations golimumab.com/journal/10. 2) disease activity (low. anakinra. or identified and the data were abstracted. and vaccination.1002/ onlinelibrary. agents (AB.com/journal/10.com/journal/10.wiley. biologic agents in vasculi. Qualitative reviews RA. Similar to the strategy for the trexate.60 (good) for DMARDs. and vaccination (see below). organic gold compounds. and 3) DMARDs or biologic agents were used for agents were dually abstracted by 2 abstractors (AB. data entry. In addition. eases other than RA. With the exception of assessment of golimumab.1002/(ISSN)2151-4658). Two reviewers independently screened the titles Development of clinical scenarios. Unless mumab.1002/(ISSN)2151-4658). and gold were not included in the recommendations based review articles. and meta-analyses. Any disagreements were resolved nant clinical thresholds and treatment decision branch by consultation with the lead reviewer (JAS). goli- erature was included in the evidence synthesis.g. abstracts and titles.com/ dence report using the data abstracted from the published journal/10. AJ). rituximab (HA. we developed an evi- version of this article at http://onlinelibrary. 26 articles related to biologic months. full-text review by the 2 reviewers met or exceeded 0. investigators. After siderations that reflected: 1) disease duration (early versus excluding duplicates. 3 newer biologic agents that had they were identified by the literature search and met the been added since the 2008 recommendations) (see Supple- article inclusion criteria (see Supplementary Appendix 3. and 4) study duration of at least 6 months formed by reviewers using a standardized Microsoft Ac- (see Supplementary Appendix 2. and sul.wiley. pleted September 22.wiley. Anak. ERV).wiley. studies were included if they met all of the following criteria: 1) original study in English language with an abstract. AJ). The data entry errors were less than 3%. minocycline. review arti. available in the online comprehensive literature review.g. Selection criteria for articles reviewing efficacy/adverse events.

certolizumab pegol. rituximab. available in the online version of this article at http:// onlinelibrary.g. the evidence available for these 2011 recommendations relied on the use of the 1987 ACR RA classification criteria. and gold were considered but not included due to their infrequent use in RA and/or the lack of new data since 2008. available in the online version of this article at http:// onlinelibrary. low-income populations.g. TB ! tuberculosis. or bony erosions by radiograph (38–40) RA remission A joint ACR/EULAR task force defined remission as a tender joint count. or sulfasalazine DMARD combination Combinations including 2 drugs. moderate. When a particular drug is not recommended. Latin America. most of which are methotrexate based. ‡ New classification criteria for RA (ACR/EULAR collaborative initiative) have been published (23). or tocilizumab Biologic agents Anti-TNF biologic or non-TNF biologic (8 biologic agents.com/journal/10. EULAR ! European League Against Rheumatism. which increases if any physical activity is undertaken (13) CDC-defined risk factors for Close contacts of persons known or suspected to have active TB. methotrexate " hydroxychloroquine.. however.g. total bilirubin. Definitions of key terms and key assumptions for clinical scenarios for the 2012 ACR recommendations update for the treatment of RA* Definitions KEY TERMS DMARDs† Hydroxychloroquine. DI ! disability index. † Azathioprine. and high as per validated common scales (Table 3 and Supplementary Appendix 4. methotrexate. CDC ! Centers for Disease Control and Prevention. Disease activity and prognosis assessments performed between 3 and 6 months after initiation or change in therapy. and infants. positive rheumatoid factor or anti–cyclic citrullinated peptide antibodies (33–37). and triple therapy (methotrexate " hydroxychloroquine " sulfasalazine) Anti-TNF biologics Adalimumab. leflunomide.com/journal/10. with only a few therapy exceptions (e. foreign-born persons from latent TB infection areas with a high incidence of active TB (e.. or anginal pain. NYHA ! New York Heart Association. long-term care facilities. and the presence of ascites and encephalopathy.. C-reactive protein (mg/dl) level. anti-TNF ! anti–tumor necrosis factor. Asia. minocycline. persons who visit areas with a high prevalence of active TB. since literature review preceded the publication of the new criteria. swollen joint count.. children. HAQ DI or similar valid tools).1002/(ISSN)2151-4658)§ 6. Examples of scenarios for which agreement is not achieved noted explicitly (see Supplementary Appendix 6. Cost not considered. not exceptional cases 2. residents and employees of congregate settings whose clients are at an increased risk for active TB (e. minocycline. Africa. cyclosporine. possibly including medically underserved. dyspnea.3 (41) Child-Pugh classification Scoring system based upon the levels of albumin. leflunomide. and Russia). or persons who abuse drugs or alcohol. sulfasalazine " hydroxychloroquine). infliximab. and adolescents exposed to adults who are at an increased risk for latent M tuberculosis infection or active TB (14) KEY ASSUMPTIONS 1. Felty’s syndrome). . methotrexate " leflunomide.wiley. excluding anakinra) Early RA RA disease duration #6 months Established RA RA disease duration !6 months or meeting the 1987 ACR classification criteria (24)‡ Disease activity Categorized as low. with a survival rate of 70–80% (12) NYHA class III and IV NYHA class III includes patients with cardiac disease resulting in marked limitation of physical activity with less than ordinary physical activity causing fatigue. but no symptoms at rest. and prothrombin time. NYHA class IV includes patients with cardiac disease resulting in inability to carry on any physical activity without discomfort and symptoms of cardiac insufficiency or that the anginal syndrome may be present even at rest. and homeless shelters).. presence of rheumatoid nodules.g. please see 2008 recommendations (1) 3. palpitation. We anticipate that in the near future. or sulfasalazine Non-methotrexate DMARDs Hydroxychloroquine. HAQ ! Health Assessment Questionnaire. Assume that a clinical indication exists (based upon disease activity) for use of each treatment option * ACR ! American College of Rheumatology.wiley. or golimumab Non-TNF biologics Abatacept. RA vasculitis. and patient global assessment of "1 each or a simplified Disease Activity Score of "3. § Agreement as defined by the RAND/UCLA Appropriateness Method. it does not imply that it is contraindicated 5. methotrexate " sulfasalazine. etanercept. health care workers who serve clients who are at an increased risk for active TB. although can be assessed as early as 3 months 8. extraarticular disease (e. Alternate therapeutic choices taken into account 4. RA ! rheumatoid arthritis. Patients with a score of 10 or more (in the class C category) have a prognosis with a 1-year survival rate of $50%. Optimal dose of medication (as defined by the treating clinician) given for 3 months (in lieu of total duration of therapy) before therapy escalation or switching 7.2012 ACR RA Treatment Recommendations 629 Table 2. data using the new classification criteria may be available for evidence synthesis and formulating recommendations. Eastern Europe. populations defined locally as having an increased incidence of latent Mycobacterium tuberculosis infection or active TB. DMARDs ! disease-modifying antirheumatic drugs. correctional facilities. Patients with class A or B have a better 5-year prognosis.1002/(ISSN)2151-4658) or the treating clinician’s formal assessment (26–32) Poor prognosis Presence of 1 or more of the following features: functional limitation (e. Focus on common patients.g. especially if visits are frequent or prolonged.

We provided CEP members The task force panelists agreed upon certain assump- with manuscript abstracts and requested full-text articles tions and qualifying statements on which they based their to help inform decisions. We asked them to use the stances. For example. ranges. one-third or more TFP cluded both new considerations and questions considered members rating the scenario in the 1 to 3 range and one- in the 2008 recommendations.0 to "26 High activity: %26 3) current medication regimen. including disper- based on 1) review of each of the previous 2008 scenarios sion of the scores.0 Moderate activity: %10. and rating instructions.0 to 4. available in the dian rating of 7 to 9. 2010.1 High activity: %5. clinical scenar.0 Moderate activity: %2. specify- provided them with the evidence report. Those scenario permutations with online version of this article at http://onlinelibrary. “The patient has active established RA and has failed an A median score of 1 to 3 indicated “not appropriate” and adequate trial of an Anti-TNF [anti–tumor necrosis factor] 7 to 9 indicated “appropriate” for taking action defined in biologic because of adverse events.0) (45) Low activity: %3. Scenarios in.8 to 10. cyclosporine.26–3. as defined in the 2008 ACR eration. A second round of ratings by panel members occurred use of the FDA definitions of “serious” and “non-serious” after extensive in-person discussion of the prior ratings adverse events (10).0 to 10 Clinical Disease Activity Index (range Remission: "2.0) (43) Low activity: %2.0 High activity: !8.” In most circum- ios. the recommenda- .0 Moderate activity: %11. Instruments to measure rheumatoid arthritis disease activity and to define remission Thresholds of disease Instrument activity levels Patient Activity Scale (PAS) or PAS-II Remission: 0–0. After the TFP meeting was complete. the switch to another Anti-TNF biologic after failing etaner. we used a modified Delphi process “uncertain.71 to #8. third or more rating it in the 7 to 9 range) were classified as For this 2012 update. Based on the ratings. recommendations were derived from directly transcribing the final clinical scenario ratings. ment among the panelists (i. new evidence and with infrequent use (anakinra). ing “moderate or high disease activity.7 Moderate activity: 3. Is it appropriate to the scenario (2– 4). The TFP is referred to as the “panel” in the Methods parsimonious recommendations. median ratings in the 4 to 6 range and those with disagree- com/journal/10. was pro- and 2) review of newly developed scenarios to address vided to the task force panelists.4) (44) Low activity: !2.6 (range 0–9. when rat- and the recommendations that follow. For the first round ings favored a drug indication for both moderate and high of ratings we contacted panel members by e-mail and disease activity. switching between therapies. An example of a clinical scenario is: permutation using a 9-point Likert appropriateness scale. the recommendations included only positive and evidence report and their clinical judgment to rate the not negative statements. For example. and 3) Conversion of clinical scenarios to ACR RA treatment exclusion of 1 biologic agent without additional relevant recommendations. Rating the appropriateness of clinical scenarios by the scenario permutations were collapsed to yield the most TFP.0 High activity: %4.0 High activity: %22 Disease Activity Score in 28 joints Remission: #2.” At a face-to-face meeting with both the TFP and obtained consensus (defined as !70% agreement) and the CEP members on November 15. For all eventual recommendations. see above) or without additional relevant new data.1 Simplified Disease Activity Index Remission: "3. and 4) presence of poor “appropriateness” of the clinical scenarios under consid- prognostic factors (yes or no. azathioprine. discussion and subsequent ratings of the scenarios (Table The CEP members also recommended the following: 1) 2).1002/(ISSN)2151-4658). The panelists individually rated each scenario recommendations).630 Singh et al Table 3.6 to #3.0 to 22.25 (range 0–10) (31) Low activity: 0. the anony- from the CEP for inclusion of relevant clinical scenarios mous first round of ratings by the panel.e.2 Moderate activity: !3.2 to "5. RAND/UCLA appropriateness panel score required a me- cept?” (see Supplementary Appendix 6. and median scores. 2) exclusion of 3 DMARDs used very and review of the evidence supporting each scenario.8 0–76. and gold.e.0 to 2..0 Routine Assessment of Patient Index Remission: 0–1.0 Data 3 (range 0–10) (42) Low activity: %1.3 to "11. one recommendation was given.3 (range 0–86..wiley. infrequently (i.

wiley. ma. are shown in Supplementary Appendix 7. the DMARDs or biologic agents as part of their RA therapy ratings were similar for medications within a drug cate. ommendation targeting remission or low disease activity dence). for DMARDs and biologic agents are for patients with dix 7. The recommendations in the text vided comments. available in the online version of this article at established RA.wiley. We first describe a rec- JMK. Since many lished RA (section 1C). agents: early RA (indications. We specifically note instances where a particular medication was recommended but others in its group were In the figures. meeting the 1987 ACR RA classification criteria). (Table 5) gory. 2012 update only. Two additional community-based rheuma. Biologic Agents in Patients Who Qualify for In patients with early RA. AFK and LWM. tioned. the panel recommends the use of DMARD reviewed through the regular journal review process and monotherapy both for low disease activity and for moder- by more than 30 ACR members serving on the ACR Guide. or standards of 1. level of evidence A–C) (details ACR Board of Directors. Terms used in the the use of an anti-TNF biologic with or without methotrex- recommendations are defined in Table 2. the level of or remission (Table 2) in all patients with early RA (Figure evidence is provided following each recommendation. change (1). the strength of evidence some of the 2008 ACR RA recommendations that did not was assigned using the methods from the American Col. Next. the panel also recommends biologic agents for the treatment of RA. Indications for starting. following order: Infliximab is the only exception and the recommendation is to use it in combination with methotrexate. Areas of uncertainty by the panel (that did not lege of Cardiology (11). new clinical scenarios regarding the use of DMARDs and In patients with early RA. . ate in patients who have high disease activity with poor mendations are listed in the 4 sections below and in the prognostic features (Figure 1. since in many instances. 2151-4658). ACR peer review of recommendations. and nostic features (Figure 1. Target low disease activity or remission. and 3) level of evidence C: data were derived from con- sensus opinion of experts. 1. the panel recommends the use Treatment of RA of DMARD combination therapy (including double and This 2012 ACR recommendations update incorporates the triple therapy) in patients with moderate or high disease evidence from systematic literature review synthesis and activity plus poor prognostic features (Figure 1. 4. 2) level of evidence B: data were derived at http://onlinelibrary. the manuscript was with early RA.wiley. Recommendations for the Use of DMARDs and com/journal/10. or CHF who qualify for RA management a biologic agent applies to all patients. and actions to be taken by the health care provider are tologists independently reviewed the manuscript and pro.1002/(ISSN)2151-4658). resuming. This is followed by recommendations Level C evidence often denoted a circumstance where for DMARD or biologic agent use in early RA (section 1B). The 3 subsections below define recom- http://onlinelibrary. The evidence was rated by 4 panel experts (JO and ing DMARDs or biologic agents. The re- along with details of the level of evidence supporting mainder of panel recommendations regarding indications these recommendations (see Supplementary Appen. ACR Quality of Care Committee.2012 ACR RA Treatment Recommendations 631 tions focused on when to initiate specific therapies rather 3. a range is sometimes recommends targeting either low disease activity (Table 3) provided for the level of evidence. regardless of prog- (Table 4) nostic features. level of evidence C) and established RA (Figure 2. Three levels of evidence were lead to recommendations) are noted in Supplementary specified: 1) level of evidence A: data were derived from Appendix 8 (available in the online version of this article multiple RCTs. Figure 2). Vaccination in patients starting or currently receiving phabetically within category). shown as rectangles. but not as 1. decision points are shown as diamonds not endorsed. level of recommendations from 2008 (1) and rates updated and evidence A–C). 1B. Screening for TB in patients starting or currently re- than when an alternate therapy should not be used. medical literature addressed the general topic under dis. whereas Figures 1–3 also incorporate For each final recommendation. available in the online version of this article at http://onlinelibrary. level of evidence C) receiving any DMARD or biologic agent. level of evidence A and B). recommendations had multiple components (in most 1A.com/journal/10. Use of biologic agents in patients with hepatitis. multiple medication options). ate or high disease activity with the absence of poor prog- lines Subcommittee. we provide recommendations for initiating and cussion but it did not address the specific clinical situa. non-TNF biologic listed al.1002/(ISSN) from a single randomized trial or nonrandomized studies. anti-TNF biologic. The panel cases. and discrepancies were resolved by consensus. Figure 1) followed by 1C.com/journal/10.1002/(ISSN) mendations for initiating and switching therapies in estab- 2151-4658) lished RA (Figure 2). for others. adding. Indications for and switching DMARDs and biologic monotherapy. where each rated half of the evi. The 2012 recom. the recommendation to use/switch to a DMARD or lignancy. switching between DMARDs and biologic agents in estab- tions or scenarios reviewed by the panel. CEP and TFP members reviewed and below and in Tables 4 and 5 represent the results of the approved all final recommendations. In patients struction of the recommendations. in RA (section 1A). Most ceiving biologic agents as part of their RA therapy of the recommendations were formulated by drug category (Figure 3) (DMARD. case studies. Early RA (disease duration #6 months). Established RA (disease duration !6 months or established RA (indications and switching. Where the prognosis is not men- 2. Following con. or switch- care.

level of evidence A and B). level of evidence B and C). a patient still has mod. a patient still has moderate or high If a patient still has moderate or high disease activity disease activity. MTX " HCQ. anti-TNF biologic because of a serious adverse event. add or switch to an anti-TNF If a patient has moderate or high disease activity after biologic (rectangle C of Figure 2.wiley. defined as a disease duration <6 months. minocycline.. level of evidence If a patient has high disease activity after failing an A–C). or leflunomide should be to a lack or loss of benefit.. presence of rheumatoid nodules. Felty’s syndrome). * Definitions of disease activity are discussed in Tables 2 and 3 and Supplementary Appendix 4 (available in the online version of this article at http://onlinelibrary. level of evidence B and C). Figure 2. 2012 American College of Rheumatology recommendations update for the treatment of early rheumatoid arthritis (RA). erate or high disease activity. and sulfasalazine " HCQ). failing an anti-TNF biologic because of a nonserious ad- . anti-TNF ! anti–tumor necrosis factor. and bony erosions by radiograph (38). then metho. For the level of evidence supporting each recommendation. † Patients were categorized based on the presence or absence of 1 or more of the following poor prognostic features: functional limitation (e. of a non-TNF biologic. hydroxychloroquine.com/journal/10. with some exceptions (e.1002/(ISSN)2151-4658). after 3 months of anti-TNF biologic therapy and this is due trexate. which is most commonly MTX based.g. Switching among biologic agents due to lack of benefit If after 3 months of DMARD monotherapy (in patients or loss of benefit. and triple therapy (MTX " HCQ " sulfasalazine) as defined in Table 2. as an alternative to the DMARD recom. leflunomide [LEF]. without poor prognostic features). biologic or a non-TNF biologic is recommended (rectan- If after 3 months of methotrexate or methotrexate/ gles F and G of Figure 2. or high. and sulfasala- zine). positive rheumatoid factor or anti– cyclic citrullinated peptide antibodies (33–37). level of evidence B and C). please see Supplementary Appendix 7 (available in the online version of this article at http://onlinelibrary.g. mendation just noted above. level therapy or after a second DMARD. of evidence C). Health Assessment Questionnaire score or similar valid tools).632 Singh et al Early RA Low High Disease Activity* Moderate Target Low Without Features of Poor With Without With Features of Poor Disease Prognosis † Prognosis† Activity or Remission Combination DMARD Anti-TNF with or without MTX DMARD monotherapy therapy Or DMARD monotherapy Or (double and triple Combination DMARD therapy HCQ and MTX therapy)‡ (double and triple therapy)‡ Figure 1. the panel recommends add. anticipation that a longer time may be required for efficacy nation therapy. or events.. level of evidence C). An assessment period If a patient has moderate or high disease activity after 3 of 6 months was chosen rather than 3 months.1002/(ISSN)2151-4658) and were categorized as low. ‡ Combination DMARD therapy with 2 DMARDs. DMARD ! disease- modifying antirheumatic drug (includes hydroxychloroquine [HCQ]. then add another non-methotrexate after 6 months of a non-TNF biologic and the failure is due DMARD or switch to a different non-methotrexate DMARD to a lack or loss of benefit. MTX " sulfasalazine.com/journal/10. rituximab (rectangles C and D of Figure 2. switch to another non-TNF (rectangle B of Figure 2.wiley. Switching among biologic agents due to harms/adverse ing or switching to an anti-TNF biologic. methotrexate [MTX]. MTX " LEF. DMARD combination. abatacept. extraarticular disease (e. If after 3 months of intensified DMARD combination switch to a non-TNF biologic (rectangle E of Figure 2. biologic or an anti-TNF biologic (rectangles F and G of Switching from DMARDs to biologic agents. Initiating and switching among DMARDs.g. moderate. a patient deteriorates If a patient still has moderate or high disease activity from low to moderate/high disease activity. RA vasculitis. due to the months of methotrexate monotherapy or DMARD combi. switching to another anti-TNF added (rectangle A of Figure 2.

g. where reassessment is recommended at 6 months due to a longer anticipated time for peak effect. infliximab. or high.2012 ACR RA Treatment Recommendations 633 Established RA Low Disease Low Disease Activity* Activity* with Poor Prognosis† without OR Poor Prognosis† Moderate/ High Disease Activity MTX monotherapy or Combination DMARD therapy DMARD monotherapy (including double or triple therapy)‡ Reassess§ Reassess§ B. the option is to add or switch to an anti-TNF biologic. ** Serious adverse events were defined per the US Food and Drug Administration (FDA. Add OR switch to anti-TNF biologic # Remission Abatacept OR Rituximab Reassess§ Reassess†† If serious adverse OR OR if non-serious if any adverse event** adverse event** event ‡‡ E. extraarticular disease (e. sulfasalazine " HCQ).g. certolizumab pegol.com/journal/10. or an adverse event requiring intervention to prevent permanent impairment or damage. or sulfasalazine. MTX. and bony erosions by radiograph (38).1002/(ISSN)2151-4658). † Features of poor prognosis included the presence of 1 or more of the following: functional limitation (e. * Definitions of disease activity are discussed in Tables 2 and 3 and Supplementary Appendix 4 (available in the online version of this article at http://onlinelibrary. †† Reassessment after treatment with a non-TNF biologic is recommended at 6 months due to anticipation that a longer time to peak effect is needed for non-TNF compared to anti-TNF biologics. § Reassess after 3 months and proceed with escalating therapy if moderate or high disease activity in all instances except after treatment with a non-TNF biologic (rectangle D). the management algorithm may begin at an appropriate rectangle in the figure.g. Disease-modifying antirheumatic drugs (DMARDs) include hydroxychloroquine (HCQ). The FDA definition of serious adverse event includes death. presence of rheumatoid nodules. positive rheumatoid factor or anti– cyclic citrullinated peptide antibodies (33–37).com/journal/10. HCQ or LEF¶ to another (as appropriate) DMARD Reassess§ Reassess§ Target Low Disease D. Switch to a non-TNF biologic F. Add MTX. moderate. rituximab. methotrexate (MTX).wiley. please see Supplemen- tary Appendix 7 (available in the online version of this article at http://onlinelibrary. Felty’s syndrome). LEF. Add or switch A.. Add or switch to Activity or C. HCQ. life-threatening event. defined as a disease duration >6 months or meeting the 1987 ACR classification criteria. Health Assessment Questionnaire score or similar valid tools). RA vasculitis. initial or prolonged hospitalization. and triple therapy (MTX " HCQ " sulfasalazine). leflunomide (LEF). and golimumab. all other adverse events were considered nonserious adverse events.. Switch to another type or category of anti-TNF or non-TNF biologic Figure 2. etanercept. Anti–tumor necrosis factor (anti-TNF) biologics include adalimumab.1002/(ISSN)2151-4658) and were categorized as low. azathioprine and cyclosporine were considered but not included). For the level of evidence supporting each recommendation. ‡ Combination DMARD therapy with 2 DMARDs. or sulfasalazine.. MTX " LEF. DMARD monotherapy refers to treatment in most instances with HCQ. minocycline may also be used. which is most commonly MTX based. Depending on a patient’s current medication regimen. with few exceptions (e. or tocilizumab (therapies are listed alphabetically). congenital anomaly. MTX " HCQ. . MTX " sulfasalazine.wiley. MTX. 2012 American College of Rheumatology (ACR) recommendations update for the treatment of established rheumatoid arthritis (RA). disability. see below). ¶ LEF can be added in patients with low disease activity after 3– 6 months of minocycline. where appropriate. Non-TNF biologics include abatacept. ‡‡ Any adverse event was defined as per the US FDA as any undesirable experience associated with the use of a medical product in a patient. and sulfasalazine (therapies are listed alphabetically. # If after 3 months of intensified DMARD combination therapy or after a second DMARD has failed. rather than only at the top of the figure. in few instances. minocycline. Switch to anti-TNF biologic OR non-TNF biologic Reassess§ G.

regardless of risk fac- biologic agent if those patients would otherwise qualify for tors for LTBI (diamond A of Figure 3).634 Singh et al Table 4. The panel recommends that etanercept biologic in RA patients with CHF that is New York Heart could potentially be used in RA patients with hepatitis C Association (NYHA) class III or IV and who have an ejec- requiring RA treatment (Table 4). with a history of a solid cancer within the past 5 years owing to the exclusion of such patients from participation 2. patient’s medical history to identify risk factors for TB Malignancies. solid malignancies more than 5 years ago or who have The panel recommends the tuberculin skin test (TST) or been treated for nonmelanoma skin cancer more than 5 interferon-#–release assays (IGRAs) as the initial test in all years ago. prothrombin time. ‡ Little is known about the effects of biologic therapy on solid cancers treated within the past 5 years. for all recommendations except for initiation of biologic erable adverse events) and in RA patients with treated agents in patients being treated for latent TB infection chronic hepatitis B with Child-Pugh class B and higher [LTBI]. CHF. with a survival rate of 70 – 80% (12). The panel only recommends starting or resuming ritux- TNF biologic (rectangle F of Figure 2. 3) a failing a non-TNF biologic because of an adverse event previously treated melanoma skin cancer. malignancy within the last 5 years. palpitation. § NYHA class III ! patients with cardiac disease resulting in marked limitation of physical activity. malignancy. verse event. NYHA ! New York Heart Association. or CHF. It recommends the this RA management strategy (Table 4). The Child-Pugh classification liver disease scoring system is based on the presence of albumin. Patients with a score of 10 or more (in the class C category) have a prognosis with 1-year survival being $50%. for details of Child-Pugh classification. please refer to Table 2. or congestive heart failure* Level of Comorbidity/clinical circumstance Recommended Not recommended evidence Hepatitis Hepatitis C Etanercept C Untreated chronic hepatitis B or with treated chronic Any biologic agent C hepatitis B with Child-Pugh class B and higher† Malignancy Treated solid malignancy %5 years ago or treated Any biologic agent C nonmelanoma skin cancer %5 years ago Treated solid malignancy within the last 5 years or Rituximab C treated nonmelanoma skin cancer within the last 5 years‡ Treated skin melanoma‡ Rituximab C Treated lymphoproliferative malignancy Rituximab C Congestive heart failure NYHA class III/IV and with an ejection fraction of Anti-TNF biologic C "50%§ * For definitions and key terms. Little is logic or an anti-TNF biologic (rectangle F of Figure 2. in clinical trials and the lack of studies examining the risk malignancy. switch to another anti-TNF biologic or a non. Less than ordinary physical activity causes fatigue. 2012 American College of Rheumatology recommendations update for the use of biologic agents in patients otherwise qualifying for the rheumatoid arthritis treatment with a history of hepatitis. the panel recommends starting or resuming any RA patients starting biologic agents. Patients with class A or B have a better prognosis of 5 years. † Therapy defined as an antiviral regimen deemed appropriate by an expert in liver diseases. level known about the effects of biologic therapy in patients of evidence C). of recurrent cancer in this subgroup of patients. For patients who have been treated for (specified by the CDC) (Table 2). The panel also recommends not using biologic agents in RA patients with untreated chronic hepatitis B (disease 3. qualifying for more aggressive treat. or anginal pain. If any physical activity is undertaken. Use of biologic agents in RA patients with hepatitis. see Table ommends screening to identify LTBI in all RA patients 2) (12). The panel recommends not using an anti-TNF Hepatitis B or C. switch to another non-TNF bio. The panel did not make recommendations regard. Symptoms of cardiac insufficiency or of anginal syndrome may be present even at rest. regard- ing the use of any biologic agent for treatment in RA less of the presence of risk factors for LTBI (diamond A of patients with a history of hepatitis B and a positive hepa. ment (level of evidence C for all recommendations). due to exclusion of these patients from most randomized controlled trials. NYHA class IV ! patients with cardiac disease resulting in inability to carry out any physical activity without discomfort. total bilirubin. The panel rec- (Table 4. 2) a previously treated If a patient has moderate or high disease activity after nonmelanoma skin cancer within the last 5 years. level of evidence B imab in RA patients with: 1) a previously treated solid and C). ascites. being considered for therapy with biologic agents. discomfort is increased (13). use of the IGRA over the TST in patients who had previ- . They are comfortable at rest. anti-TNF ! anti–tumor necrosis factor. where the level of evidence is B). Figure 3) (14). and encephalopathy. dyspnea. ously treated lymphoproliferative malignancy. tion fraction of 50% or less (Table 4) (13). or 4) a previ- (serious or nonserious). It recommends that clinicians assess the titis B core antibody. TB screening for biologic agents (level of evidence C not treated due to contraindications to treatment or intol.

The level of evidence supporting each recommendation for TB reactivation was “C. 2012 American College of Rheumatology recommendations update for tuberculosis (TB) screening with biologic agent use. No Latent or Active TB Negative Chest Positive (presume uninfected) § Radiograph¶ C.” except for initiation of biologic agents in patients being treated for latent TB infection. sputum.g. Latin America. children. rather than only at the top of the figure. Eastern Europe. even with a negative repeat TST or IGRA. and infants. or persons who abuse drugs or alcohol. possibly including medically underserved. Africa.g. Negative Sputum for Positive AFB (to rule out active TB)# Latent TB** Active TB** Completion of at least 1 month Completion of treatment for treatment for latent TB** active TB** Start (or resume) biologic immediately D. foreign-born persons from areas that have a high incidence of active TB (e.. the management may begin at an appropriate rectangle in the figure. and adolescents exposed to adults who are at an increased risk for latent M tuberculosis infection or active TB (14). † Interferon-#–release assay (IGRA) is preferred if the patient has a history of BCG vaccination. These patients need monitoring for clinical signs and symptoms of recurrent TB disease. Asia. and homeless shelters). long-term care facilities.. †† Patients who test positive for TST or IGRA at baseline often remain positive for these tests even after successful treatment of TB. health care workers who serve clients who are at an increased risk for active TB. and Russia).g. Initial Biologic Agents Negative TST or IGRA† * Positive Repeat/ Rescreen (only if TB risk factors‡ present) B. populations defined locally as having an increased incidence of latent Mycobacterium tuberculosis infection or active TB. § If the patient is immunosuppressed and false-negative results are more likely. especially if visits are frequent or prolonged. . since repeating tests will not allow help in diagnosis of recurrent TB. ‡ Risk factors for TB exposure are defined based on a publication from the US Centers for Disease Control and Prevention as: close contacts of persons known or suspected to have active TB.2012 ACR RA Treatment Recommendations 635 TB Screening for A. ¶ Chest radiograph may also be considered when clinically indicated in patients with risk factors. Depending on a patient’s current therapy. residents and employees of congregate settings whose clients are at an increased risk for active TB (e.” * Anergy panel testing is not recommended. # Obtain respiratory (e.. ** In a patient diagnosed with latent or active TB. correctional facilities. screen annually for Latent TB†† Figure 3. If risk factors for future or ongoing TB exposure. bronchoalveolar lavage fluid) or other samples as clinically appropriate for acid-fast bacilli (AFB) smear and culture and consider referral to a TB specialist for further evaluation and treatment. persons who visit areas with a high prevalence of active TB. consider repeating screening test(s) with tuberculin skin test (TST) or IGRA. low-income populations. consider referral to a specialist for the recommended treatment. where the level of evidence was “B.

influ- graph and. ** According to the RAND/UCLA Appropriateness Method.636 Singh et al Table 5. † The Centers for Disease Control and Prevention also recommends a one-time pneumococcal revaccination after 5 years for persons with chronic conditions such as rheumatoid arthritis (RA). recombinant (human examination to check for the presence of active TB (dia. Discussion tive TB.. as applicable (Figure 3). These patients biologic agents. please refer to Table 2. 2012 American College of Rheumatology recommendations update regarding the use of vaccines in patients with RA starting or currently receiving DMARDs or biologic agents* Recombinant Live attenuated Killed vaccines vaccine vaccine Influenza Human Herpes Pneumococcal† (intramuscular) Hepatitis B‡ papillomavirus zoster Before initiating therapy DMARD monotherapy " " " " " Combination DMARDs§ " " " " " Anti-TNF biologics¶ " " " " " Non-TNF biologics# " " " " " While already taking therapy DMARD monotherapy " " " " " Combination DMARDs " " " " " Anti-TNF biologics¶ " " " " Not recommended** Non-TNF biologics# " " " " Not recommended** * Evidence level was C for all of the vaccination recommendations. ously received a BCG vaccination. DMARDs ! disease- modifying antirheumatic drugs. # Non-TNF biologics include abatacept.g. cine (recombinant) should be undertaken in RA patients pressed RA patients with risk factors for LTBI and negative already taking a DMARD or a biologic agent (Table 5). panel members judged it as “not appropriate” and therefore it qualifies as “not recommended” (median score on appropriateness scale was 1). ¶ Anti-TNF biologics include adalimumab. the panel recommends that a repeat The panel recommends vaccination with herpes zoster TST or IGRA could be considered 1–3 weeks after the vaccine in RA patients already taking a DMARD. or work in situations where TB exposure rigorous evidence-based group consensus process. and hepatitis B). a negative TST nation with indicated pneumococcal (killed). For definitions and key terms. due to the high false. and HPV vac- bility that a patient has LTBI. Accordingly. rent TB. anti-TNF ! anti–tumor necrosis factor. panel recommends that all killed (pneumococcal. hepatitis B (killed). Treatment with biologic agents can be initiated or resumed after 1 month of latent TB treatment with antitubercular medications and after completion of the treatment of ac. ceiving DMARDs or biologic agents. data . § DMARDs include hydroxychloroquine. The is likely while they continue treatment with biologic 2012 update addresses the use of DMARDs and biologic agents (diamond D of Figure 3). Vaccination in patients starting or currently receiv- positive test rates for TST (Figure 3). the panel recommends appropriate antitubercular mendations for details about dosing and timing issues treatment and consideration of referral to a specialist. We updated the 2008 ACR RA recommendations for the The panel recommends annual testing in RA patients treatment of RA (1) using the scientific evidence and a who live. travel. rituximab. leflunomide. cluded a comprehensive updated literature review. in immunosup. multiple sex partners in the previous 6 months. with few exceptions) or triple therapy (hydroxychloroquine " methotrexate " sulfasalazine). intravenous drug abuse. Patients who test positive agents. " ! recommend vaccination when indicated (based on age and risk). the use of biologic for TST or IGRA at baseline can remain positive for these agents in high-risk patients. a subsequent sputum enza intramuscular. and vaccination in patients with RA re- need monitoring for clinical signs and symptoms of recur. methotrexate. one-time revaccination is recommended if they were vaccinated !5 years previously and were age #65 years at the time of the primary vaccination. RA patients with a negative live attenuated (herpes zoster) vaccinations should be un- screening TST or IGRA may not need further evaluation in dertaken before starting a DMARD or a biologic agent the absence of risk factors and/or clinical suspicion for TB. Since patients with RA may have false-negative TST or It also recommends that. and monds B and C of Figure 3). All vac- initial negative screening (diamond A of Figure 3). and sulfasalazine (listed alphabetically) and combination DMARD therapy included double (most methotrexate based. and tocilizumab (listed alphabetically). since repeating tests will not help in the diagnosis The rigorous process to which we referred above in- of recurrent TB. 4. cines should be given based on age and risk. if not previously done. initial screening tests. The initial or repeat TST or IGRA should have a chest radio. (Table 5). etanercept. ‡ If hepatitis risk factors are present (e. For persons ages !65 years. and physi- If the RA patient has active or latent TB based on the test cians should refer to vaccine instructions and CDC recom- results. minocycline. TB screening with the use of tests even after successful treatment of TB. certolizumab pegol. papillomavirus [HPV] vaccine for cervical cancer). vacci- IGRA results due to immunosuppression. golimumab. if suggestive of active TB. related to vaccinations. influenza or IGRA should not be interpreted as excluding the possi. ing DMARDs or biologic agents as part of their RA ther- The panel recommends that RA patients with a positive apy (level of evidence C for all recommendations). and infliximab (listed alphabetically). intramuscular (killed). health care personnel). switching between therapies.

” League Against Rheumatism collaborative initiative) were they are likely to be applicable to a majority of RA patients. such as nonsteroidal antiinflammatory drugs and sive treatment in patients with early RA than in the 2008 intraarticular and oral corticosteroids. in part. ties and nuances of patient care in the real world. Recommen- fore. In addition. pies) were not within the purview of this update. Consistent with the example. the risk clinical trial extensions and observational data. It is im- for TB reactivation has become an increasingly common portant to note that the limited evidence available support- concern for clinicians and patients treating RA patients ing this recommendation comes primarily from non-RA with biologic agents.2012 ACR RA Treatment Recommendations 637 review by a panel of international experts. We speculate that this may be logic therapies (such as physical and occupational thera- related to several reasons: 1) the expectation that the ear. and other individual considerations. our TB screening and vaccination recom. This occurred when ratings mendations are concordant with the CDC recommenda. the vides a comprehensive approach for many RA patients. prehensive array of relevant clinical decisions has led to The 2008 recommendations and 2012 update attempt to many recommendations that combine literature-based simplify the treatment algorithms for patients and provid. in the context of patient preferences. As always. and only a clinician’s mendations (2– 4). The algorithm recommended pro. data using the new RA each RA patient. this article does not recommend a specific target for dations regarding the use of other antiinflammatory med- all patients. and use of a As with all recommendations. For example. recommendation statement. many of these new tion of the live herpes zoster vaccine among older patients recommendations (approximately 79%) were associated and then resuming the biologic agent shortly thereafter. low sideration of risks/benefits by the individual patient and disease activity may be an acceptable target. sus. ications. field of rheumatology as well as provided patients and The need to create recommendations that cover a com- health care providers with multiple options for treatment. published in September 2010 (23). But for other physician. classification criteria (23) may be available for evidence comorbidities. the panel did not vote on the possibility of tem- common need to extrapolate from clinical experience in porarily holding biologic therapy to facilitate administra- the absence of higher-tier evidence. each patient is appropriately left to the clinician caring for We anticipate that in the future. Of note. Several recommendations address this important forth. both in appropriate in patients with previously treated solid ma- early and established disease phases. recommendations cannot adequately convey all uncertain- rate the evidence from the 2008 process and comprehen. data and expert opinion. and nonpharmaco- ACR recommendations. the decision about what the target should be for search agendas and recommendations updates. clinical judgment for the 2012 recommendations relied on the use of the must be used. populations that included cancer patients. assessment in collaboration with the patient allows for the Because we used the same method for this update as the best risk– benefit analysis on a case-by-case basis. coupled with our formal group process rather than only tions facing both patients with RA and the treating health the approved indications from regulatory agencies. minimal additional information was found in the broader In some cases the panelists did not make a specific literature search. decide to develop broader RA guidelines that include ther- . immunizations are very important in patients certain. synthesis and formulating recommendations. scenario or when there was inability to reach consensus. on ex- aspect of vaccination of RA patients. The emergence of several new therapies for 1987 ACR RA classification criteria (24) because our liter- RA in the last decade has led to great excitement in the ature review preceded the publication of the new criteria. lignancy within the last 5 years or a previously treated Recommendations also provide guidance regarding nonmelanoma skin cancer within the last 5 years. not exceptional cases. although lier the treatment the better the outcome. All recommendations were based on scientific evidence These recommendations aim to address common ques. we were able to incorpo. rituximab was recommended as choices for treatments of patients with active RA. In particular. the ACR may life and reduce work-related disability (15–22). and malignancy. this recommendation was grounded. CHF. therapeutic decisions are best left to the careful con- sion should be the target of therapy. reflected uncertainty over a particular potential clinical tions. RA remis. 2) the thought these may be important components of RA treatment and that joint damage is largely irreversible so prevention of could also be included in separate reviews or recommen- damage is an important goal. Because these recom. These areas could be the subject of future re- patients. and 3) the data that early dations. In the future. Since the recommendations were derived though new classification criteria for RA (ACR/European considering the “common patients. These recommendations provide clinicians with evidence. recommendations related to gluco- intensive therapy may provide the best opportunity to corticoid use in RA have been published by other profes- preserve physical function and health-related quality of sional organizations (25). In The goal for each RA patient should be low disease these cases. but in others. these recommendations well-accepted validated process for developing recom. given a lack of clear evidence or clear consen- activity or remission. with level C evidence. In ideal circumstances. which is treatment choices in RA patients with comorbidities such a level C recommendation since the evidence is based on as hepatitis. These 2008 ACR RA recommendations. Al- care providers. the panel recommended more aggres. There. the studies evaluated although not all patients. pert consensus and serves to highlight an important evi- mendations were heavily informed by CDC guidance and dence gap in RA management. apply to common clinical scenarios. For sively update the recommendations. For example. and thus are labeled as level C ers. panel ratings did not achieve the level of appropriateness Due to an increasing awareness of risk of preventable needed to recommend other biologic therapies in this cir- diseases such an influenza and pneumonia (especially in cumstance since most of the panelists’ ratings were “un- the elderly).” Like many of the other recommendations put with RA.

Transplantation: endorsed by the Heart Rhythm Society. Cochrane Database Syst Rev 2010. Sensitivity and specificity of the RAND/UCLA Ap- efit assessment. 2. Dougados. Cabello JB. Cochrane Data- base Syst Rev 2009.59:762– 84. Saag.201:870 – 83. et al.33:159 –74.638 Singh et al apies that are not in this article. Kavanaugh A. Christensen R. and the Yorkshire Early Arthritis Register Consortium. O’Dell. . 17. AUTHOR CONTRIBUTIONS Walker D. Moynihan. As with this 2012 update. Suarez-Almazor ME. Evaluation and Management of Heart Failure). Chang DJ. D. Saag KG. Developing quality indicators for elderly patients undergoing ios. Bern- cussions with patients. Kahan JP. Kremer. Comparison of methotrexate monotherapy with a Study conception and design. Curtis lowing the same methodology used to develop the 2008 JR. 7. St. Juhl E. In addition. Jain. The appropriateness method. the ACR staff (Ms Regina Parker and Ms Amy Miller) diagnosis and management of chronic heart failure in the for assistance in organizing the face-to-face meeting. These rec. Agrawal. mann. Agrawal. patient preferences. Patkar. Singh. Keenan AM. with early rheumatoid arthritis. J Clin Epide- practical economic considerations. Singh.4:CD007848.htm.2:CD007649. American College of Rheumatology 2008 recommen- ACR RA recommendations. et al. J Am Coll Surg 2005. 1. Mudano. Quinn M. Beukelman. Shekelle PG. Ganiats TG. Saag. Suarez-Almazor. URL: http://www. We sen PK. 9. should be used as a guide for clinicians treating RA abdominal operations. coverage of health care services. scenarios for these medications were not in- cluded in this update. ommendations. land. FDA. Bejarano V. Burls A. Bharat.59:510 – 4. We ican Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the thank Dr. Galvez Munoz JG. patients. early or long-standing rheumatoid arthritis. 4. Conaghan PG. Biometrics 1977. and aza. In summary. Khanna. early. Comparison of employability outcomes among patients with Analysis and interpretation of data. McGory ML. Emery P. Med Decis Making ment decision can only be made by the clinician in dis. Arthritis Rheum Kavanaugh. King.Clair EW. for providing data from their 14. Singh JA. 10. Francis GS. CDC. which focus on common clinical scenar. Certolizumab pegol Addendum. and coronary revascularization and hysterectomy. Kolba. Prognostic value of Child-Turcotte cri- thank Dr. Ko CY. Ruiz Garcia of Médico Adjunto de la Unidad de Hospital. Shekelle PG.49: 1–51. O’Dell. Heart Association’s classification of cardiovascular disease as part of the patient’s complete Problem List. Furst. Gluud C. Breedveld FC. Cochrane Data- treatments. Teng GG. Effect of the early use of the anti–tumor necrosis All authors were involved in drafting the article or revising it factor adalimumab on the prevention of job loss in patients critically for important intellectual content. Rubenstein LZ. and all authors ap. evolving cutting-edge care of RA patients. Curtis. Beg S. Paulus. Robertson integrity of the data and the accuracy of the data analysis. Leong. Christensen E. to all of the data in the study and takes responsibility for the 16.4:430 –5. 8. 22:385–90. 15. Saag. Schlichting P. Fink A. Baker D. Lancet 2008. stein SJ. Bridges. Dougados. Singh JA.fda. Koch GG. Leape LL. More. new evidence on the benefits and harms of existing binder R. Anthony Turkiewicz and Dr. Lopez-Olivo MA. Agrawal. Curtis. Buch- apies.gov/ ACKNOWLEDGMENTS safety/medwatch/howtoreport/ucm053087. we provide updated recommendations for REFERENCES the use of nonbiologic and biologic treatments in RA fol. Spain. 3. Bae.54:1004 –10. Suarez-Almazor. 2004.1:CD008341. due to the Bridges. Beukelman. Kavanaugh. Wells GA. Winthrop. Furst. ización a Domicilio. US Department of Health and Human Services. berculosis infection. Patkar. Durez P. Finney C. et al. Bharat. MMWR Mortal Morb Wkly Rep 2000. Chin MH. Arthritis Rheum 2008. toid arthritis.24:228 –31. Cheryl Perry of the University of Alabama at teria in medically treated cirrhosis. Therapies that were approved after the (CDP870) for rheumatoid arthritis in adults. Arthritis covered in 2008. including consideration of comorbidities propriateness Method to identify the overuse and underuse of and concomitant medications. Morris DC. for reviewing 12. Matteson. Clin Cardiol 1999. Singh JA.112:e154 –235. Anuntiyo J. Rheum 2008. Hurst JW. Kamberg CJ. Khanna. What is a serious adverse event? 2011. We thank our 2 clinical colleagues. Shekelle P. Patkar. Moreland. 372:375– 82. Golimumab for rheuma- tions are not intended to determine criteria for payment or toid arthritis. and changes in policies to reflect the rapidly base Syst Rev 2009. Park RE. We thank Dr. anakinra. et al. Alexander RW. domised. Singh G. Schousboe. Jobanputra P. Tocilizumab for rheuma- the ACR plans to periodically update RA treatment recom. King. they are not comprehensive. Kremer. for categorical data. et al. 11. 6. Hunt SA.59: proved the final version to be published. Smolen J. et al. parallel treatment trial. While these recommendations dations for the use of nonbiologic and biologic disease-mod- are extensive and include new areas and new agents not ifying antirheumatic drugs in rheumatoid arthritis. Bharat. Paulus. Developed in ham) for providing expert advice regarding new literature collaboration with the American College of Chest Physicians related to clinical scenarios of infection risk in the context and the International Society for Heart and Lung of biologic agents. Noorbaloochi S. Hall S. Dou. Saiz Cuenca ES. miol 2001. Chatham. Dr. Lopez-Olivo MA. taking into account their risk/ben. cyclosporine. Beukelman. Targeted tuberculin testing and treatment of latent tu- Cochrane systematic review on certolizumab pegol in RA. Cochrane Database Syst Rev 2010. Landis JR. Bala M. Feldman AM. original literature review are not included in these recom. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Bombardier. Fauerholdt L. moderate to severe rheumatoid arthritis (COMET): a ran- gados. double-blind. Cir- culation 2005. mendations depending upon the availability of new ther. Michael Saag (University of Alabama at Birming. Singh. Gary Feldman. combination of methotrexate and etanercept in active. ACC/AHA 2005 guideline update for the port. Singh had full access 1467–74. 5. Acquisition of data. The measurement of observer agreement mendations. et al. Abraham WT. Ruiz Garcia V. Dr. The use of the New York for her help in copyediting this manuscript. Birmingham Center for Clinical and Translational Science 13. Hepatology 1984. Furst. with the clear understanding that the best treat.7:CD008331. Reece R. and adult: a report of the American College of Cardiology/Amer- Ms Amy Miller for help in revision of the manuscript. Volk. Jain. Han C. thioprine. 2008. These recommenda. Patkar NM. Ander- the recommendations and providing initial comments. We thank Ms Mary Elkins Melton for administrative sup. infrequent use of gold.

Arthritis Rheum 2004. sion in patients with rheumatoid arthritis. Dougados M. A simplified disease activity index for rheuma- 2005. Ann Rheum Dis 41. Boers M.32:9 – 44. Pincus T. A comparison of etanercept and 37. 43. et al. The definition and measurement of League Against Rheumatism provisional definition of remis- disease modification in inflammatory rheumatic diseases. Funovits J. Minimal disease activity for rheumatoid arthritis: a of Disease Activity in Rheumatology (RADAR). Stucki G.62:2569 – 81. Nell VP.21:755– 87. The ford) 2003. Ann Rheum Dis 1977. without rulers. Keystone E. 27. Fransen J. Han C. Edworthy SM. Clin Rheumatol 2007. Ann Rheum Dis 2003. Michaud K. Akay G. Radiographic changes in early rheuma- criteria: an American College of Rheumatology/European toid disease.49 Suppl:S214 –24. and radiological efficacy of initial vs delayed treatment with 36. Anderson JJ. Arthritis Rheum Dis Clin North Am 2006. for the Active-Controlled Study of Patients rheumatoid factor isotypes on disease activity and severity in Receiving Infliximab for the Treatment of Rheumatoid Arthri.32:2016 –24. Jidell E. Pincus T. Berglin E.63:573– 86. observational studies. Cantagrel A. Arthritis Rheum (MDHAQ) and Routine Assessment of Patient Index Data 2005.54:716 –22. Gatterova J. EULAR recommendations for the man. Goekoop-Ruiterman YP. Turgay M. and Rheuma- preliminary definition. Kalden JR. Rheum Dis 2009. Yazici Y. 20.7:R796 – matoid arthritis. Smolen JS. and clinical 45. Breedveld FC. Agrawal S. et al. Brooks PM. Infliximab treatment maintains employabil. Becker JC. Smolen JS. 44. Neogi T. Bathon JM. Boers M. Bresnihan B. Aletaha D. Johansson T.22:1586 –93. Ann 23. van Tuyl LH. Aletaha D. Misra R. Best Goldsmith C. Smolen JS.38:727–35. Shea B. A practical guide to scoring len JS. Smolen JS.35:206 –15.52:3873–9. van Riel PL. Meyer O. Clin tis of Early Onset Study Group. Pflugbeil S. Kinikli G. Pincus T. Emery P. Brook A. Arthritis Res Ther 2005. Emery P. Nell VP. Arthritis toid arthritis: association with severity of disease in estab- Rheum 2006. Wolfe F. Autoantibodies can be prognostic markers N Engl J Med 2000. Bathon JM. Maini RN. Acute phase reactants add little to compos- 29. Bathon 34. Van der Kooij SM.69:964 –75. van der Heijde D. Tesser JR. Aletaha D. et al. J Rheumatol Eberl G. Strand CV. Ann 25. de nated peptide before and at disease onset. Vencovsky J. Stamm T. sion in rheumatoid arthritis for clinical trials. Michaud K. Sedova L. Clin Exp Rheumatol 2005. Wells G. 2010 rheumatoid arthritis classification 38. vits J. with the DAS28 based on erythrocyte sedimentation rate.52:2625–36. Bombardier C. Dougados M. methotrexate in patients with early rheumatoid arthritis. Smolen JS.26:538 – 45. Kerstens PJ. 42. Breedveld FC. Gaujoux-Viala C.Clair EW.68:1153– 8. The American College of Rheumatology (ACR) core ite disease activity indices for rheumatoid arthritis: validation data set and derivative “patient only” indices to assess rheu.42:244 –57. Dubois A. Dougados M. and comparison thritis. .65:39 – 43. Remission and active disease in rheumatoid arthritis: a Multi-Dimensional Health Assessment Questionnaire defining criteria for disease activity states. Aggarwal A. Sundin U. Emery P. Uffmann M. et al. Cifaldi M. Felson DT. 40. Rheum Dis 2003. predicted by presence of antibodies against cyclic citrulli- 21.2012 ACR RA Treatment Recommendations 639 18. controlled trial. trials: the Patient Activity Scale (PAS/PAS-II). Wells G. A composite disease activity Rheum 2003. calculators. Rheum 2011. Keystone E. Ward MM. Stamm T. Rapid Assessment et al. Anticitrullinated protein/peptide antibody toid arthritis. scale for clinical practice. Smo. et al. of a clinical activity score. Machold K. MH. et al. Disease Activity Score-28 (DAS28). et al. Revicki D.50:3432– mans G. liminary definition of improvement in rheumatoid arthritis. Teng J. St. Schiff M. Pesakova V. toid Arthritis Disease Activity Index (RADAI). disease-modifying antirheumatic drugs. Tokgoz G. 13. Combination of infliximab Rheumatol 2007. Silman AJ. (DAS28) and European League Against Rheumatism response Cooper NS. Disease Activity Score 30.31:315–24. le Cessie S. Ann Rheum Dis 2009. Bergman M. J Rheumatol Suppl 2002. Labarre C. Aletaha D.65:453– 8. Arnett FC. Goupille P. and limitations in questionnaire use for regulatory purposes. Effects of JM. Fries JF. Schiff MH. van Zeben D. Ann Rheum Dis 2006. Keystone EC. Felson DT. Wells GA. of an erosive disease in early rheumatoid arthritis. Arthritis Rheum 1988. Chen N. Felson DT. Hall- randomized. et al.32:2410 –5. et al. infliximab plus methotrexate in patients with early rheuma. Smolen J. van der Heijde DM. Funo- 2010. and methotrexate therapy for early rheumatoid arthritis: a 35. assays in early rheumatoid arthritis for predicting five year 22. J Rheumatol 2008. Zhang B. Arthritis 31. Ates A. et al. Rheumatology (Ox- 32. Bing. Machold KP. et al. (DAS).36:71–3. Machacek S. Emery P.68:954 – 60. Landewe R. McShane DJ. ham CO III. toid arthritis for use in clinical practice. (RAPID) scores in 10-20 seconds for use in standard clinical 28. et al. Arthritis Rheum 2005. Arthritis Rheum 1995.26:201– 4. Corbett M. American College of Rheumatology pre. 19. Adalimumab plus Disease Activity Score is not suitable as the sole criterion for methotrexate improved SF-36 scores and reduced the effect of initiation and evaluation of anti–tumor necrosis factor ther- rheumatoid arthritis (RA) on work activity for patients with apy in the clinic: discordance between assessment measures early RA. League Against Rheumatism collaborative initiative. et al. Arthritis 39.62:120 – 6. patients with rheumatoid arthritis: a comparative study. Clinical disease onset. Furst D. et al. Wadell G. Radiological outcome in rheumatoid arthritis is 43. Validation of the 28-joint Disease Activity Score 24. care. Schiff radiographic damage. et al. Bloch DA. Kimel M. Rheum 2010.23 Suppl:S109 – 806. The American Rheumatism Association criteria based on C-reactive protein against disease progres- 1987 revised criteria for the classification of rheumatoid ar. Kafkova J. Fleischmann RM. Preventing joint damage as the best measure of agement of rheumatoid arthritis with synthetic and biological biologic drug therapy. websites or computers. 33. Pract Res Clin Rheumatol 2007. Simon LS. J Rheumatol 2005. Martin RW. Smolen JS. lished RA. Pincus T. American College of Rheumatology/European 26. and by IgA-RF at Vries-Bouwstra JK.62:427–30. Furst D. Wolfe F. Autoantibodies in rheuma- ity in patients with early rheumatoid arthritis.