Arthritis & Rheumatism (Arthritis Care & Research)
`Vol. 59, No. 6, June 15, 2008, pp 762–784
`DOI 10.1002/art.23721
`© 2008, American College of Rheumatology
`SPECIAL ARTICLE
`
`American College of Rheumatology 2008
`Recommendations for the Use of Nonbiologic and
`Biologic Disease-Modifying Antirheumatic Drugs
`in Rheumatoid Arthritis
`KENNETH G. SAAG,1 GIM GEE TENG,1 NIVEDITA M. PATKAR,1 JEREMY ANUNTIYO,2
`CATHERINE FINNEY,2 JEFFREY R. CURTIS,1 HAROLD E. PAULUS,2 AMY MUDANO,1 MARIA PISU,1
`MARY ELKINS-MELTON,1 RYAN OUTMAN,1 JEROAN J. ALLISON,1 MARIA SUAREZ ALMAZOR,3
`S. LOUIS BRIDGES, JR.,1 W. WINN CHATHAM,1 MARC HOCHBERG,4 CATHERINE MACLEAN,5
`TED MIKULS,6 LARRY W. MORELAND,7 JAMES O’DELL,5 ANTHONY M. TURKIEWICZ,1 AND
`DANIEL E. FURST2
`
`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 determination
`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.
`
`Introduction
`The majority of patients with a confirmed diagnosis of
`rheumatoid arthritis (RA) use nonbiologic disease-modify-
`
`ing antirheumatic drugs (DMARDs) and the rate of biologic
`DMARD use is rising rapidly (1,2). The American College
`of Rheumatology (ACR) has not updated its recommenda-
`
`Dr. Saag’s work was supported by the Agency for Health-
`care Research and Quality (grant U18-H510389), the Uni-
`versity of Alabama, Birmingham Center for Education and
`Research on Therapeutics of Musculoskeletal Diseases, and
`a grant from the American College of Rheumatology. Drs.
`Pisu, Allison, and Moreland’s work was supported by a
`grant from the American College of Rheumatology. Dr.
`Furst’s work was supported by a grant from the American
`College of Rheumatology and the NIH.
`1Kenneth G. Saag, MD, MSc, Gim Gee Teng, MD, Nivedita
`M. Patkar, MD, MSPH, Jeffrey R. Curtis, MD, MPH, Amy
`Mudano, MPH (current address: Blue Cross and Blue Shield
`of Alabama, Birmingham), Maria Pisu, PhD, Mary Elkins-
`Melton, BA, Ryan Outman, MS, Jeroan J. Allison, MD, MS,
`S. Louis Bridges, Jr., MD, PhD, W. Winn Chatham, MD,
`Anthony M. Turkiewicz, MD: University of Alabama, Bir-
`mingham; 2Jeremy Anuntiyo, MD, Catherine Finney, MD,
`Harold E. Paulus, MD, Daniel E. Furst, MD: University of
`California, Los Angeles; 3Maria Suarez Almazor, MD, MPH:
`University of Texas, MD Anderson, Houston; 4Marc Hoch-
`berg, MD, MPH: University of Maryland, Baltimore; 5Cathe-
`rine MacLean, MD, PhD, James O’Dell, MD: University of
`California, Los Angeles, RAND Corporation, Santa Monica,
`and West Los Angeles VAMC; 6Ted Mikuls, MD, MSPH:
`
`762
`
`University of Nebraska, Omaha; 7Larry W. Moreland, MD:
`University of Pittsburgh, Pittsburgh, Pennsylvania.
`Dr. Saag has received consultant fees (less than $10,000
`each) from Roche, UCB, Nitec, and Amgen and research
`support from Abbott, Amgen, Centecor, Roche, and Wyeth.
`Dr. Curtis has received consultant
`fees, speaking fees,
`and/or honoraria (less than $10,000 each) from Roche,
`Merck, Procter and Gamble, Eli Lilly, UCB, and Novartis
`and research support from Amgen, Eli Lilly, Merck, Novar-
`tis, Procter and Gamble, and Roche. Dr. Paulus has received
`consultant fees (less than $10,000 each) from Amgen, Roche
`and Mathematica. Dr. Chatham has received speaking fees
`and honoraria (less than $10,000 each) from Bristol-Myers
`Squibb and Amgen. Dr. Hochberg has received consultant
`fees (less than $10,000 each) from Amgen and Bristol-Myers
`Squibb. Dr. MacLean owns stock and/or holds stock options
`in WellPoint. Dr. Mikuls has received speaking fees (less
`than $10,000 each) from Genentech and Amgen and unre-
`stricted grants from Abbott, Amgen, and Bristol-Myers
`Squibb. Dr. Moreland has received consultant fees, speaking
`fees, and/or honoraria (less than $10,000 each) from Roche,
`Bristol-Myers Squibb, Centocor, Pfizer, Amgen, Incyte, and
`Genentech. Dr. O’Dell has received consultant fees and speak-
`ing fees (less than $10,000) from Abbott. Dr. Turkiewicz has
`received consultant fees and speaking fees (less than $10,000)
`
`Medac Exhibit 2049
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 00001
`
`

`

`Recommendations for the Use of Nonbiologic and Biologic DMARDs in RA
`
`763
`
`tions for nonbiologic DMARDs since 2002 (3) and has not
`previously developed recommendations
`for biologic
`agents. Although past guidelines have been derived from
`an informal consensus approach, we used a formal group
`process to develop recommendations that were as evi-
`dence-based as possible.
`To develop these new recommendations on behalf of the
`ACR, following the principles delineated by the Appraisal
`of Guidelines for Research and Evaluation (AGREE) Col-
`
`from Pfizer, honoraria (less than $10,000 each) from Amgen,
`Wyeth, and Hoffman-LaRoche, and consultant fees, speak-
`ing fees, and honoraria (more than $10,000) from Abbott. Dr.
`Furst has received consultant fees, speaking fees, and/or
`honoraria (less than $10,000 each) from Abbott, Actelion,
`Amgen, Array, Biogenidec, Bristol-Myers Squibb, Centocor,
`Genentech, Gilead, GlaxoSmith-Kline, Encysive, Nitec, No-
`vartis, Roche, TAP, UCB, Wyeth, and Xoma and research
`support from Actelion, Bristol-Myers Squibb, Celgene, Ge-
`nentech, Gilead, Novartis, Roche, and UCB.
`Members of the Core Expert Panel: Kenneth G. Saag, MD,
`MSc, Jeffrey R. Curtis, MD, MPH, Harold E. Paulus, MD,
`Jeroan J. Allison, MD, MS, Maria Suarez Almazor, MD,
`MPH, S. Louis Bridges, Jr., MD, PhD, W. Winn Chatham,
`MD, Marc Hochberg, MD, MPH, Catherine MacLean, MD,
`PhD, Ted Mikuls, MD, MSPH, Larry W. Moreland, MD,
`James O’Dell, MD, Anthony M. Turkiewicz, MD, Daniel E.
`Furst, MD.
`Members of the Task Force Panel: Claire Bombardier, MD,
`MSc (University of Toronto, Toronto, Ontario, Canada),
`Robin K. Dore, MD (University of California, Los Angeles),
`Linda F. Golodner, BA (National Consumers League, Wash-
`ington, DC), Sean Hennessy, PharmD, PhD (University of
`Pennsylvania School of Medicine, Philadelphia), Arthur F.
`Kavanaugh, MD (University of California, San Diego),
`Dinesh Khanna, MD, MSC (University of Cincinnati, Cincin-
`nati, Ohio, current address: University of California, Los
`Angeles), Joel M. Kremer, MD (Albany Medical Center, Al-
`bany, NY), Amye L. Leong, MBA (US Bone and Joint Decade,
`North Wales, PA), Eric L. Matteson, MD, MPH (Mayo Clinic,
`Rochester, MN), John T. Schousboe, MD, MS (Park Nicollet
`Clinic, St. Louis Park, MN, and University of Minnesota,
`Minneapolis), Anna N. A. Tosteson, ScD (Dartmouth Medi-
`cal School, Lebanon, NH), Peter Tugwell, MD (University of
`Ottawa, Ottawa, Ontario, Canada), Yusuf Yazici, MD (New
`York University Hospital for Joint Diseases, New York).
`Additional members of the University of Alabama, Bir-
`mingham (UAB) and University of California, Los Angeles
`(UCLA) Working Groups: Timothy Beukelman, MD, Maria
`I. Danila, MD, MS, Jeffrey Faggard, MD, Angelo Gaffo, MD,
`Allyson McDonough, MD, Raj Nair, MD, Bita Shakoory, MD,
`Martha Verchot, MS, MLS (UAB), Paul Maranian, MS,
`Shruti Scott, MPH (UCLA).
`Content Specific Expert Advisors: Kevin L. Winthrop, MD,
`MPH (tuberculosis; Oregon Health and Science University,
`Portland), Gregory J. Gores, MD (hepatology; Mayo Clinic,
`Rochester, MN), Michael Saag, MD (human immunodefi-
`ciency virus; University of Alabama, Birmingham), Paul
`Shekelle, MD, PhD (RAND/UCLA Appropriateness Method;
`University of California, Los Angeles).
`The American College of Rheumatology is an indepen-
`dent, professional, medical, and scientific society, which
`does not guarantee, warrant, or endorse any commercial
`product or service.
`Address correspondence to Daniel E. Furst, MD, Univer-
`sity of California, Los Angeles Rehabilitation Institute, 1000
`Veteran Avenue, Room 32-59, Los Angeles, CA 90025. E-
`mail: furst@mednet.ucla.edu.
`Submitted for publication December 10, 2007; accepted in
`revised form March 13, 2008.
`
`Figure 1. Methodologic process for the American College of
`Rheumatology recommendations for the use of biologic and non-
`biologic disease-modifying antirheumatic drug therapies. RAND/
`UCLA ⫽ Research and Development/University of California at
`Los Angeles.
`
`laboration (4), we first conducted a systematic review of
`scientific evidence to create an evidence report and draft
`guidelines. We addressed each of the 5 domains prespeci-
`fied by the ACR, namely: 1) indications for use; 2) screen-
`ing for tuberculosis (TB; biologic DMARDs only); 3) mon-
`itoring for side effects; 4) assessing the clinical response;
`and 5) the roles of cost and patient preferences in decision-
`making (biologic DMARDs only). A Working Group and a
`Core Expert Panel (CEP) of clinicians and methodologists
`guided the development of these recommendations. We
`next convened a Task Force Panel (TFP) of internationally-
`recognized clinicians, methodologists, and patient repre-
`sentatives with broad expertise in the use of nonbiologic
`and biologic DMARD therapies, evidence-based medicine,
`patient preference, and health care economics. They were
`to critique and rate proposed recommendations using a
`well-accepted group process, the modified Research and
`Development/University of California at Los Angeles
`(RAND/UCLA) Appropriateness Method (5) (Figure 1). Al-
`though the TFP and CEP considered drug-specific indica-
`tions from the US Food and Drug Administration (FDA)
`and other regulatory authorities, in some cases the TFP
`extrapolated recommendations outside the present bounds
`of approved labeling. Although terminology used by reg-
`ulatory agencies varies, in this article we refer to biologic
`agents as drugs.
`Disseminated under the aegis of the ACR, we recognize
`that recommendations surrounding certain issues (e.g.,
`cost considerations and TB testing approaches) may not be
`generalizable outside North America; however, we hope
`that these recommendations will have relevance to arthri-
`tis practitioners throughout the world.
`To better reflect the underlying purpose of the en-
`deavor, the output from this project is termed recommen-
`dations, rather than guidelines. These recommendations
`were developed for specialist clinicians familiar with as-
`sessing RA disease activity and disease severity. Applying
`these recommendations to clinical practice requires in-
`
`Page 00002
`
`

`

`764
`
`Saag et al
`
`dividualized patient assessment and clinical decision-
`making. The recommendations developed are not
`in-
`tended to be used in a “cookbook” or prescriptive manner
`or to limit a physician’s clinical judgment, but rather to
`provide guidance based on clinical evidence and expert
`panel input.
`
`Methods for Development of ACR RA
`Recommendations
`Systematic literature review: sources and databases.
`Literature searches for both nonbiologic and biologic
`DMARDs relied predominantly on PubMed (from January
`1, 1966 through January 31, 2007 and from January 1, 1998
`through February 14, 2007, respectively). For biologic
`DMARDs, systematic searches were also conducted using
`EMBASE, SCOPUS, Web of Science, and the International
`Pharmaceutical Abstracts
`(IPA) computerized biblio-
`graphic databases (through June 20, 2006) by applying
`medical subject headings (MeSH) and relevant keywords
`(see Appendix A, available at the Arthritis Care & Research
`Web site at http://www.interscience.wiley.com/jpages/
`0004-3591:1/suppmat/index.html). For both nonbiologic
`and biologic DMARDs, we supplemented searches by check-
`ing references cited in published systematic reviews and
`by reference to the bibliographies of the articles extracted
`from the literature reviews. To ensure as complete a listing
`as possible of available important literature, the CEP and
`TFP identified additional studies.
`Data from the FDA Adverse Event Reporting System and
`unpublished data from product manufacturers or investi-
`gators were not solicited or included in the systematic
`review unless they were identified by the literature search
`and met the inclusion criteria.
`
`Literature search domains. Literature on the following
`nonbiologic DMARDs was examined: azathioprine, hydroxy-
`chloroquine,
`leflunomide, methotrexate, minocycline,
`organic gold compounds, sulfasalazine, and, when appro-
`priate, combination therapy with methotrexate plus cyclo-
`sporine, methotrexate plus hydroxychloroquine, metho-
`trexate plus leflunomide, methotrexate plus sulfasalazine,
`sulfasalazine plus hydroxychloroquine, and methotrexate
`plus hydroxychloroquine plus sulfasalazine. Additionally,
`the medical literature was examined for 6 biologic agents:
`etanercept, infliximab, adalimumab, anakinra, abatacept,
`and rituximab.
`The 2 principles of our maximally inclusive search ap-
`proach were to address indications and therapeutic re-
`sponse to nonbiologic DMARDs and biologic agents for
`RA, and to address the potential adverse events of non-
`biologic and biologic DMARDs including TB for biologic
`DMARDs. Cost and patient preference were addressed for
`biologic DMARDs but not nonbiologic DMARDs, based on
`the specific ACR mandate for cost recommendations.
`Subheadings, MeSH terms, and synonyms for the 6 bio-
`logic DMARDs and the 6 nonbiologic DMARDs (plus 5
`nonbiologic DMARD combinations) were imputed as “sub-
`stance names” and as “text words” that were applied to the
`medical databases. Details of the search strategy are listed
`in Appendix A (available at the Arthritis Care & Research
`
`Web site at http://www.interscience.wiley.com/jpages/
`0004-3591:1/suppmat/index.html).
`
`Literature search limits and article selection criteria.
`Appropriate studies addressing the use of nonbiologic
`DMARDs and biologic agents were identified within
`each of the 5 domains that were specified by the ACR.
`Our literature search was limited to original research in-
`volving human subjects, published in English, and having
`abstracts. The search identified 3,878 citations for non-
`biologic DMARDs and 6,818 citations of potential in-
`terest for biologic therapies (see Appendix B, available at
`the Arthritis Care & Research Web site at http://www.
`interscience.wiley.com/jpages/0004-3591:1/suppmat/index.
`html). Seven reviewers (3 for biologics, 4 for nonbiologics)
`screened each title and abstract for relevance to the do-
`mains.
`Reviewers excluded articles based on abstract review if:
`1) the report was a meeting abstract, case series, or case
`report with ⬍30 patients or the study duration was ⬍6
`months; 2) nonbiologic DMARDs were used for non-RA
`conditions (e.g., psoriatic arthritis, systemic lupus ery-
`thematosus); 3) biologic DMARDs were used in health
`conditions not included in the FDA label (e.g., Wegener’s
`granulomatosis); or 4) biologic DMARDs were used in
`conditions not relevant to the ACR domains of interest
`(e.g., the use of rituximab in the treatment of lymphoma).
`Review articles and meta-analyses were excluded from our
`systematic reviews. However, meta-analyses were exam-
`ined later to find other references, and they were refer-
`enced in supplementary qualitative reviews on selected
`adverse event domains (e.g., perioperative, vaccinations,
`pregnancy).
`After exclusions based on abstract review, 801 full-
`text articles were retrieved and considered further for
`full review. This number included 515 articles that fo-
`cused on nonbiologic DMARDs, 226 that focused on bio-
`logic DMARDs, and 60 that focused on cost. For non-
`biologic DMARDs, a consensus of 2 reviewers determined
`articles not appropriate for full review. For biologic agents,
`the full text of all articles was reviewed by 2 independent
`reviewers by applying the same criteria as for nonbiologic
`DMARDs. If there was discordance on whether to include
`a study, it was resolved by a third reviewer. After addi-
`tional exclusion of reviews, non–English language articles,
`nondomain topics, unapproved disease indications, lack
`of clinical outcomes of interest, non–FDA-approved regi-
`mens, study duration ⬍6 months, and case series (n ⬍30),
`the final number of included articles for biologic agents was
`125 (see Appendices B and C, available at the Arthritis Care
`& Research Web site at http://www.interscience.wiley.com/
`jpages/0004-3591:1/suppmat/index.html). Twenty-eight ar-
`ticles that also addressed cost factors associated with bio-
`logic agents were included. For nonbiologic DMARDs,
`the number of included articles was 142 (see Appendix
`B, available at the Arthritis Care & Research Web site
`at http://www.interscience.wiley.com/jpages/0004-3591:1/
`suppmat/index.html).
`Each article about nonbiologic DMARDs was reviewed
`and key article elements entered into a database by 1 of
`4 reviewers. A random 5% of the articles were re-reviewed
`
`Page 00003
`
`

`

`Recommendations for the Use of Nonbiologic and Biologic DMARDs in RA
`
`765
`
`Table 1. Instruments used to measure rheumatoid arthritis disease activity*
`
`Instrument (ref.)
`
`Score range
`
`Disease Activity Score in 28 joints (253)
`Simplified Disease Activity Index (103)
`Clinical Disease Activity Index (103)
`Rheumatoid Arthritis Disease Activity Index (254)
`PAS or PASII (14)
`Routine Assessment Patient Index Data (255)
`
`0–9.4
`0.1–86.0
`0–76.0
`0–10
`0–10
`0–30
`
`Thresholds of disease activity
`
`Low
`
`ⱕ3.2
`ⱕ11
`ⱕ10
`⬍2.2
`⬍1.9
`⬍6
`
`Moderate
`
`⬎3.2 and ⱕ5.1
`⬎11 and ⱕ26
`⬎10 and ⱕ22
`ⱖ2.2 and ⱕ4.9
`ⱖ1.9 and ⱕ5.3
`ⱖ6 and ⱕ12
`
`High
`
`⬎5.1
`⬎26
`⬎22
`⬎4.9†
`⬎5.3
`⬎12
`
`* Methods for calculating various instrument scores are shown in Appendix E (available at the Arthritis Care & Research Web site at http://
`www.interscience.wiley.com/jpages/0004-3591:1/suppmat/index.html). PAS ⫽ Patient Activity Scale.
`† Median.
`
`by one reviewer; concordance on this re-review was
`⬎80%. For biologic agents, the article review was per-
`formed by 1 reviewer and checked by a second reviewer.
`Discordance on the database entries was resolved by con-
`sensus between the 2 reviewers, and in the event of con-
`tinuing disagreement, the opinion of a third reviewer was
`considered final. For each included article, study charac-
`teristics were summarized in tabular and graphic format,
`and a synthesis of the systematic literature review was
`developed into a comprehensive evidence report and used
`to craft clinical scenarios (described below and in Appen-
`dix D, available at the Arthritis Care & Research Web site
`at http://www.interscience.wiley.com/jpages/0004-3591:
`1/suppmat/index.html).
`
`Quality assessment of articles included in the literature
`review. The quality of randomized controlled trials (RCTs)
`was assessed by 2 reviewers using the Jadad instrument
`(6). Higher scores on this 5-point scale indicate higher
`quality. Articles related to nonbiologic DMARDs had a
`median Jadad score of 3 (interquartile range [IQR] 2– 4).
`For biologic DMARDs, articles reviewed for these recom-
`mendations had a median Jadad score of 5 (IQR 3–5),
`reflecting the more modern study designs for the biologic
`DMARDs.
`For observational studies (case– control and cohort), we
`used the Newcastle-Ottawa Scale (NOS) (range 0 –9) (7).
`Higher scores on this scale indicate higher quality. For
`nonbiologic DMARD articles reviewed, the median NOS
`score was 3 (IQR 2.25–3.75), while the median NOS score
`for the biologic DMARDs was 7 (IQR 5–8), reflecting the
`newer literature and study designs for the biologic DMARDs.
`
`Defining important clinical factors necessary for thera-
`peutic decision-making. Modified Delphi process by the
`CEP to establish key parameters for decision scenarios.
`After establishing a diagnosis of RA, risk assessment is
`crucial for guiding optimal treatment. We used a modified
`Delphi process (8) to reach consensus and enrich response
`categories on questions related to key clinical thresholds
`and decision branch points of RA treatment strategies.
`This included definitions of what constituted DMARD fail-
`ure, definitions of poor prognosis, categories of potential
`contraindications to DMARD use, and reasons for discon-
`tinuation of DMARDs.
`
`To apply results from research studies to clinical prac-
`tice, the CEP recommended that RA disease duration, dis-
`ease activity, and factors related to a poor prognosis in RA
`be explicitly defined and used to help formulate practical
`recommendations (see below).
`RA disease duration. Based on RA disease duration in-
`tervals commonly used in published RA clinical trials,
`disease duration thresholds were chosen to help with clin-
`ical decision-making. There were 3 categories of disease
`duration: ⬍6 months (considered to be equivalent to early
`disease), 6 –24 months (considered to be equivalent to
`intermediate disease duration), and ⬎24 months (consid-
`ered to be long or longer disease duration). For biologic
`therapies, early disease was further subdivided by disease
`duration of ⱕ3 months or 3– 6 months, when disease ac-
`tivity was high.
`RA disease activity assessment. Several
`indices to
`measure RA disease activity have been developed, each of
`which has advantages and disadvantages (9 –15). Recent
`composite and patient-reported disease activity measures,
`many of which do not require laboratory testing, are
`summarized in Table 1 and Appendix E (available at
`the Arthritis Care & Research Web site at http://www.
`interscience.wiley.com/jpages/0004-3591:1/suppmat/index.
`html). Evidence-based guidelines require clear definitions
`of disease activity to make rational therapeutic choices,
`but it is not possible or appropriate to mandate use of
`a single disease activity score for the individual physician,
`and different studies have used different definitions. There-
`fore, the TFP was asked to consider a combined estimation
`of disease activity, which allowed reference to many past
`definitions. With the instruments in Table 1 as a guide, we
`rated RA disease activity in an ordinal manner as low,
`moderate, or high, as previously requested by the CEP
`(Table 1). The TFP was then asked to make judgments
`based on these cut points.
`Prognostic factors for RA. RA patients with features of a
`poor prognosis have active disease with high tender and
`swollen joint counts, often have evidence of radiographic
`erosions, elevated levels of rheumatoid factor (RF) and/or
`anti– cyclic citrullinated peptide (anti-CCP) antibodies
`(16 –20), an elevated erythrocyte sedimentation rate,
`and/or an elevated C-reactive protein level (21,22). Older
`age, female sex, genotype (HLA–DRB1 shared epitope),
`worse physical functioning based on the Health Assess-
`
`Page 00004
`
`

`

`766
`
`Saag et al
`
`ment Questionnaire (HAQ) score, and cigarette smoking
`are also important predictors for a worse RA outcome,
`radiographic progression, early disability, and morbidity
`(such as increased risk of the need for joint replacement)
`(23–31). Through a modified Delphi process, the CEP se-
`lected the following as the most clinically important mark-
`ers of poor prognosis: functional limitation (e.g., HAQ
`Disability Index), extraarticular disease (e.g., vasculitis,
`Sjo¨gren’s syndrome, RA lung disease, etc.), RF positivity
`and/or positive anti-CCP antibodies (both characterized
`dichotomously, per CEP recommendation), and/or bony
`erosions by radiography. For the purposes of selecting
`therapies, physicians should consider the presence of
`these prognostic factors at the time of the treatment deci-
`sion. Although these prognostic factors are not exclusive,
`they are commonly used and have good face validity.
`Including combinations of these factors to guide decision-
`making would have added untenable complexity to a pro-
`cess that involved deliberate consideration of every per-
`mutation in a separate clinical scenario.
`
`RAND/UCLA appropriateness method using the TFP.
`The RAND/UCLA appropriateness process
`(32–34),
`which incorporates elements of the nominal and Delphi
`methods, was used to craft the final recommendations
`from clinical scenarios. These clinical scenarios, which
`described the potential key permutations of particular
`therapeutic considerations, were drafted by the investiga-
`tors and CEP, based on the evidence report (Figure 1 and
`Appendix D, available at the Arthritis Care & Research
`Web site at http://www.interscience.wiley.com/jpages/
`0004-3591:1/suppmat/index.html). Via e-mail, the TFP re-
`ceived these clinical scenarios, instructions for grading
`scenarios, and definitions of all variables. Using a 9-point
`Likert scale, panelists were asked to use the evidence
`report and their clinical judgment to rate the appropriate-
`ness of various clinical scenarios pertaining to key clinical
`parameters (e.g., “In a patient who has had an inadequate
`response to a nonbiologic DMARD, has RA of 6 months
`duration, poor RA prognostic features, and moderate RA
`disease activity, would it be appropriate to add or switch
`to an anti–tumor necrosis factor ␣ [anti-TNF␣] agent?”).
`An initial set of scenario ratings occurred before each TFP
`meeting, and a second set of ratings occurred after discus-
`sion of the evidence at each TFP meeting. Disagreement
`regarding a specific scenario (e.g., disagreement with the
`initiation of combination therapy with methotrexate and
`hydroxychloroquine in mild early RA) was defined when
`one-third or more of the panelists rated a scenario in the
`lowest 3 points of the appropriateness scale (ordinal scores
`1, 2, or 3) and one-third or more of the panelists rated the
`same scenario in the highest 3 points (ordinal scores 7, 8,
`or 9). In the absence of disagreement, a median rating in
`the lowest 3 points classified a scenario permutation as
`“inappropriate,” and a median rating in the upper 3 points
`classified a scenario as “appropriate.” Those scenario per-
`mutations rating in the 4 – 6 range together with those with
`disagreement were classified as “uncertain.”
`The dispersion of the scores and ranges plus each in-
`dividual’s own score was shown to each panelist. The
`
`median score provided the degree of agreement. In most
`circumstances, the recommendations for indications, con-
`traindications, and safety monitoring for use of therapeutic
`agents include only positive statements. For example, it
`was agreed that methotrexate should be used in the setting
`of early RA without features of a poor prognosis. In con-
`trast, there was no agreement regarding the use of ritux-
`imab in that circumstance, so no statement or recommen-
`dation was made. As another example, the TFP believed
`that hydroxychloroquine was not contraindicated for pa-
`tients with acute serious bacterial infection. Since this was
`a negative statement (no contraindication), no recommen-
`dation was provided. For some particularly contentious
`areas (e.g., the use of biologic agents during pregnancy or
`the use of nonbiologic agents during the perioperative
`period), an absence of consensus is documented, and we
`directly state that no recommendation is provided. An
`absence of consensus and consequent lack of a positive
`statement should not be construed to indicate that the TFP
`did not consider these issues important, only that consen-
`sus was not reached, often due to absent or conflicting
`evidence. In these areas, therapeutic decisions are left to
`the careful consideration of risks/benefits by the patient
`and physician.
`The anonymous ratings of the first round of ordinal
`voting were reviewed with the panelists at each meeting.
`The CEP were invited to participate during all the discus-
`sions with the TFP but were nonvoting participants.
`Through these discussions, the reasons for any uncertainty
`were identified, and resolution of discordance was at-
`tempted by modification of the clinical scenarios, clarifi-
`cation of definitions, or acknowledgment of discordance
`between clinical experience and the medical literature. In
`addition, the TFP identified important clinical situations
`that were not discussed during the face-to-face meeting or
`during the 4 subsequent Internet teleconferences. When
`identified and necessary, additional clinical questions
`were recommended by the panelists, formulated into de-
`cision scenarios, and evaluated using the same process.
`All clinical scenarios were subjected to at least 2 rounds of
`voting.
`
`Conversion of clinical scenarios to ACR RA treatment
`recommendations. Following the second round of voting,
`recommendation statements were developed from a direct
`distillation of the scenario votes, and these statements
`were reviewed by the CEP. Although more than 2,000
`clinical scenarios were graded by the TFP, there were very
`few areas of inconsistency or illogical results. When in-
`consistent or illogical findings were identified, the TFP
`was asked to reconsider and in some cases revote on these
`scenarios, using a new Delphi process.
`
`Rating the strength of evidence for recommendations.
`For each final recommendation, the strength of evidence
`was assigned using the methods of the American College
`of Cardiology (35) as follows: 1) for level of evidence A,
`data were derived from multiple RCTs or meta-analyses;
`2) for level of evidence B, data were derived from a single
`
`Page 00005
`
`

`

`Recommendations for the Use of Nonbiologic and Biologic DMARDs in RA
`
`767
`
`randomized trial or nonrandomized studies; 3) for level of
`evidence C, data were derived from consensus opinion of
`experts, case studies, or standards of care. In many circum-
`stances, level C evidence denoted a circumstance in which
`medical literature (potentially including randomized tri-
`als, observational studies, or case series) might have ad-
`dressed the general topic under discussion, but the litera-
`ture did not address the specific clinical situations or
`scenarios reviewed by the TFP. For example, an RCT
`might have addressed only RF-positive patients, but the
`recommendation focused on patients without markers of a
`poor prognosis (i.e., those who were RF negative). This
`situation required a combination of judgment, extrapola-
`tion of the evidence, and group consensus. We have de-
`noted this particular circumstance as level C* evidence.
`In studies with more than 1 treatment arm, if each arm
`was efficacious when compared with baseline, the study
`was considered appropriate to support all DMARDs stud-
`ied. The average disease duration of a study was consid-
`ered when choosing appropriate reports for a duration
`category: ⬍6 months, 6 –24 months, and ⬎24 months. Sur-
`rogates for poor prognosis (see above) were extracted and
`used when possible. For example, if ⬎50% of patients in a
`nonbiologic DMARD arm were RF positive and the
`DMARD was shown to be efficacious, then the study was
`used to support a consensus statement for using that
`DMARD in RA patients who had a feature suggestive of a
`poor prognosis (Table 1).
`
`ACR peer review of recommendations. Following con-
`struction of the recommendations, the ACR invited peer
`review by the ACR Guidelines Subcommittee members,
`ACR Quality of Care Committee members, and the ACR
`Board of Directors, and more than a dozen individuals
`from these groups responded with reviews and recommen-
`dations. In addition, ACR members were given an oppor-
`tunity to provide feedback at a session at the 2007 Annual
`Scientific Meeting held in Boston, MA. The recommenda-
`tions were ultimately subject to the regular journal review
`process.
`
`Periodic re-review and updates of ACR recommenda-
`tions. Although we used the most up-to-date literature
`available through February 2007 for our systematic review,
`rapid changes are occurring in evidence regarding nonbio-
`logic and biologic therapeutics. Changing third-party cov-
`erage (e.g., through Medicare Part D) also may affect drug
`availability and patient preferences for therapies. These
`and other ongoing changes will inform decision-making
`about efficacious and safe use of biologic and nonbiologic
`DMARDs. In order to ensure that ACR guidelines and
`recommendations remain up to date, the ACR Quality of
`Care Committee will solicit periodic updates to these rec-
`ommendations depending on the availability of new ther-
`apies, new evidence on the benefits and harms of existing
`treatments, changing opinions on what patient outcomes
`are considered important, and changes in policies on the
`resources available for health care.
`
`ACR Recommendations for the Use of Nonbiologic
`and Biologic DMARDs in RA
`
`Indications for starting or resuming a nonbiologic or
`biologic DMARD. These ACR recommendations focus on
`the use of nonbiologic and biologic therapies for the treat-
`ment of RA on the background of optimal and appropriate
`use of nonmedical therapies (e.g., physical and occupa-
`tional therapies) as well as antiinflammatory pharmaco-
`logic interventions (e.g., nonsteroidal antiinflammatory
`drugs [NSAIDs], intraarticular and oral glucocorticoids).
`Glucocorticoids, NSAIDs, and ot