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:
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)
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
762
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-
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-
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.
Recommendations for the Use of Nonbiologic and Biologic DMARDs in RA 763
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 DMARDswas 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
764 Saag et al
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 �3 months or 3–6 mo
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