SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

Objective

To evaluate the quality of clinical practice guidelines (CPGs) and consensus statements (CS) for the treatment of rheumatoid arthritis with tumor necrosis factor α (TNFα) antagonists.

Methods

We searched for CPGs and CS on the use of infliximab, etanercept, and/or adalimumab for the treatment of rheumatoid arthritis, published through October 10, 2006. Sources included electronic databases (Medline, EMBase, BIOSIS, etc.), guideline registries, and pertinent Web sites. Review of 4,915 citations revealed 16 CPGs and 20 CS. Two independent reviewers evaluated development methods of selected studies using the 23-item Appraisal of Guidelines for Research and Evaluation (AGREE) instrument and compared recommendations between guidelines.

Results

Of the 16 guidelines, only 5 (31%) were based on a systematic review of relevant research evidence. Only 4 (25%) of the guidelines fulfilled ≥60% of the AGREE criteria. AGREE scores were lower for guidelines from rheumatology societies than government agencies when reporting scope and purposes (P = 0.03), stakeholder involvement (P = 0.03), and clarity and presentation (P = 0.01). Guidelines scored higher than CS in most domains. Overall, guideline recommendations were consistent with respect to the use of biologic agents after failure of disease-modifying antirheumatic drugs, but differed or did not provide specific guidance on tests for screening.

Conclusion

Guidelines for introducing TNFα antagonists in rheumatoid arthritis often fail to meet expected methodologic criteria and therefore vary significantly in quality and with respect to some recommendations for patient assessment and management.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

Evidence-based clinical practice guidelines (CPGs) are defined by the Institute of Medicine as “a set of systematically developed statements to assist practitioner and patient decisions about appropriate health care for one specific clinical condition or disease area” (1). Likewise, consensus statements (CS) are documents representing the collective opinion of an expert panel whose sole objective is to help clinicians use the most agreed-upon way to diagnose and treat certain diseases. CS differ from guidelines in that they do not provide specific algorithms for practice. However, both do provide the basis for applying research-based implementation methods and integrate, in most instances, scientific evidence with individual clinical expertise and consideration of patient preferences in specific areas of health care (2).

Over the past 20 years, numerous evidence-based CPGs and CS have been developed by diverse health care systems and societies, providing methods to improve the decision-making process (3). However, with the exponential increase in CPG and CS production, concerns about their quality have risen (4, 5). To become a more effective means for improving health care, recommendation statements need to have maximal validity, based on the systematic selection and use of evidence, and a rigorous, multidisciplinary development process (2). Various authors have found deficiencies in the methods used for guideline development and the manner in which guidelines are presented (6). In an effort to establish a standard instrument for assessing the quality of CPGs, the Appraisal of Guidelines Research and Evaluation (AGREE) project was initiated in 1998. The AGREE collaboration has developed a validated, generic instrument that can be used to evaluate CPGs in any disease area (7, 8). The AGREE instrument focuses on the methods used for developing guidelines and the quality of the reporting of guidelines; the instrument does not address the clinical content of recommendations or the quality of supporting evidence. The instrument has been acknowledged as an accredited standard in guideline development by the World Health Organization (9).

A good example of recent CPG and CS proliferation is seen in the field of rheumatology, where new targeted biologic therapies have been developed for treating rheumatoid arthritis (10). Incorporation of tumor necrosis factor α (TNFα) antagonists into the treatment of rheumatoid arthritis has raised new challenges, such as when it is best to introduce such therapy, or when it should be reassessed (11). These agents appear to be more effective than traditional therapy, work faster, and are well tolerated. However, they are expensive, with annual costs ranging from $10,000 to $15,000, compared with a few hundred dollars for more traditional treatments such as methotrexate. In addition, although these drugs have an adequate safety profile, serious adverse events such as severe infections or tuberculosis reactivation can occasionally occur. In an attempt to provide guidance regarding these questions and reduce variability in clinical practice, several groups in various countries have developed CPGs and CS regarding the use of TNFα antagonists for treating rheumatoid arthritis.

The aim of this study was to conduct a systematic review of CPGs and CS for the use of TNFα antagonists in patients with rheumatoid arthritis and to assess their quality using the AGREE instrument. The ultimate goal of this research is to encourage better CPG and CS development in all areas of medicine, by evaluating scientific shortcomings in current recommendations for newly acquired therapeutics.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

Data sources and searches.

A literature search was undertaken to identify published articles concerning the use of TNFα antagonists for treating rheumatoid arthritis as part of a health technology report conducted for the Canadian Agency of Drugs and Technologies in Health. The general principles of our search strategy have been described previously (11). We searched Medline, EMBase, ToxFile, BIOSIS Previews, The Cochrane Library, clinical trial registries, and guideline collections including the following, among others: National Guideline Clearinghouse, Canadian Task Force on Preventive Health Care, Canadian Medical Association, Scottish Intercollegiate Guidelines, and New Zealand Guidelines Group. In addition, we searched regulatory sites, Web sites of health technology assessment agencies and relevant specialty societies, and various other evidence-based resources such as the American College of Physicians Journal Club, Bandolier, Clinical Evidence, Emergency Care Research Institute databases, and Turning Research into Practice. Search terms included “rheumatoid arthritis,” “arthritis,” “infliximab,” “etanercept,” “adalimumab,” “monoclonal antibody cA2,” “TNFR-Fc fusion protein,” and “D2E7 antibody.” The search was systematically repeated and new results were incorporated on a regular basis through October 10, 2006. The search criteria had neither language nor publication date restrictions. For articles written in languages other than English, German, or the romance languages, an electronic translator was used for primary translation or translation support (http://babelfish.altavista.com/). All databases and other information sources were cross-referenced to check for duplicate citations. Electronic searches were supplemented by hand searching the bibliographies of retrieved systematic reviews for references not otherwise found.

Study selection.

The process for selecting articles followed 3 steps. In step 1, titles, abstracts, or both for all articles retrieved by our literature searches were screened by 2 independent reviewers (MAL-O, ZO) for potential relevance to this study. The definition we used for a CPG was that described above by the Institute of Medicine (1). Recommendations were defined as a list of procedures focused on a specific area for the improvement and standardization of clinical practice. A CS was defined as a document representing the collective opinion of an expert panel not based on systematically reviewed evidence. In step 2, all articles and documents including words such as “guideline,” “consensus,” “recommendations,” “parameters,” and “standards” and those that discussed treatment for rheumatoid arthritis were considered eligible. For all relevant articles identified, copies of the articles were retrieved, and their reference lists scanned for additional relevant articles; when identified, copies of these articles were also retrieved. Reviewer agreement about which articles were relevant was obtained by consensus, with a third party adjudicating when needed. We excluded from further analysis: 1) abstracts from meetings and 2) documents not containing recommendations for clinical practice (e.g., systematic or narrative reviews, editorials). The criteria for inclusion of articles in step 3 were as follows: 1) the article included an explicit statement identifying itself as a “guideline” or “consensus,” 2) the guideline or consensus was produced at national or international levels by medical associations or governmental bodies, and 3) the guideline or consensus discussed and made recommendations concerning the use of TNFα antagonists.

Quality appraisal.

The quality of each selected CPG and CS was evaluated independently by 2 reviewers (MAL-O, MAK) using the AGREE instrument; differences were resolved by consensus in all instances.

The AGREE Collaboration recommends that each guideline be assessed by at least 2 appraisers (3). The AGREE instrument consists of 23 items organized into 6 domains; the purpose of each domain is to measure a distinct dimension of guideline quality (3). The 6 domains and their individual item content are shown in Table 1.

Table 1. Appraisal of Guidelines for Research and Evaluation (AGREE) instrument (7)*
  • *

    Domain scores are calculated by adding the scores of all items within a domain and transforming that score to a percentage of the maximum possible domain score. This standardized domain score is obtained as follows: (observed score– minimum possible score) / (maximum possible score– minimum possible score) (3). CPG = clinical practice guideline.

Scope and purpose3 itemsThe overall objective(s) of the guideline is(are) specifically described
  The clinical question(s) covered by the guideline is(are) specifically described
  The patients to whom the guideline is meant to apply are specifically described
Stakeholder involvement4 itemsThe guideline development group includes individuals from all relevant professional groups
  The patients' views and preferences have been sought
  The target users of the guideline are clearly defined
  The guideline has been piloted among target users
Rigor of development7 itemsSystematic methods were used to search for evidence
  The criteria for selecting the evidence are clearly described
  The methods used for formulating the recommendations are clearly described
  The health benefits, side effects, and risks have been considered in formulating the recommendations
  There is an explicit link between the recommendations and the supporting evidence
  The guideline has been externally reviewed by experts prior to its publication
  A procedure for updating the guideline is provided
Clarity and presentation4 itemsThe recommendations are specific and unambiguous
  The different options for management of the condition are clearly presented
  Key recommendations are easily identifiable
  The guideline is supported with tools for application
Applicability3 itemsThe potential organizational barriers in applying the recommendations have been discussed
  The potential cost implications of applying the recommendations have been considered
  The guideline presents key review criteria for monitoring and/or audit purposes
Editorial independence2 itemsThe guideline is editorially independent from the funding body
  Conflicts of interest of guideline development members have been recorded
Overall assessment in accordance with AGREE recommendations (8)  
 RecommendedHigh overall quality“If a guideline was rated high (scores 3 or 4) on a majority of items and most domain scores are above 60%, this would indicate that the guideline has high overall quality and could be considered for use in practice without provisos or alterations.”
 Recommended with provisosModerate overall quality“If a guideline was rated high and low (scores 1 or 2) on a similar number of items per domain and most domain scores were 30% to 60%, this would indicate that the guideline has moderate overall quality and could be recommended with provisos.”
 Not recommendedLow overall quality“If a guideline was rated low on a majority of items, and most domain scores were less than 30%, this would indicate that the guideline has low overall quality, serious shortcomings, and should not be recommended for use in practice.”
 Unsure “Unsure if the appraisers would recommend the CPG for practice.”

Each item is rated on a 4-point scale, where 4 indicates strongly agree (that the guideline meets the criterion), 3 indicates agree, 2 indicates disagree, and 1 indicates strongly disagree. Although a single quality score is not encouraged by the AGREE Collaboration, a section for overall assessment is included. This section requires the appraiser to make a judgment about the overall quality of the CPG. Appraisers are asked whether they would strongly recommend, recommend (with provisos or alterations), not recommend, or are unsure if they would recommend the CPG for practice (3). The number of highly rated items within a domain and level of quality across domain scores determine the overall assessment of each guideline (see Table 1).

We calculated quadratic-weighted kappa across AGREE domains and for each individual domain. Kappa was used as a measure of interrater agreement for the 2 raters' ordinal item assessments (1 = strongly disagree to 4 = strongly agree). Although there are no absolute cutoffs for interpreting kappa coefficients, in broad terms, a kappa <0.2 suggests poor agreement, while a kappa >0.8 suggests very good agreement beyond chance levels. Next, AGREE domain scores, based on the 2 raters' original item assessments, were calculated according to AGREE methodology, and intraclass correlation coefficients were calculated to assess domain and total score variability and reviewer contribution to that variability. Finally, we used the continuous domain scores from each reviewer to calculate Pearson's correlation coefficients to reflect the level of association between raters' scores across AGREE domains and for each individual domain. This provided supplementary evidence of agreement based on continuous score calculations.

CS are widely used in practice; in some instances, they may become the most valuable aids for clinicians if no guidelines have been developed. To the authors' knowledge, there is no designed instrument for the appraisal of CS. Consequently, CS were also evaluated using the AGREE criteria and then compared with CPGs with respect to quality. We decided to use the AGREE criteria to be able to make direct comparisons about the quality of guidance documents. Nevertheless, CS scores should be read with some caution: the less rigorous development of a CS differs from that expected of a high-quality CPG. Generally, lower AGREE scores for CS can be anticipated.

In addition to guideline quality, we compared guideline recommendations in 3 areas addressed by all of our identified guidelines: 1) criteria for initial indication of TNFα antagonists during treatment of rheumatoid arthritis, 2) doses and administration, and 3) screening, monitoring, and evaluations needed before or after treatment.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

Our search strategy identified 4,915 citations. Ultimately, we included 16 CPGs and 20 CS that reported recommendations on using TNFα antagonists in rheumatoid arthritis patients. A flow diagram that depicts the selection process is shown in Figure 1.

thumbnail image

Figure 1. Selection process. After our first step, only 64 citations were considered relevant to the topic and were selected for further review. In step 2, the review of citations revealed 39 articles that were systematically developed statements on the treatment of patients with rheumatoid arthritis. The remaining 25 were excluded because they were considered documents that did not contain recommendations for clinical practice (20 narrative reviews and 5 editorials). Adjudication was needed for only 2 articles. In step 3, 3 of 39 citations were excluded because they did not address the use of tumor necrosis factor α (TNFα) antagonists.

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The 16 CPGs and 20 CS were developed between 2000 and 2006 in 16 different countries, and 9 CS involved more than 1 country (Table 2). Twenty-six were published in English and 10 in other languages (Portuguese, Spanish, Italian, German, and Dutch). Eight of 16 CPGs and 1 CS covered treatment for rheumatoid arthritis in general but included recommendations for prescribing TNFα antagonists (12–20); the other 27 (75%) were specific to the use of TNFα antagonists (21–47); of these, 3 focused on infliximab only (27, 35, 38) and 1 on etanercept only (28). Five (31%) guidelines and 1 (5%) CS based their recommendations on a systematic review conducted by the authors (12, 13, 18, 20, 25, 26), but only 1 of these reported an explicit search strategy (18). Six (38%) guidelines and 12 (60%) CS did not report funding sources, 4 (25%) guidelines and 8 (40%) CS reported funding by pharmaceutical companies (18, 19, 22, 26, 29, 30, 32, 34, 36, 40, 42, 44), and 6 guidelines reported funding by national agencies (12, 14, 20, 23, 27, 28).

Table 2. Summary of characteristics of included studies*
Study, year (ref.)CountryTopicGroupSystematic reviewFundingGrading systemTreatment algorithm included
  • *

    SIGN = Scottish Intercollegiate Guidelines Network; RA = rheumatoid arthritis; BSR = British Society for Rheumatology; TNFα = tumor necrosis factor α; NR = not reported; SER = Sociedad Española de Reumatología; GUIPCAR = Guía de Práctica Clínica para el Manejo de Artritis Reumatoide en España; ACR = American College of Rheumatology; NICE = National Institute for Clinical Excellence; NHS = National Health Service; SBR = Sociedade Brasileira de Reumatologia; RCN = Royal College of Nursing; SAMA = South African Medical Association; SARAA = South African Rheumatism and Arthritis Association; MSD = Merck, Sharp, and Dohme; SIR = Societa Italiana di Reumatologia; ISR = Irish Society of Rheumatology; JCR = Japan College of Rheumatology; IFX = infliximab; MHLW = Ministry of Health, Labor and Welfare; SAR = Sociedad Argentina de Reumatologia; BHPR = British Health Professionals in Rheumatology; FSR = French Society of Rheumatology; ETN = etanercept; NA = not applicable; KPDGR = Kommission Pharmakotherapie der Deutschen Gesellschaft für Rheumatologie; WHO = World Health Organization; RAED = Turkish Rheumatology Research and Education Society; CRA = Canadian Rheumatology Association; HMS = Hannover Medical School; NVR = Nederlandse Vereniging voor Reumatologie; HKSR = Hong Kong Society or Rheumatology; SPR = Sociedade Portuguesa de Reumatologia.

  • Comprehensive search in 1 database (Medline) or selected from international journals.

  • Recommendations based on a health technology assessment or a previous guideline.

  • §

    Listed as member/sponsor in sources of evidence but no conflict of interests were reported.

  • Suggested algorithm for IFX infusion.

  • #

    Reproduction of BSR guidelines.

  • **

    All authors disclosed conflict of interest, but no financial support was reported.

Guidelines       
SIGN, 2000 (12)ScotlandEarly RASIGNYesSIGNYesYes
BSR, 2001 (21)UKTNFαBSRNoNRYesNo
SER, 2001 (18)SpainRA in generalGUIPCARYesNovartis, AbbottYesYes
ACR, 2002 (14)USRA in generalACRNoACRNoYes
NICE, 2002 (22)UKTNFαNHSNoSchering-Plough, Wyeth§NoNo
SBR, 2002 (17)BrazilRA in generalSBRNoNRNoYes
RCN, 2003 (23)UKTNFαNHSNoNICENoYes
SAMA, 2003 (19)South AfricaRA in generalSARAANoMSD, SearleNoYes
SIR, 2004 (16)ItalyEarly RASIRNoNRYesYes
BSR, 2005 (26)UKTNFαBSRYesSchering-Plough, Wyeth, AbbottNoNo
ISR, 2005 (24)#IrelandTNFαISRNoNRNoNo
JCR, 2005 (27)JapanIFXJCRNoMHLWNoNo
SAR, 2005 (15)ArgentinaRA in generalSARNoNRYesNo
BSR, 2006 (20)UKRA in generalBSR, BHPRYesBSRYesYes
FSR, 2006 (25)FranceTNFαFSRYesNRYesNo
JCR, 2006 (28)JapanETNJCRNoMHLWNoNo
Consensus statements       
Furst, 1999 (29)InternationalTNFαNANoAmgen, Centocor, Immunex, Knoll AG, Schering-Plough, Wyeth AyertsNoNo
Furst, 2000 (30)InternationalTNFαNANoPharmaceutical support not specifiedNoNo
KPDGR, 2000 (31)GermanyTNFαKPDGRNoNRNoNo
Smolen, 2000 (32)EuropeTNFαNANoSchering-PloughNoNo
Emery, 2001 (33)Europe, USTNFαWHONoNRNoNo
Furst, 2001 (34)InternationalTNFαNANoPharmaceutical support not specifiedYesNo
Akkoc, 2002 (35)TurkeyIFXRAEDNoNRNoNo
Furst, 2002 (36)InternationalTNFαNANoPharmaceutical support not specifiedYesNo
Haraoui, 2002 (37)CanadaBiologicsCRANoNR**YesNo
Hulsemann, 2002 (38)GermanyIFXHMSNoNRNoYes
Manger, 2002 (39)GermanyTNFαKPDGRNoNRNoNo
Furst, 2003 (40)InternationalTNFαNANoPharmaceutical support not specifiedYesNo
NVR, 2003 (41)The NetherlandsTNFαNVRNoNRNoNo
Furst, 2004 (42)InternationalTNFαNANoPharmaceutical support not specifiedYesNo
Bykerk, 2004 (13)CanadaEarly RACRAYesNRNoNo
SER, 2004 (43)SpainTNFαSERNoNRNoNo
Furst, 2005 (44)InternationalTNFαNANoPharmaceutical support not specifiedYesNo
HKSR, 2005 (45)ChinaTNFαHKSRNoNRNoNo
Manger, 2005 (46)GermanyTNFαKPDGRNoNRNoNo
SPR, 2005 (47)PortugalTNFαSPRNoNRNoNo

Guideline authors used different methods to evaluate the evidence upon which recommendations were based and the recommendations themselves. Nine (56%) guidelines did not grade either the evidence they cited or their recommendations (14, 17, 19, 22–24, 26–28). One guideline coded evidence on the basis of study design but did not link this to recommendations (21). Only 6 (38%) graded the evidence and explicitly linked this evidence to recommendations (12, 15, 16, 18, 20, 25). Each of these 6 guidelines used a different grading system: 1) Scottish Intercollegiate Guidelines Network (SIGN) key to evidence statements and grades of recommendations (48), 2) Hadorn scale (49), 3) Agency for Healthcare Research and Quality scheme (50), 4) Cook et al (51) and Sackett (52) grade systems, 5) the grading system suggested by the Royal College of Physicians of London (53), and 6) the grading system proposed by Shekelle et al (54). Only 5 (25%) CS graded their recommendations; all 5 used the grading system proposed by Shekelle et al (54).

The recommendations of several studies were based on the review of large randomized controlled trials comparing a TNFα antagonist with a placebo or another therapy. The most relevant reported trials for each drug were 1) the Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) (55), a 54-week multicenter study of 428 patients who were randomly assigned to 1 of 5 treatment arms contrasting 4 different doses of infliximab plus methotrexate versus methotrexate alone; 2) The Etanercept and Methotrexate in Patients with Early Rheumatoid Arthritis (ERA) (56), a study monitoring 632 patients randomly assigned to 1 of 3 groups comparing 2 different doses of etanercept versus methotrexate; and 3) the Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab (D2E7) in Rheumatoid Arthritis (ARMADA) (57), a multicenter study including 271 patients randomly assigned to 1 of 4 groups that received different doses of adalimumab or placebo. Relevant studies included in each guideline and consensus are listed in Supplemental Appendix A available in the online version of this article at http://www3.interscience.wiley.com/journal/77005015/home.

Quality assessment.

Table 3 shows the scores for each guideline and consensus statement for each of the 6 quality domains evaluated with AGREE; it also includes the overall assessment score and overall assessment rating. To calculate the overall assessment score, we summed the scores of individual items across all domains and applied the same formula given by the AGREE Collaboration for developing a standardized domain score (3, 8). Only 4 (25%) guidelines fulfilled ≥60% of the AGREE criteria (12, 18, 20, 21). We observed lower scores for guidelines from organizations specializing in rheumatology for 1) item 4 of the AGREE instrument (all relevant professional groups included), 2) item 9 (search methods), and 3) item 10 (methods used for formulating recommendations). CS had lower AGREE scores than CPGs: all CS scored <60% on the AGREE overall assessment, with mean scores ranging from 18–47%.

Table 3. Domain scores and overall assessments according to the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument*
Study, year (ref.)Domain scores, %Overall assessment
Scope and purposeStakeholder involvementRigor of developmentClarity and presentationApplicabilityEditorial independenceNo. of domains >60%%RatingNo. of items scored 3 or 4
  • *

    R = recommend; WNR = would not recommend; see Table 2 for additional definitions.

  • Recommended with provisos.

Guidelines          
SIGN, 2000 (12)94758696170270R16
BSR, 2001 (21)675855923375362R15
SER, 2001 (18)895076966100270R16
ACR, 2002 (18)784629673375349R12
NICE, 2002 (22)10050241006750359R11
SBR, 2002 (17)72171775050435R8
RCN, 2003 (23)897124925625357R13
SAMA, 2003 (19)78292971675343R8
SIR, 2004 (16)7817219600436R8
BSR, 2005 (26)9450486711100357R14
ISR, 2005 (24)78291463017432R7
JCR, 2005 (27)7817409660443R8
SAR, 2005 (15)8983867110438R9
BSR, 2006 (20)10071571009492180R18
FSR, 2006 (25)94505288110454R13
JCR, 2006 (28)3921335800629WNR3
Consensus statements          
Furst, 1999 (29)67332129675433R5
Furst, 2000 (30)89254046050541R9
KPDGR, 2000 (31)5629103300621WNR4
Smolen, 2000 (32)8313173308525WNR5
Emery, 2001 (33)10033247100438R8
Furst, 2001 (34)67134346025534R5
Akkoc, 2002 (35)6733125800528WNR7
Furst, 2002 (36)83254383050447R12
Haraoui, 2002 (37)83443381725536R7
Hulsemann, 2002 (38)9425197100435R6
Manger, 2002 (39)6717216700430R5
Furst, 2003 (40)83294575050447R10
NVR, 2003 (41)6117173308522WNR4
Furst, 2004 (42)72255558642545R8
Bykerk, 2004 (13)8325316768438R8
SER, 2004 (43)1004266300433R7
Furst, 2005 (44)100173388050446R11
Manger, 2005 (46)611353800518WNR3
HKSR, 2005 (45)72382158170535R9
SPR, 2005 (47)6121197108430R7

For ordinal item assessments, interrater assessment agreement across AGREE domains was good, with a weighted kappa coefficient of 0.73 (95% confidence interval 0.67–0.78). The intraclass correlation coefficient for the overall AGREE score was 0.79, with only 3.3% of score variability attributable to appraisers. For continuous domain scores, interappraiser correlation was strong across AGREE domains (r = 0.83, P < 0.001). Interrater score agreement for the individual AGREE domains was moderate to strong and ranged from 0.35 to 0.88.

Comparisons among guidelines.

Mean domain scores for the recommended and recommended with provisos guidelines are shown in Table 4. As expected, the domain scores for the CPGs with an overall rating of recommend according to the AGREE instrument tended to be higher than the domain scores for the CPGs with an overall rating of recommend with provisos. The weakest domains for both CPG quality groups were 1) applicability, which evaluates organizational and cost implications of applying the guideline (an explanation for not reporting such implications may be the barriers to implementing change), and 2) editorial independence, which evaluates if recommendations made were editorially independent and free from conflicts of interest. The major differences between the recommend and recommend with provisos CPGs were in the domains of stakeholder involvement, rigor of development, and clarity of presentation.

Table 4. Comparison of mean domain scores among recommended guidelines and guidelines recommended with provisos*
DomainRecommended guidelines (n = 4)Guidelines recommended with provisos (n = 11)Effect sizeP
Mean score, %Min/max95% CIMean score, %Min/max95% CI
  • *

    Min/max = minimum/maximum; 95% CI = 95% confidence interval.

  • Corrected for natural limits.

  • Cohen's d.

Scope and purpose8867/10064–1008472/10078–900.30.7
Stakeholder involvement6450/7545–82358/7122–481.80.006
Rigor of development6855/8645–923014/5222–392.80.008
Clarity and presentation9692/10090–1008062/10070–901.50.005
Applicability386/940–100180/672–340.60.4
Editorial independence670/1000–100360/10012–600.80.3

No statistical differences were found when comparing mean domains for CPGs that focused on TNFα antagonists and those that covered general treatment for rheumatoid arthritis.

The mean domain scores for 1) scope and purpose, 2) stakeholder involvement, and 3) clarity and presentation were higher for the CPGs written on behalf of government agencies than domain scores for the CPGs written by specialty societies (P = 0.03, 0.03, and 0.01, respectively) (Table 5).

Table 5. Comparison of mean domain scores among guidelines written on behalf of government agencies and those written by specialty agencies*
DomainGovernment agencies (n = 3)Rheumatology societies (n = 12)Effect sizeP
Mean score, %Min/max95% CIMean score, %Min/max95% CI
  • *

    Min/max = minimum/maximum; 95% CI = 95% confidence interval.

  • Corrected for natural limits.

  • Cohen's d.

Scope and purpose9489/10081–1008039/10069–901.20.03
Stakeholder involvement6550/7532–98368/7123–491.70.03
Rigor of development4424/860–1004014/7628–520.20.9
Clarity and presentation9692/10085–1008058/10070–901.40.01
Applicability4617/670–100170/940–341.10.2
Editorial independence250/500–87420/10015–700.50.4

When comparing mean domain scores for guidelines and consensus statements, all domain scores were lower for the consensus statements except for 2: scope and purpose, and editorial independence (P = 0.4 and 0.08, respectively) (Table 6).

Table 6. Comparison of mean domain scores among guidelines and consensus statements*
DomainGuidelines (n = 16)Consensus statements (n = 20)Effect sizeP
Mean score, %Min/max95% CIMean score, %Min/max95% CI
  • *

    95% CI = 95% confidence interval.

  • Corrected for natural limits.

  • Cohen's d.

Scope and purpose8239/10074–907856/10072–840.30.4
Stakeholder involvement418/7530–52224/3818–261.10.004
Rigor of development4014/8630–50275/5521–330.70.04
Clarity and presentation8358/10076–905629/8848–641.6< 0.001
Applicability220/948–3630/171–51.00.02
Editorial independence410/10021–61200/7510–300.60.08

Comparison of recommendations.

The guidelines were relatively consistent in the clinical trials they cited as evidence for drug treatment recommendations (data not shown). Guidelines varied with respect to outcomes reported. The outcomes used to report efficacy of TNFα antagonists were as follows: 1) American College of Rheumatology response criteria (58), 2) Disease Activity Score, 3) radiologic score, 4) toxicity, and, in some instances, 5) quality of life. Seven (44%) guidelines reported 1 or more clinical outcomes (12, 14, 18, 21, 22, 25, 28); another 7 (44%) did not report any clinical outcomes but presented recommendations based on published CS (17, 19), CPGs (20, 23, 24), or trials (15, 16); and 2 guidelines used original data but did not report outcomes (26, 27). Table 7 shows how the guidelines compared with respect to indications for therapy. Guideline recommendations were consistent with respect to the timing of introduction of TNFα antagonists.

Table 7. Recommendations: indications for therapy*
Guideline, year (ref.)Anti-TNFα reportedIndications for prescriptionDefinition of active diseaseDefinition of failure of standard therapyContraindicationsSpecial recommendationsCriteria for withdrawalPrescription of TNFα before and after surgery
  • *

    DMARDs = disease-modifying antirheumatic drugs; DAS28 = 28-joint Disease Activity Score; SJC = swollen joint count; TB = tuberculosis; [UPWARDS ARROW] = increased; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; MTX = methotrexate; ADM = adalimumab; TJC = tender joint count; WBCs = white blood cells; INH = isoniazid; HIV = human immunodeficiency virus; HBV = hepatitis B virus; HCV = hepatitis C virus; see Table 2 for additional definitions.

  • In 2003, adalimumab was not approved for use in South Africa.

  • If the physician thinks that the advantage of anti-TNFα treatment outweighs its safety in patients with latent TB infection, prophylactic treatment with isoniazid (0.3 mg/day) is recommended.

  • §

    Patients also required to have WBC count >4,000/mm3 and peripheral blood lymphocyte count >1,000/mm3 in addition to negative β-D-glucan in sera.

SIGN, 2000 (12)ETN, IFXFailure of DMARDsInfectionMonitor for continued efficacy
Malignancy
BSR, 2001 (21)ETN, IFXActive RADAS28 >5.1≥2 DMARDs (≥6 months)PregnancyUse of DAS28Malignancy
Failure of DMARDsNursingToxicity
     Infection Pregnancy 
     Malignancy Infection 
       Inefficacy (DAS28 <3.2) 
SER, 2001 (18)ETN, IFXFailure of DMARDs≥6 SJC Erosions≥2 DMARDs (≥3 months)InfectionUse of DASInfection
Malignancy Active TB 
     Multiple sclerosis Neoplasmas 
ACR, 2002 (14)ETN, IFXETN as a monotherapySynovitis [UPWARDS ARROW]ESR/CRPNo response to MTX (≥3 months)Infection
ETN step-up combination    
IFX as initial combination    
  Both after failure of DMARDs      
NICE, 2002 (22)ETN, IFXActive RASame as BSR 2001InfectionNo consecutive useToxicity
Failure of DMARDs  Heart failureLack of response (3 months) 
SBR, 2002 (17)ADM, ETN, IFXFailure of DMARDs≥2 DMARDsPregnancyMonitor TBInfection
Infection   
     Multiple sclerosis   
     Malignancy   
RCN, 2003 (23)ADM, ETN, IFXSame as BSR 2001 (21)Same as BSR 2001InfectionMonitor DASRashes/reactions during administration≥2 weeks before/after surgery
TBInfection
Demyelinating diseaseCardiac function
Weight
SAMA, 2003 (19)IFX, ETN, ADMSame as BSR 2001 (21)≥6 SJC/TJC [UPWARDS ARROW]ESR/CRP≥3 DMARDs (≥6 months)InfectionMonitor TB
SIR, 2004 (16)ADM, ETN, IFXAggressive RA (progressive structural damage)≥3 DMARDs (≥3 months)Lack of response (12 weeks)
  Failure of DMARDs      
BSR, 2005 (26)ADM, ETN, IFXActive RASame as BSR 2001PregnancyCaution in pulmonary fibrosisToxicity2–4 weeks before surgery and after wound healing is satisfactory
Failure of DMARDs(When other DMARDs are relatively contraindicated, TNFα antagonists may be considered very early in the course of the disease in MTX-naive patients)NursingSwitching can be usefulNo DAS28 improvement >1.2
Contraindications of DMARDs InfectionPregnancy
 MalignancyInfection
ISR, 2005 (24)ADM, ETN, IFXSame as BSR 2005 (26)Same as BSR 2005≥2 DMARDs (≥3 months)Same as BSR 2005 (26)Switching can be usefulSame as BSR 2005
JCR, 2005 (27)IFXActive RA≥6 SJC/TJC [UPWARDS ARROW]ESR/CRP§Same as ACR 2002InfectionINH for latent TB infection
Failure of MTXMalignancy   
  WBCs ≥4,000/mm3Demyelinating disease   
SAR, 2005 (15)ADM, ETN, IFXActive RA≥2 DMARDs (≥6 months)InfectionMonitor HIV, HBV, HCV
Failure of DMARDs Demyelinating diseaseMonitor TB  
  Contraindications of DMARDs Heart failure PregnancyCardiac function INH for latent TB infection  
     Lymphoproliferative disorders   
BSR, 2006 (20)ADM, ETN, IFXCost and ease of administrationSame as NICE 2000 and BSR 2005InfectionSwitching can be useful
Patient's lifestyleAutoimmune diseases Lymphoma
FSR, 2006 (25)ADM, ETN, IFXActive RADAS28 >5.1 [UPWARDS ARROW]ESR/CRP≥2 DMARDs (≥3 months)InfectionAny of the 3 compounds can be used first MonitoringAcute infection Precancerous lesions
Failure of DMARDsMalignancy 
Contraindications of DMARDsDemyelinating disease 
Aggressive RA (progressive structural damage)Heart failure Pregnancy 
JCR, 2006 (28)ETNFailure of DMARDs≥6 SJC/TJC≥2 DMARDsInfectionsINH for latent TBAcute infection
  WBCs ≥4,000/mm3[UPWARDS ARROW]ESR/CRP§ (≥3 months)Malignancy infection  
     Heart failure   
     Pancitopenia   
     Demyelinating disease   

All guidelines (except SIGN [12]) recommended the use of TNFα antagonists for patients with active rheumatoid arthritis in whom standard therapy had failed. There were small differences among guidelines in the definition of active rheumatoid arthritis, but the pattern of variation in definitions was associated with guideline publication date and the research sources used in the development of a guideline. Some guidelines defined failure of standard therapy as failure of success with at least 2–3 disease-modifying antirheumatic drugs administered over the course of 6 months or more, whereas other guidelines defined failure as a lack of response to methotrexate at maximum dosages of 25 mg/week administered for at least 3–4 months. The recommended dosages were similar in all guidelines for adalimumab (40 mg every other week or per week) and etanercept (10–25 mg twice a week or 50 mg once a week). The standard dosage for infliximab ranged from 3–10 mg/kg, and the frequency of administration varied at 4-, 6-, and 8-week intervals. Most guidelines recommended infliximab induction at 0, 2, and 6 weeks, with the coadministration of methotrexate or other disease-modifying antirheumatic drugs.

Additionally, the guidelines differed with respect to tests before and during TNFα treatment. Most guidelines highly encouraged considering the risk-to-benefit ratio during the initial assessment of possible candidates for TNFα antagonists to assess broader infection risk. The majority recommended screening in patients with a previous diagnosis of tuberculosis, but only 7 (44%) guidelines recommended chest radiography and a tuberculin test for the initial assessment of possible candidates for TNFα antagonists (15, 20, 24–28). All agreed with the need for monitoring toxicity on a regular basis (range 2–12 months), but there was less agreement with respect to 1) the need for blood chemistry studies, 2) a complete blood cell count, and 3) serologic tests. Only 3 guidelines encouraged the use of a systematic evaluation of a minimum set of parameters, including joint pain and inflammation during TNFα treatment (18, 21, 23).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

There has been a proliferation of CPG and CS development in all fields of medicine, including rheumatology. Here, we report the results of the first comparison of the quality of CPGs and CS on TNFα antagonists in rheumatoid arthritis. CPG quality was assessed using the AGREE instrument, which has been previously validated (7). Our results demonstrate that the quality of CPGs on TNFα antagonists in the treatment of rheumatoid arthritis is modest in general and varies from guideline to guideline. There is also a trend for most guidelines to overlook domains of applicability (i.e., organizational barriers, potential costs, and criteria for monitoring) and editorial independence (i.e., sources of guideline development funding and conflicts of interest).

As anticipated, we found that mean domain scores for CPGs with an overall rating of recommend according to the AGREE instrument were higher in all domains than for CPGs with an overall rating of recommend with provisos, although only 3 domains were statistically different (stakeholder involvement, rigor of development, and clarity and presentation). The quality scores for the guidelines developed by rheumatology societies were lower than those obtained for guidelines developed by government agencies (scope and purpose, stakeholder involvement, and clarity and presentation). Low scores for guidelines from organizations specializing in rheumatology compared with higher scores for CPGs from national agencies might reflect the national agencies' tradition of using a multidisciplinary approach, relying heavily on clinical trials versus expert opinion, and having less conflict of interest with respect to industry (9). Additionally, low scores can also be explained by bad reporting, because when no information is provided about an assessment item, the resultant domain score will be lower, even though it may not mean that the study was inappropriately developed.

We also evaluated CS using the AGREE criteria, and CS domain scores were compared with those obtained by the CPGs. In general, lower scores were observed in CS. Even though the AGREE instrument has not been designed for evaluating CS and lower scores are expected, our intention was to review and assess those resources most widely used by physicians for decision making.

Guidelines differed in key domains related to the sourcing, interpretation, and application of research evidence. Some guidelines linked their recommendations to a large body of evidence, whereas others presented scarce evidence. A few guidelines graded their recommendations, although the grading systems and grades used were not consistent, whereas the majority did not. Differences and shortcomings in these varying grading systems were confusing and hinder adequate interpretation (2).

Overall, the domains with high scores and those with low scores were similar for CPGs that focused on TNFα antagonists and those that covered general treatment for rheumatoid arthritis. One possible explanation for this finding is that the high-scoring domains correspond to aspects of guideline development that are more commonly accepted. Poor scores for the domains applicability and editorial independence highlight the need to improve reporting on the implications of the application of new guidelines and the right practitioners have to know whether guidelines have been developed under conditions free from or with managed conflict of interest. When dissemination and implementation are envisioned from the early stages of the development process, guidelines can contribute to significant changes in practice (54).

Among the various appraisal checklists for CPGs, we opted for the AGREE instrument because it has proven efficacy in assessing recommendations (59). It should be pointed out that the AGREE instrument is designed to guide evaluation of the methodologic quality of guidelines and the reporting of guideline development processes. However, good methodologic quality and explicit reporting do not ensure optimal recommendations. Well-reported guidelines can contain inaccurate recommendations (9).

Although the AGREE Collaboration highly recommends having more than 2 appraisers when the instrument is used for research purposes, it has been found that when evaluating CPGs, the process is more important than the scoring (60). Without proper training, adding more than 2 appraisers with different perspectives may increase rating variability/disagreements (60). Ultimately, the ideal approach for CPG appraisal is one where potential users with clinical and methodologic skills review a CPG by using the AGREE instrument to facilitate the process of determining guideline quality and relevance (60).

Our findings are consistent with other studies (7, 61), particularly concerning the variation of the quality scores for the guidelines. Attempts to evaluate the quality of guidelines have generally shown poor adherence to quality standards (9, 61). This is of particular concern for guidelines developed by medical societies because they reach a broader audience that expects to be able to use guidelines as standards of care.

To the authors' knowledge, this review is the first attempt to separately evaluate consensus statements from guidelines. In summary, CPGs and CS for the use of new biologic agents in rheumatoid arthritis vary in quality and are not always consistent. Recommendations for clinical practice for emerging therapies must be rigorously developed using evidence-based methods, include full participation of stakeholders, link the strength of evidence to recommendations, be explicit in their guidance, fully disclose potential conflicts of interest, and consider policy and health care delivery. Our findings suggest that further efforts may be required to ensure the highest possible quality for clinical recommendations of emerging therapies.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

Dr. Suarez-Almazor had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Lopez-Olivo, Ortiz, Skidmore, Suarez-Almazor.

Acquisition of data. Lopez-Olivo, Kallen, Ortiz, Skidmore, Suarez-Almazor.

Analysis and interpretation of data. Lopez-Olivo, Kallen, Ortiz, Suarez-Almazor.

Manuscript preparation. Lopez-Olivo, Kallen, Ortiz, Skidmore, Suarez-Almazor.

Statistical analysis. Lopez-Olivo, Kallen.

Obtained funding. Suarez-Almazor.

Administrative, technical, or material support. Suarez-Almazor.

Study supervision. Suarez-Almazor.

ROLE OF THE SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

The Canadian Agency for Drugs and Technologies in Health approved the design, conduct, and publication of the technology assessment report on which this study was based. The agency had no role in the collection, management, analysis, and interpretation of the data presented here, or in the preparation, review, or approval of the manuscript, or the decision to publish this study.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information

We are grateful to Vanessa Cox, BS, statistician at the Department of General Internal Medicine, The University of Texas M. D. Anderson Cancer Center for her valuable contributions to the conduct of this manuscript, and to Stephanie Deming, Department of Scientific Publications, The University of Texas M. D. Anderson Cancer Center, for her thoughtful comments.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE SPONSOR
  9. Acknowledgements
  10. REFERENCES
  11. Supporting Information
FilenameFormatSizeDescription
ACR_24207_sm_Appendix.doc78KAppendix A: Relevant Trials Cited in Studies

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