Abbreviations
- ACR
American College of Rheumatology
- AGREE
Appraisal of Guidelines for Research & Evaluation
- APLAR
Asia Pacific League of Associations for Rheumatology
- CRA
Canadian Rheumatology Association
- csDMARD
conventional synthetic disease-modifying antirheumatic drug
- DMARD
disease-modifying antirheumatic drug
- EULAR
European League Against Rheumatism
- GRADE
Grading of Recommendations Assessment, Development and Evaluation
- HCQ
hydroxychloroquine
- JAK
Janus kinase
- LEF
leflunomide
- MTX
methotrexate
- NICE
National Institute for Health and Care Excellence
- RA
rheumatoid arthritis
- SIGN
Scottish Intercollegiate Guidelines Network
- SR
systematic review
- SSZ
sulfasalazine
- tsDMARD
targeted synthetic disease-modifying antirheumatic drug
Key Messages
Nine evidence-based guidelines were identified that recommend the use of conventional synthetic disease-modifying antirheumatic drugs as a first-line therapy for patients with rheumatoid arthritis prior to using biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors.
Methotrexate monotherapy was the most commonly recommended conventional synthetic disease-modifying antirheumatic drug recommended as first-line therapy by the included guidelines.
Eight of the included guidelines recommend combination therapy using multiple conventional synthetic disease-modifying antirheumatic drugs if monotherapy is ineffective and 4 included guidelines recommend the use of glucocorticoids in combination with conventional synthetic disease-modifying antirheumatic drugs.
Context and Policy Issues
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that can affect the entire body.1,2 RA is characterized by inflammation in the lining of the joints and other tissue, causing swelling, pain, and stiffness, which can lead to permanent joint damage.1 RA is a debilitating chronic disease and people with RA are often at a higher risk of mortality because of associated comorbidities such as cardiovascular disease.3,4 In Canada, approximately 374,000 people aged 16 or older are currently living with diagnosed RA and approximately 1% of the global population is affected by RA.1 The prevalence and incidence of diagnosed RA generally increases with age and females in Canada are more likely to experience diagnosed RA compared to males.1
There is no cure for RA; however, early diagnosis and treatment can play a large role in reducing symptoms, preventing lasting joint damage, and reducing the risk of developing comorbidities.1,2 Early treatment for RA (e.g., as soon as a patient is diagnosed) can mean that disease remission is more likely.2 A “treat-to-target” strategy is often used in RA management, where the target for patient treatment is remission or low disease activity when remission is not possible.5
Disease-modifying antirheumatic drugs (DMARDs) are commonly used course in the treatment for RA because they slow disease progression and provide symptom relief.4 RA treatment regimens can consist of conventional synthetic DMARDs (csDMARDs), biologic DMARDs, or targeted synthetic DMARDs (tsDMARDs). Common csDMARDs include methotrexate (MTX), leflunomide (LEF), sulfasalazine (SSZ), and antimalarials such as hydroxychloroquine (HCQ).4 Biologic DMARDs usually include either tumour necrosis factor inhibitors or non-tumour necrosis factor inhibitors. Janus kinase (JAK) inhibitors are a commonly used tsDMARD in advanced RA treatment.5 csDMARDs were the first DMARD agents approved for RA treatment, are the most commonly prescribed treatment for RA, and are typically the least expensive.4 csDMARD monotherapy is typically the first course of treatment for newly diagnosed individuals. However, if disease progression continues, then additional csDMARDs may be added as a “step-up” approach, followed by adding or switching to biologic DMARDs or JAK inhibitors if disease progression does not slow down.4,5 Glucocorticoids are also commonly used on a short-term basis in the treatment of RA. Glucocorticoids, which have anti-inflammatory and immunosuppressive effects, may also be used as an adjunct therapy when a patient is starting a new DMARD treatment or changing from one DMARD to another.6 DMARD therapy for the treatment and management of RA has shown to be effective in providing symptom relief and slowing disease progression; however, there are a variety of treatment approaches that may be used to manage RA disease progression and evidence-based guidance is helpful in determining the best course of action for patients with RA.
The purpose of this report is to review the evidence-based guidelines regarding the use of csDMARD therapy prior to the use of biologic DMARDs or JAK inhibitors. Evidence-based guidelines containing recommendations related to the use of csDMARDs, combination approaches for csDMARD therapy, csDMARD trial periods, and combining glucocorticoids with csDMARD therapy will be sought for this report and any relevant recommendations will be summarized.
Research Question
What are the evidence-based guidelines regarding the use of conventional disease-modifying antirheumatic drugs prior to the use of biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors for the treatment of rheumatoid arthritis?
Methods
Literature Search Methods
A limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and rheumatoid arthritis. A search filter was applied to limit retrieval to clinical practice guidelines. The search was also limited to documents published between January 01, 2011 and April 05, 2021.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in .
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in , they were duplicate publications, or were published prior to 2011. Guidelines with unclear methodology were also excluded and only the most recent version of each guideline was eligible for inclusion in this report.
Critical Appraisal of Individual Studies
The included publications were critically appraised by one reviewer using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument for guidelines as a guide.7 Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
Summary of Evidence
Quantity of Research Available
A total of 268 citations were identified in the literature search. Following the screening of titles and abstracts, 228 citations were excluded and 40 potentially relevant reports from the electronic search were retrieved for full-text review. Nine potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 40 publications were excluded for various reasons and 9 publications met the inclusion criteria and were included in this report. Appendix 1 presents the PRISMA8 flow chart of the study selection. Additional references of potential interest are provided in Appendix 5.
Summary of Study Characteristics
Nine relevant evidence-based guidelines9–17 were identified. The characteristics of the included evidence-based guidelines are subsequently summarized. Many of the identified evidence-based guidelines include information related to the general management and treatment of RA; however, only information related to recommendation for the use of csDMARD therapy prior to biologic DMARDs or JAK inhibitors will be presented in this report. Additional details regarding the characteristics of included guidelines are provided in Appendix 2.
Study Design
The 9 relevant guidelines were developed by the European League Against Rheumatism (EULAR),9 the Asian Pacific League of Associations for Rheumatology (APLAR),10 the French Society for Rheumatology,11 the Brazilian Society of Rheumatology,12 the NICE–National Institute of Health and Care Excellence,13 the American College of Rheumatology (ACR),14 the ICARUS Project by Todoerti et al.,15 the Canadian Rheumatology Association (CRA),16 and the Scottish Intercollegiate Guidelines Network (SIGN).17
Each evidence-based guideline9–17 was informed by a systematic review (SR) of evidence regarding the management and treatment of patients with RA. The quality of the evidence informing the recommendations and the strength of the recommendations were appraised using a variety of methods. Three guidelines9,11,15 determined the level of evidence and strength of recommendations using the Oxford Centre for Evidence-Based Medicine tool.18 For the tool, the level of evidence ranges from 1 (high-quality evidence including SRs of randomized controlled trials) to 5 (very low-quality evidence including expert opinion).18 Based on the quality of evidence used to inform the recommendations, each recommendation is graded between A (recommendation is based on consistently high-quality evidence) to D (recommendation is based on consistently low-quality evidence).18 The Grading of Recommendations Assessment, Development and Evaluation (GRADE)19 approach was used to evaluate the quality of evidence used to inform the recommendations for 4 guidelines.10,12–14 However, strengths of recommendations were only reported in the ACR guideline.14 According to GRADE, evidence quality can be rated as “high,” “moderate,” “low,” or “very low.” The guideline by the CRA16 sought previous evidence-based guidelines within the SR process and appraised the quality of existing guidelines using the AGREE model.7 A custom grading system was used to give the evidence informing the recommendation a designation between 1 (high-quality evidence) and 4 (very low-quality evidence) and the strength of recommendation a designation between “A” (strong recommendation) and “D” (consensus recommendation). This customized grading system was informed by the original levels of evidence and strengths of recommendations from each included guideline identified from the SR. One guideline by SIGN17 used an internal methodology to grade the quality of evidence used to inform recommendations. This grading system designated recommendations between “A” (recommendation based on high-quality evidence) and “D” (recommendation based on very low-quality evidence).
Six guidelines9,10,12,14–16 were developed using a voting process to determine the agreement of the drafted recommendations and 3 guidelines were developed through consensus.11,13,17
Country of Origin
Five guidelines were intended for broad use in Europe9 or for use in specific European nations including France,11 Italy,15 Scotland,17 and the UK, in general.13 The guideline from APLAR was intended for use in the Asian-Pacific region.10 The guideline from the Brazilian Society of Rheumatology was intended for use in Brazil.12 Two guidelines were intended for use in North America, specifically in Canada16 and the US.14
Patient Population
The intended users for each of the guidelines were rheumatologists or other health care professionals providing care for patients with RA.9–17 The target population for each of the guidelines was adult patients with RA.9–17
Relevant Interventions
The evidence-based guidelines considered a broad range of recommendations for the treatment of patients with RA. The interventions that were relevant to this report were csDMARDs as a first-line therapy for the treatment of patients with RA.9–17 The guideline by Todoerti et al.15 focused primarily on the use of MTX for the treatment of rheumatic diseases, with a focus on patients with RA.
Outcomes
The included guidelines considered relevant patient-related outcomes like treatment efficacy,9,12,16,17 patient safety,9,12,15–17 quality of life,11,13 disease activity and patient functionality,10,11,13,14,16 and cost of csDMARDs.14
Summary of Critical Appraisal
An overview of the critical appraisal using the AGREE II7 instrument follows. Additional details regarding the strengths and limitations of the included guidelines are provided in Appendix 3.
In each included guideline, the scope and purpose were described, including the overall objective of the guideline and population of interest. Five of the included guidelines12–14,16,17 clearly described the health questions covered by the guideline. Six of the guidelines9,11,13,14,16,17 provided a description of the guideline development groups, which included relevant professionals in the field of rheumatology and members of the target population. Each guideline used a systematic method to search for, collect, and appraise the quality of evidence; however, 4 guidelines10–12,15 provided limited or no information regarding the inclusion criteria. Seven guidelines10,12–16 provided an explicit link between the recommendations and supporting evidence. Five guidelines9,10,13,14,17 provided a clear indication that the guidelines and recommendations were externally reviewed prior to publication. Each guideline presented recommendations clearly, with the key recommendations easily identified, and gave different options for RA management. One guideline13 described barriers and facilitators for recommendations application, provided advice for putting recommendations into practice, addressed potential resource implications of recommendations, and presented monitoring and auditing criteria within the guideline. Four guidelines10,12,13,17 provided clear indication that any views from the funding bodies did not influence the content of the guideline; for the remaining 5 guidelines,9,11,14–16 it was unclear whether the recommendations were influenced by funders. Five guidelines9,11–14 provided information related to competing interests among the guideline development groups, while 3 guidelines did not provide information10,15,16 and 1 provided unclear information.17 Three of the 5 guidelines that provided information with competing interests did not report how these were addressed;9,11,12 however, 2 guidelines providing details regarding the actions taken to address competing interests were provided.13,14
Summary of Findings
The main recommendations are subsequently summarized. Appendix 4 presents the detailed recommendations and supporting evidence.
Guidelines
Each guideline provided recommendations regarding the use of csDMARDs as first-line therapy for patients with RA prior to the use of biologic DMARDs, JAK inhibitors, or other tsDMARDs.9–17 Furthermore, the guidelines provided recommendations regarding which csDMARDs should be considered at certain stages of a patient’s RA progression, the use of combination therapy as a treatment option, and the use of glucocorticoids in combination with regular DMARD treatment. None of the included guidelines provided recommendations regarding the length of the time csDMARDs should be used prior to switching to or adding biologic DMARDs or JAK inhibitors.
Recommendations Regarding csDMARDs as First-Line Therapy
Each of the 9 included guidelines9–17 recommend csDMARDs as the first-line treatment for patients diagnosed with RA (strong recommendation for 5 guidelines,9,11,15–17 conditional recommendation for 1 guideline,14 and strength or recommendation not reported for 3 guidelines).10,12,13 Seven of the included guidelines9–12,14–16 recommend that MTX monotherapy should be the csDMARD of choice to begin treatment for patients with RA. The guideline from ACR specifies csDMARD monotherapy should be used over double or triple therapy and that MTX should be used as a first-line treatment for patients with a moderate to high severity of RA.14 Additionally, the ACR guideline recommends MTX monotherapy, as evidence favours MTX monotherapy because of clinical benefits, lower risk, and cost.14 These recommendations were based on evidence that was assessed to be moderate- to high-quality. The guideline from NICE13 recommends that MTX, LEF, or SSZ monotherapies be offered as first-line treatment or within the first 3 months of persistent symptoms for RA (quality of evidence and strength of recommendation not reported). Lastly, the SIGN guideline recommends MTX and SSZ be considered as first-line therapy because of evidence of favourable efficacy and toxicity profiles (moderate- to high-quality evidence; strong recommendation).17
Recommendations Regarding Treatment Approach for csDMARDs
Five included guidelines9–13 provide recommendations regarding alternative csDMARD treatment options for when MTX is not well-tolerated or not reaching targeted treatment results. These 5 guidelines recommended that LEF, SSZ, or HCQ be used as alternative options for csDMARD monotherapy.9–13 Additionally, APLAR recommends that iguratimod, bucillamine, cyclosporine, intramuscular gold, or tacrolimus can be considered as alternatives to MTX depending on availability.10 Where reported, these recommendations were based on high-,9,11 moderate-,10 and low-quality evidence,9 and the strength of the recommendations ranged from strong to weak.9,11 The guideline by NICE did not report the quality of evidence or strength of recommendation13 and the guideline by APLAR and the Brazilian Society of Rheumatology did not report the strength of recommendation.10,12
Six of the included guidelines provide recommendations regarding the use of a combination approach for csDMARD treatment in patients for whom RA monotherapy is inadequate or not well-tolerated,11–13,15–17 and 3 guidelines provided recommendations for the use of a combination approach when disease activity is moderate to high.10,14,16 Six included guidelines recommend the use of combination therapy with csDMARDs when MTX monotherapy produces an inadequate response or is not well-tolerated.11–13,15–17 The Brazilian Society of Rheumatology and NICE recommend that LEF, SSZ, or HCQ be used in combination with MTX when monotherapy has failed (high level of agreement for the Brazilian Society of Rheumatology; quality of evidence and strength or recommendation not reported for NICE).12,13 The CRA recommends that MTX and LEF should be used with caution because of an association with high toxicity (high level of evidence; strong recommendation).16 Two recommendations by the French Society for Rheumatology and Todoerti et al. specify that combination therapy with both csDMARDs and biologic DMARDs should be considered (high level of evidence; moderate to strong recommendation).11,15 The APLAR, ACR, and CRA guidelines recommend combination therapy with csDMARDs when disease activity is moderate to high.10,14,16 APLAR recommends that combination csDMARD therapy be considered for patients with high disease activity, but that patients be monitored closely for therapy-related toxicities (low quality of evidence; low strength of recommendation).10 The ACR recommendation specifies that when disease activity remains moderate to high when using csDMARD monotherapy, combination therapy with csDMARDs or adding biological DMARDs should be considered over csDMARD monotherapy (low to moderate quality of evidence; strong recommendation).14
Recommendations Regarding Combination Therapy With Glucocorticoids
Four included guidelines9,11,13,16 provide recommendations regarding the use of glucocorticoids in combination with csDMARD for the treatment of RA. EULAR and French Society for Rheumatology strongly recommend that short-term glucocorticoids be considered when changing csDMARD treatment but tapered as rapidly as clinically feasible (high-quality evidence).9,11 Similarly, the NICE guidelines recommend that short-term glucocorticoids be considered when starting a new csDMARD treatment regime (quality of evidence and strength of recommendation not reported).13 The CRA guideline recommends that glucocorticoids be added to csDMARD treatment as part of an initial treatment strategy or bridging therapy (high quality of evidence; strong recommendation), and that they be tapered as rapidly as clinically feasible (very low quality of evidence; consensus-based recommendation).16 Lastly, the SIGN guideline17 recommends the use of low-dose oral corticosteroids in combination with csDMARDs (high-quality evidence; strong recommendation).
Limitations
No recommendations related to the trial period for csDMARDs prior to switching or adding biologic DMARDs or JAK inhibitors were identified; therefore, no summary can be provided. One included guideline that was published in 2012 was intended for use in Canada.16 Given differences in available treatments and the organization of care around the world, the applicability of the other guidelines to the Canadian context is unclear. There is a large variety of available csDMARDs that can be used to treat RA, but many of the recommendations in this report only focus on common csDMARDs such as MTX, LEF, SSZ, and HCQ. Only one guideline by APLAR10 provided a limited recommendation specifying the use of other available csDMARDs including cyclosporine, intramuscular gold, or tacrolimus.
Conclusions and Implications for Decision- or Policy-Making
This review comprised 9 evidence-based guidelines9–17 that provide recommendations regarding the use of csDMARD therapy, prior to using biologic DMARDs or JAK inhibitors, in patients with RA. These guidelines were developed by rheumatology associations in different countries and regions in Europe, North America, the Asian-Pacific region, and Brazil. Similar recommendations were found across each included guideline, including using csDMARD therapy as first-line treatment for patients starting treatment for RA,9–17 providing alternative recommendations for which csDMARDs to use as first-line treatment,9–13 using combination therapy when monotherapy is not effective,10–17 and adding glucocorticoids to treatment when switching or bridging between therapies.9,11,13,16 Furthermore, these recommendations have remained consistent over the past decade despite new evidence being used to inform more recent recommendations.
Overall, the guidelines included in this report generally support the use of csDMARDs as first-line therapy prior to switching to or adding biologic DMARDs or JAK inhibitors, are in favour of combination therapy with other csDMARDs when monotherapy is ineffective or not well-tolerated, and recommend glucocorticoid use for switching or bridging between csDMARD treatment.
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Appendix 5. References of Potential Interest
Previous CADTH Reports
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