Abstract
Introduction
Rheumatoid arthritis usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions. The aims of treatment are to relieve pain and swelling, and to improve function. In addition, disease-modifying antirheumatic drugs (DMARDs) may reduce disease progression.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in people with rheumatoid arthritis who have not previously received any disease-modifying antirheumatic drug treatment? How do different drug treatments compare in people with rheumatoid arthritis who have either not responded to or are intolerant of first-line disease-modifying antirheumatic drugs? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2005 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 62 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adalimumab, anakinra, antimalarial drugs, azathioprine, ciclosporin, corticosteroids, cyclophosphamide, etanercept, infliximab plus methotrexate, leflunomide, methotrexate (alone; or plus sulfasalazine plus hydroxychloroquine), oral gold, parenteral gold, penicillamine, sulfasalazine.
Key Points
Rheumatoid arthritis is a chronic inflammatory disorder that mainly affects the peripheral joints and surrounding tissue.
It usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions.
The aims of treatment are to relieve pain and swelling, and to improve function. In addition, disease-modifying antirheumatic drugs (DMARDs) may reduce disease progression.
The DMARD methotrexate is widely used as first-line treatment in people with rheumatoid arthritis because of consensus about its effectiveness in practice.
Sulfasalazine and combined treatment with methotrexate and sulfasalazine are as effective as methotrexate in improving pain, joint swelling, and function in people with early rheumatoid arthritis who have not previously received DMARDs.
Antimalarials may improve symptoms and function in DMARD-naïve people, and are reasonably well tolerated, but radiological evidence of erosion is more marked with antimalarials than with sulfasalazine.
There is a variety of DMARDs available for second-line treatment of rheumatoid arthritis, and we found no clear evidence that one is superior.
Methotrexate, sulfasalazine, penicillamine , and leflunomide cause similar improvements in symptoms and function when given to people as second-line DMARD treatment, although methotrexate causes fewer adverse effects.
The combination of methotrexate plus sulfasalazine plus hydroxychloroquine is more effective in reducing measures of disease activity in people receiving second-line treatment than any of the drugs used alone. Adding the cytokine inhibitors infliximab or etanercept to methotrexate is more effective than using methotrexate alone.
Although antimalarials and oral gold seem to improve clinical disease activity when given as second-line treatment, they are not as effective as methotrexate or sulfasalazine. Although parenteral gold is more effective than oral gold, it leads to higher levels of toxicity than most of the other commonly used DMARDs.
Ciclosporin offers short-term control of rheumatoid arthritis when used as second-line treatment, but is associated with nephrotoxicity.
We don′t know whether cyclophosphamide is as effective as other DMARDs for second-line treatment.
Cytokine inhibitors may offer an alternative to traditional DMARDs for second line treatment of rheumatoid arthritis, but more research is needed.
Etanercept may be as effective as methotrexate in improving symptoms, function, and radiological evidence of progression, but more evidence for its effect is needed
Azathioprine is less effective and is less well tolerated than methotrexate.
We don't know whether anakinra or adalimumab are as effective as other DMARDs for second-line treatment.
Although widely used for the initial short-term relief of clinical disease activity in rheumatoid arthritis, we don't know how corticosteroids compare with other drugs for first or second-line treatment.
About this condition
Definition
Rheumatoid arthritis is a chronic inflammatory disorder. It is characterised by chronic pain and swelling that primarily affects the peripheral joints and related periarticular tissues. It usually starts as an insidious symmetrical polyarthritis, often with non-specific symptoms such as malaise and fatigue.
Incidence/ Prevalence
Studies from the USA have suggested age-adjusted incidence rates of between 0.7 and 0.4 per 1000 person years at risk, but data from European studies suggest a slightly lower incidence rate (0.25/1000 person years). With the exception of some Native American populations where incidence is higher, there is marked consistency in the prevalence of rheumatoid arthritis worldwide. All studies suggest a female incidence rate between two and three times higher than the male rate, and that incidence rates increase progressively with age.
Aetiology/ Risk factors
The cause of rheumatoid arthritis is, as yet, unknown. Genetic factors, hormonal influences, obesity, diet, and cigarette smoking have all been implicated as risk factors. The most widely accepted cause of rheumatoid arthritis is an infection with a micro-organism in a genetically susceptible host.
Prognosis
Rheumatoid arthritis is a chronic condition. In most cases, it follows a course of relapses and remissions (polycyclic pattern). Relapses ("flares") are associated with generalised pain, swelling, and stiffness, which may affect most joints simultaneously. People with rheumatoid arthritis have reduced life expectancy compared with healthy controls, as shown by a longitudinal cohort study undertaken in the UK including 1010 people with rheumatoid arthritis (standardised all-cause mortality among men: 1.45, 95% CI 1.22 to 1.71; standardised all-cause mortality among women: 1.84, 95% CI 1.64 to 2.05). People with rheumatoid arthritis also have excess cardiovascular disease mortality (standardised cardiovascular mortality among men: 1.36, 95% CI 1.04 to 1.75; standardised cardiovascular mortality among women: 1.93, 95% CI 1.65 to 2.26).
Aims of intervention
The aims of rheumatoid arthritis management are not only symptom control during active disease flares, but also suppression of disease activity in order to prevent permanent joint damage, and reducing long-term disability, with minimal adverse effects of treatment.
Outcomes
Patient global assessment; physician global assessment (as assessed by Likert scale etc); pain scores (as measured by visual analogue scale, Likert scale); early morning stiffness; tender joint count, swollen joint count, or both as assessed by Ritchie articular index; disability (as measured by walking distance, dressing, getting in/out of bath); overall function as measured by validated scales such as the American College of Rheumatology core response criteria; Disease Activity Score; European League Against Rheumatism response criteria (based on the Disease Activity Score); radiological erosions (as measured by Sharp or Larsen scores) at 1 year; quality of life; mortality; cardiovascular mortality; adverse effects including neutropenia, anaemia, thrombocytopenia, abnormal liver function, proteinuria, skin rashes, shortness of breath, pulmonary reactions.
Methods
BMJ Clinical Evidence search and appraisal June 2005. The following databases were used to identify studies for this review: Medline 1966 to June 2005, Embase 1980 to June 2005, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials Issue 2, 2005. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributors for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language including at least 20 people. Studies are at least single blind. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. There was no minimum length of follow-up required to include studies and we did not exclude on the basis of size of follow-up. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for rheumatoid arthritis
| Important outcomes | Disease activity, pain, swollen joints, functional status, mortality, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of drug treatments in people with rheumatoid arthritis who have not previously received any disease-modifying antirheumatic drug treatment? | |||||||||
| 2 (310) | Disease activity | Methotrexate v sulfasalazine v methotrexate plus sulfasalazine | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for conflicting results. Directness point deducted for inconsistent use of corticosteroids |
| 3 (371) | Joint pain or tenderness | Sulfasalazine v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for poor follow-up. Directness point deducted for inconsistent use of corticosteroids |
| 3 (371) | Disease severity (patient/physician global assessment) | Sulfasalazine v placebo | 4 | –2 | –1 | –1 | 0 | Very low | Quality point deducted for poor follow-up and incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for inconsistent use of corticosteroids |
| 1 (60) | Disease severity | Sulfasalazine v hydroxychloroquine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (145) | Joint pain/tenderness | Hydroxychloroquine v placebo | 4 | –1 | 0 | -1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inconsistent use of corticosteroids |
| 2 (145) | Disease severity | Hydroxychloroquine v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality point s deducted for sparse data and use of unvalidated scoring system. Directness point deducted for inconsistent use of corticosteroids |
| 1 (56) | Joint pain/tenderness | Oral corticosteroids v chloroquine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| How do different drug treatments compare in people with rheumatoid arthritis who have either not responded to or are intolerant of first-line disease-modifying antirheumatic drugs? | |||||||||
| 2 (529) | Disease activity | Infliximab plus methotrexate v methotrexate alone | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (2246) | Disease activity | Leflunomide v methotrexate | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (554) | Disease activity | Leflunomide v sulfasalazine | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results at different endpoints |
| 17 treatment groups, (507) | Disease activity | Methotrexate v sulfasalazine | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between treatment groups |
| 20 treatment groups, (588) | Disease activity | Methotrexate v antimalarial drugs | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between treatment groups |
| 35 treatment groups, (1774) | Disease activity | Methotrexate v oral gold | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between treatment groups |
| 37 treatment groups plus 2 RCTs, (1081) | Disease activity | Methotrexate v parenteral gold | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between treatment groups |
| 31 treatment groups, (857) | Disease ac tivity | Methotrexate v penicillamine | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between treatment groups |
| 24 treatment groups plus 2 RCTs (825) | Disease activity | Methotrexate v azathioprine | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for no direct comparison between interventions in one review |
| 2 (273) | Disease activity | Methotrexate plus sulfasalazine plus hydroxychloroquine v sulfasalazine plus hydroxychloroquine v methotrexate alone | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (686) | Disease activity | Etanercept plus methotrexate v etanercept alone v methotrexate alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for unclear use of corticosteroids |
| 37 treatment arms plus 1 RCT (1067) | Disease activity | Penicillamine v azathioprine | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between interventions in review |
| 1 (92) | Disease activity | Penicillamine v ciclosporin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 30 treatment groups plus 3 RCTs (927) | Disease activity | Penicillamine v sulfasalazine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for inclusion of review with methodological flaws |
| 48 treatment arms (2083) | Disease activity | Penicillamine v oral gold | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between interventions |
| 19 treatment groups plus 2 RCTs (667) | Disease activity | Sulfasalazine v antimalarial drugs | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for no direct comparison between interventions in two reviews |
| 34 treatment groups (1733) | Disease activity | Sulfasalazine v oral gold | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between interventions |
| 36 treatment groups plus 3 RCTs (1258) | Disease activity | Sulfasalazine v parenteral gold | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for no direct comparison between interventions in two reviews |
| 37 treatment arms plus 1 RCT (1854) | Disease activity | Hydroxychloroquine v oral gold | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results and poor follow-up. Directness point deducted for no direct comparison of interventions in review |
| 39 treatment arms (962) | Disease activity | Hydroxychloroquine v parenteral gold | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between interventions |
| 2 (169) | Disease activity | Azathioprine v ciclosporin | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and statistical flaws |
| 1 (121) | Disease activity | Azathioprine v parenteral gold v cyclophosphamide | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (632) | Disease activity | Etanercept v methotrexate | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (948) | Disease activity | Adalimumab v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (891) | Disease activity | Anakinra v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (144) | Disease activity | High-dose corticosteroids v lower-dose corticosteroids | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and poor follow-up. Consistency point deducted for conflicting results |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.
Glossary
- American College of Rheumatology (ACR) criteria
for assessing response includes seven measures in its core data set: swollen joint count, tender joint count, patient assessment of global status, an acute phase reactant [erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)], health professional assessment of global status, physical function, and pain. Improvement criteria for the are based on improvement of at least 20% in both tender and swollen joint counts, and three of the five additional measures (ACR 20), and corresponding ACR 50, 50% improvement, and ACR 70, 70% improvement.
- Disease Activity Score (DAS)
is a clinical index of disease activity that combines information from swollen joints, tender joints, erythrocyte sedimentation rate (ESR), and general health or global disease activity measured on a visual analogue scale.
- European League Against Rheumatism (EULAR) response criteria
classifies trial participants as “good”, “moderate”, or “non-responders” using individual change from baseline in Disease Activity Score.
- Health Assessment Questionnaire (HAQ)
assesses eight functional categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. For each of these domains, patients report the amount of difficulty they have had in performing two to three specific activities in the previous week, assessing each activity on a scale from 0 (without any difficulty) to 3 (unable to do). By convention, the HAQ Disability Index (HAQ-DI) is expressed on a scale from 0 to 3 units, representing the mean of the eight domain scores. A HAQ-DI of 0 indicates no functional disability, while a HAQ-DI of 3 indicates severe functional disability.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Larsen score
Assesses radiological damage by scoring joints from 0 (normal) to 5; possible score range 0–250.
- Likert scale
When responding to a Likert questionnaire item, respondents specify their level of agreement to a statement. Traditionally a 5 point scale is used: strongly disagree, disagree, neither agree nor disagree, agree, strongly agree.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Ritchie articular index
A graded assessment of 26 joint regions to assess tenderness plus a 44 joint count to assess swelling.
- Sharp score
Assesses radiological damage by measuring erosions and joint space narrowing in 44 different joints and reporting an aggregated score ranging from 0 to 448.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
References
- 1.Silman AJ. Rheumatoid arthritis. In: Silman AJ, Hochberg MC, eds. Epidemiology of the rheumatic diseases, 2nd ed. Oxford, Oxford Press, 2004: chapter 2, 31–71. [Google Scholar]
- 2.Masi AT. Articular patterns in the early course of rheumatoid arthritis. Am J Med 1983;75(suppl6A):16–26. [DOI] [PubMed] [Google Scholar]
- 3.Goodson N, Marks J, Lunt M, et al. Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s. Ann Rheum Dis 2005;64:1595–1601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sharp JT, Lidsky MD, Collins LC, et al. Methods of scoring the progression of radiological changes in rheumatoid arthritis. Correlation of radiologic, clinical and laboratory abnormalities. Arthritis Rheum 1971;14:706–720. [DOI] [PubMed] [Google Scholar]
- 5.Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn (Stockh) 1977;18:481–491. [DOI] [PubMed] [Google Scholar]
- 6.Dougados M, Combe B, Cantagrel A, et al. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 1999;58:220–225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Haagsma CJ, van Riel PL, de Jong AJ, et al. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 1997;36:1082–1088. [DOI] [PubMed] [Google Scholar]
- 8.The Australian Multicentre Clinical Trial Group. Sulfasalazine in early rheumatoid arthritis. J Rheumatol 1992;19:1672–1677. [PubMed] [Google Scholar]
- 9.Hannonen P, Mottonen T, Hakola M, et al. Sulfasalazine in early rheumatoid arthritis. A 48-week double-blind, prospective, placebo-controlled study. Arthritis Rheum 1993;36:1501–1509. [DOI] [PubMed] [Google Scholar]
- 10.Williams HJ, Ward JR, Dahl SL, et al. A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. Arthritis Rheum 1988;31:702–713. [DOI] [PubMed] [Google Scholar]
- 11.Nuver-Zwart IH, van Riel PL, van de Putte LB, et al. A double blind comparative study of sulfasalazine and hydroxychloroquine in rheumatoid arthritis: evidence of an earlier effect of sulfasalazine. Ann Rheum Dis 1989;48:389–395. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Van der Heijde DM, van Riel PL, Nuver-Zwart IH, et al. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989;1:1036–1038. [DOI] [PubMed] [Google Scholar]
- 13.Clark P, Casas E, Tugwell P, et al. Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial. Ann Intern Med 1993;119:1067–1071. [DOI] [PubMed] [Google Scholar]
- 14.Anon. A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA Study. Am J Med 1995;98:156–168. [DOI] [PubMed] [Google Scholar]
- 15.Pavelka K Jr, Sen KP, Peliskova Z, et al. Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: a double blind comparison of two dose regimens. Ann Rheum Dis 1989;48:542–546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Tett SE, Cutler DJ, Beck C, et al. Concentration-effect relationship of hydroxychloroquine in patients with rheumatoid arthritis – a prospective, dose ranging study. J Rheumatol 2000;27:1656–1660. [PubMed] [Google Scholar]
- 17.Fielder A, Graham E, Jones S, et al. Royal College of Ophthalmologists guidelines: ocular toxicity and hydroxychloroquine. Eye 1998;12:907–909. [DOI] [PubMed] [Google Scholar]
- 18.Criswell LA, Robinson VA, Saag KKS, et al. Moderate-term, low-dose corticosteroids for rheumatoid arthritis. In: The Cochrane Library, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 1998, primary sources Medline; hand searches of Arthritis and Rheumatism, Scandinavian Journal of Rheumatology, Arthritis and Rheumatism abstracts, and references of all identified studies; and contact with authors of unpublished manuscripts. [Google Scholar]
- 19.Gotzsche PC, Johansen HK. Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis. In: The Cochrane Library, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 2004, primary sources Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), and hand searches of reference lists. [Google Scholar]
- 20.Blumenauer B, Judd M, Cranney A, et al. Infliximab for the treatment of rheumatoid arthritis. In: The Cochrane Library, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002; primary sources Biological Abstracts, Cinahl, Current Contents, Dissertation Abstracts, EBM Reviews, Healthstar, and Medline. 12137712 [Google Scholar]
- 21.Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumour necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552–1563. [DOI] [PubMed] [Google Scholar]
- 22.Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354:1932–1939. [DOI] [PubMed] [Google Scholar]
- 23.Osiri M, Robinson VA, Shea BJ, et al. Leflunomide for treating rheumatoid arthritis. In: The Cochrane Library, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002, primary sources Medline, Embase, Healthstar, Current Contents, Cochrane Controlled Trials Register, Cochrane Musculoskeletal Specialized Register, hand searches of reference lists and abstracts from the American College of Rheumatology annual scientific meetings, and contact with experts. 12535423 [Google Scholar]
- 24.Bao C, Chen S, Gu Y, et al. Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase II clinical trial. Chin Med J (Engl) 2003;116:1228–1234. [PubMed] [Google Scholar]
- 25.Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 1990;33:1449–1461. Search date 1989; primary sources Medline, hand searches of reference lists of retrieved articles and of Arthritis Rheum and Scand J Rheumatol. [DOI] [PubMed] [Google Scholar]
- 26.Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum 1992;35:1117–1125. Search date 1990; primary sources Medline, hand searches of reference lists of retrieved articles and of Arthritis Rheum and Scand J Rheumatol. [DOI] [PubMed] [Google Scholar]
- 27.Weinblatt ME, Polisson R, Blotner SD, et al. The effects of drug therapy on radiographic progression of rheumatoid arthritis. Results of a 36-week randomized trial comparing methotrexate and auranofin. Arthritis Rheum 1993;36:613–619. [Erratum in: Arthritis Rheum 1993;36:1028] [DOI] [PubMed] [Google Scholar]
- 28.Rau R, Herborn G, Karger T, et al. A double blind randomized parallel trial of intramuscular methotrexate and gold sodium thiomalate in early erosive rheumatoid arthritis. J Rheumatol 1991;18:328–333. [PubMed] [Google Scholar]
- 29.Rau R, Herborn G, Karger T, et al. A double-blind comparison of parenteral methotrexate and parenteral gold in the treatment of early erosive rheumatoid arthritis: an interim report on 102 patients after 12 months. Semin Arthritis Rheum 1991;21:13–20. [DOI] [PubMed] [Google Scholar]
- 30.Alarcon GS, Lopez-Mendez A, Walter J, et al. Radiographic evidence of disease progression in methotrexate treated and nonmethotrexate disease modifying antirheumatic drug treated rheumatoid arthritis patients: a meta-analysis. J Rheumatol 1992;19:1868–1873. Search date 1991; primary sources ′the English language literature on the treatment of rheumatoid arthritis with methotrexate and hand searches of abstracts from national meeting of the American College of Rheumatology 1988-1991. [PubMed] [Google Scholar]
- 31.Jeurissen ME, Boerbooms AM, van de Putte LB, et al. Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double-blind study. Ann Intern Med 1991;114:999–1004. [DOI] [PubMed] [Google Scholar]
- 32.Jeurissen ME, Boerbooms AM, van de Putte LB, et al. Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty-eight-week randomized, double-blind trial. Arthritis Rheum 1991;34:961–972. [DOI] [PubMed] [Google Scholar]
- 33.Willkens RF, Urowitz MB, Stablein DM, et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1992;35:849–856. [DOI] [PubMed] [Google Scholar]
- 34.Willkens RF, Sharp JT, Stablein D, et al. Comparison of azathioprine, methotrexate, and the combination of the two in the treatment of rheumatoid arthritis. A forty-eight-week controlled clinical trial with radiologic outcome assessment. Arthritis Rheum 1995;38:1799–1806. [DOI] [PubMed] [Google Scholar]
- 35.Willkens RF, Stablein D. Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial. J Rheumatol Suppl 1996;44:64–68. [PubMed] [Google Scholar]
- 36.Whiting-O'Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnormalities: a meta-analysis. Am J Med 1991;90:711–716. Search date not reported; primary sources ′computerized literature search for all English language studies reporting liver biopsy data on patients with psoriasis, psoriatic arthritis, or rheumatoid arthritis receiving low-dose methotrexate.′ [PubMed] [Google Scholar]
- 37.Barrera P, Laan RFJM, Van Riel PLCM, et al. Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis 1994;53:434–439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Patatanian E, Thompson DF. A review of methotrexate-induced accelerated nodulosis. Pharmacotherapy 2002;22:1157–1162. Search date 2001; primary sources Medline, Toxline, and Embase and hand searches of reference lists of key articles. [DOI] [PubMed] [Google Scholar]
- 39.Ince A, Yazici Y, Hamuryudan V, et al. The frequency and clinical characteristics of methotrexate (MTX) oral toxicity in rheumatoid arthritis (RA): a masked and controlled study. Clin Rheumatol 1996;15:491–494. [DOI] [PubMed] [Google Scholar]
- 40.O'Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. New Engl J Med 1996;334:1287–1291. [DOI] [PubMed] [Google Scholar]
- 41.O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:1164–1170. [DOI] [PubMed] [Google Scholar]
- 42.Paulus HE, Williams HJ, Ward JR, et al. Azathioprine versus D-penicillamine in rheumatoid arthritis patients who have been treated unsuccessfully with gold. Arthritis Rheum 1984;27:721–727. [DOI] [PubMed] [Google Scholar]
- 43.van Rijthoven AW, Dijkmans BA, Goie The HS, et al. Comparison of cyclosporine and D-penicillamine for rheumatoid arthritis: a randomized, double blind, multicenter study. J Rheumatol 1991;18:815–820. [PubMed] [Google Scholar]
- 44.Weinblatt ME, Reda D, Henderson W, et al. Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials. J Rheumatol 1999;26:2123–2130. Search date 1998; primary sources Medline, Excerpta Medica, and Derwent Drug File. [PubMed] [Google Scholar]
- 45.Jones G, Halbert J, Crotty M, et al. The effect of treatment on radiological progression in rheumatoid arthritis: a systematic review of randomized placebo-controlled trials. Rheumatology 2003;42:6–13. Search date 2000; primary sources Cochrane Controlled Trials Register; Medline; Embase; hand searches of bibliographies of reviews, papers, and conference proceedings of the American College of Rheumatology; and contact with pharmaceutical companies and authors. [DOI] [PubMed] [Google Scholar]
- 46.Bird HA, Le Gallez P, Dixon JS, et al. A single-blind comparative study of auranofin and hydroxychloroquine in patients with rheumatoid arthritis. Clin Rheumatol 1984;3:57–66. [DOI] [PubMed] [Google Scholar]
- 47.Ahern MJ, Harrison W, Hollingsworth P, et al. A randomised double-blind trial of cyclosporin and azathioprine in refractory rheumatoid arthritis. Aust N Z J Med 1991;21:844–849. [DOI] [PubMed] [Google Scholar]
- 48.Kruger K, Schattenkirchner M. Comparison of cyclosporin A and azathioprine in the treatment of rheumatoid arthritis – results of a double-blind multicentre study. Clin Rheumatol 1994;13:248–255. [DOI] [PubMed] [Google Scholar]
- 49.Boers M, Dijkmans BA, van Rijthoven AW, et al. Reversible nephrotoxicity of cyclosporine in rheumatoid arthritis. J Rheumatol 1990;17:38–42. [PubMed] [Google Scholar]
- 50.Yocum DE, Klippel JH, Wilder RL, et al. Cyclosporin A in severe, treatment-refractory rheumatoid arthritis. A randomized study. Ann Intern Med 1988;109:863–869. [DOI] [PubMed] [Google Scholar]
- 51.Berg KJ, Forre O, Djoseland O, et al. Renal side effects of high and low cyclosporin A doses in patients with rheumatoid arthritis. Clin Nephrol 1989;31:232–238. [PubMed] [Google Scholar]
- 52.Boers M, Dijkmans BA, van Rijthoven AW, et al. Reversible nephrotoxicity of ciclosporin in rheumatoid arthritis. J Rheumatol 1990;17:38–42. [PubMed] [Google Scholar]
- 53.Blumenauer B, Judd M, Cranney A, et al. Etanercept for the treatment of rheumatoid arthritis. In: The Cochrane Library, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003; primary sources Biological Abstracts, Current Contents, Dissertation Abstracts, EBM Reviews, and all Cochrane electronic databases, hand searches of proceedings of major rheumatology conferences and of reference lists from standard rheumatology textbooks, comprehensive reviews, and identified clinical trials and contact with content experts and pharmaceutical companies that manufacture etanercept. 14584021 [Google Scholar]
- 54.Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363:675–681. [DOI] [PubMed] [Google Scholar]
- 55.Currey HL, Harris J, Mason RM, et al. Comparison of azathioprine, cyclophosphamide, and gold in treatment of rheumatoid arthritis. BMJ 1974;3:763–766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.den Broeder A, van de Putte L, Rau R, et al. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol 2002;29:2288–2298. [PubMed] [Google Scholar]
- 57.van de Putte LB, Rau R, Breedveld FC, et al. Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study. Ann Rheum Dis 2003;62:1168–1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 2004;63:508–516. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Furst DE, Schiff MH, Fleischmann RM, et al. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003;30:2563–2571. [PubMed] [Google Scholar]
- 60.Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50:1400–1411. [DOI] [PubMed] [Google Scholar]
- 61.Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998;41:2196–2204. [DOI] [PubMed] [Google Scholar]
- 62.Bresnihan B, Newmark R, Robbins S, et al. Effects of anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-week randomized, placebo-controlled trial. J Rheumatol 2004;31:1103–1111. [PubMed] [Google Scholar]
- 63.Nuki G, Bresnihan B, Bear MB, et al. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:2838–2846. [DOI] [PubMed] [Google Scholar]
- 64.Cohen SB, Woolley JM, Chan W, et al. Interleukin 1 receptor antagonist anakinra improves functional status in patients with rheumatoid arthritis. J Rheumatol 2003;30:225–231. [PubMed] [Google Scholar]
- 65.Cohen SB, Moreland LW, Cush JJ, et al. A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis 2004;63:1062–1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Fleischmann RM, Schechtman J, Bennett R, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheum 2003;48:927–934. [DOI] [PubMed] [Google Scholar]
- 67.Tesser J, Fleischmann R, Dore R, et al. Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis. J Rheumatol 2004;31:649–654. [PubMed] [Google Scholar]
- 68.Schiff MH, DiVittorio G, Tesser J, et al. The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions. Arthritis Rheum 2004;50:1752–1760. [DOI] [PubMed] [Google Scholar]
- 69.Saag KG, Criswell LA, Sems KM, et al. Low-dose corticosteroids in rheumatoid arthritis. A meta-analysis of their moderate-term effectiveness. Arthritis Rheum 1996;39:1818–1825. Search date 1994; primary sources Medline, hand searches of reference lists of retrieved articles and of Arthritis Rheum and Scand J Rheumatol. [DOI] [PubMed] [Google Scholar]
- 70.Vischer TL, Sinniger M, Ott H, et al. A randomized, double-blind trial comparing a pulse of 1000 with 250 mg methylprednisolone in rheumatoid arthritis. Clin Rheumatol 1986;5:325–326. [DOI] [PubMed] [Google Scholar]
- 71.Iglehart IW III, Sutton JD, Bender JC, et al. Intravenous pulsed steroids in rheumatoid arthritis: a comparative dose study. J Rheumatol 1990;17:159–162. [PubMed] [Google Scholar]
- 72.Shipley ME, Bacon PA, Berry H, et al. Pulsed methylprednisolone in active early rheumatoid disease: a dose-ranging study. Br J Rheumatol 1988;27:211–214. [DOI] [PubMed] [Google Scholar]