| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Published online 20 September 2005
Immunological therapies for rheumatoid arthritis
Department of Rheumatology, Southampton General Hospital, and MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK
Correspondence to: Dr C. J. Edwards, Department of Rheumatology, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD. E-mail: cedwards{at}soton.ac.uk
 |
Abstract |
|---|
Top
Abstract
Advances in the treatment...Rheumatoid arthritis (RA) is a chronic inflammatory arthritis of the synovial joints that causes loss of function and a shortened life expectancy. In the last 10 years there have been major advances in the treatment of RA, including more aggressive use of disease-modifying anti-rheumatic drugs and the development of immune therapies targeted to molecules and cells important in the immunopathogenesis of RA. Molecular messengers that travel between cells (cytokines) have been found to be of major importance. Blocking the cytokine tumour necrosis factor
(TNF-) produces significant improvement in RA, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. The use of cytokine blockers has shown the extent to which immune and inflammatory pathways are shared in a number of inflammatory diseases. There has also been an important proof of principle that blocking single cytokines can produce profound effects in inflammatory diseases. |
Advances in the treatment of rheumatoid arthritis |
|---|
Rheumatoid arthritis (RA) is a chronic inflammatory arthritis of the synovial joints that causes loss of function, disability, a shortened life expectancy and considerable health care costs1–3. RA is present in ~1% of the adult population of the UK, and is more common in women.4
In the last 10 years there have been major advances in the treatment of RA. This has included more aggressive use of disease-modifying anti-rheumatic drugs (DMARDs) and the development of immune therapies specifically targeted to molecules and cells important in the immunopathogenesis of RA. A realization that RA is particularly destructive to synovial joints in the first few years of disease has led to an increased use of DMARDs at an early stage.5 These drugs have also been used more frequently in combination with other DMARDs. This more aggressive approach to therapy is reflected in the guidelines for the treatment of RA from the American College of Rheumatology.6 Most DMARDs have been discovered serendipitously rather than by design. They are associated with problems due to lack of efficacy and side effects. In particular, ~10% of RA patients fail to show any response to traditional DMARDs. Consequently, rheumatologists have been searching for new therapies.
The therapeutic targeting of specific aspects of the immune response in RA followed a decade or more of laboratory work that had identified key signals and molecules involved in the immunopathogenesis of RA. Molecular messengers that travel between cells (cytokines) have been found to be of major importance. In particular, the cytokine tumour necrosis factor- (TNF-) has been shown to be a key factor in the pathology of RA.7 The development of targeted biological therapies to block cytokines such as TNF has been one of the major advances in medicine in the last 20 years.8 In addition, the use of these new therapies has not been restricted to rheumatological diseases and is having a major impact in the treatment of other inflammatory diseases including inflammatory bowel disease and psoriasis.9 Observations of the effect of immune manipulation in different diseases are providing new insights into their immune pathology.
|
The problem of uncontrolled rheumatoid arthritis |
|---|
RA produces both disability through uncontrolled synovial joint damage and a reduced lifespan. The mortality associated with severe RA is similar to that for non-Hodgkin lymphoma and type II diabetes mellitus.10 Early death is largely a result of increased incidence of ischaemic heart disease, infection and malignancy.11
Uncontrolled RA leads to synovial joint damage that results in progressive loss of skeletal function. The joint damage is caused by invasion of inflamed synovial membrane, which lines the synovial joints, through the articular cartilage and subchondral bone. These small areas of damage, described as erosions, accumulate to destroy individual joints. The disability that occurs secondary to joint damage can be measured using tools such as the Health Assessment Questionnaire (HAQ). As disability increases, health care costs spiral upwards.12 Direct health-care costs for treating the consequences of RA are high, and ~30% of patients are unable to work within 10 years of onset of RA.13 Individuals living with RA bear the physical and psychological burden of disability and continuous pain. In addition, patients often complain of overwhelming fatigue, a symptom that is rarely considered by clinicians.
|
The immunopathogenesis of rheumatoid arthritis |
|---|
Once molecular biologists and immunologists started to identify the key cells and molecules of importance in the pathogenesis of RA, the hunt was on for targets for new therapies. Conventional views of RA pathogenesis assume that an as yet unknown antigen (self or non-self) is presented on an antigen-presenting cell (monocyte-macrophage, dendritic cell etc) attached to a class II major histocompatibility complex (MHC II) molecule.14–16 The antigen in this form is then presented to a T lymphocyte which binds to it through its T-cell receptor (TCR), forming a complex of antigen, MHC II and TCR. Other co-stimulatory molecules, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), are also involved in the interaction between T lymphocyte and antigen-presenting cell that produces a message within the T lymphocyte. This message activates intercellular signalling molecules and results in activation of the T lymphocyte. The T lymphocyte releases intercellular messages in the form of cytokines that have a number of actions important in the initiation of an inflammatory response. Inflammatory cytokines of importance in RA include TNF-
and interleukins 1 and 6 (IL-1 and IL-6). Some cytokines, called chemokines, attract inflammatory cells which travel to the synovial joint. These include interleukin 8 (IL-8) and RANTES. Other cytokines, such as vascular endothelial growth factor (VEGF), stimulate the formation of new blood vessel growth, or angiogenesis, which allows access of an influx of inflammatory cells and the blood supply to support the expanding volume of inflamed synovial membrane. The influx of inflammatory cells is dependent on cells sticking to intercellular adhesion molecules such as Vß3. As other inflammatory cells become activated, they produce inflammatory cytokines in turn. Monocyte-macrophages and fibroblasts in the synovial membrane produce TNF- and IL-1. Both TNF- and IL-1 produce cartilage destruction in synovial joints.17,18 These cytokines also stimulate the production of cartilage-degrading enzymes including the matrix metalloproteinases.19 A number of anti-inflammatory cytokines, receptor antagonists and soluble cytokine receptors, including interleukin 10 (IL-10), are produced in the synovial joint.20,21 However, the anti-inflammatory effect is not strong enough to stop the inflammation and, despite increased amounts of these molecules, inflammatory damage continues. It is still unclear why, once activated, the immune response initiated in RA fails to turn itself off. RA is strongly associated with the autoantibody rheumatoid factor (RF) produced by B cells. The exact role of B cells in RA is uncertain. However, the recent demonstration that blocking B cells in RA leads to clinical improvement has made the subject fashionable again.22–24
|
Immunological therapies for rheumatoid arthritis |
|---|
The first attempts at immunotherapy for RA were targeted at cells rather than molecules. The perceived importance of T lymphocytes in the initiation of RA resulted in attempts to alter the immune response by depleting T lymphocytes.25 However, this approach was largely unsuccessful. Aiming at T cells had seemed logical as they have a key role in initiating and directing immune responses. During this period other groups were targeting inflammatory cytokines, with a major effort focused on the inflammatory cytokine TNF-
. These molecules are much further downstream in the immune response but produce many of the symptoms and destructive effects seen in RA.26
|
|
|
Tumour necrosis factor
blockade from bench to bedside
The development of targeted immunological therapies for the treatment of RA demonstrates how laboratory advances can lead to treatments over a period of several years. In the early 1980s TNF- had been identified in the synovial membrane of individuals with RA.27 By the late 1980s specific antibodies had been produced to block TNF-. The first of these was CA2 (later named infliximab), a chimaeric mouse antibody that had been produced to reduce the chance of adverse allergic reactions and tolerance secondary to the production of antibodies to a foreign protein.28A mouse–human chimaeric antibody contains the whole of the variable regions of a mouse antibody attached to human constant regions. This produces an antibody that is approximately 25% mouse and 75% human. Initially, CA2 was used as a tool for the further determination of the importance of TNF- in the pathogenesis of RA. Experiments carried out at the Kennedy Institute of Rheumatology in London suggested that TNF- had a key role in the inflammation of the synovial joint seen in RA. Many experiments on the importance of cytokines in RA relied on the use of cells from synovial membranes harvested from synovial joints normally discarded during joint replacement surgery. Early experiments had shown that cultures of these synovial membrane cells continued to produce a number of inflammatory molecules, including the cytokines IL-1 and TNF-, for several days after harvesting.29,30 When TNF- was blocked using antibodies such as CA2 it appeared that it had a unique position in the hierarchy of inflammatory cytokines. Blocking TNF- also blocked the production of other cytokines, including IL-1.31 Subsequent experiments demonstrated the efficacy of TNF- blockade in animal models of RA. This included significant improvements in the collagen-induced arthritis model of RA in DBA1 mice.32 In the early 1990s, TNF blocking antibodies were first administered intravenously to human subjects with RA in a very successful pilot study.33
Tumour necrosis factor inhibition
Initial results of TNF blocking antibodies in an open-label study showed significant improvements in measures of disease activity, which persisted with re-treatment.34,35 These included reduction in swelling and tenderness in joints and a reduced acute phase response, with decreased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Visual analogue measures of the general health of patients also improved. This study was followed by a double-blind placebo-controlled trial showed efficacy in individuals with active RA.36 Subsequently, longer-term studies have also shown a reduction in joint damage as measured by a reduced number of erosions and less joint-space narrowing.37
These initial clinical trials demonstrated the efficacy of blocking TNF- with an intravenously administered monoclonal antibody (infliximab). However, other clinical trials were also demonstrating that TNF could be blocked using soluble TNF receptors. TNF- acts through two cell-membrane-bound receptors, the p55 and p75 receptors. Binding a p75 TNF receptor to the Fc portion of human IgG1 antibody (IgG1–p75 receptor fusion protein) produced another way of blocking TNF.38,39 This approach was used to produce the anti-TNF agent etanercept, with trials showing that it was effective in reducing both disease activity scores and joint damage over time.40,41 Subsequently, a further TNF blocking antibody (adalimumab), with similar efficacy to both infliximab and etanercept, has become available.42,43. Adalimumab is a fully human antibody with no rodent components.
During the development of infliximab it became apparent that some individuals receiving this treatment produced antibodies against this agent. The formation of these human anti-chimaeric antibodies (HACA) can result in a gradual reduction of efficacy as the HACA neutralizes the infliximab. The production of these antibodies was not surprising because infliximab consists of a partially mouse-derived chimaeric antibody. The use of the DMARD methotrexate in conjunction with infliximab reduced this antibody production. In addition, it now appears that the concurrent use of methotrexate also increases the efficacy of infliximab.44,45 Further studies have shown that the use of methotrexate with etanercept and adalimumab also increases the efficacy of these treatments.42,46
The use of TNF blocking therapies has also been associated with some significant side effects.47 These have been rare, but include reactivation of latent Mycobacterium tuberculosis, increased risk of other infections, injection/infusion site reactions, induction of autoantibodies and autoimmune diseases, and worsening of severe heart failure. Screening individuals for tuberculosis before they commence TNF blocking therapy largely overcomes the problems with reactivation of M.tuberculosis.48 It also appears that this complication is more commonly associated with infliximab than the other TNF blocking agents. Although described, the induction of autoimmunity by TNF blocking agents is rare. TNF blockade can also induce autoantibodies such as antinuclear antibodies (ANAs), less often anti-double-stranded DNA antibodies (dsDNA) and sometimes systemic lupus erythematosus (SLE).47,49,50 Initial concerns that TNF blockade might produce increased numbers of lymphomas and other malignancies do not appear to have been realized. However, more follow-up will be needed before definite conclusions can be drawn.
Looking for other sites to block The blockade of other cytokines and immunological pathways might also produce benefit in RA.51–53 IL-1 was thought to be an ideal candidate for blockade as this cytokine is particularly damaging to cartilage and bone in RA.54 A number of attempts at IL-1 blockade have been tried. The currently available IL-1 blocking therapy is anakinra, an IL-1 receptor antagonist that binds to the cell-bound IL-1 receptor and inhibits the binding of endogenous IL-1.55 There has been some success with this approach, and disease activity scores have been improved. The effect does not appear to be as strong as for TNF blockade and, despite being licensed in the UK, anakinra is rarely used to treat RA. However, it has been used effectively to treat adult Still’s disease and Muckle–Wells syndrome.56
A number of other targets are currently being explored for their potential as new immune therapies. They include new TNF- blockers of a similar kind to those already available and inhibitors of other cytokines such as IL-6. The IL-6 inhibitor MRA has shown promise in phase II studies and is undergoing further development.57,58 MRA consists of a humanized anti-IL-6 receptor monoclonal antibody that blocks the action of IL-6. It is likely that blocking different cytokines will produce different effects on the RA disease process. This will increase our knowledge of the importance of different inflammatory pathways in RA. Other immunological therapies in development rely on blocking molecules important in the close interactions (co-stimulation) between T lymphocytes and antigen-presenting cells such as CTLA-4.59–61
In the last few years increasing attention has been paid to targeting B lymphocytes in RA. Rituximab is an antibody directed against the B-lymphocyte cell surface marker CD20 (CD20 is not present on all plasma cells or on very early B cells). Rituximab was developed for the treatment of B-cell lymphomas, but studies of its use in severe RA has demonstrated good efficacy.24
|
Using biological therapies in the clinic: licensed treatments and national guidelines |
|---|
The anti-TNF antibodies infliximab and adalimumab, the TNF receptor fusion protein etanercept and the IL-1 inhibitor anakinra are all licensed in the UK for the treatment of RA. The National Institute for Clinical Excellence (NICE) produced guidance for the use of etanercept and infliximab in March 2002 and is due to review this in the near future.62 Present guidance recommends that etanercept and infliximab can be used to treat active RA which has failed to respond to a least two DMARDs. NICE also recommended that the British Society for Rheumatology (BSR) guidelines for prescribing TNF blockers should be followed. These were produced in 2001 and updated in July 2004.63 There is also international consensus on the use of these therapies for the treatment of RA.64
|
Inducing remission |
|---|
Remission in RA rarely occurs spontaneously. However, it remains the goal of those treating individuals with RA. The definition of remission is controversial, but it is common to define it on the basis of a disease activity score (DAS) <2.4.65 The DAS is a composite score of a joint count of tender and swollen joints, ESR and a patient visual analogue score (VAS) of perceived health status. The best possible treatment of individuals with tight control of disease activity using DMARDs can produce clinical remission in some individuals.66 However, at present TNF blockade is the only therapy which consistently stops continuing joint damage through erosions.
With remission as the ultimate goal of therapy, attempts have been made to increase numbers of individuals achieving remission. Use of TNF blockade in early RA appears to allow induction of remission that may continue for several months or years using conventional DMARDs such as methotrexate as maintenance therapy.67–69 Rituximab also appears to produce a prolonged depletion of B lymphocytes, and improvement in disease activity may also last for several months or years.70
|
Immune-mediated inflammatory diseases |
|---|
The use of TNF blockers is also effective in other inflammatory disease,71 including ankylosing spondylitis, psoriatic arthritis and psoriasis, Crohn’s disease and some rarer inflammatory diseases including systemic vasculitis72 and Behcet’s disease.73,74 This demonstrates that particular cytokines are important in a number of different inflammatory diseases. These cytokines are constituents of ‘public pathways’ of inflammation. In contrast, some cytokines are specific to a particular disease and define a unique part of its pathology and are part of a ‘private pathway’.
TNF blockade is not effective in all inflammatory diseases. Indeed, in some diseases it has led to a worsening of the clinical situation. TNF blockade worsened the clinical course in trials of therapy for multiple sclerosis.75 Thus inflammatory diseases can be classified on the basis of their response to TNF and other immunological therapies. This will lead to a greater understanding of the important inflammatory pathways in different diseases.
An understanding of the shared inflammatory networks of many inflammatory diseases has led to the definition of these diseases as immune-mediated inflammatory diseases (IMIDs). This approach does not recognize the conventional boundaries defined by the traditional specialities of internal medicine. Patients with these illnesses may be better cared for by specialists in inflammatory disease, and in some institutions the care of these individuals is being centralized in IMID centres.
|
The future |
|---|
As experience in using immunological therapies for the treatment of RA is gained, the exact role of these agents will become better defined. There will also be the opportunity to observe large cohorts of treated individuals and monitor them for unexpected adverse effects. An example of this has come from a large database of 4000 individuals with RA on treatment with anti-TNF agents included in the BSR Biologics Register.76 This has recently identified a small number of individuals with progressive interstitial lung disease while receiving TNF blockers and azathioprine. This observation requires further exploration. The addition of therapies targeted at different immunological mediators and cells will also lead to increased understanding of the immunopathogenesis of RA.
The clinical use of cytokine blockers has shown the extent to which immune and inflammatory pathways are shared in a number of inflammatory diseases. Blocking TNF has shown this cytokine to be of key importance in the pathology of RA, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease.
The advances in therapy that have occurred in the treatment of RA have been enormous. There has also been an important proof of principle that blocking single cytokines can produce profound effects on inflammatory diseases. However, the greatest effect is on the individuals who suffer with these diseases. Before the availability of TNF blockers, the 10% of individuals with the most aggressive RA were effectively untreatable. The vast majority of these individuals are now treated effectively.
However, these treatments remain expensive, and the use of protein-based biological therapies requires subcutaneous or intravenous administration. The current therapies have proved that blocking immune mediators, including TNF, can have a significant effect on RA and other inflammatory diseases. The challenge for the future is to develop novel cheaper therapies using small-molecule technology that can be given orally.
|
References |
|---|
- Wong JB, Ramey DR, Singh G (2001) Long-term morbidity, mortality, and economics of rheumatoid arthritis. Arthritis Rheum, 44, 2746–9.[Medline]
- Lajas C, Abasolo L, Bellajdel B et al. (2003) Costs and predictors of costs in rheumatoid arthritis: a prevalence-based study. Arthritis Rheum, 49, 64–70.[Medline]
- Markenson JA (1991) Worldwide trends in the socioeconomic impact and long-term prognosis of rheumatoid arthritis. Semin Arthritis Rheum, 21(Suppl 1), 4–12.[Medline]
- Symmons D, Turner G, Webb R et al. (2002) The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford), 41, 793–800.
- Fuchs HA, Pincus T (1992) Radiographic damage in rheumatoid arthritis: description by nonlinear models. J Rheumatol, 19, 1655–8.[Medline]
- American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines (2002) Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum, 46, 328–46.[Medline]
- Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M (1989) Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet, 29, 244–7.
- Feldmann M, Maini RN (2003) Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med, 9, 1245–50.[Medline]
- Reimold AM (2003) New indications for treatment of chronic inflammation by TNF-alpha blockade. Am J Med Sci, 325, 75–92.[Medline]
- Scott DL, Shipley M, Dawson A, Edwards S, Symmons DP, Woolf AD (1998) The clinical management of rheumatoid arthritis and osteoarthritis: strategies for improving clinical effectiveness. Br J Rheumatol, 37, 546–54.
[Free Full Text] - Kvalvik AG, Jones MA, Symmons DP (2000) Mortality in a cohort of Norwegian patients with rheumatoid arthritis followed from 1977 to 1992. Scand J Rheumatol, 29, 29–37.[Medline]
- Lajas C, Abasolo L, Bellajdel B et al. (2003) Costs and predictors of costs in rheumatoid arthritis: a prevalence-based study. Arthritis Rheum 49, 64–70.
- Wolfe F, Hawley DJ (1998) The longterm outcomes of rheumatoid arthritis. Work disability: a prospective 18 year study of 823 patients. J Rheumatol, 25, 2108–17.[Medline]
- Choy EH, Panayi GS (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med, 344, 907–16.
[Free Full Text] - Panayi GS (1993) The immunopathogenesis of rheumatoid arthritis. Br J Rheumatol, 32 (Suppl 1), 4–14.
- Jenkins JK, Hardy KJ, McMurray RW (2002) The pathogenesis of rheumatoid arthritis: a guide to therapy. Am J Med Sci, 323, 171–80.[Medline]
- Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Ann Rev Immunol, 14, 397–440.[Medline]
- Feldmann M, Brennan FM, Chantry D et al. (1990) Cytokine production in the rheumatoid joint: implications for treatment. Ann Rheum Dis, 49, 480–6.[Medline]
- Martel-Pelletier J, Welsch DJ, Pelletier JP (2001) Metalloproteases and inhibitors in arthritic diseases. Best Pract Res Clin Rheumatol, 15, 805–29.[Medline]
- Isomaki P, Luukkainen R, Saario R, Toivanen P, Punnonen J (1996) Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium. Arthritis Rheum, 39, 386–95.[Medline]
- Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M (1994) Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med, 179, 1517–27.
[Abstract/Free Full Text] - Keystone EC (2005) B cells in rheumatoid arthritis: from hypothesis to the clinic. Rheumatology (Oxford), 44 (Suppl 2), ii8–12.
- Panayi GS (2005) B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology (Oxford), 44 (Suppl 2) ii3–7.
- Edwards JC, Szczepanski L, Szechinski J, et al. (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med, 350, 2572–81.
[Abstract/Free Full Text] - Choy EH, Kingsley GH, Panayi GS 91998) Anti-CD4 monoclonal antibodies in rheumatoid arthritis. Springer Semin Immunopathol, 20, 261–73.
- Klareskog L, Ronnelid J, Holm G (1995) Immunopathogenesis and immunotherapy in rheumatoid arthritis: an area in transition. J Intern Med, 238, 191–206.[Medline]
- Buchan G, Barrett K, Turner M, Chantry D, Maini RN, Feldmann M. Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1 alpha. Clin. Exp. Immunol. 1988 Sep;73(3):449–55.[Medline]
- Knight DM, Trinh H, Le J et al. (1993) Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol, 30, 1443–53.[Medline]
- Brennan FM, Chantry D, Jackson AM, Maini RN, Feldmann M (1989) Cytokine production in culture by cells isolated from the synovial membrane. J Autoimmun, 2 (Suppl) 177–86.
- Feldmann M, Brennan FM, Chantry D et al. (1990) Cytokine production in the rheumatoid joint: implications for treatment. Ann Rheum Dis, 49, 480–6.
- Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M (1989) Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet, ii, 244–7.
- Williams RO, Feldmann M, Maini RN (1992) Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci USA, 89, 9784–8.
[Abstract/Free Full Text] - Elliott MJ, Maini RN, Feldmann M et al. (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum, 36, 1681–90.[Medline]
- Elliott MJ, Maini RN, Feldmann M et al. (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum , 36, 1681–90.
- Elliott MJ, Maini RN, Feldmann M et al. (1994) Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet, 344, 1125–7.[Medline]
- Elliott MJ, Maini RN, Feldmann M et al. (1994) Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet, 344, 1105–10.[Medline]
- Lipsky PE, van der Heijde DM, St Clair EW et al. (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med, 343, 1594–1602.
[Abstract/Free Full Text] - Scallon BJ, Trinh H, Nedelman M, Brennan FM, Feldmann M, Ghrayeb J (1995) Functional comparisons of different tumour necrosis factor receptor/IgG fusion proteins. Cytokine, 7, 759–70.[Medline]
- Williams RO, Ghrayeb J, Feldmann M, Maini RN (1995) Successful therapy of collagen-induced arthritis with TNF receptor-IgG fusion protein and combination with anti-CD4. Immunology, 84, 433–9.[Medline]
- Moreland LW, Baumgartner SW, Schiff MH et al. (1997) Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)–Fc fusion protein. N Engl J Med, 337, 141–7.
[Abstract/Free Full Text] - Moreland LW, Schiff MH, Baumgartner SW et al. (1999) Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med, 130, 478–86.
[Abstract/Free Full Text] - Weinblatt ME, Keystone EC, Furst DE et al. (20030 Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum, 48, 35–45.[Medline]
- Furst DE, Schiff MH, Fleischmann RM et al. (2003) 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, 30, 2563–71.
[Abstract/Free Full Text] - Maini R, St Clair EW, Breedveld F et al. (1999) Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet, 354, 1932–9.[Medline]
- Maini RN, Breedveld FC, Kalden JR et al. (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum, 41, 1552–63.[Medline]
- Klareskog L, van der Heijde D, de Jager JP et al. (2004) 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, 363, 675–81.[Medline]
- Botsios C (2005) Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases. Autoimmun Rev, 4, 162–70.[Medline]
- Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD (2003) Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum, 48, 2122–7.[Medline]
- Shakoor N, Michalska M, Harris CA, Block JA (2002) Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet, 359, 579–80.[Medline]
- Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN (2000) Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum, 43, 2383–90.[Medline]
- Taylor PC (2003) Anti-cytokines and cytokines in the treatment of rheumatoid arthritis. Curr Pharm Des, 9, 1095–1106.[Medline]
- Singh R, Robinson DB, El-Gabalawy HS (2005) Emerging biologic therapies in rheumatoid arthritis: cell targets and cytokines. Curr Opin Rheumatol, 17, 274–9.[Medline]
- Pollard L, Choy E (2005) Rheumatoid arthritis: non-tumor necrosis factor targets. Curr Opin Rheumatol, 17, 242–6.[Medline]
- Kay J, Calabrese L (2004) The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford), 43 (Suppl 3), iii2–9.
- Cohen SB (2004) The use of anakinra, an interleukin-1 receptor antagonist, in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am, 30, 365–80.[Medline]
- Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello CA (2005) Rapid responses to anakinra in patients with refractory adult-onset Still’s disease. Arthritis Rheum, 52, 1794–1803.[Medline]
- Nishimoto N, Yoshizaki K, Miyasaka N et al. (2004) Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum, 50, 1761–9.[Medline]
- Choy EH, Isenberg DA, Garrood T et al. (2002) Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum, 46, 3143–50.[Medline]
- Kremer JM, Westhovens R, Leon M et al. (2003) Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med, 349, 1907–15.
[Abstract/Free Full Text] - Ruderman EM, Pope RM (2005) The evolving clinical profile of abatacept (CTLA4-Ig): a novel co-stimulatory modulator for the treatment of rheumatoid arthritis. Arthritis Res Ther, 7 (Suppl 2), S21–5.
- Malmstrom V, Trollmo C, Klareskog L (2005) Modulating co-stimulation: a rational strategy in the treatment of rheumatoid arthritis? Arthritis Res Ther, 7 (Suppl 2), S15–20.
- National Institute for Clinical Excellence (2002) Report 36. Guidance on the Use of Etanercept and Infliximab for the Treatment of Rheumatoid Arthritis. London: NICE.
- British Society for Rheumatology (2004) Update of BSR Guidelines for Prescribing TNF Blockers in Adults with Rheumatoid Arthritis. London: British Society for Rheumatology.
- Furst DE, Breedveld FC, Kalden JR et al. (2003) Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003). Ann Rheum Dis, 62 (Suppl 2), ii2–9.
[Free Full Text] - Balsa A, Carmona L, Gonzalez-Alvaro I, Belmonte MA, Tena X, Sanmarti R (2004) Value of Disease Activity Score 28 (DAS28) and DAS28-3 compared to American College of Rheumatology-defined remission in rheumatoid arthritis. J Rheumatol, 31, 40–6.
[Abstract/Free Full Text] - Grigor C, Capell H, Stirling A et al. (2004) Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet, 364: 263–9.[Medline]
- Quinn MA, Conaghan PG, O’Connor PJ et al. (2005) Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum, 52, 27–35.[Medline]
- St Clair EW, van der Heijde DM, Smolen JS et al. (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum, 50, 3432–43.[Medline]
- Emery P, Seto Y (2003) Role of biologics in early arthritis. Clin Exp Rheumatol, 21(Suppl 31), S191–4.[Medline]
- Edwards JC, Leandro MJ, Cambridge G (2004) B lymphocyte depletion therapy with rituximab in rheumatoid arthritis. Rheum Dis Clin North Am, 30, 393–403.[Medline]
- Reimold AM (2003) New indications for treatment of chronic inflammation by TNF-alpha blockade. Am J Med Sci, 325, 75–92.
- Booth A, Harper L, Hammad T et al. (2004) Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 15, 717–21.
[Abstract/Free Full Text] - Sarwar H, McGrath H Jr, Espinoza LR (2005) Successful treatment of long-standing neuro-Behcet’s disease with infliximab. J Rheumatol, 32, 181–3.
[Abstract/Free Full Text] - Wechsler B, Sable-Fourtassou R, Bodaghi B et al. (2004) Infliximab in refractory uveitis due to Behcet’s disease. Clin Exp Rheumatol, 22(Suppl 34), S14–16.
- Mohan N, Edwards ET, Cupps TR et al. (2001) Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum, 44, 2862–9.[Medline]
- Griffiths I, Silman A, Symmons D, Scott DG. BSR Biologics Registry (2004) Rheumatology (Oxford), 43, 1463–4.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||