The management of RA has changed substantially in the last 10-15 years as a result of new insights into the course of the disease and proliferation of the number of therapeutic agents for its treatment (Bingham et al., 2004). Drugs used in the treatment of RA have been traditionally divided into the so-called first- and second-line drugs. First-line drugs include NSAIDs, which have a rapid sup-pressive effect on signs of inflammation, including pain and stiffness. Second-line drugs, also called DMARDs, influence the disease process more fundamentally by decreasing disease activity, slowing down the progression of joint damage, and preserving functional capacity (Bingham et al., 2004). Glucocorticosteroids are usually considered a separate category and can be used in different ways and are still indispensable to treat a certain number of patients affected by RA. A better understanding of the pathophysiology of RA has enabled scientists to develop a new class of drugs, termed 'biologicals' that tackle the key inflammatory cytokines like TNF-a. These include monoclonal antibodies, soluble cytokine receptors, and natural antagonists. The first two biologicals developed for the treatment of RA were the TNF-a inhibiting agents, namely etanercept and infliximab. Thereafter, newer agents were developed, including anakinra, a recombinant form of the naturally occurring IL-1 (Ra), and ad-alimumab, a fully human monoclonal antibody against TNF-a.
9.1. Management of early and established active inflammatory disease
Probably the greatest advance in recent DMARDs treatment has been the early aggressive management of active RA disease, be it as monotherapy or in combination (Bingham et al., 2004). Previously, a therapeutic pyramid consisted of initial conservative therapy with NSAIDs until erosions were observed, at which point treatment was switched to DMARDs added in slow succession as disease progressed (American College of Rheumatology Subcommitee on Rheumatoid Arthritis Guidelines, 2002). Nowadays, early DMARD therapy is becoming standard in those with potential for disease progress; several studies have demonstrated that early treatment decreases disease progression, slows radiographic progression, and reduces the severity of the disease affecting the overall morbidity and mortality. Conventional DMARDs, however, have several limitations like slow onset of action, induction of partial remission, and modest 5-year retention rates. The quest for an ideal DMARD thus continues (Chen and Wie, 2005).
A variety of recent studies showed an increased efficacy of a combination therapy with DMARDs in patients with disease that does not respond adequately to monotherapy.
Combination therapy may be applied according to different designs (step-up, step-down, parallel, and bridging designs). In clinical practice, the step-up and bridging variants are most frequently used. Interestingly, several studies have shown that combination of DMARDs does not lead to more tox-icity.
The recently developed biologic agents (anti-TNF and anti-IL-1 targeted therapies) have shown impressive clinical results. TNF-blocking agents already show effects within days of administration. These agents have to be administered at regular intervals, and, therefore, suppress inflammation, rather than cure the disease (Subramanian and Handa, 2004). These drugs may determine increased susceptibility to infections, development of antibodies against the agents, and seldom development of autoimmune syndromes. Early treatment with these drugs seems to reduce disease progression substantially and to increase the remission rates.
However, these agents are very expensive and they are currently reserved for people who have failed at least one DMARD including methotrex-ate (MTX).
End-stage disease is dominated by joint destruction and the extensive drug therapy may be somewhat less important, whereas a multidisciplinary approach (including surgical and rehabilitative approaches) may help the patients to face severe joint damage and the loss of function and the disability.
Assessment of these patients should consider the distinction between destructive lesions and active synovitis, and the latter should be treated appropriately.
However, primary goals include preservation and maximization of function and prevention of disability. In case of severe disability, handicaps should be overcome by adapting the environment (Bingham et al., 2004).
NSAIDs are widely used for relief of pain and stiffness in RA (Pham and Hirschberg, 2005). These are usually the first drugs commenced following disease onset and often prior to assessment by a rheumatologist.
In most patients, steroids rapidly reduce the level of inflammation, but are associated with significant toxicity when a high cumulative dose is given (Bijlsma et al., 2005). Short-term steroids and low dosage (5-10mg/day) can be useful as bridge therapy waiting for DMARDs to start working. Calcium, vitamin D, hormone replacement therapy, and biphosphonates have all been used to prevent steroid-induced bone loss.
Antimalarials hydroxychloroquine (HCQ) and chloroquine (CQ) has low efficacy when used as monotherapy, but is sometimes used as first-line therapy in mild disease (Tutor-Ureta and Yebra-Bango, 2005). Recently, its use in severe disease has increased following studies showing additional efficacy of combination therapy in patients with refractory disease.
Sulfasalazine (SSA) is used in many centres as the first-line DMARD. SSA reduces the rate of bone erosions in early (van der Heijde et al., 1989) and established disease (Pullar et al., 1987).
MTX, an antagonist of folate metabolism, is used commonly (increasingly first line) both alone and in combination with other DMARDs (commonly SSA and/or hydroxychloroquine) (Prod-awich et al., 2005; Strand et al., 2005). It is normally given with folic acid to reduce the incidence of toxicity. MTX has been shown to reduce the progression of erosions when used first line. MTX is normally given orally once a week (range dose 7.5-25 mg), but can also be given parenterally if there is concern regarding bioavailabity or in order to prevent gastric toxicity.
Leflunomide (LEF) is currently licensed only as monotherapy, although studies are underway with combination therapy with SSA or MTX. In clinical studies, LEF reduces disease activity and radiological progression (Smolen et al., 1999).
Cyclosporine (CsA) monotherapy has been shown to be efficacious in the treatment of RA (Tugwell, 1992) and to reduce radiographic progression. It is often used in combination therapy with MTX (Sarzi-Puttini et al., 2005a, b).
Injectable gold (sodium aureothiomalate) and oral gold (auranofin) are no longer first-line therapies and tend to be used in patients who have failed treatment with MTX and SSA.
9.6. Biological agents
9.6.1. anti-TNF-a monoclonal antibody therapy
The introduction of TNF blockade such as infliximab, etanercept, and adalimumab has been a breakthrough in the management of severe refractory RA.
Infliximab, a recombinant chimeric antibody produced by mouse myeloma cells, contains sequences from human IgG1 constant and mouse variable regions, is specific for the membrane-bound or secreted or extracellular space TNF-a of humans and chimpanzees, and prevents TNF from binding to its membranous and soluble receptors. Infliximab is registered by the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) as therapy for treatment-resistant RA, treatment-resistant moderate to severe Crohn's disease (CD), and CD with fistulas (Elliott et al., 1994; Present et al., 1999). It is now approved for the treatment of ankylosing spondylitis (AS), psoriasis and psoriatic arthritis. (Braun et al., 2002).
Etanercept, a fusion protein (decoy receptor) secreted by Chinese ovary (CHO) cells, combines the ligand-binding portion of human TNF receptor 2(TNFR2 = p75 = CD120b) with sequences of human IgG1. Unlike TNFR1 (p55 = CD120a), TNFR2 is a constitutive membrane receptor that is inducible upon stimulation and can be found on the surface of almost all cells except red blood cells and resting lymphocytes. Etanercept is approved by the FDA and the EMEA for use in treatment-resistant RA as well as for severe active and progressive RA and treatment-resistant polyarticular juvenile chronic arthritis. It is also approved by the FDA for treatment-resistant psoriatic arthritis, and it has a beneficial effect in AS (Moreland et al., 1996; Genovese et al., 2002; Kietz et al., 2001; Mease et al., 2000; Brandt et al., 2004).
Adalimumab is a recombinant human immuno-globulin G1 monoclonal antibody that is specific for human TNF. It specifically binds to circulating and cell surface TNF-a and blocks its interaction with p55 and p75 cell surface TNF receptors. The first fully human anti-TNF-a monoclonal antibody was approved for the treatment of moderate to severe RA by the FDA in 2002 and by the EMEA in September 2003 (Keystone and Haraqui, 2004; Furst et al., 2002; Scheinfeld, 2005).
Anakinra is the first biologic drug that has been developed specifically as an interleukin (IL)-1 Ra and is derived from an endogenous IL-1Ra. The drug blocks the activity of IL-1 in synovial joints, reducing the inflammatory and joint destructive processes associated with RA (Waugh and Perry, 2005). In randomized, placebo-controlled trials of up to 52-weeks duration, anakinra has shown efficacy both as monotherapy and in combination with other DMARDs in adults with RA (Furst, 2004). It is subcutaneously administered (dosage 150 mg/day) and is generally well tolerated.
Rituximab is an anti-CD20 monoclonal antibody that causes depletion of B cells. It is a novel targeted therapy for the treatment of RA and it appears to be highly effective and safe (Kimby, 2005).
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