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A number of disease modifying anti-rheumatic drugs (DMARDs) have been used in the treatment of RA, which include cytotoxic, immunosuppressive and antimalarial drugs (Doan and Massarotti 2005). Currently early aggressive treatment of RA with DMARDs is used, often deploying methotrexate alone or in combination with other DMARDs such as sulphasalazine and or

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hydroxychloroquine (Sokka et al, 2008; Gaujoux-Viala et al, 2010). Although there are therapies that are effective in targeting structural damage associated with RA, there are no current therapies to prevent the disease progression in OA and ultimately patients often undergo total joint replacements.

Biological therapies have developed as a result of increasing knowledge of the pathogenesis of RA. They target proinflammatory cytokines, principally TNF, IL- 1 and IL-6 and also T and B cells that are involved in the disease processes.

TNF inhibitors include infliximab, a chimeric monoclonal antibody to TNF, etanercept, a soluble TNF receptor construct and adalimumab, a humanised monoclonal antibody to TNF (Tak and Kalden 2011). Anakinra, a recombinant human IL-1 receptor antagonist, is used to inhibit IL-1, though is not always as effective as the TNF inhibitors due to systemic application (Mertens and Singh 2009) and tocilizumab a humanised IL-6 receptor antibody to inhibit IL-6 (Tak and Kalden 2011; Nurmohamed 2009). Newer biological therapies target B and T cells and include rituximab which is a chimeric monoclonal antibody to CD20 expressed on B cells and abatacept which is an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody which blocks the activation of T cells (Tak and Kalden 2011; Nurmohamed 2009). In addition, non-steroidal inflammatory drugs (NSAIDs) and glucocorticoids may be used to help control inflammation (Doan and Massarotti 2005). These may be used in both RA and OA.

1.12.2 Anti-Cytokine OA Therapies

The success of some of the anti-cytokine therapies in RA has prompted investigation of their effectiveness in OA. There have been a number of anti­

cytokine therapies tested in clinical trials and animal models of OA. Anti-IL-1 therapies tested include: Anakinra, a recombinant IL-1Ra and IL-1Ra gene therapy using retroviral or adenoviral vectors. In vivo, intra-articular injections of IL-1Ra protected against the development of cartilage lesions in OA, in part by a reduction in MMP-1 expression (Caron et al, 1996). In clinical trials intraarticular injections of recombinant human IL-1Ra in patients with knee OA was well tolerated with no acute inflammatory reaction, however in a 12 week randomised trials Anakinra failed to provide effective relief from knee OA symptoms compared to placebo controls suggesting that IL-1 Ra is ineffective in treating OA (Chevalier et al, 2009) IL-1Ra gene therapy delivered by

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intraarticular injections in animals models of OA reduced the severity of cartilage lesions, disease progression and activity (Pelletier et al, 1997;

Fernandes etal, 1999; Frisbie etal, 2002; Zhang etal, 2004). Furthermore anti­

inflammatory drug licofelone displayed cartilage protective effects and reduced the volume of cartilage loss in patients with symptomatic OA (Raynauld et al, 2009). Anti-TNF therapies include Adalimumb and Infliximab both are monoclonal anti-TNF antibodies. In clinical trials patients with hand OA treated with Adalimumb failed to display signs of improved OA symptoms (Magnano et al, 2007). However, intra-articular injections of Infliximab reduced pain symptoms and lesion progression in patients with hand OA whilst displaying no systemic adverse reactions (Fioravanti etal, 2009).

Development of disease modifying drugs for the treatment of osteoarthritis (disease modifying anti osteoarthritic drugs (DMAODs)) is not as advanced as for RA. Treatments tend to target pain and inflammation rather than the underlying disease mechanisms. They include the use of NSAIDs and COX-2 inhibitors and intra-articular injections of corticosteroids and hyaluronic acid.

Nutraceuticals such as glucosamine sulphate are also in common usage but their efficacy is uncertain (Goldring 2006). There is therefore a need to develop effective DMAODs, targeting key events such as cartilage breakdown, which may involve inhibiting cytokine actions, informed by use of these therapies in RA, or actions of catabolic enzymes such as selected MMPs and ADAMTSs (Murphy and Nagase 2008; Goldring 2006).

1.12.3 Targeting MMPs and ADAMTS

The inhibition of MMPs is an attractive target for OA therapy, since IL-1 p and TNFa increase the expression of a number of MMPs involved in the pathogenesis of OA. However, the use of broad-spectrum MMP inhibitors has had little success, due to their toxicity caused by non-selectivity of MMP inhibition (Murphy and Nagase 2008; Krzeski etal, 2007; Tu etal, 2008). Other, more specific inhibitors of MMPs are now being investigated, that have different Zn-binding groups (Tu et al, 2008; Clutterbuck et al, 2009). The main target for MMP inhibition is MMP-13 as it is predominantly up-regulated in OA cartilage and has the ability to cleave triple helix collagens and aggrecan (Dahlberg et al, 2000). In vivo studies have shown that inhibition of MMP-13 using a highly

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selective inhibitor reduced cartilage degradation without inducing fibroplasias in a rat model of musculoskeletal syndrome side effects (Johnson et al, 2007).

The inhibition of ADAMTS-4 is another possible therapeutic target for preventing cartilage breakdown in OA, and unlike MMPs; ADAMTSs have a narrower substrate selectivity (Tortorella etal, 2009).

1.12.4 Targeting OA Signalling Pathways

Inhibition of IL-1 p signalling pathways is another potential target for OA therapies. Since NFkB activation regulates the expression of cytokine and chemokines, inflammatory mediators and matrix degrading enzymes in OA, inhibition of this pathway may be of therapeutic value in the treatment of OA (Marcu et al, 2010). The inhibition of NFkB in animal models of RA was shown to reduce inflammation and cartilage breakdown, however the significance of this in OA models has yet to be determined (Marcu et al, 2010). Furthermore other signalling pathways including MAPK may also provide new therapeutic targets in the treatment of OA (Kapoor etal, 2011).