Description of the condition
Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease with predominant joint involvement. RA affects the synovial lining of many joints and tendon sheaths resulting in irreversible joint damage and deformities (Lee 2001). It is associated with significant morbidity, mortality and impaired quality of life (Wong 2001; Health Canada 2003).
RA is a common auto-immune disorder with disease prevalence between 0.1% and 5% (Spector 1990; Peschken 1999). Peak age onset is between 50 and 75 years and women are affected 2 to 3 times more often than men (Spector 1990). The etiology of RA is multifactorial with role of environmental and genetic factors. The hallmark of disease is activation of immune cells and inflammation. There is involvement of T-cells, B-cells, macrophages and mast cells (Firestein 2003; Woolley 2003). These cells produce cytokines such as tumor necrosis factor (TNF)-alpha, Interferon-gamma (IFN- γ), Granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-1, 6, 13, 15 and 17, which have important role in inflammation and are therefore targets for therapy (McInnes 2007; McInnes 2011). There is also role of numerous other mediators of inflammation in disease pathogenesis.
The disease mainly affects joints and joint involvement is classically polyarticular and symmetric and may lead to destruction of joint structures leading to deformity. Other accompanying clinical symptoms are pain and morning stiffness. Since it is a systemic inflammatory condition, extraarticular manifestations are common and include anaemia, fatigue, cutaneous involvement (subcutaneous ("rheumatoid") nodules, ulcers and neutrophilic dermatosis), eye involvement (uveitis, scleritis, ulcerative keratitis), pleuropericarditis, myocarditis, lung parenchymal diseases, neuropathy, splenomegaly, Sjögren's syndrome, vasculitis, and renal disease (Akil 1995).
Description of the intervention
The general principles of treatment are directed towards the pain/symptomatic management, control of synovitis and prevention of further joint injury. The pharmacologic therapy includes non-biologic disease-modifying anti-rheumatic drugs (DMARDs), biologic agents and Nonsteroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents as adjuncts (Saag 2008). The choice of treatment depends on level of disease activity, stage of therapy and patient preference. DMARDs improve disease activity and decrease the natural progression leading to significant clinical improvement. DMARDs are now the mainstay of therapy and include non-biologics and biologics. The non-biologic DMARDs including methotrexate (Suarez-Almazor 2000), hydroxychloroquine (Suarez-Almazor 2000a), sulfasalazine (Suarez-Almazor 2000b), and leflunomide (Osiri 2003), have shown to significantly improve all clinical outcomes and delay radiologic progression in well-conducted systematic reviews and meta-analyses. However, a significant proportion of RA patients do not respond to non-biologic DMARDs or are unable to tolerate them long term. Biologic DMARDs generally target cytokines or their receptors or cell surface molecules involved in RA pathogenesis and tend to work more quickly than non-biologic DMARDs (van Vollenhoven 2009). These include anti-cytokine therapies, such as the TNF-alpha inhibitors, etanercept (Lethaby 2013), infliximab (Blumenauer 2002), adalimumab (Navarro-Sarabia 2005), golimumab (Singh 2010), and certolizumab pegol (Ruiz 2011); the IL-1 receptor antagonist, anakinra (Mertens 2009); and the IL-6 receptor antagonist tocilizumab (Singh 2010a). Other biologics are T-cell co-stimulation blocker, abatacept (CTLA4-Ig) (Maxwell 2009), and the anti-CD20 B-cell depleting monoclonal antibodies, rituximab, ofatumumab and ocrelizumab. Newer therapies also include janus kinase inhibitors, tofacitinib (Feist 2013), which block the cytokine signalling involved in lymphocyte mediated immune responses in RA.
B-cell depleting antibodies were developed with the aim of depleting the B-cell clones responsible for producing the autoantibodies, thereby resulting in sustained remission (Edwards 2001). Anti-CD20 monoclonal antibodies have shown significant clinical improvement and improvement in disease activity alone and in combination with other DMARDs (Shaw 2003; Singh 2009). Rituximab, a B-cell depleting monoclonal anti-CD20 antibody, has also shown improvement in DMARDs and anti-TNF resistant RA (Cohen 2006; Jois 2007). Ofatumumab is another antibody of the same class which is approved for treatment of chronic lymphocytic leukemia (NCI 2013). Ofatumumab is a human Immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically binds to the human CD20 antigen inducing potent B-cell lysis.
How the intervention might work
Ofatumumab is unique in its epitope which is more proximal and distinct from the epitope recognized by rituximab or by other anti-CD20 monoclonal antibodies (Teeling 2006). The proximity of this epitope probably accounts for the high efficiency of B-cell killing observed with ofatumumab in both in vitro and in vivo preclinical studies (Teeling 2004; Ostergaard 2010; Taylor 2011). The significant role of B-cells in RA and the uniqueness of ofatumumab's epitope resulting in more efficient killing than other B-cell deleting antibodies makes it ideal for use in RA (Ruuls 2008). It has demonstrated significant clinical efficacy compared to placebo in active RA patients (with inadequate response to methotrexate), in phase II and III clinical trials (Ostergaard 2010; Taylor 2011). A double-blind multi-center phase III trial also showed significant clinical improvement in ofatumumab treated patients compared to placebo (Taylor 2011). The common adverse effects reported were rash and urticaria. Other adverse effects include infusion reactions, pruritis, headache, nasopharyngitis, hypersensitivity and dyspnoea. The infections were more frequent in ofatumumab group however, serious infections were rare and comparable to placebo (Taylor 2011). A single-blind, phase I/II study comparing subcutaneous ofatumumab with placebo in RA showed that subcutaneous route also resulted in profound and prolonged B-cell depletion without significant adverse events (Kurrasch 2013).
Why it is important to do this review
The current drawbacks in use of biologics include the inconvenience of intravenous administration, the high costs and the adverse events, preventing their wide use as first-line therapy. However, if high quality evidence shows a significant improvement in symptoms and radiological progression without significantly increased risk of adverse events; it could be a new hope for patients with RA. So, there is a need for a critical appraisal of randomized controlled trials (RCTs) to assess ofatumumab in patients with RA. This Cochrane review including a rigorous assessment of the risk of bias, of the most up-to-date evidence will provide more definitive evidence regarding the efficacy and safety of ofatumumab in RA patients and will help clinicians make informed decisions on its use for treating patients with RA. This systematic review will also be helpful in generating an overview of biologics as treatment therapies in RA (Singh 2009; Singh 2011; Tugwell 2011).