**2.5.2 Disease Modifying Antirheumatic Drugs (DMARDs)**

DMARDs are used with NSAIDs and/or prednisone to slow joint destruction caused by RA over time. Examples of these drugs are methotrexate, injectable and oral gold, penicillamine, azathioprine, chloroquine, hydroxychloroquine, and sulfasalazine. DMARDs, particularly methotrexate, have been the standard for aggressively treating RA. Recently, studies have shown that the most aggressive treatment for controlling RA may be the combination of methotrexate and another drug, particularly biologic response modifiers (Olsen, 2006). The dual drug treatment seems to create a more effective treatment, especially for people who may not have success with or who have built up a resistance to, methotrexate or another drug alone. It appears that these combination drug therapies might become the new road to follow in treating RA. Oral corticosteroids, or steroids, are powerful anti-inflammatory drugs that are used to quickly reduce inflammation. These drugs include prednisone and prednisolone and are most often used in combination with DMARDs, which significantly enhances the benefits of DMARDs.

#### **2.5.3 Biologic response modifiers**

200 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

Among additional diagnostic tests are acute-phase reactants – the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level that correlate with the degree of synovial inflammation. They are useful for following the course of inflammatory activity in an individual patient. Other abnormalities include hypergannaglobulinemia, thrombocytosis, and eosinophilia. These occur more often in patients with severe disease, high RF titer,

In more recent years, a number of new exciting therapeutic options have become available, especially with the development of the biologic drugs, thus causing evolution of rheumatological science to spiral. This trend reflects the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. This therapeutic philosophy has drawn on the model of oncology, with early diagnosis and aggressive treatment. While this has been in parallel with and to an extent dependent upon, sophisticated new imaging techniques such as MRI, clinicians have thought along these lines for many years (Emery, Gough, 1991).A number of these therapies are outlined below, including the various biological modifiers, in particular, anti-tumour necrosis factor-α agents and interleukin-1 (IL-1) receptor antagonists, which have been developed in recognition of the role of pro-inflammatory cytokines in RA. Also notable, is the current interest centering on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. The main categories of medications used to

It has been shown that NSAIDs cause quite distinct and severe biochemical damage during drug absorption (uncoupling of mitochondrial oxidative phosphorylation proving to be most important) which results in increased intestinal permeability. All commonly used NSAIDs, apart from aspirin and nabumetone, are associated with increased intestinal permeability in man. Whilst reversible in the short term, it may take months to improve following prolonged NSAID use (Bjarnason et al, 1993). Avoiding NSAIDs is advisable in

DMARDs are used with NSAIDs and/or prednisone to slow joint destruction caused by RA over time. Examples of these drugs are methotrexate, injectable and oral gold, penicillamine, azathioprine, chloroquine, hydroxychloroquine, and sulfasalazine. DMARDs, particularly methotrexate, have been the standard for aggressively treating RA. Recently, studies have shown that the most aggressive treatment for controlling RA may be the combination of methotrexate and another drug, particularly biologic response modifiers (Olsen, 2006). The dual drug treatment seems to create a more effective treatment, especially for people who may not have success with or who have built up a resistance to, methotrexate or another drug alone. It appears that these combination drug therapies might become the new road to follow in treating RA. Oral corticosteroids, or steroids, are powerful anti-inflammatory drugs that are used to quickly reduce inflammation. These drugs include prednisone and

rheumatoid modules, and extra-articular manifestations.

**2.5 Trends in pharmacological and biological therapy** 

**2.5.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)** 

patients with inflammatory bowel disease (Kane et al, 2001).

**2.5.2 Disease Modifying Antirheumatic Drugs (DMARDs)** 

treat RA considered below.

"Biologics" directly modify the immune system by inhibiting cytokines or B and T immune cells, which contribute to inflammation. Two types of agents can be used to eliminate circulating TNF: recombinant soluble receptors and monoclonal antibodies to TNF. There are three agents that were originally approved for patients with RA which inhibit the action of TNF-α; – infliximab, etanercept and adalimumab. Two additional novel TNF antagonists, Certolizumab pegol and Golimumab have recently been indicated for patients with RA for the treatment of moderate to severe, active RA in adult patients when the response to conventional DMARDs including methotrexate, has been inadequate.

Etanercept, a soluble TNF receptor, is labeled for use in monotherapy and combination therapy with methotrexate for arthritis (NICE guidelines, 2002). The TNF- α blocking agent infliximab is labelled for use in combination with methotrexate for the treatment of RA (NICE guidelines, 2002). Adalimumab is a recombinant human IgG1 monoclonal antibody that binds TNF-α, thereby precluding binding to its receptor. Enthusiastic support for early intervention with TNF- inhibitors for patients with RA comes with a strong safety message. Although infusion reactions and other AEs are infrequent, they may be very serious in some patients, in particular when complications associated with opportunistic infections occur. Certolizumab pegol, which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn's disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy (Ruiz et al, 2011). Significant improvements were observed at 24 weeks and at 52 weeks with the approved dose of 200 mg certolizumab pegol. The most common adverse events with certolizumab pegol 200 mg were: upper respiratory tract infections, hypertension and nasopharyngitis (Ruiz et al, 2011). Golimumab is a humanized inhibitor of Tumor necrosis factor-alpha, recently approved for the treatment of RA. Recent Cochrane systematic review (Singh et al, 2010), identified four Randomised Control Trials with 1,231 patients treated with golimumab and 483 patients treated with placebo. The authors concIuded that Golimumab-treated patients were significantly more likely to achieve remission, low disease activity and improvement in functional ability compared to placebo (all statistically significant). No significant differences were noted between golimumab and placebo regarding serious adverse events, infections, serious infections, lung infections, tuberculosis, cancer, withdrawals due to adverse events and inefficacy and deaths.

#### **2.5.4 Interleukin 1 receptor antagonists**

Interleukin 1 is a pro-inflammatory cytokine produced by stimulated monocytes, macrophages and some specialised synovial lining cells. IL-1 receptor antagonist competes with IL-1 for binding to the receptor, subsequently down regulating IL-1 actions. By stimulating the release of matrix metalloproteinases and increasing bone resorption by effects on osteoclasts, IL-1 has been shown to have a significant role in RA pathogenesis, particularly in regards cartilage and bone erosion. Mice deficient of IL-1 receptor antagonist, demonstrate the development of inflammatory arthritis similar to RA (Horai et al, 2000). In

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 203

antibodies, which down-regulate autoantibody responses. Felson et.al. studied the efficacy of SPA column treatment in comparison to a control group who received apheresis without column plasma perfusion (i.e., a sham arm) in a randomized double-blind study and his trial (Felson et al, 1999) reported that staphylococcal protein A column therapy was efficacious in patients with RA with 31.9% of 47 patients in the SPA group experiencing improvement in comparison to 11.4% in the control group (P=0.019). However, it appears that appropriate patient selection is essential. In general, it is recommended that such patients should be refractory to standard modes of therapy, and a risk versus benefit versus

In economic terms, arthritis accounts for a substantial proportion of the overall economic burden of illness in society (Goetzel et al, 2004). The burden of illness is more evident in the more numerous musculo-skeletal conditions, including back pain and osteoathritis, where there has been documented limited therapeutic progress leading to a much bigger global impact on national health and social and economic spending. Further, the less readily pathologically classifiable disorders, such as chronic pain syndromes and disability itself,

Some evidence indicates that comorbid depression interacts with physical illness to amplify the expected level of disability associated with physical disability (Katon et al, 2002). Hansen et al (2002) demonstrated that mentally disordered medical inpatients use health care more heavily than patients without mental health problems, even after adjusting for medical disease severity. Depression is one of the major challenges facing clinical medicine. Unipolar depression was ranked fifth among the leading causes of disability worldwide in 2000 and projections indicate that by 2020 it will be ranked second only to ischemic heart disease (Murray et al, 1997). In addition to negative health consequences, depression may contribute to unemployment, loss of work productivity, and increased health care costs in persons with arthritis (Li et al, 2006). The association between these two conditions has particular relevance in the elderly population, where a substantial proportion of the burden of depression is related to chronic physical illnesses, including arthritis, which has an attributable risk of 18.1% (95% confidence interval, 9.9-25.6%) (Dunlop et al, 2004). It is unclear whether indirect costs exceed direct medical costs overall, although it appears that patients and families, rather than health care services, incur a majority of the economic costs

Norbert Schmitz and his team (2007) recently examined the synergistic effect of depression and chronic conditions on disability. The results of this population-based study demonstrated that arthritis/rheumatism represented one of the leading disability category at 16, 8%, second only to "back problems" group. The presence of depression substantially increased the number of disability days, e.g. depression increased the Odds Ratio for functional disability from 2.1 in chronic conditions to 6.3 in chronic conditions with

Medical illness and major depression co-occur at high levels in epidemiological and clinical settings. Thus, while the prevalence of depression in nonmedical populations is estimated to be between 5% and 10% in primary care (Simon et al, 2002) and at 8 – 15% in hospital-based

cost metric should be carefully considered.

remain areas of unmet need and huge economic impact.

**3. Burden of illness** 

early in disease.

comorbid depression.

**3.1 Psychiatic morbidity in Rheumatoid Arthritis** 

addition, patients with RA have been shown to have lower IL-1 receptor antagonist levels than anticipated for the level of IL-1 in the joint (Arend et al, 1998). It was hypothesized that addressing this imbalance, with a recombinant IL-1 receptor antagonist could be beneficial in RA and anakinra was thus developed for this purpose (Fleischmann et al, 2003). Anakinra is administered by daily subcutaneous injection. The recombinant humanized anti-IL-6 receptor antibody tocilizumab is an innovative drug for the treatment of rheumatoid arthritis. Tocilizumab is generally well tolerated and efficacious in patients refractive to conventional DMARD therapies (Ohsugi, Kishimoto, 2008).

#### **2.5.5 Abatacept**

Abatacept selectively modulates the co-stimulatory signal required for full T cell activation. The agent, which binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and thus preventing T cell activation, acts earlier in the inflammatory cascade than do other biologic therapies by directly inhibiting the activation of T cells and the secondary activation of macrophages and B cells. Abatacept is administered in a 30min infusion. Kremer provided data that originated from his clinical trial (Kremer et al, 2005), demonstrating that the combination of abatacept and methotrexate improves the signs and symptoms, physical functioning, and quality of life of patients with active RA.

#### **2.5.6 B cell depletion therapy**

Contrary to the long held view that RA is a predominantly T cell mediated disease, the important role of B cells in disease aetiology is supported by development and trials with B cell depletion therapies notably rituximab. B cells contribute to the pathogenesis of RA via a number of proposed mechanisms including; presentation of antigen complexes with IgG to T cells, and T cell independent generation of TNF-α by tissue macrophages after stimulation by oligomeric IgG rheumatoid factor (RF) immune complexes (Fleischmann et al, 2003). In addition, the ability of IgG RF B cells to self perpetuate due to secretion of own antigen, provided rationale for the proposal that elimination of the RF B cell clones may result in prolonged disease remission (Edwards et al, 1999).

#### **2.5.7 Protein-A immunoadsorption therapy**

Immunoadsorption is increasingly used to treat antibody-mediated autoimmune diseases. In its very basic form, it is a therapy that filters blood to remove antibodies and immune complexes that promote inflammation. Recent introduction of staphylococcal protein A (Prosorba) column, as an intervention for treatment-resistant, moderate to severe rheumatoid arthritis has prompted increased requests for this therapy by physicians and patients alike. The basis for the salutary effects of staphylococcal protein A immunoadsorption remains obscure. Because the column becomes saturated after removal of only ~1 gm of IgG, its efficacy clearly is not based on quantitative immunoglobulin depletion. Instead, an immunomodulatory effect is believed to occur, resulting from alterations in circulating immune complexes (Kiss, 2000). Column treatment appears to reduce the population of small molecular weight circulating immune complexes. These circulating immune complexes may interfere with antigen presentation to T-helper cells, thus blocking the formation of "protective" antibodies involved in immune clearance (Kiss, 2000). Circulating immune complexes may also inhibit the formation of anti-idiotypic antibodies, which down-regulate autoantibody responses. Felson et.al. studied the efficacy of SPA column treatment in comparison to a control group who received apheresis without column plasma perfusion (i.e., a sham arm) in a randomized double-blind study and his trial (Felson et al, 1999) reported that staphylococcal protein A column therapy was efficacious in patients with RA with 31.9% of 47 patients in the SPA group experiencing improvement in comparison to 11.4% in the control group (P=0.019). However, it appears that appropriate patient selection is essential. In general, it is recommended that such patients should be refractory to standard modes of therapy, and a risk versus benefit versus cost metric should be carefully considered.
