**3. Burden of illness**

202 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

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

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

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

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

conventional DMARD therapies (Ohsugi, Kishimoto, 2008).

**2.5.5 Abatacept** 

active RA.

**2.5.6 B cell depletion therapy** 

prolonged disease remission (Edwards et al, 1999).

**2.5.7 Protein-A immunoadsorption therapy** 

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, remain areas of unmet need and huge economic impact.

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 early in disease.

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 comorbid depression.

#### **3.1 Psychiatic morbidity in Rheumatoid Arthritis**

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

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 205

visit their rheumatologists, their main focus is their RA, yet such chronic diseases can greatly impact a patient's psychosocial well-being. For these reasons the authors suggest that it is important for rheumatologists to consider addressing both the RA and the depression when they see their patients. The authors note that some physicians may not feel comfortable discussing depression with their patients and advocate the use of brief depression screening

The prevalence of anxiety has been less well studied in this population (Soderlin et al, 2000; VanDyke et al, 2004), though there is some evidence that anxiety may be even more common than depression (El-Miedany et al, 2002), a conservative estimates of the prevalence of co-

Psychiatric syndromes have significant implications for patients with rheumatoid arthritis: individuals with both arthritis and depression report increased functional disability (Vali et al, 1998) and increased levels of arthritis-related pain (Fifield et al, 1998), compared to individuals with arthritis alone. The importance of depression is further underlined by Timonen et al (2003), who reported that 90% of females with rheumatoid arthritis who committed suicide had suffered from a depressive disorder prior to suicide. It is known that the combination of depression and physical illness is associated with small increase in suicide risk, but it increases where pain is a significant part of clinical picture, especially in

Coping has been shown to have a strong association with response and adjustment to chronic illness, including arthritis, (Jensen et al, 1991; Becker et al, 2000) and as such play an important role in mediating the impact of disease activity. Coping is a general concept used to describe the cognitive, emotional and behavioural reactions to the challenging and distressing situations and events. The two questions in relation to coping styles have received rigorous attention: first, how an individual copes with the stresses of having a chronic illness, and second, why individuals faced with essentially the same stressful events may vary so significantly in their ability to adjust. A tentative answer to the two questions posed lies in realisation that just as competent immune system heals by altering bodily equilibrium, so do adaptive coping mechanisms reduce stress by influencing subjective perception of one's condition. Different coping strategies are not in themselves good or bad and all may serve a useful function at various times of illness and in particular circumstances. Active and passive coping refer to the degree of internal and external control, respectively, that a patient relies on to manage the consequences of a disease. Research generally concludes that, overall, strategies involving denial, catastrophizing, avoidance of activity and wishful thinking are less positive for individuals' well being than problemfocused or avoidance-orientated coping. Coping effectiveness is defined by its outcome and usually measured by the level of distress, health-related disability, or other symptomatology. To illustrate this point Brown and Nicassio (Brown & Nicassio, 1987) studied a sample of 361 rheumatoid arthritis patients and found that passive coping was associated with greater pain, disability and depression, whereas active coping was

Within the broader classification system that categorises coping strategies as operating principally along an engagement (e.g., approach, confrontive) versus disengagement (e.g., avoidance, escape) continuum (Carver et al., 1989; Krohne, 1996; Tobin et al., 1989), a

questionnaires before the patient's visits in order to identify problems early on.

existing somatic disorders and phobias, according to Hansen's study was 12.9%.

associated with less pain, disability and depression.

number of specific coping strategies have been identified.

the elderly.

**3.2 Coping** 

studies (Hansen et al, 2001), it is clear that medical diagnosis increases the risk for depression. Rheumatoid arthritis is associated with significant psychiatric morbidity that is often perceived, as surprisingly high. For example, Wells et al (1988) reported a lifetime psychiatric prevalence rate of 64% and a recent 6 months prevalence rate of 42% in patients with arthritis drawn from a community sample. Depression is one of the most common psychiatric conditions found in patients with arthritis: between 14% and 46% of patients with rheumatoid arthritis also fulfil the diagnostic criteria for depression (Zaphiropoulos et al, 1974; Frank et al, 1988; Creed et al, 1990; Hawley et al, 1993; Katz et al, 1993; Abdel-Nasser et al, 1998; Soderlin et al, 2000).

 Patients are very likely to have difficulty with depression while managing their arthritis. In contradiction to the needs of this patient group, all of the above cited studies demonstrate that depression is universally associated with disability and that the detection of mental disorders and the rates of psychiatric referral and treatment are extremely low.

Depression includes a spectrum of disorders that vary in severity and associated disability. Patients with a history of major depression typically have a chronic course that requires comprehensive assessment, effective monitoring and management. Chronic depression may exist independently of, but can also be exacerbated by, disease flare -ups and other illnessrelated obstacles. Moderate to severe depression can adversely affect health outcomes and quality of life in a manner similar to that of other chronic medical conditions. In addition, depression may contribute to inflammation, interfere with medical adherence, and thus compromise medical treatment and management. In this regard, a longitudinal study by Ang et al (2005) found that clinical depression resulted in a 2-fold increase in the likelihood of early mortality in a cohort of patients with RA followed over a 12-year period. All of these factors heighten the importance of detecting and managing depression in patients with arthritis. When rheumatologists do not recognise depression, the risks to patients, their families, and the health care system can be severe.

In light of the above findings, the article by Sleath et al (2008) provides evidence of a significant clinical problem in the care of patients with RA. Although depression in primary care has been well studied, no studies have examined whether rheumatologists and RA patients discuss depression during medical visits. This study by Sleath et al, included 200 RA patients from four rheumatology clinics with eight participating doctors. Patient visits were audiotaped and patients were interviewed after their medical visits using a questionnaire to measure their mental status. The results showed that almost 11% of the patients in the study had moderately severe to severe symptoms of depression and that those who were rated as being more restricted in their normal activities were significantly more likely to have these symptoms. Furthermore, only 1 in 5 of the patients who showed symptoms discussed depression with their rheumatologists and they were always the ones to bring up the topic. Even when depression was brought up, it was often not discussed at any length. Several important findings stand out in this research. First, the authors found that patients who were rated by their rheumatologists as having worse functional status were more than twice as likely to have moderately severe to severe depression. Second, only 19% of the depressed patients had the opportunity to discuss their depression during medical visits. Third, when depression was addressed, the patient initiated the discussion each time. Not once during 200 office visits did a rheumatologist bring up the topic of depression to the patient. Because the study focused only on moderately severe to severe depression, the prevalence of minor depression was not assessed. Many more patients could have been afflicted with less severe forms of depression in the sample. Lastly, when patients visit their rheumatologists, their main focus is their RA, yet such chronic diseases can greatly impact a patient's psychosocial well-being. For these reasons the authors suggest that it is important for rheumatologists to consider addressing both the RA and the depression when they see their patients. The authors note that some physicians may not feel comfortable discussing depression with their patients and advocate the use of brief depression screening questionnaires before the patient's visits in order to identify problems early on.

The prevalence of anxiety has been less well studied in this population (Soderlin et al, 2000; VanDyke et al, 2004), though there is some evidence that anxiety may be even more common than depression (El-Miedany et al, 2002), a conservative estimates of the prevalence of coexisting somatic disorders and phobias, according to Hansen's study was 12.9%.

Psychiatric syndromes have significant implications for patients with rheumatoid arthritis: individuals with both arthritis and depression report increased functional disability (Vali et al, 1998) and increased levels of arthritis-related pain (Fifield et al, 1998), compared to individuals with arthritis alone. The importance of depression is further underlined by Timonen et al (2003), who reported that 90% of females with rheumatoid arthritis who committed suicide had suffered from a depressive disorder prior to suicide. It is known that the combination of depression and physical illness is associated with small increase in suicide risk, but it increases where pain is a significant part of clinical picture, especially in the elderly.

#### **3.2 Coping**

204 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

studies (Hansen et al, 2001), it is clear that medical diagnosis increases the risk for depression. Rheumatoid arthritis is associated with significant psychiatric morbidity that is often perceived, as surprisingly high. For example, Wells et al (1988) reported a lifetime psychiatric prevalence rate of 64% and a recent 6 months prevalence rate of 42% in patients with arthritis drawn from a community sample. Depression is one of the most common psychiatric conditions found in patients with arthritis: between 14% and 46% of patients with rheumatoid arthritis also fulfil the diagnostic criteria for depression (Zaphiropoulos et al, 1974; Frank et al, 1988; Creed et al, 1990; Hawley et al, 1993; Katz et al, 1993; Abdel-

 Patients are very likely to have difficulty with depression while managing their arthritis. In contradiction to the needs of this patient group, all of the above cited studies demonstrate that depression is universally associated with disability and that the detection of mental

Depression includes a spectrum of disorders that vary in severity and associated disability. Patients with a history of major depression typically have a chronic course that requires comprehensive assessment, effective monitoring and management. Chronic depression may exist independently of, but can also be exacerbated by, disease flare -ups and other illnessrelated obstacles. Moderate to severe depression can adversely affect health outcomes and quality of life in a manner similar to that of other chronic medical conditions. In addition, depression may contribute to inflammation, interfere with medical adherence, and thus compromise medical treatment and management. In this regard, a longitudinal study by Ang et al (2005) found that clinical depression resulted in a 2-fold increase in the likelihood of early mortality in a cohort of patients with RA followed over a 12-year period. All of these factors heighten the importance of detecting and managing depression in patients with arthritis. When rheumatologists do not recognise depression, the risks to patients, their

In light of the above findings, the article by Sleath et al (2008) provides evidence of a significant clinical problem in the care of patients with RA. Although depression in primary care has been well studied, no studies have examined whether rheumatologists and RA patients discuss depression during medical visits. This study by Sleath et al, included 200 RA patients from four rheumatology clinics with eight participating doctors. Patient visits were audiotaped and patients were interviewed after their medical visits using a questionnaire to measure their mental status. The results showed that almost 11% of the patients in the study had moderately severe to severe symptoms of depression and that those who were rated as being more restricted in their normal activities were significantly more likely to have these symptoms. Furthermore, only 1 in 5 of the patients who showed symptoms discussed depression with their rheumatologists and they were always the ones to bring up the topic. Even when depression was brought up, it was often not discussed at any length. Several important findings stand out in this research. First, the authors found that patients who were rated by their rheumatologists as having worse functional status were more than twice as likely to have moderately severe to severe depression. Second, only 19% of the depressed patients had the opportunity to discuss their depression during medical visits. Third, when depression was addressed, the patient initiated the discussion each time. Not once during 200 office visits did a rheumatologist bring up the topic of depression to the patient. Because the study focused only on moderately severe to severe depression, the prevalence of minor depression was not assessed. Many more patients could have been afflicted with less severe forms of depression in the sample. Lastly, when patients

disorders and the rates of psychiatric referral and treatment are extremely low.

Nasser et al, 1998; Soderlin et al, 2000).

families, and the health care system can be severe.

Coping has been shown to have a strong association with response and adjustment to chronic illness, including arthritis, (Jensen et al, 1991; Becker et al, 2000) and as such play an important role in mediating the impact of disease activity. Coping is a general concept used to describe the cognitive, emotional and behavioural reactions to the challenging and distressing situations and events. The two questions in relation to coping styles have received rigorous attention: first, how an individual copes with the stresses of having a chronic illness, and second, why individuals faced with essentially the same stressful events may vary so significantly in their ability to adjust. A tentative answer to the two questions posed lies in realisation that just as competent immune system heals by altering bodily equilibrium, so do adaptive coping mechanisms reduce stress by influencing subjective perception of one's condition. Different coping strategies are not in themselves good or bad and all may serve a useful function at various times of illness and in particular circumstances. Active and passive coping refer to the degree of internal and external control, respectively, that a patient relies on to manage the consequences of a disease. Research generally concludes that, overall, strategies involving denial, catastrophizing, avoidance of activity and wishful thinking are less positive for individuals' well being than problemfocused or avoidance-orientated coping. Coping effectiveness is defined by its outcome and usually measured by the level of distress, health-related disability, or other symptomatology. To illustrate this point Brown and Nicassio (Brown & Nicassio, 1987) studied a sample of 361 rheumatoid arthritis patients and found that passive coping was associated with greater pain, disability and depression, whereas active coping was associated with less pain, disability and depression.

Within the broader classification system that categorises coping strategies as operating principally along an engagement (e.g., approach, confrontive) versus disengagement (e.g., avoidance, escape) continuum (Carver et al., 1989; Krohne, 1996; Tobin et al., 1989), a number of specific coping strategies have been identified.

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 207

on the hierarchical nature of coping. Three broad levels have been implicated: (a) coping styles that reflect global, dispositional, macroanalytic tendencies (e.g., monitoring-blunting, vigilance-avoidance, approach-avoidance); (b) coping strategies or modes that reflect an intermediate level in this hierarchy, and are typically indicated by summative scores on coping scales (e.g., confrontation, seeking social support, planful problem solving); and (c) coping acts or behaviors that reflect specific, situation-determined, microanalytic responses that are often indicated by individual item endorsement on a coping scale (Endler & Parker,

The literature on coping with chronic illnesses and disabilities has, likewise, generated much insight into the nature and structure of coping efforts directed at diffusing or removing the stress engendered by the associated trauma, loss, and pain. Results from these and other studies strongly suggest that coping plays a significant role during the process of psychosocial adaptation to both sudden and gradual onset of chronic illnesses and disabilities. More specifically, these results indicate that: (a) a wide range of coping efforts has been employed by persons with disabilities to deal with the stresses engendered by their conditions; (b) these numerous efforts, both problem-solving and emotional-focused coping, as well as engagement- and disengagement- type coping have been found to be adaptive; (c) different coping efforts assume different roles and are, therefore, differentially employed to regulate stressful emotions and solve problems during the adaptation process; (d) coping efforts have played both a direct role (i.e., are directly linked to measures of psychosocial adaptation to disability) and a mediator role (i.e., act as mediators between sociodemographic variables, personality attributes, disability-related factors, environmental conditions, and outcomes of psychosocial adaptation); and (e) different disabling conditions imply different functional (e.g., mobility, manipulation, fatigue, cognitive) limitations, medical courses and prognostic indicators (e.g., deteriorating, unpredictable, stable), related health problems, treatment modalities, and psychosocial reactions. Individuals cognitively appraise the situation in terms of its personal significance, and then look at the resources and options they have available. This notion helps to appreciate the variability in individual coping reactions. The coping strategies adopted by an individual are quite unique; they include the way one perceives threatening experiences and reacts to stressful events, how one manages

The effectiveness of coping strategies across the lifespan has been another area of clinical interest. Contrary to suggested belief that individuals become less efficient at coping with the demands of life as they get older, research into success of coping revealed immunity to the age process. Thus, in a recent study investigating age variance in coping across a broad range of stressors in a sample of more than 2,000 men ranging in age from the late 40s to over 90, there were no significant age differences in the reporting of negative emotional states in response to stressors, nor perceived efficacy in coping (Dunkin & Amano, 2005). In relation to gender differences, women appear to report positive and negative affects more vividly than men. In one study (Diener et al, 1999), gender accounted for 13 percent of the variance of the intensity of reported emotional experiences. There is also considerable evidence that women are more likely to use formal helping systems than are other groups, especially men and people of colour. One recent study addressed the natural coping systems of male and female students in largely young, Euro-American sample (Slattery et al, 2002).

1990; Krohne, 1996; Schwarzer & Schwarzer, 1996).

ones emotions and how one attempt to solve problems.

**3.2.6 Age and gender differences** 
