Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease that causes functional disability. It affects about 1% of the global population and imposes considerable societal costs due to health care consumption and productivity losses.1 The average direct medical care cost was US$9519 per year in 2001 for a patient with RA.2 Patients with RA are at higher risks of excess morbidity and accelerated mortality from disease and treatment-related complications. Co-existing medical conditions are major determinants of RA-associated quality of life, functional ability, work disability and mortality,3 and the impact of these in patients with RA has become a growing concern for health care providers. In addition, patients with comorbid conditions incur substantially higher medical costs.2 A comprehensive approach to RA thus requires adequate recognition and management of specific comorbidities (Table 1). However, little is known about how routinely rheumatologists consider and assess patients for comorbidity and risks. This paper presents an overview of conditions which commonly coexist with RA, and management approaches.
|Comorbidities||Common preventive measures|
|Cardiovascular diseases||• Lifestyle interventions such as diet, exercise and cessation of smoking|
|• Minimize use of glucocorticoid agents|
|• Treatment of hypertension, dyslipidemia and diabetes and folate supplementation for patients on methotrexate|
|Infection||• Routine influenza and pneumococcal vaccinations|
|• Minimize use of immunosuppressive agents|
|• Tuberculosis screening|
|Malignancy||• Routine hematologic testing|
|• Minimize use of immunosuppressive agents|
|Gastrointestinal ulceration and bleeding||• Minimize use and/or dose of NSAIDs|
|• Use gastrointestinal prophylactic agents as appropriate (e.g. proton pump inhibitors)|
|• Use COX-2 inhibitors for better gastrointestinal tolerability with caution for cardiovascular risk|
|Osteoporosis||• Lifestyle interventions such as diet, exercise and cessation of smoking|
|• Minimize use of glucocorticoid agents|
|• Calcium and vitamin D supplementation|
|• Use of prescription medicines for osteoporosis as appropriate (e.g. bisphosphonates and hormone replacement therapy)|
|• Routine bone densitometry for patients on glucocorticoid therapy|
A comorbidity that has gained much attention is the risk of cardiovascular (CV) diseases, which is the leading cause of death in patients with RA, accounting for almost 40% of their mortality.4 Patients with RA are at a two-fold increased risk of myocardial infarction and stroke,4 and congestive heart failure appears to be a greater contributor to the excess overall mortality in patients with RA than ischemia.5 Risk factors of CV disease include the traditional risk factors such as dyslipidemia, diabetes mellitus, hypertension, and smoking, and non-Framingham risk factors such as body mass index and homocysteine.6 Furthermore, RA is an independent risk factor for CV disease. ‘RA-specific’ risk factors include effects of the underlying inflammatory disease process itself, duration of RA, treatment-related complications such as accelerated atherosclerosis from glucocorticosteroid use, hyperhomocysteinemia from methotrexate (this could be further exacerbated by concomitant use of sulfasalazine), complications of renal disease and hypertension from non-steroidal anti-inflammatory drug (NSAID) use, and decreased exercise capacity.7,8 Also, rheumatoid factor-positive patients are at a higher risk of CV events following exposure to glucocorticoids.9 Thus, early identification and aggressive management of these risk factors are important. Lifestyle changes such as weight reduction in overweight patients and smoking cessation can help reduce or delay the development of comorbidities. Improved control of inflammation and functional capacity may also reduce the risk of CV disease.10 Therapeutic efforts include minimizing the use of glucocorticoids and NSAIDs, and folate substitution to lower homocysteine levels.
Infection is a major cause of death among RA patients with a standardized mortality ratio of 6.8.11 The risk of bacterial, fungal, opportunistic and viral infections in patients with RA is increased as a result of disease-related compromise of immunocompetency and the use of immunosuppressive agents and glucocorticoids.12,13 Doran et al.14 reported that 64% of patients with RA in a 40-year longitudinal study had at least one infection during follow-up, and disease-related factors were associated with the increased risk of infection. These factors included markers of more severe RA such as rheumatoid factor positivity, elevated erythrocyte sedimentation rate, extra-articular manifestations, and poor functional status. Comorbidities further increased this risk; these included diabetes mellitus, chronic lung disease, leukopenia, glucocorticoid use, and smoking.14 Infection concerns in patients with RA are likely to grow with the greater use of disease-modifying agents, including anticytokine biologic medicines, as either monotherapy or in combination with other immunosuppressive medications. The net effect of these drug treatments on overall infection risk in patients with RA remains unclear, in part because the use of oral corticosteroids in RA is likely to decrease as a result of potent steroid-sparing effects of the biologic medicines. In order to minimize morbidity and mortality from infections, close monitoring of all RA patients taking immunosuppressive drugs is essential. Prescribing physicians have an important educational role towards patients, carers, family members, and other health professionals with regard to the risk of infection with immunosuppressive agents, and the associated signs and symptoms, in order to implement appropriate medical care in a timely fashion. Common preventive measures include routine influenza and pneumococcal vaccinations and reduction in immunosuppressive drug exposure. In general, the guidelines by the Centers for Disease Control for preventing opportunistic infections in transplant patients may be a useful tool in managing patients at risk of infections.15 Patients taking antirheumatic biologic therapies should be screened for opportunistic infections and tuberculosis and receive appropriate treatment prior to the commencement of biologic treatments.13 In addition, patients for whom immunosuppressive therapies are being considered should also receive tuberculosis screening.
Patients with RA in general are at higher risk of malignancy, particularly hematopoietic cancers – this susceptibility relates to the disease itself, as well as the use of immunosuppressive drugs.16 Also, there are concerns about the risk of malignancy in patients treated with tumour necrosis factor inhibitors,17 particularly with the increase in utilization of these agents. It is challenging to ascertain the magnitude of this risk. Analysis and interpretation of infrequent adverse event data derived from randomized controlled trials are limited by factors such as insufficient power to detect rare adverse events due to small sample sizes and short follow-up periods, relatively low risk of malignancy in young patients, and the influence of immunomodulatory drugs on cancer expression. These limitations emphasize the importance of post-marketing surveillance, observational studies, and collaborative multicentre investigation in determining background rates of rare outcomes, traditional and disease-related risk factors for adverse events, and longer term effects of treatment interventions. Approaches useful for managing the risk of malignancy include regular monitoring of patients, routine hematologic testing, and minimal use of immunosuppressive agents.
The increased risks of gastrointestinal (GI) morbidity and mortality related to the use of NSAIDs13 are well recognized by the medical community. Studies have demonstrated the association between use of NSAIDs and GI ulceration and bleeding.18 Appropriate management is critical, particularly in patients at higher risk of GI toxicity (e.g. elderly, prior history of peptic ulcer disease, concomitant anticoagulation). Strategies utilized by physicians include minimizing the use and/or dose of NSAIDs, preventative and aggressive management of peptic ulcer disease such as the use of GI prophylactic agents (e.g. proton pump inhibitors),13 and the use of cyclooxygenase-2 (COX-2) inhibitors (e.g. etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) which offer advantages in lower incidence of serious GI complications (e.g. perforations, ulcers and gastric bleeding) compared with non-specific NSAIDs.18,19 However, the CV risk associated with both NSAIDs and COX-2 inhibitors has become a concern.18 Evidence derived from clinical trials indicates that CV safety varied substantially between COX-2 inhibitors.20 Further controlled studies to directly compare different COX-2 inhibitors with regard to GI and CV risks are needed to inform clinical practice.
Another well-recognized comorbidity in RA is the increased risk of osteoporosis; the risk is about two-fold higher compared with the general population.21 The pathogenesis of RA-related osteoporosis is multifactorial, relating to disease-specific factors as well as being a treatment complication secondary to glucocorticoid use.22 Further, the incidence of osteoporosis is highest among postmenopausal women.13 Osteoporosis leading to bone fracture has substantial health-related implications, including chronic pain, increased disability and increased need for long-term nursing care, thereby imposing considerable societal costs.23 Osteoporosis risk reduction can be achieved through efforts to increase exercise in patients with RA, smoking cessation, reduction of glucocorticoid exposure, calcium and vitamin D supplementation, and use of prescription medicines for osteoporosis (e.g. hormone replacement therapy and bisphosphonates) when appropriate.24 Patients with RA on glucocorticoid therapy should also undergo routine bone densitometry.24
Further confounding the effects of the abovementioned comorbidities, systemic manifestations have also been identified as a contributor to the premature mortality in patients with RA.3,25 Extra-articular manifestations have been reported as having significant impact, including vasculitis, pericarditis, scleritis, neurologic disease, and Felty's syndrome.25 The prevalence of systemic manifestations of RA is approximately 8–15%.26 A recent study also suggested that extra-articular manifestations are associated with a higher risk of CV events in patients with RA; this risk is independent of age, sex, smoking, rheumatoid factor or erosive joint damage.27 Improved recognition and prompt management of these conditions is critical to the achievement of better disease outcomes for patients with RA.
Chronic conditions, including RA, are frequently associated with psychological distress partly due to functional incapacitation.28 It is estimated that 15–20% of patients with RA suffer from depression.29 Psychological comorbidities, such as depression, are associated with negative health outcomes, higher health care costs, and higher risk of mortality in patients with RA.29,30 These often go unrecognized and undertreated among patients with RA,29 and physicians should be vigilant regarding signs and symptoms of mental illnesses and the potential additional impact on functional ability. Appropriate treatment of anxiety and/or depressive symptoms can contribute to improved physical and psychological status of patient with RA, thereby reducing its individual and societal impact.
Comorbid conditions of RA have considerable impact on RA disability and costs, and contribute to its mortality rate – making the provision of care of patients with RA even more complex. Incorporating the assessment of comorbidity into the management of RA is the new reality in order to achieve the best possible outcomes for individual patients. Research is warranted to understand how frequently rheumatologists consider comorbidity when treating patients with RA. Well-designed, long-term studies are needed to determine the effectiveness of management approaches, particularly because adverse comorbid effects might take years to occur. Better understanding of the pathogenesis and impact of these comorbidities, and improved preventive measures to enhance comprehensive management of RA, will effectively reduce the burden on patients and the community.