Disease outcome and functional capacity in rheumatoid arthritis

Disease outcome and functional capacity in rheumatoid arthritis

Authors
PJW Venables, MA, MB BChir, MD, FRCP
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS

Section Editor
James R O'Dell, MD

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: Jan 26, 2016.

INTRODUCTION — The course of rheumatoid arthritis (RA) is variable [1]. Approximately 15 to 20 percent of patients have intermittent disease with periods of exacerbation and a relatively good prognosis. However, most patients have progressive disease, with either a slow or a rapid course. The outcome of RA is dependent upon the degree of joint damage, the physical functional status of the patient, psychological health, and the presence of comorbid illness such as cardiovascular disease, infection, and B cell lymphomas. A reduced life expectancy is seen in some patients with severe RA, due to illnesses that may be the result of RA itself or the drugs used in its treatment (table 1).
Functional capacity, comorbidities, and mortality in RA are reviewed here. Cardiovascular and renal diseases associated with RA are discussed elsewhere. (See "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management" and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Heart failure and left ventricular dysfunction in rheumatoid arthritis" and "Causes and diagnosis of membranous nephropathy", section on 'Drugs, particularly penicillamine and gold' and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)" and "Causes and diagnosis of secondary (AA) amyloidosis and relation to rheumatic diseases" and "NSAIDs: Acute kidney injury (acute renal failure)".)
FUNCTIONAL CAPACITY — Loss of functional capacity in rheumatoid arthritis (RA) is a result of the summation of loss of function in individual joints. Individual joint function depends upon numerous factors:
●Severity of disease activity
●Structural integrity of a joint
●Muscle strength and tone
●General fitness of the patient
●Psychosocial factors
Assessment — Since functional capacity is an important determinant of the natural history of RA and is a useful tool for assessing the effectiveness of therapeutic interventions, many instruments for patient evaluation have been developed.
●Attempts have been made to classify and grade functional capacity based upon the patient's ability to undertake daily activities in the home, at work, or during leisure time. Restriction of physical activity, use of aids and appliances, personal assistance, and level of independence are taken into account in one widely used classification (table 2) [2].
●Functional disability indices are also based on self-report questionnaires, which have been validated, such as the Stanford Health Assessment Questionnaire (HAQ) [3-9] and the Arthritis Impact Measurement Scale Health Status Questionnaire (AIMS) [10]. The complexity of these questionnaires and the time required for completion has led to their modification and simplification for use in routine management [11]. Functional disability is predominantly due to inflammatory synovitis during the early stage of the disease, loss of structural integrity of joints at a late stage, and, depending upon the level of disease activity, a combination of both for the rest of the course of disease [12,13].
Although the HAQ is copyrighted, an English-language version and instructions are generally available free of charge, assuming compliance with user permission requirements [4].
These questionnaires are limited, however, by their emphasis on the physical impact of RA, rather than the psychological health of the patient or the familial, social, and financial consequences of the disease. Indeed, further studies have suggested that psychosocial factors may contribute between 10 to 20 percent towards disability [12,14]. All of these important issues contribute to the patient's quality of life [15]. Thus, a holistic approach to managing patients with RA requires careful attention to many potential consequences of this chronic disease.
Disability due to RA — While recognizing the limitations of self-reports of physical function, there is evidence that the common-sense notion that the combination of inflammation and joint damage leads to functional difficulty is correct. This was illustrated by the results of a Finnish population-based survey of 1095 patients with an established diagnosis of RA and 1530 age- and gender-matched controls [16]. A score on the HAQ of more than 1 suggests that a person is having difficulty with most activities of daily living. Patients were nearly eight times more likely to report moderate disability (HAQ score ≥1) than controls.
Long-term outcomes — The long-term functional outlook is variable for patients who present early in the course of their illness and are treated. As an example, in one study that prospectively followed 168 Swedish patients for 10 years or more, 94 percent continued to be independent in their daily activities [17]. The proportions of those with disabilities described as based upon HAQ scores as “almost no,” mild, moderate, and serious were 20, 28, 48, and 10 percent, respectively, at the end of observation. Almost 20 percent of patients had quiescent disease when last examined.
Use of effective disease-modifying antirheumatic drugs (DMARDs) has been increasing, and this may be having a favorable effect on the severity of disability of patients with RA. This was illustrated in a long-term study of successive cohorts of patients with RA that included 3035 patients from eight centers in North America who were followed from 1977 to 1998 [18]. Use of methotrexate (MTX) at enrollment, considered to be an indicator for effective DMARD therapy, increased from 1 to 44 percent, while prednisone use remained relatively constant (31 to 33 percent among the initial and final cohorts, respectively). Average disability as measured by HAQ declined by approximately 2 percent per year. The long-term decline in disability was not explained by other patient characteristics (ie, age, gender, race, level of education, disease duration, or length of follow-up). After adjustment for all recognized confounders, the mean decrease in HAQ disability remained 2 percent per year.
The beneficial effects of antirheumatic drug treatment on function may be determined, at least in part, by the amount of joint damage that is present at the time such therapy is initiated. This was illustrated in retrospective study data from two trials that had randomly assigned patients with moderate to severe RA, who had not responded fully to MTX, to receive either infliximab or placebo [19,20]; improvement in function as measured by HAQ was inversely correlated with the amount of baseline radiographic damage [21]. These findings suggest that interventions that are effective in preventing joint damage may be most effective in improving function when introduced as early as possible. (See "General principles of management of rheumatoid arthritis in adults".)
Impact on employment — The impact of RA on the ability to earn a living is uncertain. Early studies suggested that employment of patients with RA was approximately one-half that of unaffected individuals. However, subsequent surveys report similar employment rates among patients with or without RA. As an example, after adjustment for level of education, gender, and age among individuals in the Netherlands, the rates of employment for patients with RA compared with that of the general population were not significantly different (61 versus 65 percent, respectively) [22]. The following features related to RA have been noted to increase the likelihood of being unable to work [23-25]:
●Pain
●Impaired physical function
●Difficulty commuting to work
●Failure of antirheumatic drug therapy to produce significant improvement (eg, American College of Rheumatology 20 percent response [ACR20]) and Disease Activity Scores (eg, DAS28)
The presence of other factors is significantly associated with a decreased risk of being disabled, including [23,25]:
●Being self-employed
●Having ergonomic improvements made at the work site
●Reporting a positive attitude about the importance of work
●Having at least an ACR20 response to antirheumatic therapy
Employment status (ie, whether a patient is working or not) does not fully capture the economic impact of the disease as it relates to the workplace. The productivity of patients who continue to work may be adversely affected by disease-related absences and work restrictions. An instrument for assessment of work-related limitations, the Work Limitations Questionnaire (WLQ), may be useful for measuring the impact of RA treatments and workplace interventions on productivity [26,27].
COMORBIDITY AND MORTALITY — Patients with rheumatoid arthritis (RA) have an increased prevalence of other serious illnesses. As an example, one study of 288 patients with RA found that 54 percent of the respondents reported other chronic conditions; 20 percent rated at least one of these other conditions as severe [28]. The predominant conditions contributing to the comorbidity and mortality of RA are infections, renal impairment, lymphomas, and cardiovascular disease (table 1) [28].
Infection — Infections, particularly pulmonary, skin, and joint infections, occur with increased frequency in RA [29]. The reason is incompletely understood, but the following factors may contribute [30]:
●Immunosuppression by the disease itself or its treatment
●The presence (often subclinical) of inflammatory lung disease
●An increase in cigarette smoking
●Multiple factors associated with disability and immobility
Immunosuppression from corticosteroids and immunosuppressive agents is probably the most important [31]. However, the highest glucocorticoid doses are used in the patients with most active disease, which also may contribute to the infection risk. Consistent with this hypothesis is the observation in a population-based study of 609 RA patients and an equal number of controls that, after adjustment for corticosteroid use, leukopenia, age, cigarette smoking, and diabetes, RA remained an independent risk factor for infection [29]. The adjusted relative risk (hazard ratio) of infection that required hospitalization was 1.83 for RA patients versus controls (95% CI 1.52-2.21). (See "Major side effects of systemic glucocorticoids", section on 'Infection and immune response'.)
In contrast with the increased risk of infection associated with the use of glucocorticoids and potent immunosuppressives (discussed above), the use of nonbiologic disease-modifying antirheumatic drugs (DMARDs) does not appear to be associated with an increased risk of infection. This was illustrated in a retrospective study of 27,710 Canadian patients with RA [32]. Among patients who were not taking glucocorticoids, the relative risk (RR) of serious infection for DMARD users was not significantly different from that for nonusers (adjusted RR for DMARD users 0.92 [95% CI 0.88-1.0]). All available biologic DMARDs are associated with an increased risk of infections.
Neutropenia and increased susceptibility to infection are consequences of both Felty's syndrome and the large granular lymphocyte syndrome (see "Clinical manifestations and diagnosis of Felty's syndrome"). Even in the absence of the full-blown syndrome, mild lymphopenia is very common in RA and may increase the susceptibility to infection.
Renal disease — Renal disease is uncommon but may be due to RA itself or to drug therapy. The renal disorders include:
●Membranous nephropathy, which may be due to gold, penicillamine, RA, or nonsteroidal antiinflammatory drugs (NSAIDs). (See "Causes and diagnosis of membranous nephropathy".)
●Secondary (AA) amyloidosis due to the chronic inflammation. (See "Causes and diagnosis of secondary (AA) amyloidosis and relation to rheumatic diseases".)
●Focal mesangial proliferative glomerulonephritis of uncertain etiology, which can occur in 5 to 10 percent of patients.
●NSAID nephrotoxicity, including acute interstitial nephritis, which often occurs in conjunction with the nephrotic syndrome due to minimal change disease. Chronic NSAID therapy can also infrequently cause papillary necrosis. (See "NSAIDs: Acute kidney injury (acute renal failure)".)
Lymphoproliferative disorders — Lymphoproliferative disorders occur with increased frequency in patients with RA; incidence and mortality rates due to leukemia or lymphoma are approximately twofold higher than expected [33-37]. The lymphoma incidence increases as active RA persists and correlates with the severity of disease activity. As an example, in a retrospective case-controlled analysis of 378 Swedish RA patients with lymphoma and 378 matched RA controls, the risk of lymphoma, expressed as an odds ratio (OR), increased dramatically (OR ninth decile of disease activity, 9.4 [95% CI 3.1-28.0], OR tenth decile 61.6 [95% CI 21.0-181.0]) [38]. The most common type of lymphoma was of the diffuse large B cell type (48 percent); 12 percent of lymphomas were positive when tested for the presence of Epstein-Barr virus.
Drugs used to treat the disease, including alkylating agents, azathioprine, methotrexate (MTX), and anti-tumor necrosis factor (TNF) alpha therapy, may contribute to the risk [39], although not all patients with RA who develop malignancies have been treated with any of these drugs. In a case-control study of 23,810 patients with RA, an increased risk of developing hematologic malignancies was associated with the use of immunosuppressive agents; the relative risks were 1.18, 1.44, and 2.21 for MTX, azathioprine, and cyclophosphamide, respectively [40]. The etiology of neoplasia in such patients may include immune dysregulation and/or chronic immune activation. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Major side effects of low-dose methotrexate" and "Overview of biologic agents in the rheumatic diseases".)
Up to one-third of patients with the large granular lymphocyte (LGL) syndrome also have RA and may fulfill the clinical criteria for Felty's syndrome [41]. (See "Large granular lymphocyte leukemia in rheumatoid arthritis".)
Cardiovascular disease — Observational studies suggest that RA is associated with an increased risk of cardiovascular disease that appears to correlate with the activity and duration of the RA. This issue is discussed in detail separately. (See "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management" and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Heart failure and left ventricular dysfunction in rheumatoid arthritis".)
Mortality — RA is a potentially fatal illness [18,34,42-44]. One 1994 study, for example, followed 3501 patients with RA for up to 35 years and found that mortality was increased twofold, resulting in a decreased lifespan of 7 to 10 years (figure 1) [34]. Other studies have shown that RA patients have a 50 percent increased risk of premature mortality and that their life expectancy is decreased by 3 to 10 years [45]. Mortality directly due to RA itself was low (9.8 percent of the deaths), although precise causes were not reported.
This marked increase in mortality may reflect referral bias as many of these patients were being treated in large tertiary care centers. In a community-based study of 450 adult patients with RA, for example, the increased death rate was somewhat less than that observed in large medical centers [46]. The ratio of observed to expected deaths (standardized mortality ratio [SMR]) was 1.38 overall, with women bearing the highest risk (SMR of 1.55 and 1.07 for women and men, respectively). Additional data on this almost exclusively white North American population confirmed a modest age- and gender-adjusted increase in SMR of 1.27 (95% CI 1.13-1.41) and no significant change in the risk of premature death during the 40-year period of observation [47].
Two meta-analyses addressing cardiovascular mortality have largely confirmed these results, with SMRs of around 1.5, suggesting a 50 to 60 percent increased risk of mortality from cardiovascular disease [48,49]. One of these studies [49] showed no change in SMR over a 50-year period. Thus, improvements in therapy have not yet been accompanied by improvements in survival in relation to the general population; moreover, there has been a widening gap between mortality rates in patients with RA and the improving mortality rate in the general population [45]. Furthermore, there is an excess risk of 50 to 60 percent of cardiovascular mortality in patients with RA that has not decreased [45]. Importantly, these studies also emphasize that assessment of cardiovascular risk should be part of the routine long-term management of patients with RA.
Mechanisms by which premature mortality can occur in RA include cardiac disease, amyloidosis, transection of the cord due to cervical spine instability, and respiratory failure due to fibrosing alveolitis. Much more common causes of death were related to comorbid illnesses, particularly cardiovascular and cerebrovascular disease, infection, lymphomas, and gastrointestinal bleeding. With regard to deaths due to acute myocardial infarction, lower rates (comparable with the general population) have been noted in patients with RA diagnosed and treated since 1990s [50]. Patients with RA with a first cardiovascular event appear to have a higher mortality rate during the subsequent 30 days than those without RA [51]. The reason for the difference in fatalities (18 versus 11 percent, respectively) is uncertain. Possible explanations include a greater prevalence of severe epicardial coronary artery disease in patients with RA who present with new ischemic symptoms [52] or the presence of small vessel disease that is not amenable to angioplasty or bypass surgery [53].
Some studies have found a decrease or at least no increase in the expected number of deaths from cancer, probably reflecting the increase from other causes [54]. However, one large study of over 20,000 patients with RA reported an increased incidence of death resulting from lung cancer [55].
Patients who respond to therapy, particularly a DMARD, may have lower mortality. As an example, one long-term prospective study of 271 patients begun on MTX found that the group with more than 50 percent improvement had a SMR of 1.47 [56]; by comparison, the SMRs of patients who had no improvement or who had discontinued treatment were 4.11 and 5.56, respectively.
However a beneficial effect of MTX may or may not be confined to those who have a good response. In a cohort study of 1240 patients with RA at one clinical center in North America, 191 patients died [57]. MTX was prescribed for 588 patients; treatment decisions were not made in a randomized fashion. The group that received MTX had poorer prognostic indicators and more frequent prednisone use than the MTX-naïve group (37 versus 22 percent, respectively). Approximately 70 percent of both groups were women, and the average age was 57 years.
After adjustment for possible confounding factors including age, sex, marital status, disease duration, body mass index, disability score, blood pressure, presence of absence of diabetes, and use of cholesterol lowering drugs, the hazard ratio for all cause mortality among MTX-treated patients was 0.4 (95% CI 0.2-0.8).
When deaths were divided into those due to cardiovascular disease and those due to other causes, the hazard ratios were 0.3 and 0.6, respectively. The reduction in cardiovascular mortality risk was statistically significant, while that of non-cardiovascular mortality was not. The patients in this study were treated beginning in the 1980s and 1990s, prior to the general availability of anticytokine therapy. Use of traditional DMARDs other than MTX did not appear to have a similar survival advantage (hazard ratio 1.0).
Independent predictors of mortality include age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), elevated Disease Activity Score in 28 joints (DAS28 score), anti-cyclic citrullinated peptide (CCP) antibody, joint count, and NSAID and prednisone use, all markers of clinical severity [34,45,58-60]. A lower than ideal body weight (as indicated by a body mass index calculated as weight in kilograms divided by the height in meters squared that is <20) may be associated with increased mortality rate [61]. Other factors that may contribute to reduced longevity include the presence of extraarticular disease, depression [62], circulating immune complexes [42], increased levels of soluble tumor necrosis factor receptors [63], and the presence of certain human leukocyte antigen (HLA) DRB1 alleles (figure 1) [64]. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Complementary and alternative therapies for rheumatoid arthritis (Beyond the Basics)")
SUMMARY
●The outcome of rheumatoid arthritis (RA) is dependent upon the degree of disease activity, joint damage, the physical functional status of the patient, psychological health, and the presence of comorbid illness. (See 'Introduction' above.)
●Loss of functional capacity in RA is a result of the summation of loss of function in individual joints, which depends upon numerous factors. Since functional capacity is an important determinant of the natural history of RA and is a useful tool for assessing the effectiveness of therapeutic interventions, many instruments for patient evaluation have been developed. (See 'Functional capacity' above and 'Assessment' above.)
●The long-term functional outlook is variable for patients who present early in the course of their illness and are treated. The combination of inflammation and joint damage leads to functional impairment. The impact of RA on the ability to earn a living is uncertain. (See 'Long-term outcomes' above and 'Disability due to RA' above and 'Impact on employment' above.)
●Patients with RA have an increased prevalence of other serious illnesses. The predominant conditions contributing to the comorbidity and mortality of RA are (table 1) (see 'Comorbidity and mortality' above):
•Infections, particularly pulmonary, skin, and joint infections, which occur with increased frequency in RA (see 'Infection' above)
•Renal impairment, which is uncommon but may be due to RA itself or drug therapy (see 'Renal disease' above)
•Lymphoproliferative disorders, including lymphoma, which occur with increased frequency in patients with RA (see 'Lymphoproliferative disorders' above)
•Cardiovascular disease, which appears to correlate with the activity and duration of the RA (see 'Cardiovascular disease' above)
●RA patients have an increased risk of premature mortality, and their life expectancy is decreased, although most of the mortality is not due directly to RA itself. (See 'Mortality' above.)