To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA).
To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA).
Methotrexate (MTX)–naive patients with active early RA were randomly allocated to receive MTX plus placebo or MTX plus infliximab (3 mg/kg or 6 mg/kg) at weeks 0, 2, and 6 and then every 8 weeks through week 46. Data for patients younger than age 65 years were included in the analyses. A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available.
The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo (0.5% versus 1.3%; P > 0.5). However, the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone (8% versus 14%; P = 0.05). Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability (odds ratio 2.4; P < 0.001); this likelihood was not significantly greater in patients receiving MTX alone. The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group (P = 0.010).
The actual employment rates among patients in the 2 treatment groups were not different. However, patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone.
Epidemiologic studies in patients with rheumatoid arthritis (RA) have consistently shown that work disability is a common consequence of this disease (1–4). In patients with RA, physical function deteriorates so severely that approximately half of patients experience work disability within 10 years of disease onset (1). The overall indirect costs resulting from the loss of productivity may exceed the direct health care costs, especially for patients in whom RA is more established (5–12). Thus, RA has a financial impact on patients and their families as well as society.
Recently, biologic agents, especially tumor necrosis factor (TNF) blockers, have emerged as important therapies for RA because of their ability to reduce the signs and symptoms of disease, slow the rate of radiographic progression, and improve functional capacity (13–19). Although biologic agents are expensive and thus increase the direct costs of RA, their inhibitory effects on joint destruction may reduce the need for joint surgery and ultimately offset at least some of the increased direct costs.
Another economic aspect of a disease such as RA is its indirect costs, which includes the lost income attributed to unemployment. For patients with RA, the ability to work is lost rapidly, with 20% of patients losing employment within 2 years; this percentage increases as the duration of disease lengthens (4).
Although many studies have explored the relationship between deterioration in physical function and work disability in RA (20, 21), very few studies have examined the question of whether improvement in physical function during effective treatment affects the employability of patients. Employability comprises the self-assessed working capacity of individuals and, therefore, expands the scope of employment status to include persons who regard themselves as able to work despite having not actually entered the workforce. Such individual expectations of employment capability have been shown to predict future work resumption among unemployed patients with somatic disorders (22). The use of employability to examine the effects of disability on work status seems particularly apt for short-term studies, because securing appropriate employment within a few months may not be feasible for many unemployed patients.
The potential impact of biologic therapy on the employability of patients with RA is an important question given the expense of these increasingly used agents (18). Therefore, we evaluated the impact of TNF blockade on the employability of patients with early-stage RA who participated in the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) (19).
Details of the design of ASPIRE have been reported previously (19). Briefly, patients who were methotrexate (MTX) naive, had active RA, and had a history of persistent synovitis (for at least 3 months but no longer than 3 years from the date of diagnosis) began receiving MTX therapy with rapid dose escalation to 20 mg/week and were randomly assigned in a 5:5:4 ratio to receive either infliximab 3 mg/kg, infliximab 6 mg/kg, or placebo infusions at weeks 0, 2, and 6 and then every 8 weeks through week 46.
Clinical measures of disease activity, including the number of tender joints, the number of swollen joints, physical function, patient's and physician's assessments of disease activity, the C-reactive protein level, and the erythrocyte sedimentation rate, were evaluated at baseline and at weeks 2, 6, 14, 22, 30, 38, 46, and 54. Physical function was assessed using the Health Assessment Questionnaire (HAQ) (23). Clinical response was evaluated using the American College of Rheumatology (ACR) criteria for improvement (24).
Patients' self-reported employment data were collected at each clinical assessment study visit, from baseline through week 54. Patients were asked the following questions: “Are you currently actively employed?” and “If not, do you feel well enough to work if a job were available?” Yes and no were the possible responses to each question. A patient was categorized as “unemployable” if he or she was unemployed and felt unable to work despite job availability, or as “employable” if he or she was employed or felt well enough to work if a job were available. At each study visit, employed patients were asked how many days of work they missed because of their arthritis since their last study visit.
Only patients ages 64 years and younger were included in the employment analysis, because 65 years is the usual age for retirement (4). The analysis was conducted using an intent-to-treat principle; thus, patients were analyzed according to the treatment to which they had been randomized, regardless of the treatment they actually received. Patients for whom baseline values were missing were not included in the analysis. If a patient had at least 1 post-baseline value, the last observation was carried forward for values that were missing after baseline. An age- and sex-adjusted employment rate was estimated using logistic regression when comparisons were made between groups of patients other than the assigned treatment groups. The Cochran-Armitage test for trend was used to examine the association between employment and HAQ scores. For categorical response parameters, treatment group comparisons were made using the chi-square test. McNemar's test was used to examine change in employment status before and after treatment within each treatment group (25), and the odds ratios (ORs) and 95% confidence intervals were estimated to demonstrate the likelihood of improvement rather than deterioration in employability after treatment.
When examining the impact of treatment outcomes on patients' employability, the change in employability was compared between patients who had a 20% response according to the ACR criteria for improvement in RA (ACR20) and those who did not have an ACR20 response. These comparisons were performed using data for all patients based on the assumption that the impact of treatment outcomes on employability was the same regardless of the therapy received. The percent employability was adjusted for age, sex, and baseline physical function (HAQ scores), to make the employability rates comparable among groups, using the logistic regression model. Statistical analyses were performed using SAS version 8 software (SAS Institute, Cary, NC). All statistical tests were 2-sided and were performed at an alpha level of 0.05.
The mean ± SD disease duration of patients in ASPIRE was 0.9 ± 0.7 years (0.9 ± 0.7 years, 0.8 ± 0.7 years, and 0.9 ± 0.8 years for the placebo plus MTX, 3 mg/kg infliximab plus MTX, and 6 mg/kg infliximab plus MTX groups, respectively) (19). Because the 2 infliximab groups showed similar treatment benefits in that study (19), they were combined for subsequent analyses. At baseline, 64% of patients ages 64 years or younger were actively employed full-time or part-time, as defined in Patients and Methods. Approximately 36% of patients were not employable as a result of RA, and 9% of patients had been receiving disability compensation (Table 1).
|Status at baseline||Placebo + MTX (n = 282)||Infliximab + MTX (n = 722)||Total (n = 1,004)|
|Age ≤64 years||235||621||856|
|Age, mean ± SD years||46.8 ± 10.9||47.2 ± 10.6||46.7 ± 10.7|
|Female sex||178 (76)||437 (70)||615 (72)|
|Employable†||160 (69)||409 (66)||569 (67)|
|Actively employed||157 (67)||385 (62)||542 (64)|
|Employed full-time||127 (55)||319 (52)||446 (53)|
|Employed part-time||30 (13)||65 (11)||95 (11)|
|Unemployed||75 (32)||233 (38)||308 (36)|
|Receiving disability compensation||18 (8)||61 (10)||79 (9)|
At baseline, overall employment, employability, and full-time employment were all significantly associated with the extent of physical dysfunction, according to the Cochran-Armitage test for trend (all P < 0.001). Figure 1 shows patient employment status according to baseline HAQ score. Among patients with a baseline HAQ score ≤1.0, 80% considered themselves to be employable, and 62% were employed full-time. However, patients with a baseline HAQ score ≥2.0 had an employability rate of 38%, and 28% were employed full-time. Not surprisingly, among patients who received disability compensation, the average HAQ score was 1.72 compared with an average score of 1.47 for the remaining patients. Among patients with an HAQ score ≥1.5, 12% received disability compensation compared with 5% of those with an HAQ score <1.5 (P = 0.01).
Overall, patients treated with infliximab plus MTX had a greater likelihood of improvement rather than deterioration in employability after 54 weeks of treatment (OR 2.4, P < 0.001), while the employability status was not significantly changed for patients receiving MTX alone (P = 0.56) (Table 2). The net increase in employability was 2% in the group receiving MTX plus placebo compared with 8% in the group receiving MTX plus infliximab. Furthermore, the proportion of patients whose employability status changed from employable to unemployable between baseline and week 54 was smaller in the MTX plus infliximab group than in the group receiving MTX plus placebo (8% versus 14%; P = 0.05).
|Employability status||MTX + placebo†||Infliximab + MTX‡|
|Employable at baseline, no.||159||406|
|Unemployable at week 54, no. (%)||22 (14)||34 (8)§|
|Unemployable at baseline, no.||72||206|
|Employable at week 54, no. (%)||26 (36)||82 (40)|
|Net increase in employability, %||2||8|
However, the change in actual employment from baseline to week 54 was not significantly different between the 2 treatment groups (P > 0.5). Among the 232 patients in the MTX plus placebo group for whom baseline employment information was available, 13 patients gained employment and 16 patients lost employment over the 1-year study, resulting in a net employment loss of 1.3% (3 patients). In comparison, the net loss was 0.5% (3 patients) for the 618 patients in the MTX plus infliximab group for whom baseline employment information was available, with 31 patients gaining employment and 34 patients losing employment.
Among patients who were actively employed at baseline, a smaller proportion of those in the MTX plus infliximab group lost workdays during the trial compared with those in the MTX-alone group (P = 0.010) (Table 3). Importantly, the percentage of patients who lost >10 workdays was significantly higher in the MTX plus placebo group compared with that in the MTX plus infliximab group (16.7% versus 9.6%; P = 0.02). Moreover, 78.9% of patients in the infliximab plus MTX group lost no days from work during the observation period compared with 66.6% of patients in the MTX-only group (P < 0.01).
|Placebo + MTX||Infliximab + MTX|
|No. of patients actively employed at baseline||156||384|
|No. (%) of patients who missed days from work|
|0 days||104 (66.6)||303 (78.9)|
|1–10 days||26 (16.7)||44 (11.5)|
|>10 days||26 (16.7)||37 (9.6)|
Among patients whose employment status changed from unemployable at baseline to employable at week 54, the percentage of ACR20 responders was greater than the percentage of ACR20 nonresponders (60% versus 18%; P ≤ 0.001). Similarly, 96% of ACR20 responders retained their employable status from baseline through week 54, compared with 77% of ACR20 nonresponders (P ≤ 0.001) (Figure 2). Comparable trends were observed when the data were categorized by treatment group (Figure 3). However, among patients who were unemployable at baseline and those who were employable at baseline, a greater percentage of patients who were treated with MTX plus infliximab (both ACR20 responders and ACR20 nonresponders) were employable at week 54 compared with responders and nonresponders who were treated with MTX plus placebo; the differences between the 2 treatment groups were not statistically significant (P > 0.5) (Figure 3). An additional logistic regression model, with employability as the dependent variable and age, sex, baseline HAQ score, treatment group, ACR20 response, and the treatment group–ACR20 response interaction as independent variables, confirmed the findings presented in Figure 3. These results indicate that the ACR20 response variable was significant in predicting employability outcomes (P < 0.001), while treatment group and the treatment–response interaction were not statistically significant variables (P > 0.05).
Functional disability is one of the most important outcomes among patients with RA. Loss of physical function leaves patients unable to work or manage their daily activities. Work disability can occur early in the course of disease (4, 26–28). Moreover, to cope with increasing work disability, patients often attempt to reduce the number of working hours or change their type of work before being forced by disease-related debilitation to leave the workforce.
Work disability is related to multiple factors, including disease severity, work characteristics, and demographic characteristics (21). In particular, it is difficult to quantify work disability in economic terms for persons who do not work for pay. In addition to employment status, we collected information from ASPIRE subjects about whether they considered themselves capable of working if a job were available. This additional information expands the evaluation of work disability. Self-assessed employability was shown in another study to be an important predictor of future employment (22), providing evidence for the validity of this measure. Unemployability, as defined in this study, was an important issue for a significant proportion of patients with early-stage RA. Indeed, among the 850 patients who were younger than age 65 years, 308 (36%) were unemployed at baseline, and 281 of these (93% of unemployed patients and 33% of patients younger than age 65 years) considered themselves to be unemployable. We also observed that 9% of the patients were receiving disability compensation at this early phase of their disease, and, as expected, these patients had a higher degree of functional disability as determined by the HAQ score than did the patients who were not receiving disability payments. These results show how job loss in the early stages of RA can increase the indirect costs of the disease (9).
These data from ASPIRE show that effective treatment of patients with early RA results in favorable employment outcomes. Regardless of the treatment, patients who achieved an ACR20 response were more likely to become employable or maintain employability than were those who did not achieve an ACR20 response, indicating that employability over the course of the study was dependent on improved disease control rather than dependent on the treatment per se.
Although the 2 treatments did not significantly differ in their effects on actual employment rates, they did produce significant differences in employability outcomes. We observed that patients treated with MTX plus infliximab had a lower likelihood of losing their employability from baseline to week 54 compared with patients who received MTX alone. In addition, fewer infliximab-treated patients lost workdays during the trial period than did patients treated with MTX alone. These differences between the treatment groups were most likely attributable to the greater response rate in the MTX plus infliximab group (19). Although the differences in employability status are relatively small and of uncertain economic significance, they are noteworthy given the short observation period of 54 weeks and the potential long-term economic impact of job loss at the onset of disease.
In the present study, patients were considered to be employable if they felt well enough to work. Thus, the results are based on subjective, patient-reported data that must be interpreted with caution. The end point of “employed” or “unemployed” may be more relevant than self-reported employability as defined in this study; however, this outcome also has several limitations. First, unemployed patients with an improvement in health status may, for a variety of reasons, require an extended period of time before they actually enter or reenter the workforce. This factor may explain the absence of changes in actual employment rates for either treatment group in our 54-week study. Second, previously employed patients may choose not to reenter the workforce immediately, even if they are healthy enough to do so.
Thus, the outcome of employability focuses on the individual's self-assessed capability to work given the availability of appropriate job opportunities while discounting factors other than health status that may contribute to the patient's ability to gain employment. This outcome has been used in other studies (22, 29, 30). Importantly, the same questions were presented to all participants in this double-blind study, regardless of therapy. Given the short-term nature of the study, employability is an important outcome that has been shown to be sensitive to change and may provide information regarding the long-term economic impact of the disease.
To our knowledge, this is the first randomized, double-blind, controlled study evaluating the effect of biologic treatment on employability outcomes in patients with early RA. A previously published study assessed the association between etanercept use and employment outcomes among patients with RA (31). However, that study population primarily consisted of patients with long-standing disease who were not randomly assigned to the treatment and control groups.
Many studies have demonstrated that the ability to work is related to physical function in RA, and that physical function is linked to multiple factors, including disease activity, joint damage, and demographic characteristics. In the early stages of RA, functional disability is largely determined by disease activity, while during later stages it is increasingly dominated by the progression of joint deformity and structural bone damage (32–35). The results of another large trial of MTX and infliximab therapy (Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy; ATTRACT) showed that unemployment at baseline was highly correlated with the level of physical dysfunction (29). Results of the present study were consistent in confirming this relationship and showed that 38% of patients with severe functional disability (HAQ score >2.0) were employable at baseline, while only 28% were employed full-time (see Figure 1). In comparison, results of ATTRACT (after adjustment for age and sex) showed that only 23% of patients with the same magnitude of functional disability (severe) were employable at baseline, and that only 11% were employed full-time (29).
The difference in the employability of patients from ATTRACT and those from ASPIRE is probably attributable to the fact that a majority (81%) of patients in ATTRACT had a disease duration of >3 years and consequently had greater structural joint damage (the median baseline van der Heijde–adjusted Sharp score was 51.5) (36) compared with patients in ASPIRE (median baseline van der Heijde–adjusted Sharp score 5.25) (19). Previous studies have shown that radiographic joint damage is related to physical function and significantly predicts employment status in patients with later-stage RA (30, 32, 33, 37). The results of our analysis suggest that functional disability is also a significant predictor of employment status in patients with early RA. However, disease activity rather than structural joint damage may be the primary cause of functional disability in patients with early RA (34, 35).
It has previously been noted that patients who quit their jobs because of RA have a very low chance of returning to the workforce (3). Therefore, maintaining physical function and retaining patients in the workforce appear to be essential for reducing work disability in the early stages of disease. To achieve this goal, treatment should be initiated early in the course of RA and with sufficient intensity to rapidly attain a state of low disease activity (38, 39). The results of the current study support this approach and attest to the potential benefits of rapid disease control on the employability of patients with early RA.