To investigate the effectiveness of 4 different treatment strategies for recent-onset rheumatoid arthritis (RA) on 2-year patient-reported outcomes, including functioning and quality of life.
To investigate the effectiveness of 4 different treatment strategies for recent-onset rheumatoid arthritis (RA) on 2-year patient-reported outcomes, including functioning and quality of life.
A total of 508 patients with recent-onset RA were randomly assigned to 1) sequential monotherapy, 2) step-up combination therapy, both starting with methotrexate, 3) initial combination therapy, including a tapered high-dose prednisone, or 4) initial combination therapy with methotrexate and infliximab. Treatment was adjusted every 3 months if the Disease Activity Score (DAS) remained >2.4. The McMaster Toronto Arthritis Patient Preference Disability Questionnaire, the Short Form 36 (SF-36), and scores for pain, global health, and disease activity measured on a 100-mm visual analog scale (VAS) were compared between groups at baseline and every 3 months thereafter for 2 years.
After 2 years, all patient-reported outcomes had improved significantly from baseline, irrespective of the treatment strategy. SF-36 subscale scores approached population norms for 3 physical components, and achieved population norms (P > 0.05) for bodily pain and 4 mental components. Improvement in functioning, VAS scores, and physical items of the SF-36 occurred significantly earlier in patients treated with initial combination therapies (all comparisons after 3 months: overall P < 0.001; P < 0.05 for groups 1 and 2 versus groups 3 and 4).
All 4 DAS-driven treatment strategies resulted in substantial improvements in functional ability, quality of life, and self-assessed VAS scores after 2 years. Initial combination therapy led to significantly faster improvement in all patient-reported measures.
Rheumatoid arthritis (RA) is a chronic disabling disease, resulting in functional impairment, limitation of activities, and decreasing health-related quality of life (HRQOL). The primary objectives of treatment are to improve and maintain physical and social functioning and to maximize HRQOL (1, 2).
Traditional measurements of disease activity, such as swollen joint counts or acute-phase reactants, do not necessarily correlate closely with morbidity and mortality (3). Patient-reported outcome measures reflect changes in disease severity over time, predict long-term morbidity and mortality, and should be considered objective (3–6). Current guidelines for the management of RA recommend incorporating patient-reported measures of functioning and quality of life into clinical trials (1).
In the past 2 decades, key changes in the treatment approach for RA, combined with the development of new disease-modifying antirheumatic drugs (DMARDs), have improved the prognosis for patients with RA. Various DMARDs, including tumor necrosis factor blockers, that improve physical function have the potential to improve HRQOL in both patients with early and established RA (7–12). Recent studies have demonstrated that frequent evaluations of disease activity using validated tools combined with therapy adjustments striving for low disease activity result in better disease outcomes than routine care (13, 14). Relatively little data are present as to whether this treatment strategy also affects patient-reported outcomes. To this end, we evaluate the effects of 4 different target-driven treatment strategies on functional ability, HRQOL, and additional patient-reported outcome measures for pain, disease activity, and global health of patients with recent-onset RA enrolled in the BeSt study (15, 16). Previous results of this study indicated that initial combination therapy including prednisone or infliximab resulted in earlier clinical and functional improvement and less joint damage progression over 2 years than initial monotherapy strategies.
The BeSt study is a randomized controlled trial conducted in The Netherlands in 508 patients with recent-onset active RA. The medical ethics committees of all participating centers approved the study protocol. Patients were recruited by local rheumatologists in the participating centers. All patients gave written informed consent. The patient-reported outcome measures reported here were prespecified secondary assessments during 2 years of followup. Details of the BeSt study design and primary end points have been previously published (15, 16). Inclusion criteria consisted of a diagnosis of RA according to the American College of Rheumatology (formerly the American Rheumatism Association) 1987 criteria (17), no prior DMARD treatment, age ≥18 years, disease duration of ≤2 years, ≥6 of 66 swollen joints and ≥6 of 68 tender joints, and either an erythrocyte sedimentation rate ≥28 mm/hour or a global health score of ≥20 mm on a 0–100-mm visual analog scale (VAS; where 0 = best and 100 = worst).
Patients were randomly allocated to 1 of 4 treatment groups by variable block randomization, stratified per center: sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with a tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4). For patients failing on their medication (defined as a disease activity score [DAS] >2.4) (18) or in case of intolerable side effects, the treatment protocol described a number of subsequent treatment steps. Briefly, patients in group 1 started with methotrexate (MTX), then sulfasalazine (SSA), then leflunomide, then MTX + infliximab. Patients in group 2 also started with MTX, then MTX + SSA, then MTX + SSA + hydroxychloroquine (HCQ), then MTX + SSA + HCQ + prednisone, then MTX + infliximab. Patients in group 3 started with MTX + SSA + prednisone (tapered from 60 to 7.5 mg/day), then MTX + cyclosporin A + prednisone 7.5 mg/day, then MTX + infliximab. Patients in group 4 started with MTX + infliximab, then SSA, then leflunomide. If the DAS was ≤2.4 for at least 6 months, medication was gradually tapered until only 1 drug was administered at a maintenance dose. The DAS was measured every 3 months by a trained research nurse who remained blinded to the treatment received. Rheumatologists were not blinded for treatment strategy, but they relied on the DAS recommendations done by blinded research nurses to decide how to proceed with treatment, based on the treatment protocol. The full treatment protocol including all steps is described elsewhere (15).
Every 3 months, patient-reported outcomes were assessed by the patients themselves, under supervision of and assisted by trained research nurses who were blinded to the allocated treatment group.
Functional ability was assessed with the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) (19, 20), a semistructured interview that measures improvement in 5 impaired activities that are chosen and priority-ranked by patients at baseline. The MACTAR can be especially useful when expected between-group differences are small, e.g., in trials with active treatment in all arms such as the BeSt study, and it correlates strongly with the Health Assessment Questionnaire (HAQ) (20). The baseline weighted MACTAR score ranged from 39–59, and the followup score from 21–77. The change from baseline of the weighted score could vary from −38 (maximum deterioration) to +38 (maximum improvement) (20).
HRQOL was assessed with the Medical Outcomes Study Short Form 36 (SF-36) (21), a generic instrument that has been widely used and validated in healthy and diseased populations. It covers 8 areas of health status, including physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The SF-36 scores range from 0 (worst) to 100 (best). In addition, 2 higher order summary component scores for physical health (PCS) and mental health (MCS) can be derived using norm-based methods that standardize the score to a mean of 50 and an SD of 10 in the general population, with higher scores indicating better health (22). In RA, minimum clinically important differences identifying improvements perceptible to patients were defined as a 5–10-point change from baseline for the SF-36 subdomains and a 2.5–5-point change from baseline for the PCS and MCS scores (23). To estimate the burden of RA on HRQOL, SF-36 scores for the BeSt study population were compared with scores for an age- and sex-matched normative sample drawn from a large, random, nationwide sample of adults (n = 1,742) from the general Dutch population (24).
To provide a meaningful interpretation of the differences in HRQOL across the 4 treatment groups, we examined the responses to the following questionnaire items for each of the 8 SF-36 subscales: 1) walking 1 block (physical functioning), 2) cut down time spent at work because of physical health (role-physical), 3) pain interference (bodily pain), 4) general health rating (general health), 5) feeling tired or worn out (vitality), 6) health interferes with social activities (social functioning), 7) doing work less carefully because of emotional problems (role-emotional), and 8) feeling downhearted and blue (mental health). These items were selected because they provided the most striking interpretation of score changes on their respective scales. We derived a dichotomous variable for each of the 8 items to assess the percentage of patients in each group with or without difficulties in the 8 items at baseline, 3 months, and 2 years of followup.
Patients assessed pain, disease activity, and global health using a VAS (0–100 mm, with higher scores indicating a greater degree of severity: 0 = none, 100 = complete). All patient-reported outcome measures were collected at baseline and every 3 months thereafter during the 2-year trial except for the MACTAR, which was collected only through year 1 because with longer followup, activities selected at baseline may have become less relevant as the pattern of disability changed (20).
We performed intent-to-treat analyses. Demographic and disease characteristics were tested using the chi-square test for categorical data, and either one-way analysis of variance or Kruskal-Wallis nonparametric test for continuous data, depending on the distribution of the tested variable. The treatment effect on all patient-reported outcome measures was compared between treatment groups in 2 ways. First, the differences in mean change from baseline at 3, 6, 12, and 24 months for the MACTAR, the SF-36 PCS and MCS, and the 3 VAS were compared using a one-way analysis of variance (post hoc Tukey's honest significant difference test to correct for multiple testing). Second, improvements in patient-reported outcome measures over time were analyzed using the area under the curve approach. Area under the curve comparisons were made using linear mixed-effects models with treatment strategy, time, and their interaction as fixed effects. Because all measurements were done at fixed times, we considered different association models for the covariance structure between the repeated measures of the SF-36, the MACTAR, and the VAS data, and used the structure with the lowest Akaike information criterion value, which was an unstructured covariance matrix for all repeated measures. We chose the area under the curve approach because it allows more information about the rapidity and consistency of the response to be evaluated (25), and it is appropriate when within-patient measurements are highly correlated over time and when changes are larger at earlier assessments (12). To account for multiple testing in the 8 SF-36 subscales, initially only improvements in the PCS and MCS were compared between groups. In the case of significant differences in the PCS or MCS, relevant subscales were tested for significance. Mean SF-36 subscale scores per treatment group and time point were compared with age- and sex-matched SF-36 normative data using Student's t-tests.
Baseline characteristics among the 4 treatment groups were not significantly different (Table 1). Through 2 years, 27 (5%) patients distributed equally among the 4 groups were lost to followup. These patients were not significantly different from the patients completing the study in terms of sex, age, symptom duration at inclusion, rheumatoid factor positivity, DAS, and erosiveness, except for the baseline HAQ, which was significantly higher in patients who were lost to followup (1.7 versus 1.4; P = 0.03).
|Group 1 (n = 126)||Group 2 (n = 121)||Group 3 (n = 133)||Group 4 (n = 128)|
|Female, no. (%)||85 (68)||87 (72)||88 (66)||83 (65)|
|Age, mean ± SD years||54.4 ± 13.1||54.4 ± 13.5||54.6 ± 14.1||54.3 ± 14.3|
|Symptom duration, median (IQR) weeks||23 (14–54)||26 (14–56)||23 (15–52)||23 (13–46)|
|IgM RF positive, no. (%)||84 (67)||77 (64)||86 (65)||82 (64)|
|Erosions on baseline radiograph, no. (%)||89 (72)||82 (70)||93 (71)||93 (73)|
|DAS, mean ± SD||4.54 ± 0.9||4.47 ± 0.8||4.37 ± 0.9||4.31 ± 0.9|
|HAQ score (range 0–3), mean ± SD||1.41 ± 0.7||1.39 ± 0.6||1.42 ± 0.7||1.38 ± 0.7|
Functional ability as measured by the MACTAR improved significantly more rapidly in groups 3 and 4 than in groups 1 and 2. After 3 months, patients in groups 3 and 4 had an average improvement of 17 points versus 10 points in groups 1 and 2 (P < 0.001). At 1 year, patients in group 4 had improved by 19.3 points versus 15.2, 16.3, and 16.9 points in groups 1, 2, and 3, respectively (P = 0.01 for group 1 versus group 4) (Table 2). In the mixed-model analysis, a significant difference was found in the changes in MACTAR scores with time; groups 3 and 4 improved more than groups 1 and 2 (P < 0.001), and group 2 improved more than group 1 (P = 0.04). The difference between groups 3 and 4 was not significant (P = 0.12).
|Group 1||Group 2||Group 3||Group 4||P|
|3 months||10.6||9.5||16.7||17.3||< 0.001†|
|6 months||12.6||15.4||16.4||19.1||< 0.001‡|
|3 months||5.8||3.9||11.2||9.6||< 0.001†|
|6 months||8.0||8.5||12.5||12.4||< 0.001†|
|3 months||−15.1||−13.4||−29.2||−26.6||< 0.001†|
|6 months||−17.4||−25.5||−30.3||−30.2||< 0.001¶|
|VAS disease activity|
|3 months||−18.7||−18.2||−35.9||−34.2||< 0.001†|
|VAS global health|
|3 months||−16.8||−11.8||−22.0||−28.9||< 0.001#|
The following impaired activities at baseline were frequently mentioned by the patients: 257 (51%) patients reported housework, 106 (21%) reported work limitations, and 224 (44%) reported sleeping problems. Housework was ranked as the most important impaired activity by 25% of patients who mentioned it (mean ranking 2.8, range 1–5), work limitations by 39% of patients (mean ranking 2.6), and sleeping problems by 31% of patients (mean ranking 2.6). During the first year, increasing percentages of patients in all 4 groups reported less difficulty in these activities, with groups 3 and 4 reporting the most rapid improvements (Figure 1).
At baseline, all SF-36 subscale scores reflected values that were significantly lower than Dutch population norms for an age- and sex-matched population (24), illustrating the burden of recent-onset RA. Differences were most pronounced in the SF-36 domains of physical functioning, role-physical, and bodily pain (Figures 2A–C). Recent-onset RA also significantly impacted emotional well-being, although to a lesser extent.
Already after 3 months of treatment, all 4 groups achieved clinically relevant improvement greater than the minimum clinically important difference of 5–10 points (23) in all subscales of the SF-36, except for improvement in general health in groups 1 and 2 (Figure 2). After 2 years, normative values for an age- and sex-matched Dutch population were achieved in all groups for bodily pain, vitality, social functioning, role-emotional, and mental health. Although physical functioning, role-physical, and general health also improved across the 4 groups, 95% confidence intervals remained below population norms. Patients in group 4 reported the most rapid improvements; population norms for role-emotional and mental health were achieved after 3 months, and population norms for bodily pain, vitality, and social functioning after 6 months (Figure 2).
For the SF-36 PCS, patients in groups 3 and 4 improved more rapidly than patients in groups 1 and 2, but continued improvement in groups 1 and 2 resulted in similar progress among all groups after 1 and 2 years. All groups made moderate improvements in the SF-36 MCS; no significant differences were observed among groups at any time point (Table 2).
For the PCS, the mixed-model analysis observed significant differences between treatment groups over time. For physical function and general health perception, groups 3 and 4 showed greater improvement than groups 1 and 2; for role-physical, groups 3 and 4 improved more than group 2, and group 4 more than group 1; and for bodily pain, all groups were significantly different, with the lowest pain levels reported in group 4, then group 3, group 2, and group 1 (Figures 2A–D). For the MCS, no significant differences between treatment groups over time were observed by mixed-model analysis (Figures 2E–H).
All 4 treatment groups demonstrated clear improvements over 2 years in the selected questionnaire items of the SF-36 subscales (Table 3). The percentages of patients with any limitations in walking 1 block decreased from 56% to 30% in group 1, from 62% to 29% in group 2, from 62% to 25% in group 3, and from 50% to 23% in group 4. No significant differences were observed among groups at 2 years; at 3 months, however, a significantly higher percentage of patients in groups 1 and 2 than in groups 3 and 4 experienced pain interfering with work (16% and 22% versus 9% and 9%), judged their general health to be fair or poor (42% and 54% versus 25% and 27%), and cut down the amount of time spent on work or other activities (65% and 70% versus 51% and 48%).
|SF-36 subscale||Selected dichotomized item||Group 1||Group 2||Group 3||Group 4|
|Physical functioning||Any limitations in walking 1 block||56||30||62||29||62||25||50||23|
|Role-physical||Cut down amount of time spent on work/activities||81||31||82||31||82||34||81||37|
|Bodily pain||Pain interfered with work a lot or extremely||58||7||55||7||48||6||47||5|
|General health||Fair or poor rating of health in general||60||22||67||20||61||24||68||24|
|Vitality||Tired all or most of the time||64||37||62||32||64||34||65||36|
|Social functioning||Health interferes with social function a lot or extremely||23||11||23||9||23||6||25||6|
|Role-emotional||Did not do work/activities as carefully as usual||47||25||46||23||44||20||45||16|
|Mental health||Downhearted and blue all or most of the time||16||7||19||8||16||5||20||6|
Patient-reported VAS scores for pain, global health, and disease activity markedly improved in all 4 groups. Patients in groups 3 and 4 improved more rapidly than patients in groups 1 and 2 in all VAS measurements (overall P < 0.001 after 3 months) (Table 2). At 1 year, VAS for pain had improved significantly more in group 4 than in group 1 (−30.5 versus −21.3, P = 0.04; P > 0.05 versus other groups), as had VAS for disease activity (−38.3 versus −27.5, P = 0.03; P > 0.05 versus other groups). At 2 years, improvements were sustained without significant differences across the 4 treatment groups. The earlier improvements in VAS measurements observed in groups 3 and 4 were reflected by significant differences in area under the curve measurements using linear mixed models. VAS pain, global health, and disease activity all significantly improved over time in group 4 compared with groups 1 and 2. Additionally, there was greater improvement over time in VAS disease activity in group 3 than in group 1 (data not shown).
We evaluated the effects of RA treatments on patient-reported outcomes measuring functional ability and HRQOL in patients with recent-onset RA enrolled in the BeSt study. Our results indicate that this population had substantially diminished functioning and impaired HRQOL compared with the general Dutch population. Dynamic treatment of RA using 4 different DAS-driven treatment strategies significantly improved functioning and HRQOL across all treatment groups, without significant differences among groups after 2 years. Initial combination therapy with either prednisone or infliximab resulted in a more rapid response, as indicated by significant differences over time compared with initial monotherapy in all patient-reported measures, except the SF-36 MCS.
The MACTAR outcomes confirmed that functional capacity improved significantly earlier in the groups receiving initial combination therapy, leading to significant benefits over time in these groups compared with the groups receiving initial MTX. The benefits of initial combination therapy were supported by rapid improvements in impaired activities considered most important by the patients, i.e., housework, paid work, and sleeping, corroborating these results. Similar to data from a Finnish study (26) indicating that early remission is critical to maintain work capacity over time, the cost-utility analysis of the BeSt study demonstrated that initial combination therapy indeed resulted in more sustained working hours per week (27).
The studied population of patients with recent-onset RA reported a substantially diminished quality of life at inclusion compared with age- and sex-matched Dutch population norms. On the physical domains, the BeSt population (mean age 54 years) scored equally as low as healthy individuals age >70 years in the general Dutch population sample (24). Treatment of RA improved physical well-being, but all physical subscales remained below population norms, except for bodily pain. HRQOL scales assessing mental health and emotional well-being also improved after treatment. Although improvements in these items were less pronounced than those in the physical domains, these patients achieved population norms for all mental domains. Improvements in the PCS and MCS measures were comparable to those observed in other trials of patients with recent-onset RA (8, 9, 28). After 2 years of treatment, no significant differences in HRQOL measures were observed across the 4 strategies, but patients treated with initial combination therapies improved much more rapidly than patients treated with initial monotherapy, as reflected by significant differences over time in the physical health domains.
The patterns of improvement in the different VAS were similar to those observed for functional ability and HRQOL. Patients initially treated with MTX and infliximab reported significantly less bodily pain over time and more rapidly achieved population norms for bodily pain, vitality, social functioning, role-emotional, and mental health compared with patients initially treated with MTX, SSA, and prednisone. Since patients included in the BeSt study reportedly preferred combination therapy with infliximab to taking prednisone (29), it remains uncertain if the current results demonstrate that improved patient-reported outcomes have been influenced by patient preferences for treatment, or vice versa. Nonetheless, the fact that patients experienced more rapid improvement early on appears to be a major advantage of the initial combination therapies and may have a positive impact on treatment compliance.
Because the BeSt study was designed as a single-blind trial, the outcomes of this study may have been influenced by patient expectations of certain treatment strategies. In addition, the study design did not include a placebo arm, so we were unable to assess placebo effects on patient-reported outcomes. However, the patient-reported outcomes correlated well with the radiographic outcomes that were scored by independent readers blinded to assigned treatment, also indicating the superiority of initial combination therapy over initial monotherapy (15, 16). Additionally, patterns of the DAS over 2 years' time are also reflective of the patient-reported outcomes (16). We realize that the DAS is a composite index that includes a measurement for VAS global health. Therefore, it is likely that improvements in VAS global health reflect improvements in DAS. Together, these findings add to the existing evidence that patient-reported outcomes are valid indicators of RA disease status (30).
All patient-reported outcome measures assessed in this study indicate the initial advantages of initial combination therapies. However, certain overlap between the different patient-reported outcomes may exist. For example, it is likely that measurements like VAS global health also comprise patients' quality of life. This possible overlap should be considered when interpreting the separate P values, since these could be inflated.
The results of patient-reported outcomes in this study were achieved in a clinical trial setting, with motivated patients visiting the outpatient clinic every 3 months. The outcomes underline the recent European League Against Rheumatism recommendations (31) that tight control in patients with RA is important, especially until disease activity is low. Once that is achieved, less intense monitoring could be an option if time or funds in daily practice are limited (32).
In conclusion, recent-onset RA placed a substantial disease burden on the functioning and physical and emotional HRQOL of patients enrolled in the BeSt study. Treatment of RA with all 4 different strategies improved functional ability in the areas patients considered important, e.g., housework, paid work, sleep quality, and pain, as well as HRQOL across both the physical and the mental domains. Initial combination strategies resulted in significantly earlier improvements in all patient-reported outcomes compared with initial monotherapy with better results over 2 years' time, thus providing a powerful argument for the use of initial combination strategies. Because patient perceptions of health and a quick response to therapy can influence patient compliance to therapy and the consequent costs of RA to society, the results of this study should be considered in determining appropriate treatment strategies for patients with recently diagnosed RA.
Dr. van der Kooij had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Goekoop-Ruiterman, Hazes, Kerstens, van Zeben, Breedveld, Dijkmans, Allaart.
Acquisition of data. Van der Kooij, de Vries-Bouwstra, Goekoop-Ruiterman, Ewals, Han, Kerstens, Peeters.
Analysis and interpretation of data. Van der Kooij, Hazes, Kerstens, Breedveld, Huizinga, Dijkmans, Allaart.
Manuscript preparation. Van der Kooij, Han, Hazes, Kerstens, Breedveld, Huizinga, Dijkmans, Allaart.
Statistical analysis. Van der Kooij.
We would like to thank all patients, as well as the following rheumatologists (other than the authors) who participated in the Foundation for Applied Rheumatology Research: W. M. de Beus, MD: Medical Center Haaglanden, Leidschendam; C. Bijkerk, MD: Reinier de Graaf Gasthuis, Delft; M. H. W. de Bois, MD, G. Collée, MD: Medical Center Haaglanden, The Hague; A. H. Gerards, MD, P. A. H. M. van der Lubbe, MD: Vlietland Hospital, Schiedam; B. A. M. Grillet, MD: De Honte Hospital, Terneuzen; J. H. L. M. van Groenendael, MD: Franciscus Hospital, Roosendaal; H. M. J. Hulsmans, MD, H. K. Ronday, MD: Haga Hospital, The Hague; M. H. de Jager, MD: Albert Schweitzer Hospital, Dordrecht; J. M. de Jonge-Bok, MD (retired); M. V. van Krugten, MD: Walcheren Hospital, Vlissingen; H. van der Leeden, MD (retired); W. F. Lems, MD: Slotervaart Hospital, Amsterdam; M. F. van Lieshout-Zuidema, MD, J. Ph. Terwiel, MD: Spaarne Hospital, Hoofddorp; A. Linssen, MD (retired); C. Mallée, MD, K. S. S. Steen, MD, S. ten Wolde, MD: Kennemer Gasthuis, Haarlem; E. T. H. Molenaar, MD: Groene Hart Hospital, Gouda; H. C. van Paassen, MD, J. M. G. W. Wouters, MD: Sint Franciscus Gasthuis, Rotterdam; H. K. Markusse, MD (deceased); D. van Schaardenburg, MD: Jan van Breemen Institute, Amsterdam; P. E. H. Seys, MD: Lievensberg Hospital, Bergen op Zoom; R. M. van Soesbergen, MD (retired); P. B. J. de Sonnaville, MD: Oosterschelde Hospital, Goes; I. Speyer, MD, M. L. Westedt, MD: Bronovo Hospital, The Hague; A. E. Voskuyl, MD: VU Medical Center, Amsterdam, The Netherlands. We would also like to thank all other rheumatologists and trainee rheumatologists who enrolled patients in this study, and all research nurses for their contributions.