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Abstract
Objective To compare clinical and patient-reported outcomes (PROs) over 5 years between patients with rheumatoid arthritis (RA) in sustained remission (sREM), sustained low disease activity (sLDA) or active disease (AD) in the first year after diagnosis.
Methods All patients with RA from the treatment in the Rotterdam Early Arthritis CoHort trial, a multicentre, stratified, single-blinded trial with a treat-to-target approach, aiming for LDA (Disease Activity Score (DAS) ≤2.4), were studied. Patients were categorised into: (1) sREM (mean DAS from 6 to 12 months <1.6) (n=173); (2) sLDA (mean DAS from 6 to 12 months 1.6–2.4) (n=142); and (3) AD (mean DAS from 6 to 12 months >2.4) (n=59). Pain, fatigue, functional impairment, health-related quality of life (HRQoL), health status and productivity loss during 5 years were compared between groups. Radiographic progression (modified Total Sharp Score (mTSS)) was compared over 2 years.
Results Patients in sLDA in the first year had worse PROs during follow-up, compared with patients in sREM: pain (0–10 Likert) was 0.90 units higher (95% CI 0.52 to 1.27), fatigue (Visual Analogue Scale) was 12.10 units higher (95% CI 7.27 to 16.92), functional impairment (Health Assessment Questionnaire—Disability Index) was 0.28 units higher (95% CI 0.17 to 0.39), physical HRQoL (36-item Short Form Health Survey (SF-36) Physical Component Summary score) was 4.42 units lower (95% CI −6.39 to –2.45), mental HRQoL (SF-36 Mental Component Summary score (MCS)) was 2.95 units lower (95% CI −4.83 to –1.07), health status (European Quality of life 5-Dimensions 3-Levels (EQ-5D-3L)) was 0.06 units lower (95% CI −0.09 to –0.03) and productivity loss (0%–100%) was 7.76% higher (95% CI 2.76 to 12.75). Differences between the AD and sREM group were even larger, except for the SF-36 MCS and EQ-5D-3L. No differences in mTSS were found between groups.
Conclusion Patients with RA who reach sREM in the first year have better HRQoL and function, and less pain, fatigue and productivity loss in the years thereafter, compared with patients with RA who are in sLDA or AD in the first year.
- Rheumatoid Arthritis
- Patient Reported Outcome Measures
- Outcome Assessment, Health Care
Data availability statement
Data are available upon reasonable request. Data are available from the corresponding author upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Sustained remission (sREM) is the recommended treatment target in early rheumatoid arthritis (RA), but it is still unclear whether remission is truly superior to low disease activity (LDA) for reducing long-term adverse health effects in patients with early RA.
WHAT THIS STUDY ADDS
Patients with RA who are able to achieve early sREM, as measured with the Disease Activity Score with 3 items (swollen joint count 44, tender joint count 53 and erythrocyte sedimentation rate), show better long-term patient-reported outcomes than patients in sustained LDA.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings add to the current knowledge supporting sREM as the target to aim for in patients with early RA.
Introduction
Clinical outcomes for patients with rheumatoid arthritis (RA) have improved dramatically in the recent decades. This is partly a result of treat-to-target (T2T) strategies that aim for inactive disease. Despite these T2T strategies, patients with RA still experience pain and functional limitations and have a reduced health-related quality of life (HRQoL).1–3 RA is also associated with productivity loss, causing a high burden for both affected patients and society as a whole.4–6 To lessen the negative impact of the disease, early and targeted treatment is crucial.7–10 But what is the best target to aim for?
Current European guidelines recommend sustained remission (sREM) as treatment target in early RA.7 9 In contrast, the American College of Rheumatology (ACR) guideline, based on the same evidence, conditionally recommends low disease activity (LDA) rather than remission. Yet the ACR also states that remission is a reasonable initial target for patients with early RA.11 Thus, there is still debate about the most optimal treatment target that is both attainable in daily clinical practice and results in good clinical and patient-reported outcomes (PROs). The strict remission target is only attained by 35%–58% of patients with RA and sREM is even less common.12–14 LDA is an alternative acceptable target, especially in established RA or when remission cannot be reached.7 11 LDA is easier to attain and is achieved in approximately 49%–86% of patients with RA.14 15 Of note, there is currently no gold standard measure to assess disease activity, nor a measure to assess sREM or LDA.9
With respect to health outcomes, multiple studies have shown that remission is associated with better radiographic outcomes and functioning than LDA.9 16–20 However, aforementioned studies have several limitations. The included patients with RA had established rather than early disease, patients’ disease activity was higher than in daily clinical practice, a T2T strategy was lacking or cross-sectional data were used. In contrast, a systematic review that compared T2T strategies steered at remission with strategies steered at LDA, found no differences in radiographic progression and functional outcomes after 1–3 years of follow-up.21 Therefore, it is still unclear whether remission is truly superior to LDA for mitigating the long-term adverse health effects in patients with early RA.
In line with these conflicting results, the European Alliance of Associations for Rheumatology (EULAR) highlighted the need to determine whether to aim for either LDA or remission as optimal treatment target.7 To add to the current knowledge, this study investigates the difference in clinical outcomes and PROs among remission, LDA and higher disease activity states. The International Consortium for Health Outcomes Measurement (ICHOM) recently agreed on the most relevant PRO domains for patients with an inflammatory arthritis. These domains are pain, fatigue, activity limitation, overall emotional and physical health impact, work/school/housework ability and productivity.22 Accordingly, our aim is to examine associations between all clinical and PRO domains over the first 5 years after diagnosis in patients with early RA who are either in (1) sREM, (2) sustained LDA (sLDA) or (3) have persistent active disease (AD) between month 6 and 12 after diagnosis.
Patients and methods
Patients
Data from the treatment in the Rotterdam Early Arthritis CoHort (tREACH) trial were used. The tREACH was a multicentre, stratified, single-blinded randomised controlled trial with a T2T approach.23 Eligible patients had arthritis in ≥1 joints and a symptom duration of <1 year. The tREACH was targeted at LDA, defined as a Disease Activity Score 44 (DAS44)≤2.4.24 Extensive details on the tREACH trial can be found elsewhere.23
For the current study, we aimed to measure disease activity as objectively as possible. Previous studies have shown that patients often score high on general health despite low clinical disease activity.25 26 Therefore, we assessed disease activity with the DAS44/erythrocyte sedimentation rate (ESR)-3 item (DAS44-3 item), this is, the DAS44 without general health. Thresholds for remission, LDA and AD are <1.6, 1.6–2.4 and >2.4, respectively. For this study, we selected all patients from the tREACH trial, who fulfilled the 1987 and/or 2010 classification criteria for RA (n=425).27 28 These patients with RA were subdivided into three groups depending on their mean DAS44-3 item at 6, 9 and 12 months after inclusion:
sREM, includes patients with RA whose mean DAS44-3 item between 6 and 12 months was <1.6 and whose DAS44-3 item was never>2.4.
sLDA, includes patients with RA whose mean DAS44-3 item between 6 and 12 months was between 1.6 and 2.4.
AD, includes patients with RA whose mean DAS44-3 item between 6 and 12 months was >2.4 and whose DAS44-3 item was never<1.6.
If the DAS44-3 item was missing at either 6, 9 or 12 months, the mean DAS44-3 item was calculated using the DAS44-3 item of the other two visits. If the DAS44-3 itemwas missing at >1 visit, the mean DAS44-3 item was set to missing.
Study design
Patients in the tREACH received either (1) iTDT: initial triple disease-modifying antirheumatic drug (DMARD) therapy (methotrexate (MTX), sulfasalazine and hydroxychloroquine (HCQ)) with glucocorticoid (GC) bridging therapy oral or intramuscularly; (2) iMTX: initial MTX with or without an oral GC tapering scheme; (3) iHCQ: initial HCQ monotherapy or (4) no DMARDs: initial GC once intramuscularly or an oral tapering scheme or initial non-steroid anti-inflammatory drug monotherapy. Every 3 months, treatment was intensified if the target (DAS44≤2.4) was not reached. Medication was tapered if the DAS44 was<1.6 at two consecutive visits. If a flare (DAS44>2.4) occurred during tapering, full treatment was restarted, depending on the stage in the protocol.
Data collection
Patients visited the outpatient clinic every 3 months. At each visit the DAS44, medication usage and PROs were collected. Collected PROs were: joint pain, fatigue, functional ability, HRQoL, health status, depression and productivity loss. In addition, radiographs of the hands and feet were taken at baseline, 6 months, 1 and 2 years to assess radiographic progression.
Joint pain was measured on a 11-point Likert scale, where higher scores indicate more pain. Fatigue was measured with a Visual Analogue Scale. Scores range from 0 to 100 and higher scores indicate more severe fatigue. The Health Assessment Questionnaire—Disability Index (HAQ-DI) was used to measure functional ability.29 The total score ranges from 0 to 3 and higher scores represent more functional impairment. The 36-item Short Form Health Survey (SF-36) was used to capture HRQoL.30 It measures eight domains and each domain is scored on a 0–100 scale. Higher scores indicate a better HRQoL. A Physical Component Summary (PCS) and Mental Component Summary (MCS) score can also be calculated from these domains. Health status was measured with the European Quality of life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire.31 The EQ-5D-3L measures five health dimensions and yields a health status as compared with the general Dutch population.32 Scores range from below 0 to 1; 0 equals death and 1 equals perfect health. Depression was measured with the Hospital Anxiety and Depression Scale (HADS).33 Scores range from 0 to 21 and a score>7 is suggestive for the presence of a depression.34 Presenteeism, that is, working while sick, was used to measure productivity loss. Presenteeism was measured on a 0–10 productivity scale. This score was converted to a percentage productivity loss, where 0% indicates no impairment and 100% indicates complete impairment.
Medication data included all prescribed medication, which were extracted from the patients’ case health records.
Radiographic progression was assessed with the modified Total Sharp Score (mTSS).35 Radiographs were scored in chronological order by two out of three qualified assessors, who were blinded for treatment allocation.36 The weighted overall κ was 0.67 with 99% agreement. Median mTSS and the percentages of patients with a change>0.5 (radiographic progression) and >1.0 (the smallest detectable change) in mTSS are reported.37
Statistical analysis
To examine possible differences in patient characteristics between groups at baseline, an analysis of variance, Kruskal-Wallis test or χ2 test was used, when appropriate. To compare PROs from second to fifth year after diagnosis, a linear mixed model (LMM) with an unstructured covariance matrix was used. The model included group (sREM, sLDA and AD), time (in months), gender, initial treatment (iTDT, iMTX, iHCQ and no DMARDs) and DAS as covariates, and a random intercept (individual patients) and random slope (time). The minimal clinically important difference (MCID) per PRO was compared with the estimated mean difference between groups.38–44
We performed two sensitivity analysis. First, we used the actual DAS44-3 item at 6, 9 and 12 months, instead of the mean DAS44-3 item, to make the sREM, sLDA and AD groups. In this analysis, sREM (n=95) includes patients with a DAS44-3 item<1.6 after 6, 9 and 12 months. sLDA (n=56) includes patients with a DAS44-3 item 1.6–2.4 after 6 months and a DAS44-3 item≤2.4 after 9 and 12 months. AD (n=59) includes patients with a DAS44-3 item>2.4 after 6 months and after 9 and/or 12 months. Second, the mean DAS44 was used to create the sREM, sLDA and AD groups and compare PROs between them. For the categorisation of the groups, we used the same definition as used for the categorisation of the DAS44-3 item groups. A total of 171, 125 and 60 patients with RA were classified as sREM, sLDA and AD, respectively.
Dropout rates for sREM, sLDA and AD groups were 19%, 18% and 19% after 2 years and these rates increased significantly over the following 3 years to 59%, 62% and 78% after 5 years. Therefore, multiple imputations with chained equations (MICE) with 50 imputations were performed. Missing data were imputed for pain, fatigue, HAQ-DI, EQ-5D-3L, HADS depression, SF-36 domains and paid work. In the imputation regression models, group, time, gender, age, anticitrullinated protein antibodies status, rheumatoid factor status, initial treatment, symptom duration, DAS44-3 item and its components, mTSS and the Fatigue Assessment Scale were the independent variables. Linear regression was used for continuous variables and multinomial logit analysis for paid work. To avoid imputation of values far outside the possible range, we used truncated regression for the SF-36 domains. Since a larger proportion of work data was missing compared with the other PROs, presenteeism was imputed using MICE with 70 imputations. The same imputation model as above was used, with workhours, workdays, days worked with complaints and sick days added as independent variables. For presenteeism, we applied a predictive mean matching regression, using its five nearest neighbours.
To correct for multiple testing, a Bonferroni correction was applied to the LMMs by multiplying p values with the seven performed tests. A corrected p value≤0.05 was considered statistically significant. Analyses were performed in Stata V.17.0.
Results
Patients
A total of 425 patients from the tREACH met the 1987 and/or 2010 RA criteria, of whom 374 (88%) could be categorised into 1 of the 3 predefined disease activity groups. Of the 374 included patients, 173 (46%) patients were categorised as sREM, 142 (38%) as sLDA and 59 (16%) as AD (online supplemental figure S1). Baseline characteristics differed between groups for tender joint counts and consequently DAS44-3 item. The mean DAS44-3 item (SD) was 3.0 (0.9) in the sREM group versus 3.2 (0.9) and 3.5 (0.8) in the sLDA and AD groups. Median patient general health (IQR) was higher in the sLDA (55 (37–70)) and AD (56 (48–68)) groups compared with the sREM (44 (25–63)) group. There was a higher proportion (%) of female subjects in the sLDA (75.4) and AD (83.1) groups compared with the sREM (50.9) group (table 1).
Supplemental material
Baseline characteristics
Clinical outcomes
Although the three groups differed in their DAS44-3 item during the first year of follow-up, these differences diminished in the years thereafter. After 15 months, all three groups achieved a mean DAS44-3 item<2.4 (figure 1A). During follow-up, from second to fifth year, the AD group maintained an LDA state (mean DAS44-3 item (SD) 2.35 (0.70)). The sREM and sLDA groups remained in remission or near-remission (mean DAS44-3 item (SD) 1.25 (0.57) and 1.71 (0.62)), respectively. Over 5 years, cumulative biological DMARD usage was 17% (29/173) in the sREM group, 44% (62/142) in the sLDA group and 92% (54/59) in the AD group (p<0.0001).
Disease activity and radiological progression during follow-up. (A) Disease Activity Score with 3 items (swollen joint count 44, tender joint count 53, erythrocyte sedimentation rate) (DAS44-3 item) during follow-up per group. (B) Cumulative probability plots of 2-year radiographic progression scores in 171 patients with rheumatoid arthritis (75 patients in the sustained remission group, 68 patients in the sustained low disease activity group and 28 patients in the active disease group). Cumulative probability was calculated per group.
Radiographic damage
Little damage was observed in all patients with RA. Median mTSS (IQR) were 0 (0–1.0) in the sREM and sLDA groups and 0 (0–2.0) in the AD group after 2 years of follow-up. Radiographic progression (>0.5) occurred in 7/75 (9%) patients in the sREM group, 10/68 (15%) patients in the sLDA group and 5/28 (18%) patients in the AD group (p=0.44). Progression larger than the smallest detectable change (>1.0) occurred in 6/75 (8%), 5/68 (7%) and 3/28 (11%) of patients in the sREM, sLDA and AD group, respectively (p=0.86). The cumulative probability plots were superimposable (figure 1B).
Pain
Patients in the sLDA and AD groups experienced more pain than patients in the sREM group over the second to fifth year of follow-up. Compared with patients in sREM, mean pain scores were 0.90 units (95% CI 0.52 to 1.27) higher for the sLDA group and 1.12 units (95% CI 0.58 to 1.65) higher for the AD group, respectively (table 2, figure 2A). Although both comparisons were significant, the difference only exceeded the MCID (≥1) for the comparison of the AD group with the sREM group.38 39
Estimated mean differences in patient-reported outcomes during follow-up (1–5 years) for disease activity groups
Patient-reported outcomes over 5 years of follow-up. (A) Pain, (B) fatigue, (C) functional ability, (D) health status, (E) % of patients with a depression score>7 and (F) presenteeism during follow-up per group. Presenteeism is measured on a 0%–100% productivity loss scale, where 0 indicates no impairment and 100 indicates complete impairment. All graphs represent the mean with 95% CI. EQ-5D-3L, European Quality of life 5-Dimensions 3-Levels; HADS, Hospital Anxiety and Depression Scale; HAQ-DI, Health Assessment Questionnaire—Disability Index; VAS, Visual Analogue Scale.
Fatigue
Fatigue also differed significantly between groups from second to fifth year of follow-up. The estimated means were 12.10 units (95% CI 7.27 to 16.92) higher for the sLDA group and 15.16 units (95% CI 8.31 to 22.00) higher for the AD group, compared with the sREM group (table 2, figure 2B). The differences in fatigue exceeded the MCID of ≥10 for both the AD and the sLDA group.40
Functional ability
Patients with RA in the sLDA and AD groups experienced more functional impairment during 4 years of follow-up than the sREM group. Mean scores on the HAQ-DI were 0.28 units (95% CI 0.17 to 0.39) and 0.54 units (95% CI 0.39 to 0.69) higher in the sLDA and AD groups, respectively (table 2, figure 2C). The estimated mean differences exceeded the MCID (≥0.22).41 42
Emotional and physical well-being
Both general (EQ-5D-3L) and more specific (SF-36, HADS) questionnaire were used to measure health status and HRQoL.
Health status (EQ-5D-3L) was lower in both the sLDA group and AD group compared with the sREM group during follow-up (table 2, figure 2D). The differences were larger than the MCID threshold of 0.04 for both comparisons.44
The SF-36 PCS was significantly better in the sREM group compared with the sLDA and AD groups during follow-up (table 2). The difference between the sREM and the AD group also exceeded the MCID (≥3–5).42 43 The SF-36 MCS was significantly worse in the sLDA group (−2.95 units (95% CI −4.83 to −1.07)) compared with the sREM group, but the MCID (≥3–5) was not exceeded.42 43 In contrast, the AD group did not differ from the sREM group on the SF-36 MCS (table 2). We also examined the eight SF-36 domains at specific time points, and compared this with the general Dutch population. Both physical and emotional HRQoL domains of the sREM group were similar to the general Dutch population after 3 and 5 years.45 Both the sLDA and AD groups scored lower on physical HRQoL compared with the general population, with the AD group showing the lowest scores (figure 3).
Health-related quality of life for disease activity groups and the general Dutch population. (A) Mean health-related quality of life scores at baseline, (B) after 3 years and (C) after 5 years, measured with the 36-item Short Form Health Survey, stratified for disease activity groups and compared with the general Dutch population norms.
Finally, we assessed the percentage of patients with a possible depression, defined as an HADS depression score>7. During the total follow-up period, a possible depression was most prevalent in the sLDA group (figure 2E). After 5 years, 0% of the sREM group, 8% of the sLDA group and 3% of the AD group scored >7, respectively.
Work productivity
At baseline, 80% of the sREM, 69% of the sLDA and 68% of the AD group who were ≤65 years old had paid work. During follow-up, measured from second to fifth year after diagnosis, the proportion of patients with paid work increased to 91%, 88% and 86% in the sREM, sLDA and AD groups, respectively.
Productivity loss was 28%, 34% and 43% in the sREM, sLDA and AD groups at baseline. After 5 years, productivity loss had decreased to 12% in the sREM group, 18% in the sLDA group and 23% in the AD group. Productivity loss from second to fifth year of follow-up was higher in the sLDA and AD groups compared with the sREM group (table 2, figure 2F).
Sensitivity analyses
Our sensitivity analysis with patients categorised based on the true DAS44-3 item instead of the mean DAS44-3 item showed some differences with the original analysis. We found smaller estimated mean differences between the sLDA and sREM groups, except for presenteeism which showed a larger difference (online supplemental table S1). This also meant that the previously found differences in pain, fatigue, functional ability, HRQoL, health status and presenteeism between the sLDA and sREM groups no longer reached significance. The opposite was true for the comparison of AD and sREM, which showed larger differences in all measured PROs (online supplemental table S1). These results show that the differences between the sREM and sLDA group during follow-up might be smaller, and the differences between the sREM and AD group might be larger, compared with our results.
Additional analyses with patients categorised based on the mean DAS44 item instead of the mean DAS44-3 item showed the same results as our main analysis (online supplemental figures S2–S4 and table S2). The only exception was presenteeism, which was no longer significantly different between the sREM and sLDA group (online supplemental table S2).
Crude estimates of PROs after 3 and 5 years without adjustments for confounders (gender, initial treatment, DAS44-3 item) and based on non-imputed data are available in online supplemental table S3. Residual disease activity was most often present in the AD group. After 3 years, 85% had ≥1 tender joints and 50% had ≥1 swollen joints in the AD group, compared with 59% and 28% in the sLDA group (online supplemental table S4).
Discussion
This study investigated whether RA disease activity in the first year was associated with clinical outcomes and PROs in the four subsequent years. We found that patients who were in sLDA during the first year after their RA diagnosis experienced more pain, fatigue and functional limitations, had a lower HRQoL and health status and more productivity loss compared with patients in sREM. All aforementioned comparisons exceeded the MCID, except for the differences in pain and HRQoL. Compared with the general Dutch population, emotional and physical HRQoL of the sREM group were similar after 3 and 5 years, but the physical HRQoL of the sLDA group was lower. Radiographic progression did not differ between groups over 2 years. As expected, patients with a persistent AD in the first year had more pain and functional limitations, were more fatigued, had a lower physical HRQoL and health status and more productivity loss than patients in sREM. Importantly, the differences in PROs between disease activity groups during follow-up were found despite a strict T2T approach and the achievement of LDA (mean DAS44-3 item<2.4) in all groups after 15 months.
Our results show an association of early remission with improved long-term PROs. A previous study has shown that patients who fail to achieve a good DAS28 response in the first 12 weeks of treatment, that is, DAS28 improvement of <1.2, are less likely to achieve LDA at year 1.46 47 The EULAR recommendations also stress the importance of improvement within 3 months and achievement of the treatment target within 6 months after treatment start.7 The first 3–6 months after diagnosis thus seem to be important to achieve good outcomes during follow-up. As early as 3 months after start of treatment, differences between disease activity groups were visible and remained during follow-up. Our study, therefore, shows that the ability to achieve remission in the first 3–6 months is associated with better long-term outcomes.
Although differences between the disease activity groups were consistent for all PROs, there was one exception, namely the proportion of patients with a possible depression. The proportion of patients with a possible depression was higher in the sLDA group than in the AD group over 5 years. Although we do not know the cause of this, we could hypothesise that patients in AD are mainly focused on treating their RA, while patients in LDA may still have RA symptoms affecting their daily life, while according to their rheumatologist the treatment goal has already been achieved, which could lead to psychological problems. The relationship between disease activity and PROs has been studied previously; however, this is the first study relating early achievement of sREM and sLDA to long-term clinical outcomes and PROs, including measurement of all ICHOM domains. European guidelines recommend to strive for sREM in patients with early RA, as this results in more favourable outcomes than higher disease activity states.7 9 Our findings are in line with these recommendations.
Nevertheless, striving for the total abrogation of inflammation does not always lead to better outcomes, which was shown by three randomised clinical trials that compared a T2T strategy aimed at clinical remission with a more strict T2T strategy aimed at imaging remission, that is, the absence of subclinical inflammation on ultrasound (US) or MRI.48–50 No differences were seen in clinical, radiographic or PROs between the treatment arms, but patients in the US-guided or MRI-guided T2T arms used more DMARDs than patients in the clinical T2T arms. Similarly, striving for remission instead of LDA potentially leads to more treatment intensifications, while patients with RA who are already in a state of LDA might not always benefit from intensified treatment.51 More intensive treatment always comes at an increased risk of adverse events. Previous studies have shown that patients treated with a T2T strategy aimed at remission used more aggressive therapy than patients receiving usual care.51 It is, therefore, of utmost importance that the treatment target, remission or LDA, and its possible risks and benefits are discussed with the patient.
Moreover, patients with RA often report relevant disease symptoms even in the absence of inflammation. This residual disease activity can cause patients to be in LDA rather than remission. Regardless, patients with RA who still report relevant disease symptoms despite the absence of inflammation should be appropriately assessed and managed, which does not automatically imply more intensive treatment. Therefore, it was recently proposed that the management of RA should be based on a dual T2T: (1) control of the disease, and thus inflammation and (2) control of the illness, in other words disease impact. This dual T2T approach could potentially prevent unnecessary treatment intensifications in patients with well-controlled disease who still experience a high disease impact. A holistic approach that addresses comorbidities and the specific domains in which the patient experiences problems might be more beneficial for these patients.
A limitation of our research is the use of many PROs, which made multiple testing inevitable. To avoid false positive results, we used a Bonferroni correction and compared the estimated mean differences with published MCIDs from the literature. We also observed a high dropout rate, which particularly increased after 2 years. Most patients dropped out in the AD group and reasons for dropout might be different between the sREM and AD group, for example, inactive disease versus dissatisfaction with their treatment (online supplemental figure S1). If this was the case in our study, this would lead to an underestimation of our results. We performed multiple imputation with chained equations to account for missing PRO data. Crude estimates of our PROs after 3 and 5 years showed similar results (online supplemental table S3). This shows that our results are valid despite missing data. Nevertheless, additional research directly comparing a T2T strategy aimed at remission with a T2T strategy aimed at LDA, such as the currently ongoing TETRA-study, is needed to validate our associations.52
One of the strengths of our study is the use of all PRO domains as proposed by ICHOM.22 The differences in PROs between disease activity groups showed consistent results, reinforcing our findings. Another strength of our study is the use of a T2T strategy, which is in line with the current guidelines.9 Furthermore, the DAS44-3 item, that is, without general health, was used as outcome, since general health has been found to be influenced by multiple factors besides inflammation, such as fatigue, functional limitation and depression.53 We chose the DAS44-3 item because we tried to avoid circular reasoning. If a poor general health score caused a high DAS44, other PROs would likely be worse as well. In our opinion, the DAS44-3 item remission bests reflects control of inflammation as proposed in the recently recommended dual T2T strategy.54 However, since the DAS44 is the most commonly used in daily clinical practice, we also repeated our analyses with the DAS44 and this showed the same results (online supplemental figures S2–S4 and table S2).
In conclusion, patients with RA who were in sLDA in the first year after diagnosis had worse PROs during 5 years of follow-up than patients in sREM, despite a strict T2T approach. Our results add to the current knowledge supporting sREM as the target to aim for in patients with early RA. However, decisions to intensify treatment should always be weighed against the possibility of adverse events and patients’ wishes and needs.
Data availability statement
Data are available upon reasonable request. Data are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by medical research ethics committee of Erasmus Medical Center Rotterdam, the Netherlands (MEC-2006-252). Written informed consent was obtained from all participants according to the Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We gratefully thank all participating patients, rheumatologists and research nurses.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors SVJSH performed the statistical analysis and drafted the manuscript. PHPdJ and MV contributed to the analysis. All authors contributed to the design, revised the manuscript and read and approved the final manuscript. PHPdJ is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.