# Exploring the Disparity between Inflammation and Disability in the 10-Year Outcomes of People with Rheumatoid Arthritis

James M Gwinnutt, Sam Norton, Kimme L Hyrich, Mark Lunt, Bernard Combe, Nathalie Rincheval, Adeline Ruyssen-Witrand, Bruno Fautrel, Daniel F Mcwilliams, David A Walsh, et al.

► To cite this version:

James M Gwinnutt, Sam Norton, Kimme L Hyrich, Mark Lunt, Bernard Combe, et al. Exploring the Disparity between Inflammation and Disability in the 10-Year Outcomes of People with Rheumatoid Arthritis. Rheumatology, 2022, 61 (12), pp.4687-4701. 10.1093/rheumatology/keac137. hal-03888142

HAL Id: hal-03888142

https://hal.sorbonne-universite.fr/hal-03888142

Submitted on 9 Dec 2022

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Original article

# Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis

James M. Gwinnutt ID <fnref n="1" />, Sam Norton ID ²,³, Kimme L. Hyrich ID <fnref n="1" />,⁴, Mark Lunt ID <fnref n="1" />, Bernard Combe ID ⁵, Nathalie Rincheval⁶, Adeline Ruyssen-Witrand⁷,⁸, Bruno Fautrel⁹,¹⁰, Daniel F. McWilliams ID ¹¹,¹², David A. Walsh¹¹,¹²,¹³, Elena Nikiphorou³,<fnref n="14" />, Patrick D.W. Kiely ID ¹⁵,¹⁶, Adam Young¹⁷, Jacqueline R. Chipping¹⁸,¹⁹, Alex MacGregor ID ¹⁸,¹⁹ and Suzanne M.M. Verstappen ID <fnref n="1" />,⁴

## Abstract

**Objectives.** To identify groups of people with RA with different disability trajectories over 10 years, despite comparable levels of inflammation.

**Methods.** Data for this analysis came from three European prospective cohort studies of people with RA [Norfolk Arthritis Register (NOAR), Early RA Network (ERAN), Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR)]. Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1 January 2000, <24 months baseline symptom duration, and disability (HAQ) and inflammation [two-component DAS28 (DAS28-2C)] recorded at baseline and at one other follow-up. People in each cohort also completed patient-reported outcome measures at each assessment (pain, fatigue, depressive symptoms). Group-based trajectory models were used to identify distinct groups of people with similar HAQ and DAS28-2C trajectories over follow-up.

**Results.** This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). ESPOIR included more women and the participants were younger [mean (standard deviation) age: NOAR: 57.1 (14.6), ESPOIR: 47.6 (12.5), ERAN: 56.8 (13.8)]; women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories following the hypothesized pattern (comparable DAS28-2Cs but different HAQs) were identified. Higher pain, fatigue and depressive symptoms were associated with increased odds of being in the high HAQ trajectories.

**Conclusion.** Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function.

**Key words:** RA, disability, epidemiology, outcomes research, psychology

<footnote n="1">¹Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester,
²Health Psychology Section, Institute of Psychiatry, Psychology and Neuroscience, ³Centre for Rheumatic Diseases, Department of Inflammation Biology, Faculty of Life Sciences and Medicine, King's College London, London, ⁴NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK, ⁵University of Montpellier, ⁶Laboratory of Biostatistics and Epidemiology, University of Montpellier, Montpellier, ⁷Centre de Rhumatologie, Hôpital Purpan, ⁸Faculté de Médecine, Université Toulouse III, Paul Sabatier University, Inserm UMR1027, Toulouse, ⁹Department of Rheumatology, Sorbonne University—Assistance Publique Hôpitaux de Paris, Pitie Salpetriere Hospital, ¹⁰PEPITES team, Pierre Louis Institute of Epidemiology and Public Health, INSERM UMRS 1136, Paris, France, ¹¹Pain Centre Versus Arthritis, University of Nottingham, ¹²NIHR Nottingham Biomedical Research Centre, Nottingham, ¹³Department of Rheumatology, Sherwood Forest Hospitals NHS Foundation Trust, Sutton in Ashfield,</footnote>

<footnote n="14">¹⁴Rheumatology Department, King's College Hospital,
¹⁵Department of Rheumatology, St George's University Hospitals NHS Foundation Trust, ¹⁶Institute of Medical and Biomedical Education, St George's University of London, London, ¹⁷Centre for Health Services and Clinical Research, Life and Medical Sciences, University of Hertfordshire, Hatfield, ¹⁸Norwich Medical School, University of East Anglia and ¹⁹Rheumatology Department, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK</footnote>

<footnote>Submitted 7 January 2022; accepted 25 February 2022</footnote>

<footnote>Correspondence to: James M Gwinnutt, Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK. E-mail: James.gwinnutt@manchester.ac.uk</footnote>
Rheumatology key messages

* Previous research shows a disparity between long-term low inflammation and high disability in rheumatoid arthritis.

* This study identified groups with similar inflammation trajectories yet markedly different disability trajectories over 10 years.

* Pain, fatigue and depressive symptoms predicted higher disability group membership, independent of inflammation.

Introduction

RA is a condition characterized by inflammation of the synovial joints [1]. In the past, limited treatment options were available to control this inflammation, and therefore people with RA suffered from significant pain and disability into the long term [2]. However, following the adoption of treat-to-target strategies and the widespread use of MTX for RA in the mid-1990s and subsequently the introduction of biologic treatments in the 2000s [3, 4], the ability to control inflammation drastically improved, leading to low inflammation over time for many people with RA [5, 6].

Nonetheless, this low long-term inflammation has not translated into low levels of disability. A study from the Norfolk Arthritis Register (NOAR) showed that disability followed a 'J-shaped' trajectory over 10 years, culminating in disability levels similar to baseline [7]. The same trajectory has been observed in other UK [6], Swedish [8] and French cohorts [9], and within a longitudinal meta-analysis [10]. Furthermore, this disparity between inflammation and disability was larger in the 2000s than in the 1990s [7, 10], despite the increasing options available to control inflammation.

Disability impacts all aspects of the lives of people with RA; higher disability is associated with reductions in work capacity [11, 12] and interference in valued life activities such as seeing friends and taking care of family [13]. Furthermore, disability is potentially a significant burden for healthcare systems. Disability is the strongest predictor of healthcare costs in RA, a finding seen across several healthcare settings [14–16]. Therefore, this excess disability despite treatment of inflammation requires investigation.

Not all individuals follow the same symptom trajectory, and the progression of many long-term outcomes important to people with RA can be described using multiple subgroups or 'trajectory groups' [17–19]. The hypothesis of this research project is that the disparity between inflammation and disability seen on average in cohorts of people with RA is driven by a subgroup of people with RA characterized by low-inflammation yet high disability into the long term. The aim of this analysis was to identify this subgroup within three large-scale cohort studies of people with inflammatory arthritis, two from the UK and one from France. Then, we aimed to identify factors driving the excess disability in this subgroup.

Methods

The data for this analysis came from three inception cohorts of people with inflammatory arthritis. Participants in all three studies provided written informed consent. NOAR is a primary-care based, prospective inception cohort of people with inflammatory arthritis recruited in Norfolk, UK [20]. The inclusion criteria for NOAR are ≥2 swollen joints lasting for ≥4 weeks and being ≥16 years old. Recruitment started in 1990 and is ongoing. Participants in NOAR were assessed at baseline and then at years 1, 2, 3, 5, 7 and 10. NOAR was approved by the Cambridgeshire and Hertfordshire Research Ethics Committee (15/EE/0076).

The Early RA Network (ERAN) is a cohort of people recruited at the point of clinician diagnosis of RA from 22 outpatient rheumatology clinics in the UK and Ireland from 2002 to 2013 [21]. Participants of ERAN were seen at baseline, once between 3 and 6 months, and then annually thereafter for up to 13 years. Only the first 8 years of follow-up within ERAN were used for the current analysis due to attrition, largely driven by all centres closing to follow-up by 2018. ERAN was approved by the Trent Research Ethics Committee (01/4/047).

The *Étude et Suivi des Polyarthrites Indifférenciées Récentes* (ESPOIR) study is a cohort of people with inflammatory arthritis recruited from 14 regional centres of rheumatology across France between 2002 and 2005. The inclusion criteria for ESPOIR were >2 swollen joints lasting for >6 weeks, clinical diagnosis of RA as certain or possible, and being aged 18–70 years. Furthermore, participants were required to have received no DMARDs or glucocorticoids for >2 weeks [22]. Participants were assessed at baseline, 6 months, 12 months, 18 months, 24 months and then yearly for up to 10 years. The ESPOIR cohort study was approved by the Ethics Committee of Montpellier (020307).

For the current analysis, participants within each cohort were included if they had <24 months symptom duration at baseline, had data for disability and inflammation at baseline and one other assessment, and were recruited on or after the year 2000.

Assessments

Participants in each study reported demographics (age, gender, smoking status, symptom duration) and completed questionnaires. Research nurses measured height
and weight and performed swollen and tender joint counts at each assessment. Blood samples were taken at each assessment from which CRP was measured in NOAR and ESPOIR, and ESR in ERAN. RF (all cohorts) and anti-CCP antibody (anti-CCP; NOAR and ESPOIR only) positivity were measured from baseline blood samples. Prescription DMARD treatments were also recorded. The ERAN dataset includes the rheumatic disease comorbidity index (RDCI) [23], whereas participants of NOAR and ESPOIR self-reported comorbidities from predetermined lists (coded as 0, 1 or ≥2 comorbidities due to insufficient data to calculate RDCI). Data on baseline joint erosions were available in the ERAN and ESPOIR cohorts. X-rays were not routinely taken as part of the NOAR assessments (74.2% missing X-rays as per NOAR protocol, see Supplementary Table S1, available at Rheumatology online).

Global disease activity measures (such as the DAS28) include both inflammatory markers (swollen joint count, CRP/ESR) and patient-reported outcome measures [PROMs; tender joint counts, global health visual analogue scale (VAS)]. However, pharmacological treatment of RA aims to reduce inflammation, and previous research has shown that only the inflammatory components of the DAS28 were associated with MRI-detected synovitis [24]. Furthermore, this study aimed to identify specific factors driving disability in RA, such as inflammation and PROMs. As these factors are conflated in global disease activity measures, a measure of inflammation alone was needed. Therefore, in this analysis, inflammation was quantified using the two-component DAS28 (DAS28-2C). This measure combines swollen joint count and either CRP (NOAR, ESPOIR) or ESR (ERAN) using formulae designed to maximize the association between the scores and US synovitis [25]. Participants also completed several PROMs. Disability was assessed using the British [26] (NOAR, ERAN) and French [27] (ESPOIR) versions of the HAQ, with scores adjusted to account for device use. Participants of NOAR and ESPOIR completed pain and fatigue VAS, and participants of ERAN completed the Short-Form 36 (SF-36), which includes pain and fatigue (vitality) subscales [28]. Anxiety and depressive symptoms were assessed using the Arthritis Impact Measurement Scale (AIMS-2) [29] in NOAR, five variables from the French version of the AIMS-2 [30] in ESPOIR, and the mental health component of the SF36 in ERAN.

## Statistical analysis

Each cohort was analysed separately and in parallel, using the methods described below. Demographic and clinical characteristics were summarized using descriptive statistics, stratified by cohort. Within each cohort, subgroups of participants with similar HAQ and DAS28-2C trajectories were identified using multivariate group-based trajectory analysis [31], a longitudinal finite-mixture model. Specifically, this involved jointly estimating longitudinal models for both HAQ and DAS28-2C that estimated the baseline level of the outcome (intercept) and the rate of

change in the outcome over time (slope), with these variables used to inform the identification of trajectory subgroups (latent classes). The number of trajectory groups was selected by assessing the Akaike and Bayesian Information Criteria, entropy and posterior probability of group membership (Supplementary Document, available at Rheumatology online, for details). Within pairs of trajectories that displayed the hypothesized relationship (similar inflammation but different HAQ trajectories over follow-up), baseline predictors of being in the group characterized by higher HAQ score trajectory were assessed using multi-variable logistic regression. Missing data on baseline predictors were imputed using multiple imputation by iterative chained equations. Outcomes over 8 (ERAN) and 10 (NOAR and ESPOIR) years of follow-up were compared between trajectory groups using linear mixed models for continuous outcomes and generalized estimating equations (GEE) analysis for binary outcomes, controlling for age and gender. The associations between time-varying PROMs (pain, fatigue, anxiety and depressive symptoms) and disability were assessed using mixed effects models, controlling for age, gender, baseline comorbidity, baseline BMI, and HAQ score at the previous assessment. As the PROMs were measured on different scales [e.g. VAS pain (0–100) and AIMS (0–10)], to improve comparability, the PROMs were also standardized (i.e. rescaled to have mean of 0 and standard deviation of 1). Using standardized PROMs, model coefficients represent a change in the HAQ score for a standard deviation change in the PROMs (results in Supplementary File, available at Rheumatology online). Interaction terms were included to assess whether the association between PROMs and disability differed between trajectory groups. Trajectory analysis was performed using the traj package [32] in Stata version 14 (StataCorp: College Station, TX), and other analyses were performed using R version 3.6.0 (packages: haven [33], tidyverse [34], grid, gridExtra [35], reshape2 [36], lme4 [37], psych [38], mice [39], miceadds [40], effects [41], gee [42], broom.mixed [43]).

## Results

This analysis included 2500 people with inflammatory arthritis (NOAR = 1000, ESPOIR = 766, ERAN = 734). The ESPOIR participants were younger than the NOAR and ERAN participants [mean age (standard deviation), years: ESPOIR 47.6 (12.5); NOAR 57.1 (14.6); ERAN 56.8 (13.8)] and had a higher proportion of women (% women: ESPOIR 76.9%; NOAR 63.9%; ERAN 69.1%). The ESPOIR participants had shorter symptom duration, had more severe disease, and fewer participants were receiving csDMARDs at baseline compared with NOAR and ERAN (Supplementary Table S1, available at Rheumatology online).

## Group-based trajectory analysis

Assessment of group-based trajectory models applied to the longitudinal HAQ and DAS28-2C scores in each cohort separately resulted in the selection of a five-
group trajectory model (see Supplementary Table S2 and Supplementary Figs S1–4, available at *Rheumatology* online). Each cohort contained one trajectory group with very low HAQ and DAS28-2C scores [group 1 in Fig. 1 (yellow trajectory), termed ‘Very low inflammation—Low HAQ’) (Supplementary Table S3, available at *Rheumatology* online, for baseline characteristics). In this group, the HAQ and DAS28-2C scores remained low over follow-up. The hypothesized relationship [similar inflammation (DAS28-2C) but different disability (HAQ) trajectories] was observed in two pairs of trajectories in each cohort (Fig. 1). Within each pair, the DAS28-2C scores were similar, but one trajectory had an average HAQ score of 0.5–1.0 unit higher over

follow-up [groups 3 and 5 in Fig. 1 (dashed lines), termed ‘high HAQ’ trajectories] than the other trajectory [groups 2 and 4 in Fig. 1 (solid lines), termed ‘low HAQ’ trajectories] over 8–10 years. In each cohort, one pair of trajectories had lower disability and inflammation on average over the course of follow-up [groups 2 and 3 in Fig. 1 (purple trajectories), termed ‘Low inflammation pair’] compared with the other pair [groups 4 and 5 in Fig. 1 (green trajectories), termed ‘High inflammation pair’). In general, the inflammation scores of these trajectory groups improved over follow-up, whereas the HAQ scores were relatively stable. In summary, the five trajectory groups were: 1 = ‘Very low inflammation—Low HAQ’ (NOAR: 28.7%; ESPOIR: 24.3%; ERAN:

<figure><img src="image_2.png" /><figcaption>FIG. 1 Trajectories of inflammation and disability over follow-up from the GBTM analysis</figcaption></figure>

The HAQ component of each trajectory group's name is relative to the pair (i.e. in the 'low inflammation pair' there was one group with low HAQ and one with high HAQ). DAS28-2C: 2-component DAS; ERAN: Early RA Network, ESPOIR: Étude et Suivi des Polyarthrites Indifférenciées Récentes, GBTM: Group-Based Trajectory Model; NOAR: Norfolk Arthritis Register.
14.9%), 2 = 'Low inflammation—Low HAQ' (NOAR: 29.5%; ESPOIR: 29.8%; ERAN: 11.9%), 3 = 'Low inflammation—High HAQ' (NOAR: 19.9%; ESPOIR: 16.6%; ERAN: 28.3%), 4 = 'High inflammation—Low HAQ' (NOAR: 10.4%; ESPOIR: 17.8%; ERAN: 28.7%), and 5 = 'High inflammation—High HAQ' (NOAR: 11.5%; ESPOIR: 11.6%; ERAN: 16.2%).

## Baseline factors associated with high HAQ trajectory group membership

At baseline, participants in the 'Low inflammation—High HAQ' group were on average older, were more often women, had more comorbidities and had more severe pain, fatigue, anxiety and depressive symptoms compared with the 'Low inflammation—Low HAQ' group, despite similar inflammation (Table 1). Similar results were seen when comparing the 'High inflammation—High HAQ' group with the 'High inflammation—Low HAQ' group. Furthermore, in the low inflammation pair, the high HAQ trajectory had more erosions at baseline in ERAN and ESPOIR (data not available in NOAR). This was not seen in the high inflammation pair.

Multivariable logistic regression analysis was used to identify baseline factors associated with high HAQ trajectory membership compared with low HAQ trajectory membership. Separate models were constructed for the high and low inflammation pairs (i.e. the 'Low inflammation—High HAQ' group was compared with the 'Low inflammation—Low HAQ group' and the 'High inflammation—High HAQ' group was compared with the 'High inflammation—Low HAQ group'). Older age, being a woman vs a man, and more severe pain, fatigue and depressive symptoms were associated with increased odds of being in the higher HAQ trajectory in both the high and low inflammation pairs (Table 2; see Supplementary Table S4 and S5, available at Rheumatology online, for sensitivity analysis regarding missing data in NOAR). More comorbidities and serology status (NOAR: anti-CCP+; ERAN: RF+) were associated with greater odds of being in the high HAQ trajectories in NOAR and ERAN, although with wide confidence intervals that included the null for comorbidities. Erosions were associated with being in the high HAQ trajectory in the low inflammation pair in ERAN and ESPOIR, but not in the high inflammation pair, although the estimates were imprecise.

## Outcomes over time

The high HAQ trajectories had greater tender joint counts, pain, fatigue, depressive symptoms and anxiety than the low HAQ trajectories over follow-up in both inflammation pairs (Table 3). The high HAQ trajectories also had more comorbidities over time compared with the low HAQ trajectories across the cohorts, but with wide confidence intervals containing the null (Table 3).

Across all trajectory groups, more severe scores on PROMs (pain, fatigue, anxiety and depressive symptoms) were all associated with increasing HAQ scores measured at the same assessment (Table 4; Supplementary

Table S6, available at Rheumatology online, for unimputed analysis), independent of age, gender, baseline comorbidity and BMI, and HAQ at the previous assessments (see Supplementary Figure S5, available at Rheumatology online, for directed acyclic graph underpinning this analysis). After standardizing the PROMs to improve comparability, pain had the strongest association with HAQ (Supplementary Table S7, available at Rheumatology online). However, the relationship between PROMs and HAQ was different between the high and low HAQ trajectories (Fig. 2). Particularly in the high inflammation pairs, the association between the PROMs and HAQ score was stronger [i.e. the slope was steeper (interaction terms in Table 4)] in the low HAQ trajectory compared with the high HAQ trajectory (Fig. 2).

## Discussion

This large-scale analysis of 2500 people with RA with follow-up of 8–10 years illustrates the disparity between inflammation and disability for many people with this disease. This analysis identified two pairs of trajectories within each cohort, one classified as 'high inflammation' (groups 4 and 5) and the other classified as 'low inflammation' (groups 2 and 3). Each trajectory pair was characterized by a high and a low disability trajectory, despite similar inflammation scores. Therefore, 30–45% of people with RA were in groups characterized by potentially excess disability (i.e. groups 3 and 5: NOAR: 31.4%, ESPOIR: 28.2%, ERAN: 44.5%), over and above what would be expected from their level of inflammation. This excess disability is maintained up to a decade following onset. People in the higher disability trajectories were older, were more likely to be women and had worse pain, fatigue and mental health compared with the lower disability trajectories. In the high HAQ trajectories, the relationship between PROMs and disability was weaker compared with the low HAQ trajectories, particularly in the high inflammation pairs.

Our findings extend results from previous studies. A trajectory analysis of 9493 people with RA reported that 65% of those with controlled inflammation still reported persistent pain over 3 years [18]. A cohort of 232 people with early RA reported that 34% of participants had unacceptable pain at 5 years, and this was associated with lower inflammation at baseline [44]. Van der Elst et al. demonstrated that one in five people with rapidly and persistently controlled early RA still reported high fatigue and/or pain after 1 year of follow-up [45]. A cross-sectional analysis of 169 people with RA reported a subgroup of 57 people (33.7%) who had high pain, fatigue and depressive symptoms despite low inflammation scores [46]. In summary, for many people with RA, controlling inflammation is not sufficient to alleviate symptom burden. Our analysis illustrates these findings are consistent across several cohorts, and persist for up to a decade, with no group showing improvements in disability commencing later in follow-up, indicating once more the importance of early intervention in RA.
<table><caption>TABLE 1 Baseline characteristics of the trajectory groups</caption><thead><tr><th rowspan="3"></th><th colspan="4">NOAR</th><th colspan="4">ESPOIR</th><th colspan="4">ERAN</th></tr><tr><th colspan="2">Low inflammation</th><th colspan="2">High inflammation</th><th colspan="2">Low inflammation</th><th colspan="2">High inflammation</th><th colspan="2">Low inflammation</th><th colspan="2">High inflammation</th></tr><tr><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th></tr></thead><tbody><tr><td>N (%)</td><td>295 (29.5%)</td><td>199 (19.9%)</td><td>104 (10.4%)</td><td>115 (11.5%)</td><td>228 (29.8%)</td><td>127 (16.6%)</td><td>136 (17.8%)</td><td>89 (11.6%)</td><td>87 (11.9%)</td><td>208 (28.3%)</td><td>211 (28.7%)</td><td>119 (16.2%)</td></tr><tr><td>Age, years</td><td>55.0 (14.5)</td><td>62.8 (13.8)*</td><td>56.6 (12.7)</td><td>59.3 (15.2)</td><td>46.6 (13.1)</td><td>49.5 (9.9)*</td><td>48.7 (12.8)</td><td>52.0 (11.4)*</td><td>54.1 (13.5)</td><td>56.6 (14.5)</td><td>57.5 (12.6)</td><td>59.6 (13.5)</td></tr><tr><td>Women, N (%)</td><td>192 (65.1%)</td><td>138 (69.3%)</td><td>79 (76.0%)</td><td>86 (74.8%)</td><td>173 (75.9%)</td><td>109 (85.8%)</td><td>99 (72.8%)</td><td>79 (88.8%)</td><td>45 (51.7%)</td><td>155 (74.5%)</td><td>151 (71.6%)</td><td>102 (85.7%)</td></tr><tr><td>Symptom duration, months</td><td>7.8 (5.0)</td><td>7.8 (5.4)</td><td>8.7 (5.5)</td><td>8.7 (5.8)</td><td>3.4 (1.5)</td><td>3.7 (2.1)</td><td>3.3 (1.7)</td><td>3.7 (1.8)</td><td>10.0 (4.5)</td><td>10.0 (5.1)</td><td>10.2 (5.2)</td><td>10.1 (5.7)</td></tr><tr><td>BMI</td><td>26.9 (5.0)</td><td>27.7 (5.7)</td><td>28.0 (5.7)</td><td>29.3 (6.2)</td><td>24.9 (4.5)</td><td>25.7 (5.3)</td><td>25.7 (4.6)</td><td>26.5 (4.7)</td><td>26.6 (5.1)</td><td>27.3 (5.6)</td><td>28.6 (5.2)</td><td>29.2 (6.9)</td></tr><tr><td>BMI categories<sup>a</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Underweight</td><td>2 (0.7%)</td><td>6 (3.0%)</td><td>1 (1.0%)</td><td>3 (2.6%)</td><td>8 (3.5%)</td><td>3 (2.4%)</td><td>2 (1.5%)</td><td>3 (3.4%)</td><td>1 (1.1%)</td><td>4 (1.9%)</td><td>0 (0%)</td><td>3 (2.5%)</td></tr><tr><td>Normal weight</td><td>114 (38.6%)</td><td>60 (30.2%)</td><td>33 (31.7%)</td><td>26 (22.6%)</td><td>133 (58.3%)</td><td>63 (49.6%)</td><td>66 (48.5%)</td><td>37 (41.6%)</td><td>31 (35.6%)</td><td>69 (33.2%)</td><td>43 (20.4%)</td><td>25 (21.0%)</td></tr><tr><td>Overweight</td><td>107 (36.3%)</td><td>70 (35.2%)</td><td>36 (34.6%)</td><td>36 (31.3%)</td><td>56 (24.6%)</td><td>34 (26.8%)</td><td>45 (33.1%)</td><td>28 (31.5%)</td><td>30 (34.5%)</td><td>69 (33.2%)</td><td>83 (39.3%)</td><td>42 (35.3%)</td></tr><tr><td>Obese</td><td>70 (23.7%)</td><td>61 (30.7%)</td><td>32 (30.8%)</td><td>46 (40.0%)</td><td>31 (13.6%)</td><td>25 (19.7%)</td><td>23 (16.9%)</td><td>21 (23.6%)</td><td>15 (17.2%)</td><td>51 (24.5%)</td><td>62 (29.4%)</td><td>43 (36.1%)</td></tr><tr><td>Missing</td><td>2 (0.7%)</td><td>2 (1.0%)</td><td>2 (1.9%)</td><td>4 (3.5%)</td><td>0 (0%)</td><td>2 (1.6%)</td><td>0 (0%)</td><td>0 (0%)</td><td>10 (11.5%)</td><td>15 (7.2%)</td><td>23 (10.9%)</td><td>6 (5.0%)</td></tr><tr><td>Smoking, N (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Smoker</td><td>68 (23.1%)</td><td>41 (20.6%)</td><td>23 (22.1%)</td><td>31 (27.0%)</td><td>110 (48.2%)</td><td>62 (48.8%)</td><td>65 (47.8%)</td><td>42 (47.2%)</td><td>28 (32.2%)</td><td>62 (29.8%)</td><td>73 (34.6%)</td><td>43 (36.1%)</td></tr><tr><td>Non-smoker</td><td>189 (64.1%)</td><td>137 (68.8%)</td><td>70 (67.3%)</td><td>77 (67.0%)</td><td>118 (51.8%)</td><td>65 (51.2%)</td><td>71 (52.2%)</td><td>47 (52.8%)</td><td>59 (67.8%)</td><td>143 (68.8%)</td><td>136 (64.5%)</td><td>76 (63.9%)</td></tr><tr><td>Missing</td><td>38 (12.9%)</td><td>21 (10.6%)</td><td>11 (10.6%)</td><td>7 (6.1%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>3 (1.4%)</td><td>2 (1.0%)</td><td>0 (0%)</td></tr><tr><td>DAS28-CRP (ERAN: ESR)</td><td>3.6 (1.1)</td><td>3.8 (1.2)</td><td>4.5 (1.1)</td><td>4.9 (1.3)</td><td>4.1 (1.1)</td><td>4.5 (1.0)</td><td>5.1 (1.1)</td><td>5.1 (1.1)</td><td>4.4 (1.1)</td><td>4.6 (1.2)</td><td>4.9 (1.4)</td><td>5.5 (1.2)</td></tr><tr><td>DAS28-2C (ERAN: ESR)</td><td>2.8 (1.4)</td><td>3.0 (1.5)</td><td>4.4 (1.3)</td><td>4.1 (1.6)</td><td>3.6 (1.2)</td><td>3.8 (1.1)</td><td>4.7 (1.3)</td><td>4.5 (1.4)</td><td>3.1 (1.2)</td><td>3.3 (1.2)</td><td>3.4 (1.4)</td><td>3.6 (1.3)</td></tr><tr><td>HAQ</td><td>0.8 (0.6)</td><td>1.5 (0.5)</td><td>1.0 (0.5)</td><td>2.1 (0.5)</td><td>0.8 (0.6)</td><td>1.2 (0.6)</td><td>1.1 (0.6)</td><td>1.7 (0.6)</td><td>1.0 (0.5)</td><td>0.9 (0.6)</td><td>1.3 (0.5)</td><td>2.1 (0.4)</td></tr><tr><td>Pain VAS (ERAN: SF36-P)</td><td>36.4 (24.8)</td><td>46.8 (25.6)**</td><td>41.2 (23.8)</td><td>69.2 (22.2)**</td><td>33.5 (25.7)</td><td>45.0 (28.5)**</td><td>41.1 (28.0)</td><td>50.2 (26.1)*</td><td>47.8 (23.0)</td><td>47.0 (22.4)</td><td>40.9 (21.7)</td><td>24.3 (18.9)**</td></tr><tr><td>Fatigue VAS (ERAN: SF36-V)</td><td>42.2 (27.3)</td><td>53.0 (25.7)**</td><td>47.8 (28.6)</td><td>71.1 (21.9)**</td><td>42.9 (26.6)</td><td>53.5 (28.6)**</td><td>51.2 (26.0)</td><td>66.2 (23.3)**</td><td>46.6 (22.8)</td><td>45.0 (18.9)</td><td>36.9 (18.7)</td><td>27.4 (19.0)**</td></tr><tr><td>AIMS Depressive symptoms<sup>b</sup> (ERAN: SF36-MH)</td><td>2.89 (1.91)</td><td>3.54 (1.97)</td><td>3.01 (1.72)</td><td>4.85 (2.16)**</td><td>3.07 (1.92)</td><td>3.96 (2.01)**</td><td>4.03 (1.94)</td><td>5.21 (2.35)**</td><td>69.6 (19.6)</td><td>69.0 (18.0)</td><td>63.0 (18.0)</td><td>54.1 (20.7)**</td></tr><tr><td>AIMS Anxiety</td><td>4.00 (2.03)</td><td>4.48 (2.02)</td><td>4.23 (1.68)</td><td>5.57 (2.17)**</td><td>4.47 (2.32)</td><td>5.32 (2.14)**</td><td>5.07 (2.32)</td><td>6.11 (2.30)*</td><td></td><td></td><td></td><td></td></tr><tr><td>RF, N (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Positive</td><td>121 (41.0%)</td><td>86 (43.2%)</td><td>47 (45.2%)</td><td>39 (33.9%)</td><td>100 (43.9%)</td><td>56 (44.1%)</td><td>74 (54.4%)</td><td>40 (44.9%)</td><td>41 (47.1%)</td><td>107 (51.4%)</td><td>110 (52.1%)</td><td>77 (64.7%)</td></tr><tr><td>Negative</td><td>164 (55.6%)</td><td>108 (54.3%)</td><td>53 (51.0%)</td><td>68 (59.1%)</td><td>128 (56.1%)</td><td>71 (55.9%)</td><td>62 (45.6%)</td><td>49 (55.1%)</td><td>34 (39.1%)</td><td>66 (31.7%)</td><td>86 (40.8%)</td><td>27 (22.7%)</td></tr><tr><td>Missing</td><td>10 (3.4%)</td><td>5 (2.5%)</td><td>4 (3.9%)</td><td>8 (7.0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>12 (13.8%)</td><td>35 (16.8%)</td><td>15 (7.1%)</td><td>15 (12.6%)</td></tr><tr><td>Anti-CCP, N (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Positive</td><td>90 (30.5%)</td><td>73 (36.7%)</td><td>44 (42.3%)</td><td>35 (30.4%)</td><td>84 (36.8%)</td><td>42 (33.1%)</td><td>73 (53.7%)</td><td>36 (40.4%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Negative</td><td>187 (63.4%)</td><td>111 (55.8%)</td><td>47 (45.2%)</td><td>66 (57.4%)</td><td>144 (63.2%)</td><td>85 (66.9%)</td><td>63 (46.3%)</td><td>53 (59.6%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Missing</td><td>18 (6.1%)</td><td>15 (7.5%)</td><td>13 (12.5%)</td><td>14 (12.2%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td></td><td></td><td></td><td></td></tr></tbody><tfoot><tr><td colspan="14" style="text-align: right;">(continued)</td></tr></tfoot></table>
<table><caption>TABLE 1 Continued</caption><thead><tr><th rowspan="3"></th><th colspan="4">NOAR</th><th colspan="4">ESPOIR</th><th colspan="4">ERAN</th></tr><tr><th colspan="2">Low inflammation</th><th colspan="2">High inflammation</th><th colspan="2">Low inflammation</th><th colspan="2">High inflammation</th><th colspan="2">Low inflammation</th><th colspan="2">High inflammation</th></tr><tr><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th><th>Low HAQ</th><th>High HAQ</th></tr></thead><tbody><tr><td>csDMARD, N (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>155 (52.5%)</td><td>107 (53.8%)</td><td>57 (54.8%)</td><td>61 (53.0%)</td><td>13 (5.7%)</td><td>5 (3.9%)</td><td>11 (8.1%)</td><td>3 (3.4%)</td><td>57 (65.5%)</td><td>124 (59.6%)</td><td>131 (62.1%)</td><td>76 (63.9%)</td></tr><tr><td>No</td><td>140 (47.5%)</td><td>92 (46.2%)</td><td>47 (45.2%)</td><td>54 (47.0%)</td><td>215 (94.3%)</td><td>122 (96.1%)</td><td>125 (91.9%)</td><td>86 (96.6%)</td><td>30 (34.5%)</td><td>84 (40.4%)</td><td>80 (37.9%)</td><td>43 (36.1%)</td></tr><tr><td>Comorbidities (ERAN: RDCI)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>80 (27.1%)</td><td>34 (17.1%)</td><td>23 (22.1%)</td><td>14 (12.2%)*</td><td>130 (57.0%)</td><td>70 (55.1%)</td><td>79 (58.1%)</td><td>39 (43.8%)</td><td>0.41 (0.72)</td><td>0.64 (0.92)*</td><td>0.79 (1.1)</td><td>0.93 (1.0)</td></tr><tr><td>1</td><td>77 (26.1%)</td><td>46 (23.1%)</td><td>21 (20.2%)</td><td>18 (15.7%)</td><td>61 (26.8%)</td><td>36 (28.3%)</td><td>30 (22.1%)</td><td>24 (27.0%)</td><td></td><td></td><td></td><td></td></tr><tr><td>≥2</td><td>57 (19.3%)</td><td>48 (24.1%)</td><td>14 (13.5%)</td><td>32 (27.8%)</td><td>37 (16.2%)</td><td>21 (16.5%)</td><td>27 (19.9%)</td><td>26 (29.2%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Missing</td><td>81 (27.5%)</td><td>71 (35.7%)</td><td>46 (44.2%)</td><td>51 (44.3%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Erosions</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>–</td><td>–</td><td>–</td><td>–</td><td>20 (8.8%)</td><td>20 (15.7%)</td><td>25 (18.4%)</td><td>17 (19.1%)</td><td>19 (21.8%)</td><td>60 (28.8%)</td><td>52 (24.6%)</td><td>30 (25.2%)</td></tr><tr><td>No</td><td>–</td><td>–</td><td>–</td><td>–</td><td>208 (91.2%)</td><td>107 (84.3%)</td><td>111 (81.6%)</td><td>72 (80.9%)</td><td>66 (75.9%)</td><td>139 (66.8%)</td><td>149 (70.6%)</td><td>84 (70.6%)</td></tr><tr><td>Missing</td><td>–</td><td>–</td><td>–</td><td>–</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>2 (2.3%)</td><td>9 (4.3%)</td><td>10 (4.7%)</td><td>5 (4.2%)</td></tr></tbody></table>

See Supplementary Table S7, available at Rheumatology online, for proportions of missing data for each variable. <sup>a</sup>BMI categories: Underweight (BMI <18.5), Normal weight (BMI ≥18.5 and <25), Overweight (BMI ≥25 and <30), Obese (BMI ≥30). <sup>b</sup>Depression and anxiety measured with the Arthritis Impact Measurement Scales for NOAR and ESPOIR, SF36 mental health for ERAN. <sup>*</sup>P < 0.05, <sup>**</sup>P < 0.001 – comparing high HAQ vs low HAQ groups within each inflammation pair; t-tests used to compare continuous variables, chi² for categorical variables; AIMS: Arthritis Impact Measurement Scales; Anti-CCP: anti-CCP antibodies; csDMARD: conventional synthetic DMARD; DAS28-2C: Disease Activity Score 28-2 components; ESPOIR: Étude et Suivi des Polyarthrites Indifférenciées Récentes; ERAN: Early RA Network; N: Number; NOAR: Norfolk Arthritis Register; SF36: Short-Form 36 (SF36-MH: SF36-mental health; SF36-P: pain scale; SF36-V: vitality scale); VAS: visual analogue scale.
<table><caption>TABLE 2 Baseline predictors of high HAQ group membership compared with corresponding low HAQ group in each inflammation pair</caption><thead><tr><th rowspan="2">Variable</th><th colspan="4">Low inflammation</th><th colspan="3">High inflammation</th></tr><tr><th>NOAR, OR<br>(95% CI)</th><th>ESPOIR, OR<br>(95% CI)</th><th>ERAN, OR<br>(95% CI)</th><th>NOAR, OR<br>(95% CI)</th><th>ESPOIR, OR<br>(95% CI)</th><th>ERAN, OR<br>(95% CI)</th></tr></thead><tbody><tr><td>Age, years</td><td>1.07 (1.05, 1.09)</td><td>1.03 (1.01, 1.06)</td><td>1.02 (0.99, 1.04)</td><td>1.05 (1.02, 1.09)</td><td>1.03 (1.00, 1.06)</td><td>1.03 (1.01, 1.06)</td></tr><tr><td>Female vs male</td><td>1.59 (1.00, 2.52)</td><td>2.34 (1.19, 4.60)</td><td>4.15 (2.25, 7.68)</td><td>0.62 (0.25, 1.58)</td><td>3.48 (1.42, 8.57)</td><td>3.61 (1.80, 7.25)</td></tr><tr><td>Symptom duration, months</td><td>1.01 (0.97, 1.05)</td><td>1.09 (0.94, 1.26)</td><td>0.99 (0.93, 1.05)</td><td>0.97 (0.90, 1.04)</td><td>1.24 (1.03, 1.49)</td><td>1.01 (0.96, 1.06)</td></tr><tr><td>Current smoker vs non-smoker</td><td>1.14 (0.63, 2.06)</td><td>1.25 (0.76, 2.06)</td><td>1.01 (0.56, 1.83)</td><td>1.86 (0.65, 5.28)</td><td>1.40 (0.72, 2.72)</td><td>1.20 (0.67, 2.16)</td></tr><tr><td>BMI</td><td>1.03 (0.99, 1.07)</td><td>1.02 (0.97, 1.08)</td><td>1.02 (0.96, 1.09)</td><td>1.06 (0.99, 1.13)</td><td>1.05 (0.98, 1.13)</td><td>1.02 (0.98, 1.07)</td></tr><tr><td>Pain (VAS<sup>a</sup>, NOAR/ESPOIR; SF36<sup>b</sup>: ERAN)</td><td>1.20 (1.09, 1.31)</td><td>1.12 (1.02, 1.23)</td><td>0.88 (0.62, 1.26)</td><td>1.48 (1.23, 1.78)</td><td>1.06 (0.93, 1.20)</td><td>0.34 (0.22, 0.53)</td></tr><tr><td>Fatigue (VAS<sup>a</sup>, NOAR/ESPOIR; SF36<sup>b</sup>: ERAN)</td><td>1.15 (1.02, 1.28)</td><td>1.06 (0.96, 1.17)</td><td>0.90 (0.58, 1.38)</td><td>1.22 (0.96, 1.54)</td><td>1.22 (1.06, 1.41)</td><td>0.79 (0.54, 1.14)</td></tr><tr><td>Depressive symptoms (AIMS2: NOAR/ESPOIR; SF36<sup>b</sup>: ERAN)</td><td>1.11 (0.91, 1.34)</td><td>1.24 (1.07, 1.44)</td><td>1.15 (0.74, 1.80)</td><td>1.40 (1.01, 1.94)</td><td>1.14 (0.95, 1.37)</td><td>0.87 (0.62, 1.23)</td></tr><tr><td>Anxiety (AIMS2: NOAR/ESPOIR)</td><td>1.04 (0.86, 1.26)</td><td>1.01 (0.88, 1.15)</td><td>-</td><td>0.99 (0.67, 1.47)</td><td>1.08 (0.92, 1.27)</td><td>-</td></tr><tr><td>RF</td><td>0.85 (0.52, 1.41)</td><td>1.22 (0.65, 2.30)</td><td>1.53 (0.85, 2.75)</td><td>0.55 (0.21, 1.44)</td><td>0.96 (0.40, 2.31)</td><td>2.01 (1.07, 3.78)</td></tr><tr><td>Anti-CCP</td><td>1.79 (1.03, 3.11)</td><td>0.84 (0.43, 1.64)</td><td>-</td><td>1.21 (0.46, 3.21)</td><td>0.86 (0.35, 2.11)</td><td>-</td></tr><tr><td>Taking csDMARDs</td><td>0.85 (0.56, 1.31)</td><td>0.66 (0.20, 2.15)</td><td>0.77 (0.43, 1.36)</td><td>0.71 (0.30, 1.69)</td><td>0.60 (0.13, 2.77)</td><td>0.98 (0.55, 1.74)</td></tr><tr><td>Comorbidities (RDCI: ERAN)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 vs 0 comorbidities</td><td>1.18 (0.62, 2.26)</td><td>0.96 (0.54, 1.69)</td><td>1.42 (0.97, 2.08)</td><td>0.93 (0.31, 2.76)</td><td>1.22 (0.54, 2.75)</td><td>1.12 (0.86, 1.46)</td></tr><tr><td>2 vs 0 comorbidities</td><td>1.31 (0.73, 2.35)</td><td>0.93 (0.45, 1.91)</td><td>-</td><td>1.66 (0.53, 5.22)</td><td>1.18 (0.51, 2.74)</td><td>-</td></tr><tr><td>Erosions vs no erosions</td><td>-</td><td>1.75 (0.83, 3.68)</td><td>1.68 (0.88, 3.22)</td><td>-</td><td>1.00 (0.44, 2.29)</td><td>1.00 (0.52, 1.92)</td></tr></tbody></table>

<footnote><sup>a</sup>VAS measured in centimetres. <sup>b</sup>SF36—higher scores indicate better status. SF36 scores were standardized, therefore odds ratio represents a standard deviation increase in SF36. AIMS2: Arthritis Impact Measurement Scales 2; Anti-CCP: Anti-CCP antibody; csDAMRD: conventional synthetic DMARD; ERAN = Early RA Network; ESPOIR = Étude et Suivi des Polyarthrites Indifférenciées Récentes; NOAR = Norfolk Arthritis Register; OR = odds ratio; RDCI = Rheumatic Disease Comorbidity Index; SF36 = Short form 36; VAS = visual analogue scale.</footnote>
<table><caption>TABLE 3 Comparison of the outcomes over 10 years between the high and low HAQ trajectories, stratified by inflammation pair and cohort, mean difference (95% CI)ª</caption><thead><tr><th rowspan="2"></th><th colspan="2">NOAR</th><th colspan="2">ESPOIR</th><th colspan="2">ERAN</th></tr><tr><th>Low-inflammation: high HAQ vs low HAQ</th><th>High-inflammation: high HAQ vs low HAQ</th><th>Low-inflammation: high HAQ vs low HAQ</th><th>High-inflammation: high HAQ vs low HAQ</th><th>Low-inflammation: high HAQ vs low HAQ</th><th>High-inflammation: high HAQ vs low HAQ</th></tr></thead><tbody><tr><td colspan="7"><strong>Trajectory components</strong></td></tr><tr><td>DAS28-2C (NOAR/ESPOIR: CRP, ERAN: ESR)</td><td>0.17 (0.03, 0.30)</td><td>-0.13 (-0.35, 0.10)</td><td>0.04 (-0.07, 0.15)</td><td>-0.17 (-0.36, 0.02)</td><td>0.40 (0.22, 0.58)</td><td>0.11 (-0.10, 0.32)</td></tr><tr><td>HAQ</td><td>0.86 (0.81, 0.91)</td><td>1.22 (1.13, 1.30)</td><td>0.63 (0.59, 0.66)</td><td>0.94 (0.87, 1.01)</td><td>0.39 (0.33, 0.44)</td><td>0.72 (0.66, 0.77)</td></tr><tr><td colspan="7"><strong>Additional PROMs</strong></td></tr><tr><td>Pain VAS/SF36-pain<sup>b</sup> (ERAN)</td><td>18.0 (15.1, 21.0)</td><td>27.0 (23.1, 31.0)</td><td>11.0 (8.3, 13.8)</td><td>21.3 (17.0, 25.5)</td><td>-13.7 (-17.2, -10.2)</td><td>-15.8 (-19.0, -12.5)</td></tr><tr><td>Fatigue VAS/SF36-vitality<sup>b</sup> (ERAN)</td><td>19.5 (15.9, 23.0)</td><td>23.4 (18.1, 28.6)</td><td>14.1 (10.6, 17.7)</td><td>22.1 (17.3, 26.9)</td><td>-10.3 (-14.4, -6.2)</td><td>-10.6 (-14.0, -7.3)</td></tr><tr><td>AIMS Depressive symptoms/SF36-mental health<sup>b</sup> (ERAN)</td><td>1.0 (0.7, 1.3)</td><td>1.9 (1.5, 2.4)</td><td>1.2 (0.9, 1.5)</td><td>1.8 (1.3, 2.2)</td><td>-7.0 (-10.6, -3.4)</td><td>-11.8 (-15.3, -8.2)</td></tr><tr><td>AIMS Anxiety</td><td>0.8 (0.5, 1.1)</td><td>1.7 (1.2, 2.1)</td><td>1.2 (0.8, 1.6)</td><td>1.7 (1.2, 2.1)</td><td>-</td><td>-</td></tr><tr><td colspan="7"><strong>DAS28 and components</strong></td></tr><tr><td>DAS28-CRP/DAS28-ESR (ERAN)</td><td>0.50 (0.37, 0.64)</td><td>0.69 (0.48, 0.91)</td><td>0.29 (0.18, 0.40)</td><td>0.44 (0.25, 0.63)</td><td>0.48 (0.28, 0.69)</td><td>0.39 (0.17, 0.61)</td></tr><tr><td>Swollen joint count (28)</td><td>0.35 (0.05, 0.66)</td><td>0.72 (-0.25, 1.70)</td><td>0.06 (-0.16, 0.29)</td><td>-0.57 (-1.12, -0.01)</td><td>1.13 (0.56, 1.69)</td><td>0.41 (-0.37, 1.18)</td></tr><tr><td>Tender joint count (28)</td><td>2.86 (2.06, 3.67)</td><td>7.22 (5.56, 8.88)</td><td>1.61 (1.03, 2.19)</td><td>3.41 (2.15, 4.67)</td><td>1.61 (0.81, 2.41)</td><td>3.14 (1.92, 4.37)</td></tr><tr><td>CRP/ESR (ERAN)</td><td>1.52 (-0.09, 3.12)</td><td>-4.10 (-10.11, 1.92)</td><td>0.47 (-0.68, 1.61)</td><td>2.94 (0.09, 5.78)</td><td>2.14 (-1.11, 5.40)</td><td>0.57 (-3.06, 4.19)</td></tr><tr><td>Comorbidities</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Presence of comorbidities<sup>c</sup> (ERAN: RDCI)</td><td>OR 1.17 (0.80, 1.71)</td><td>OR 1.61 (0.93, 2.80)</td><td>OR 1.41 (0.82, 2.42)</td><td>OR 1.91 (0.87, 4.21)</td><td>0.28 (0.07, 0.49)<sup>d</sup></td><td>0.07 (-0.17, 0.31)<sup>d</sup></td></tr></tbody></table>

<footnote>ªAdjusted for age and gender. ᵇSF36 = higher scores indicate lower pain/fatigue/better mental health. ᶜNOAR and ESPOIR were analysed using generalized estimating equations analysis (GEE). ᵈMean difference rather than OR for comorbidities data in ERAN, as the RDCI, which is a continuous measure, was used. DAS28-2C: 2-component DAS28; ESPOIR: Étude et Suivi des Polyarthrites Indifférenciées Régentes; ERAN: Early RA Network; NOAR: Norfolk Arthritis Register; OR: odds ratio; PROMs: Patient-Reported Outcome Measures; RDCI: Rheumatic Disease Comorbidity Index; VAS: Visual Analogue Scale.</footnote>
<table><caption>TABLE 4 Interactions between high/low HAQ trajectory group and patient-reported outcomes predicting HAQ score, stratified by inflammation pair and cohort</caption><thead><tr><th rowspan="2"></th><th colspan="3">Pain</th><th colspan="3">Fatigue</th><th colspan="3">Anxiety</th><th colspan="3">Depressive symptoms</th></tr><tr><th>VAS Pain* coef.</th><th>High/low HAQ coef.</th><th>Interaction</th><th>VAS Fatigue* coef.</th><th>High/low HAQ coef.</th><th>Interaction</th><th>Anxiety coef.</th><th>High/low HAQ coef.</th><th>Interaction</th><th>Depressive symptoms coef.</th><th>High/low HAQ coef.</th><th>Interaction</th></tr></thead><tbody><tr><td>NOAR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Low inflammation pair</td><td>0.09 (0.08, 0.11)</td><td>0.62 (0.51, 0.72)</td><td>-0.02 (-0.04, -0.01)</td><td>0.05 (0.04, 0.06)</td><td>0.55 (0.44, 0.66)</td><td>0.00 (-0.02, 0.01)</td><td>0.05 (0.03, 0.07)</td><td>0.58 (0.48, 0.68)</td><td>0.00 (-0.02, 0.02)</td><td>0.06 (0.04, 0.07)</td><td>0.57 (0.48, 0.66)</td><td>0.002 (-0.02, 0.02)</td></tr><tr><td>High inflammation pair</td><td>0.08 (0.06, 0.10)</td><td>0.84 (0.68, 0.99)</td><td>-0.03 (-0.05, -0.002)</td><td>0.06 (0.04, 0.08)</td><td>0.89 (0.71, 1.07)</td><td>-0.02 (-0.05, 0.003)</td><td>0.05 (0.01, 0.08)</td><td>0.85 (0.69, 1.02)</td><td>-0.02 (-0.05, 0.01)</td><td>0.05 (0.01, 0.09)</td><td>0.88 (0.70, 1.07)</td><td>-0.03 (-0.06, 0.01)</td></tr><tr><td>ESPOIR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Low inflammation pair</td><td>0.06 (0.05, 0.07)</td><td>0.39 (0.34, 0.44)</td><td>-0.0004 (-0.01, 0.01)</td><td>0.03 (0.03, 0.04)</td><td>0.35 (0.30, 0.41)</td><td>0.01 (0.001, 0.02)</td><td>0.03 (0.03, 0.04)</td><td>0.32 (0.26, 0.38)</td><td>0.02 (0.01, 0.03)</td><td>0.07 (0.06, 0.08)</td><td>0.31 (0.25, 0.37)</td><td>0.02 (0.01, 0.04)</td></tr><tr><td>High inflammation pair</td><td>0.09 (0.08, 0.10)</td><td>0.69 (0.60, 0.78)</td><td>-0.04 (-0.06, -0.03)</td><td>0.07 (0.06, 0.08)</td><td>0.66 (0.56, 0.77)</td><td>-0.02 (-0.03, -0.01)</td><td>0.07 (0.06, 0.08)</td><td>0.69 (0.58, 0.80)</td><td>-0.02 (-0.04, -0.003)</td><td>0.11 (0.09, 0.12)</td><td>0.69 (0.59, 0.79)</td><td>-0.03 (-0.05, -0.01)</td></tr><tr><td>ERAN</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Low inflammation pair</td><td>-0.01 (-0.01, -0.01)</td><td>0.12 (-0.04, 0.27)</td><td>0.00 (-0.001, 0.003)</td><td>-0.008 (-0.01, -0.005)</td><td>SF36 - Vitality</td><td>0.0003 (-0.002, 0.003)</td><td>-0.01 (-0.01, -0.004)</td><td>SF36 - Mental health</td><td>0.001 (-0.002, 0.004)</td><td>-0.001 (-0.004, 0.001)</td><td>-0.002 (-0.004, 0.001)</td></tr><tr><td>High inflammation pair</td><td>-0.01 (-0.01, -0.01)</td><td>0.41 (0.32, 0.51)</td><td>0.001 (-0.001, 0.003)</td><td>-0.0002 (-0.002, 0.003)</td><td>SF36 - Pain</td><td>0.23 (0.07, 0.38)</td><td>-0.01 (-0.004, 0.002)</td><td>SF36 - Mental health</td><td>0.001 (-0.002, 0.004)</td><td>-0.001 (-0.004, 0.001)</td><td>-0.002 (-0.004, 0.001)</td></tr></tbody></table>

Analyses controlling for age, gender, baseline comorbidity and BMI, and lagged HAQ, missing data imputed using multiple imputation. *VAS in cm. AIMS: Arthritis Impact Measurement Scales; ERAN: Early RA network; ESPOIR: Étude et Suivi des Polyarthrites Indifférenciées Récentes; NOAR: Norfolk Arthritis Register; SF36: short form (36); VAS: visual analogue scale.
<figure><img src="image_3.png" /><figcaption>Fig. 2 Interactions between high and low HAQ group status and patient-reported outcomes predicting HAQ score</figcaption></figure>

Stratified by inflammation status and cohort (unimputed results). The figure indicates that, for many PROMS, the association between PROM score and HAQ score was stronger in the lower-HAQ trajectory within each inflammation pair (i.e. the slope was steeper in the low-HAQ trajectory compared with the high-HAQ trajectory). The x-axis of the ERAN analyses reversed, as higher scores on the SF36 indicated better outcomes. AIMS: Arthritis Impact Measurement Scales, ERAN: Early RA network, ESPOIR: Étude et Suivi des Polyarthrites Indifférenciées Récentes, NOAR: Norfolk Arthritis Register, SF36: short form (36), VAS: visual analogue scale.
As PROMs (e.g. pain, fatigue, mental health) are the most consistent predictors of long-term function [47], we investigated the relationship between these PROMs and disability, both when measured at baseline and longitudinally. Baseline and time-varying pain, fatigue and mental health were all associated with high HAQ trajectory membership. In 2006, Aletaha et al. described reversible and irreversible components of disability in RA [48], whereby the reversible component of disability is driven by current inflammation and the irreversible component driven by joint damage and co-existing conditions. This analysis demonstrates the potential impact of comorbidities and erosion, showing that baseline erosions predicted high HAQ trajectory membership in ESPOIR and ERAN and that the high HAQ trajectories had more comorbid conditions compared with the low HAQ trajectories [49, 50]. Erosions at baseline could be as a result of treatment delays, further emphasizing the importance of early treatment in RA. Furthermore, the current analysis suggests that a third component of RA disability may comprise pain, fatigue and mental health, given the large differences in disability between pairs of trajectory groups with similar inflammation yet large differences in these PROMs. Whereas pain, fatigue and poor mental health may not be as irreversible as joint erosion, they are challenging to ameliorate in people with RA and may require both pharmacological and non-pharmacological interventions not targeting inflammation [51–53].

Despite the higher PROM scores in the high HAQ trajectories compared with the lower HAQ trajectories, a surprising result was the interaction between trajectory membership and PROMs when predicting disability. This analysis reported a weaker association between PROMs and disability in the high HAQ trajectories compared with the low HAQ trajectories. This observation could be due to the ceiling effect of the HAQ score [54], particularly as this was primarily seen in the high inflammation pair with HAQ scores nearer the top of the scale.

The strengths of this analysis include the large sample size and long-term follow-up, meaning that the disparity between inflammation and disability in people with RA over 10 years could be precisely characterized for the first time. The cohorts were well phenotyped, meaning a large array of potential factors driving disability could be assessed. However, as these were inception rather than treatment cohorts, early treatment response could not be investigated. While the inclusion criteria were similar between the three cohorts, there were several differences between the demographic and clinical characteristics of the cohorts at baseline, due to when participants were recruited (with ESPOIR's participants recruited earlier in the disease process compared with NOAR and ERAN). The participants of ESPOIR were on average 8–10 years younger than the NOAR and ERAN cohorts. This could in part be explained by the higher rate of smoking in the ESPOIR population and the inclusion criterion of being <70 years old at baseline. While age was controlled for in the regression analyses of this project,

the large difference in age between the cohorts may still be affecting comparisons between studies. There were also a number of differences in terms of the PROMs included in the three studies (i.e. the measures of pain, fatigue, mental health). A further limitation of this study was the use of different blood sample analyses across the cohorts, with ESR used in ERAN and CRP in NOAR and ESPOIR when calculating the DAS28-2C. As yet, the comparability of the DAS28-2C-ESR and DAS28-2C-CRP has not been established. Despite these limitations, the consistent results across the three cohorts suggest generalizability of the findings. While these cohorts had large samples, some effect estimates had wide confidence intervals and overlapped the null, and therefore some caution should be taken when interpreting these estimates. There was a significant proportion of missing data in some of the PROMs in the NOAR cohort, which clustered in the participants recruited earlier in the cohort and could result in bias in the reported associations. Multiple imputation was used to impute missing data, and further sensitivity analysis indicated minimal missing data bias (Supplementary Table S7, available at Rheumatology online). The names of the trajectory groups (i.e. high/low inflammation) are used in relation to one another, rather than based on external definitions of high and low inflammation. However, as these cohorts are representative samples of the population of people with RA, these results indicate that there is excess disability evident in RA across the spectrum of inflammation levels seen in clinical care. The scales to measure mental health across the three cohorts were necessarily brief, given the large amount of data collected at each assessment. However, they do not provide an unambiguous measurement of depressive symptoms or anxiety. Lastly, there was significant attrition over follow-up. This was particularly substantial in ERAN, meaning only 8 years of follow-up could be included.

In conclusion, this analysis illustrates that ~30–45% of people with RA have excess disability (i.e. discordant with inflammation level), and that this excess disability is seen across inflammation levels. This excess disability is persistent, with disparity remaining at least up to 10 years following onset. People with RA in the high disability trajectories had more severe pain, fatigue and depressive symptoms compared with those in low disability trajectories, despite similar inflammation levels. This indicates the urgent need to address pain, fatigue and depressive symptoms, for example by psychological interventions for people with RA, in order to curtail long-term disability.

## Acknowledgements

The authors thank the participants involved in NOAR, ERAN and ESPOIR, as well as the clinical staff at each of the recruiting centres. Thanks also to the data management team at the University of Manchester, University of Nottingham and University of Montpellier. The views expressed are those of the author(s) and not
necessarily those of the NHS, the NIHR or the Department of Health. Review of the manuscript was undertaken by J.M.G., S.N., K.L.H., M.L., B.C., N.R., A.R.-W., B.F., D.F.M., D.A.W., E.N., A.Y., P.K., J.R.C., A.M. and S.M.M.V.; J.M.G., S.N., K.L.H. and S.M.M.V. were responsible for the study concept and design; acquisition of data was undertaken by B.C., N.R., A.R.-W., B.F., D.F.M., D.A.W., E.N., A.Y., P.K., J.R.C., A.M. and S.M.M.V.; analysis and interpretation of data was undertaken by J.M.G., S.N., K.L.H., M.L. and S.M.M.V.

**Funding:** This work was supported by the Medical Research Council (through a Skills Development Fellowship for J.M.G.), Versus Arthritis (grant number 21755) and the NIHR Manchester Biomedical Research Centre and the NIHR Nottingham Biomedical Research Centre. The ESPOIR cohort was supported by an unrestricted grant from Merck Sharp and Dohme (MSD) allocated for the first 5 years. Two additional grants from INSERM were obtained to support part of the biological database. The French Society of Rheumatology, Abbvie, Pfizer, Lilly, and more recently Fresenius and Galapagos also supported the ESPOIR cohort study. The ERAN cohort was supported by unrestricted grants from Wyeth Pharmaceuticals, and the UK Healthcare Commission supported creation of the ERAN database.

**Disclosure statement:** There were no competing interests directly relevant to this manuscript. Other disclosures include: J.M.G.: grants (Bristol-Myers Squibb); S.N.: none; K.L.H.: grants (Bristol-Myers Squibb, Pfizer), honoraria (Abbvie); M.L.: none; B.C.: grants (Novartis, Pfizer, Roche), honoraria (Abbvie, Bristol-Myers Squibb, Gilead-Galapagos, Janssen, Lilly, Merck, Novartis, Pfizer, Roche-Chugai); N.R.: none; A.R.-W.: consulting (Pfizer, Abbvie, Novartis, Lilly, Janssen), honoraria (Abbvie, Bristol-Myers Squibb, Galapagos, Fresenius-Kabi, Mylan-Viatris, MSD, Novartis, Lilly, UCB, Pfizer, Roche-Chugai, Sanofi), support for attending meetings (Abbvie, Amgen, Fresenius-Kabi); B.F.: none; D.F.M.: grants (Pfizer, Eli Lilly); D.A.W.: grants (Pfizer, Eli Lilly), consulting (Pfizer, Abbvie, GSK, Reckitt-Benckiser, Galapagos, Eli Lilly), honoraria (Pfizer, Abbvie); E.N.: grants (Pfizer, Lilly), honoraria (Celltrion, Pfizer, Sanofi, Gilead, Galapagos, Abbvie, Lilly); P.D.W.K.: honoraria (Lilly, Galapagos, Vifor); A.Y.: none; J.R.C.: none; A.M.: none; S.M.M.V.: none.

## Data availability statement

The data underlying this article cannot be shared publicly for the privacy of individuals who participated in the study. The data will be shared on reasonable request to the principal investigators of each of the three datasets (NOAR: A.M., ERAN: D.A.W., ESPOIR: B.C.).

## Supplementary data

Supplementary data are available at *Rheumatology* online.

## References

1. Smolen JS, Aletaha D, Barton A *et al.* Rheumatoid arthritis. Nat Rev Dis Primers 2018;4:18001.

2. Scott DL, Symmons DP, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987;1:1108-11.

3. Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS. Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol 2003;21(5 Suppl 31):S179-S85.

4. Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167-79.

5. Gwinnutt JM, Symmons DPM, Macgregor AJ *et al.* Twenty-year outcome and association between early treatment and mortality and disability in an inception cohort of patients with rheumatoid arthritis: results from the Norfolk Arthritis Register. Arthritis Rheumatol 2017; 69:1566-75.

6. Carpenter L, Nikiphorou E, Kiely PDW *et al.* Secular changes in the progression of clinical markers and patient-reported outcomes in early rheumatoid arthritis. Rheumatology 2020;59:2381-91. kez635.

7. Gwinnutt JM, Symmons DPM, Macgregor AJ *et al.* Have the 10-year outcomes of patients with early inflammatory arthritis improved in the new millennium compared with the decade before? Results from the Norfolk Arthritis Register. Ann Rheum Dis 2018;77:848-54.

8. Kapetanovic MC, Lindqvist E, Nilsson JA *et al.* Development of functional impairment and disability in rheumatoid arthritis patients followed for 20 years: relation to disease activity, joint damage, and comorbidity. Arthritis Care Res (Hoboken) 2015;67: 340-8.

9. Courvoisier N, Dougados M, Cantagrel A *et al.* Prognostic factors of 10-year radiographic outcome in early rheumatoid arthritis: a prospective study. Arthritis Res Ther 2008;10:R106.

10. Carpenter L, Barnett R, Mahendran P *et al.* Secular changes in functional disability, pain, fatigue and mental well-being in early rheumatoid arthritis. A longitudinal meta-analysis. Semin Arthritis Rheum 2019;50:209-19.

11. Boot CRL, de Wind A, van Vilsteren M *et al.* One-year predictors of presenteeism in workers with rheumatoid arthritis: disease-related factors and characteristics of general health and work. J Rheumatol 2018;45:766-70.

12. Gwinnutt JM, Leggett S, Lunt M *et al.*; RAMS and BRAGGSS co-investigators. Predictors of presenteeism, absenteeism and job loss in patients commencing methotrexate or biologic therapy for rheumatoid arthritis. Rheumatology (Oxford) 2020;59:2908-19.

13. Katz PP, Morris A, Yelin EH. Prevalence and predictors of disability in valued life activities among individuals with rheumatoid arthritis. Ann Rheum Dis 2006;65:763-9.

14. Wallman JK, Eriksson JK, Nilsson JA *et al.* Costs in relation to disability, disease activity, and health-related quality of life in rheumatoid arthritis: observational data from Southern Sweden. J Rheumatol 2016;43:1292-9.

15. Ohinmaa AE, Thanh NX, Barnabe C *et al.* Canadian estimates of health care utilization costs for rheumatoid
arthritis patients with and without therapy with biologic agents. Arthritis Care Res (Hoboken) 2014;66:1319-27.

16 Michaud K, Messer J, Choi HK, Wolfe F. Direct medical costs and their predictors in patients with rheumatoid arthritis: a three-year study of 7,527 patients. Arthritis Rheum 2003;48:2750-62.

17 Norton S, Sacker A, Dixey J *et al.* Trajectories of functional limitation in early rheumatoid arthritis and their association with mortality. Rheumatology (Oxford) 2013; 52:2016-24.

18 McWilliams DF, Dawson O, Young A *et al.* Discrete trajectories of resolving and persistent pain in people with rheumatoid arthritis despite undergoing treatment for inflammation: results from three UK cohorts. J Pain 2019;20:716-27.

19 Druce KL, Jones GT, Macfarlane GJ, Verstappen SM, Basu N. The longitudinal course of fatigue in rheumatoid arthritis: results from the Norfolk Arthritis Register. J Rheumatol 2015;42:2059-65.

20 Symmons DP, Barrett EM, Bankhead CR, Scott DG, Silman AJ. The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br J Rheumatol 1994;33:735-9.

21 Garwood W. The Early Rheumatoid Arthritis Network (ERAN). Musculoskeletal Care 2004;2:240-4.

22 Combe B, Benessiano J, Berenbaum F *et al.* The ESPOIR cohort: a ten-year follow-up of early arthritis in France: methodology and baseline characteristics of the 813 included patients. Joint Bone Spine 2007;74: 440-5.

23 England BR, Sayles H, Mikuls TR, Johnson DS, Michaud K. Validation of the rheumatic disease comorbidity index. Arthritis Care Res (Hoboken) 2015;67:865-72.

24 Baker JF, Conaghan PG, Smolen JS *et al.* Development and validation of modified disease activity scores in rheumatoid arthritis: superior correlation with magnetic resonance imaging-detected synovitis and radiographic progression. Arthritis Rheumatol 2014;66:794-802.

25 Hensor EMA, McKeigue P, Ling SF *et al.* Validity of a two-component imaging-derived disease activity score for improved assessment of synovitis in early rheumatoid arthritis. Rheumatology (Oxford) 2019;58:1400-9.

26 Kirwan JR, Reeback JS. Stanford Health Assessment Questionnaire modified to assess disability in British patients with rheumatoid arthritis. Br J Rheumatol 1986; 25:206-9.

27 Guillemin F, Braincon S, Pourel J. [Measurement of the functional capacity in rheumatoid polyarthritis: a French adaptation of the Health Assessment Questionnaire (HAQ)]. Rev Rhum Mal Osteoartic 1991;58:459-65.

28 Jenkinson C, Stewart-Brown S, Petersen S, Paice C. Assessment of the SF-36 version 2 in the United Kingdom. J Epidemiol Community Health 1999;53:46-50.

29 Meenan RF, Mason JH, Anderson JJ, Guccione AA, Kazis LE. AIMS2. The content and properties of a revised and expanded Arthritis Impact Measurement Scales Health Status Questionnaire. Arthritis Rheum 1992;35:1-10.

30 Pouchot J, Guillemin F, Coste J, Brégeon C, Sany J. Validity, reliability, and sensitivity to change of a French version of the arthritis impact measurement scales 2 (AIMS2) in patients with rheumatoid arthritis treated with methotrexate. J Rheumatol 1996;23: 52-60.

31 Jones B, Nagin DS. Advances in group-based trajectory modeling and an SAS procedure for estimating them. Sociol Methods Res 2007;35:542-71.

32 Jones B, Nagin D. A note on a Stata plugin for estimating group-based trajectory models. Sociol Methods Res 2013;42:608-13.

33 Wickham H, Miller E. haven: Import and Export 'SPSS', 'Stata' and 'SAS' Files. R package version 2.3.1. 2020. https://CRAN.R-project.org/package=haven (15 June 2021, date last accessed).

34 Wickham H, Averick M, Bryan J *et al.* Welcome to the tidyverse. J Open Source Softw 2019;4:1686.

35 Auguie B. gridExtra: Miscellaneous Functions for "Grid" Graphics. 2017. https://CRAN.R-project.org/package=gridExtra (28 February 2020, date last accessed).

36 Wickham H. Reshaping Data with the reshape Package. J Stat Softw 2007;21:20.

37 Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw 2015;67: 1-48.

38 Revelle W. psych: Procedures for Psychological, Psychometric, and Personality Research 2020 [15.6.21]. https://CRAN.R-project.org/package=psych (15 June 2021, date last accessed).

39 van Buuren S, Groothuis-Oudshoorn L. mice: multivariate imputation by chained equations in R. J Stat Softw 2011;45:1-67.

40 Robitzsch A, Grund S. miceadds: Some Additional Multiple Imputation Functions, Especially for 'mice'. 2020. https://CRAN.R-project.org/package=miceadds (28 February 2020, date last accessed).

41 Fox J, Weisberg S. An R companion to applied regression, 3rd edn. Thousand Oaks, CA: Sage, 2019.

42 Carey V, Lumley T, Ripley B. gee: Generalized Estimation Equation Solver, 2019. https://CRAN.R-project.org/package=gee (29 July 2021, date last accessed).

43 Bolker B, Robinson D. broom.mixed: Tidying Methods for Mixed Models, 2020. https://CRAN.R-project.org/package=broom.mixed (9 September 2021, date last accessed).

44 Eberhard A, Bergman S, Mandl T *et al.* Predictors of unacceptable pain with and without low inflammation over 5 years in early rheumatoid arthritis—an inception cohort study. Arthritis Res Ther 2021;23:169.

45 Van der Elst K, Verschueren P, De Cock D *et al.* One in five patients with rapidly and persistently controlled early rheumatoid arthritis report poor well-being after 1 year of treatment. RMD Open 2020;6:e001146.

46 Lee YC, Frits ML, Iannaccone CK *et al.* Subgrouping of patients with rheumatoid arthritis based on pain, fatigue,
inflammation, and psychosocial factors. Arthritis
Rheumatol 2014;66:2006–14.

47 Gwinnutt JM, Sharp CA, Symmons DPM, Lunt M, Verstappen SMM. Baseline patient reported outcomes are more consistent predictors of long-term functional disability than laboratory, imaging or joint count data in patients with early inflammatory arthritis: a systematic review. Semin Arthritis Rheum 2018;48:384–98.

48 Aletaha D, Smolen J, Ward MM. Measuring function in rheumatoid arthritis: identifying reversible and irreversible components. Arthritis Rheum 2006;54:2784–92.

49 Navarro-Compán V, Landewé R, Provan SA et al. Relationship between types of radiographic damage and disability in patients with rheumatoid arthritis in the EURIDISS cohort: a longitudinal study. Rheumatology (Oxford) 2015;54:83–90.

50 Radner H, Smolen JS, Aletaha D. Impact of comorbidity on physical function in patients with rheumatoid arthritis. Ann Rheum Dis 2010;69:536–41.

51 McWilliams DF, Walsh DA. Pain mechanisms in rheumatoid arthritis. Clin Exp Rheumatol 2017;35(Suppl 107(5)):94–101.

52 Katz P. Causes and consequences of fatigue in rheumatoid arthritis. Curr Opin Rheumatol 2017;29:269–76.

53 Matcham F, Galloway J, Hotopf M et al. The impact of targeted Rheumatoid Arthritis pharmacological treatment on mental health: a systematic review and network meta-analysis. Arthritis Rheumatol 2018;70:1377–91.

54 Uhlig T, Haavardsholm EA, Kvien TK. Comparison of the Health Assessment Questionnaire (HAQ) and the modified HAQ (MHAQ) in patients with rheumatoid arthritis. Rheumatology (Oxford) 2006;45:454–8.