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Rheumatoid arthritis
Original research
Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis
  1. Khaldoun Chaabo1,
  2. Estee Chan1,
  3. Toby Garrood1,
  4. Zoe Rutter-Locher1,
  5. Alex Vincent2,
  6. James Galloway3,
  7. Sam Norton3 and
  8. Bruce W Kirkham1
  1. 1Rheumatology, Guy's and St Thomas' Hospitals NHS Trust, London, UK
  2. 2Guy's and St Thomas' Hospitals NHS Trust, London, UK
  3. 3Academic Department of Rheumatology, King's College London, London, UK
  1. Correspondence to Dr Bruce W Kirkham; bruce.kirkham{at}gstt.nhs.uk

Abstract

Introduction Despite better therapies and strategies, many people with rheumatoid arthritis (RA) have persistent pain, often from abnormal pain processing, now termed nociplastic pain. However, RA patients with fibromyalgia (FM), a central nociplastic pain syndrome, also have power doppler ultrasound (PDUS+) joint inflammation. To understand the complex causes of pain, we performed clinical examination and patient-reported outcome measures (PROMs) plus comprehensive PDUS evaluation not previously combined.

Methods In a cross-sectional study of sequential RA patients with at least moderate DAS28 erythrocyte sedimentation rate disease activity, we assessed 66/68 joints for swelling and tenderness, respectively, FM American College of Rheumatology 2010 diagnostic criteria, completed PROMs for function, quality of life and mood, alongside PDUS examination of 44 joints. Statistical analysis included logistic regression modelling and regularised (lasso) logistic regression methods.

Results From 158 patients, 72 (46%) patients met FM criteria, with significantly worse tender joint counts and PROMs, but no differences in PDUS compared with the non-FM group. Categorising patients by PDUS+ joint presence and/or FM criteria, we identified four distinct groups: 43 (27.2%) patients with −FM−PD, 43 (27.2%) with −FM+PD, 42 (26.6%) with +FM−PD and 30 (19%) with +FM+PD. Both FM+ groups had worse PROMs for fatigue, mood and pain, compared with the FM− groups. We were unable to develop algorithms to identify different groups.

Conclusion The unexpected group −FM−PD group may have peripheral nociplastic pain, not commonly recognised in rheumatology. Only 46% of patients demonstrated PDUS+ inflammation. However clinical examination and PROMs did not reliably differentiate groups, emphasising PDUS remains an important tool.

  • Fibromyalgia
  • Arthritis, Rheumatoid
  • Patient Reported Outcome Measures

Data availability statement

Data are available upon reasonable request. Almost all data used in the analysis is included in the tables and supplementary files.

http://creativecommons.org/licenses/by-nc/4.0/

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/.

https://doi.org/10.1136/rmdopen-2023-003784

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Modern terminology describes three pain mechanisms: nociceptive pain caused by tissue damage or inflammation; neuropathic pain caused by nerve injuries, and nociplastic pain resulting from dysfunction of normal pain mechanisms in the absence of usual stimuli. Persistent pain in patients with rheumatoid arthritis (RA) may be related to fibromyalgia (FM), a central nociplastic state, but detailed analysis of the causes of pain in RA is unclear.

    WHAT THIS STUDY ADDS

    • In patients with RA in moderate or severe DAS28 erythrocyte sedimentation rate states, only 73/158 patients (46%) had active inflammatory RA by ultrasound (US), with a similar proportion meeting criteria for FM and 27% not having inflammatory synovitis or FM. US was important to detect the 30 patients with both inflammatory synovitis and concomitant FM.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • We believe that 27% of patients in the group without inflammatory synovitis and FM might have peripheral nociplastic pain, a state frequently discussed in the pain literature but only recently described in rheumatology. Awareness of this pain state may provide new therapeutic opportunities. The overall high incidence of non-inflammatory symptoms contributing to disease activity will encourage more detailed assessments of RA activity with US providing important information.

    Introduction

    Rheumatoid arthritis (RA) is a chronic inflammatory arthritis which can cause significant pain, disability and irreversible joint damage.1 The main goals for therapy stated by patients, are reduction of pain to low levels and preservation of function.2–4 Targeted therapy strategies have improved outcomes for many patients with reduced swollen joint counts (SJCs) and measures of inflammation such as the erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) and have achieved a major goal of reducing progressive joint damage.5 6 Unfortunately, it is now clear from multiple studies that patient global assessments, tender joint counts (TJCs) and pain scores remain high even as levels of inflammation and synovitis have reduced.7 8

    This awareness that persistent pain is an important unresolved issue in rheumatology is now increasingly recognised.9 A first step to improve this situation is to better characterise patient signs and symptoms and understand the different causes of pain. Use of pain focused patient-reported outcome measures (PROMs) such as the painDETECT questionnaire, initially used and validated in neuropathic sciatic pain, is now used in arthritis as it has many features consistent with nociplastic-like pain. Recently, quantitative sensory testing of pain processing, confirms many people with RA experience increased nociplastic pain.10–13 These factors contribute to the overall pain experience, in addition to nociceptive pain caused by inflammation. Fibromyalgia (FM), often associated with abnormal central pain processing is estimated to affect as many as one-third of people with RA.13 14 However, none of these studies have clearly identified which subjects have inflammatory joint activity, another potent cause of pain, making it difficult to determine the causes of pain. Although PROMs indicate high pain burden, the differentiation of whether the pain derives from inflammatory causes or more pain specific pathways such as pain sensitisation is difficult to define.

    This study aims to understand the extent to which people with RA with active disease have evidence for nociplastic-like pain in addition to nociceptive pain caused by inflammation. The specific objective of this study is to accurately characterise the causes of pain in patients with RA with moderate and high disease activity (defined by DAS28(ESR)), as these patients had not achieved widely agreed goals of therapy for RA and will be considered for increased therapy.5 6 We collected detailed clinical features, serological markers and PROMS, together with a comprehensive ultrasound (US) examination of 44 joints. It is then possible to group patients with active inflammatory joint disease detected by comprehensive US power doppler (PD) assessment and associated variables into those with possible (secondary) FM. The hypothesis is that three groups exist (inflammatory RA (−FM+PD), fibromyalgic RA (+FM−PD) and a combined group (+PD+FM)), with the −FM+PD and +FM−PD predicted from clinical and patient-reported outcome data.

    Methods

    Design and participants

    This cross-sectional observational study recruited sequential patients with RA meeting American College of Rheumatology (ACR) classification criteria,15 with a DAS28(ESR) score greater than 3.2, from the rheumatology clinics at Guy’s Hospital, after giving informed consent. Patients who were not on stable therapy or had received a steroid injection within 1 month were excluded. Recruitment took place between 2017 and 2018.

    Patient and public involvement

    The research questions were designed as a result of discussions between researchers and patients, who highlighted that pain is a key research priority. Patient partners provided important feedback on the low attention paid to the causes of pain in patients with RA and how DAS-led therapy did not improve well-being in many patients, encouraging us to carry out this study. Patients also gave feedback on the PROMs used in this study. We have already discussed the results of our study with our patient partners.

    Measures

    Background demographic and disease information obtained from notes review included current and previous medications, comorbidities, age, sex, disease duration, rheumatoid factor and anti-cyclic citrullinated peptide antibody status. For the current analysis patients were classified as screening positive for FM according to the FM ACR 2010 criteria.16

    Patients were assessed by a rheumatologist for 66 SJC, 68 TJC, FM tender points16 and physician global visual analogue scale (VAS). The following data were collected at study visit: patient pain VAS, patient global health VAS and PROMs of Widespread Pain Index (WPI),16 symptom severity score (somatic and fatigue),16 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Total summed score, range 0–52, higher score represents more fatigue,17 Health Assessment Questionnaire Disability Index (HAQ-DI),18 Quality of Life Questionnaire, EQ-5D, range 0–1; 1 means full health, 0 means a state as bad as death,19 Generalised anxiety disorder assessment-7 (GAD-7)20 (anxiety, mild anxiety, score 5–9; moderate anxiety, score 10–14; severe anxiety, score ≥15), Patient Health Questionnaire-9 (PHQ-9) (depression, mild depression, score 5–9; moderate depression, score 10–14; moderately severe depression, score 15–19; severe depression, score ≥20)21 and PHQ-1522 (somatic symptoms, mild somatic symptoms, score 5–9; moderate somatic symptoms, score 10–14; severe somatic symptoms, score ≥15). Blood tests for ESR and CRP were taken unless available within the previous 28 days.

    At the same visit, patients had 44 joints imaged by US by a second physician trained in musculoskeletal US and blinded to the results of the clinical assessment. Scanning was performed using Logic 9 (GE Healthcare) scanner with a 14 MHz transducer. US views were taken using standardised transducer orientation, with PRF set at 1.4 kHz and PD gain set to just below the threshold where PD signal disappeared. Grey scale (GS) still images and 3s PD images were recorded. The stored US scans were subsequently scored using the OMERACT working group on US scoring system23 by a trained reader. To ensure these readings were reliable, a second trained reader independently assessed the score reliability of 10 randomly selected scans. Both readers were blind to clinical and laboratory results. A semi-quantitative score was used to grade GS and PD for each joint (0 no GS or PD signal, 1=minimal, 2=moderate, 3=severe) and a total was derived for each patient for each of GS and PD.

    A modified Larsen score24 was made of hand radiographs taken within 3 years of study to assess radiographic joint damage status, by a reader blind to clinical, laboratory and US results.

    Statistical analysis

    Data were recorded on a MedSciNet database. Descriptive statistics included frequencies and percentages for categorical data and mean and SD for continuous variables, or median and IQR where data were heavily skewed. Between group differences were assessed using Mann-Whitney U tests and Kruskal-Wallis tests for continuous variables and χ2 tests for categorical variables. Kappa statistics were used to compare agreement between the two US readers. Binomial logistic regression was used to identify predictors of whether patients met or did not meet FM criteria (FM+/−). Multinomial logistic regression to identify predictors of subgroups defined by the presence or absence of at least one power doppler ultrasound (PDUS+) joint (PD+/−) and met or did not meet FM criteria, adjusted for age, sex, disease duration and seropositivity. In addition to these models, given the exploratory nature of the study and number of predictors considered, we used the least absolute shrinkage and selection operator (lasso) to undertake variable selection and regularisation to identify the minimal subset of predictors that best distinguished between groups. The penalty parameter (lambda) for these analyses was based on the model with the lowest extended Bayesian Information Criterion. For all analyses we use a complete case approach to deal with missing data, which is appropriate given the level of missing data was low for all variables. Demographic and patient-reported questionnaire data were completed for all patients. US was missing for two patients (1.2%) and serological markers for four (2.4%), with only physician VAS (8.2%) and hand radiographs (8.9%) missing for more than 5% of patients. Missing data has little impact on most models except the regularised logistic models used for predictor selection, which were restricted to 137 (87%) of the total 158 patients. All analyses were undertaken in Stata V.17.1.

    Results

    Participants

    158 patients were enrolled and completed the questionnaires, clinical examination and US assessments. Demographic and clinical details are shown in table 1. Most patients were female with a median disease duration of 10 years. The agreement between the two US readers assessed by kappa statistics for PD kappa was 0.7869, indicating excellent agreement between readers. GS kappa was 0.4955, which is rated as good agreement.

    View this table:
    Table 1

    Demographic and clinical characteristics by whether fibromyalgia diagnostic criteria met (N=158)

    Factors associated with those meeting FM criteria

    Similar demographics were found in the 72 (46%) patients meeting FM ACR 2010 diagnostic criteria (15), compared with the patients who did not (n=86, 54%). In the FM group, more people were seropositive, and TJC, FM tender points, patient global, pain VAS values, DAS28(ESR) and DAS28(CRP) values were higher than the non-FM group. In contrast, no difference in physician global VAS score or SJC was noted. The PROMS, WPI, Symptom Severity Score 2a (fatigue), Symptom Severity Score 2b (somatic), FACIT-F score total, HAQ-DI total, EQ-5D QoL score, GAD-7 anxiety total, PHQ-9 depression total and PHQ-15 somatic symptom total, all had significantly worse scores in the FM group. Thirty patients in the FM group had US evidence of joint inflammation, not significantly different from the non-FM group. Total doppler US and modified Larsen hand radiographic scores were higher in the non-FM group. Similar proportions of both groups received DMARDs, glucocorticoids and non-TNFi biological therapies, while fewer patients in the FM group received TNFi therapy. Variables used to define FM (WPI, Symptom Severity Score 2a, Symptom Severity Score 2b) were strongly correlated with all self-reported variables (HAQ, EQ-5D, GAD-7, PHQ-9, PHQ-15, TJC), but only weakly correlated with markers of synovitis (total PD, modified Larsen score, SJC, ESR, CRP) (online supplemental figure 3).

    Logistic regression models regressed meeting the FM criteria onto a range of clinical and self-reported predictor variables (online supplemental figure 4). Unadjusted models indicated significant associations for lower EQ-5D utility score, higher TJC, greater difference between tender and SJCs, higher DAS28, higher pain VAS, higher patient VAS, greater number of tender points, higher FACIT-F score, higher symptoms of depression and anxiety (PHQ-9, GAD-7 and Patient Health Questionnaire Anxiety and Depression Scale (PHQADS)) and greater PHQ-15 somatic symptoms. Additional adjusted analyses confirmed these associations after controlling for age, gender, disease duration and seropositivity. A fully adjusted multivariable model, including all significant predictors as well as age, gender, disease duration and seropositivity, highlighted greater number of tender points and higher FACIT-F score as independently associated with meeting FM criteria after accounting for other variables (online supplemental figure 5).

    Patient subgroups based on US and FM criteria

    As shown above, FM and active doppler positive joints coexist in some patients confirming our previous study.25 To gain insights into clinically useful patient groups, we grouped patients by the presence or absence of at least one PDUS+ joint (PD+/−) and meeting/not meeting FM criteria (FM+/−). Grouping in this way may generate four potential groups represented as, −FM−PD, −FM+PD, +FM−PD and +FM+PD. Patients meeting the criteria for all four groups were found, with 43 (27.2%) patients in the −FM−PD group, 43 (27.2%) in the −FM+PD group, 42 (26.6%) in the +FM−PD group and 30 (19%) in the +FM+PD group (data summarised table 2 and figures 1 and 2). Comparing the groups using multinominal logistic regression with the −FM−PD group as base outcome, the −FM+PD group related positively to PHQADS total and negatively to FACIT-F scores. The +FM−PD group related positively to the FM tender point count and FACIT-F scores, while the +FM+PD group related positively to the FM tender point count (online supplemental tables 4 and 5).

    Figure 1
    Figure 1

    Boxplots displaying individual data points for clinical measures, visual analogue scale scores, C reactive protein, erythrocyte sedimentation rate and Larsen radiographic scores by subgroup. Subgroups are defined by presence or absence of at least one PDUS+ joint (PD+/−) and meeting/not meeting FM criteria (FM+/−). FM, fibromyalgia; PD, power doppler.

    Figure 2
    Figure 2

    Boxplots displaying individual data points for patient-reported outcome measures by subgroup. Subgroups are defined by presence or absence of at least one PDUS+ joint (PD+/−) and meeting/not meeting FM criteria (FM+/−). FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; FM, fibromyalgia; GAD, Generalised Anxiety Disorder; HAQ, Health Assessment Questionnaire; PD, power doppler; PHQ, Patient Health Questionnaire.

    View this table:
    Table 2

    Demographic and clinical characteristics by whether fibromyalgia diagnostic criteria met and inflammatory status (N=158)

    The selection of factors best distinguishing the four groups was assessed using regularised (lasso) logistic regression (detailed results are provided in online supplemental tables 6–8). The best fitting model for the −FM−PD group indicated that membership of this group was best predicted by seropositivity, higher physician global VAS score and lower FACIT-F total score, and fewer FM tender points. Membership of the +FM−PD group was best predicted by higher FM tender point score, higher PHQ-15 and higher FACIT-F total score and lower physician global VAS score and lower modified Larsen hand radiograph score. Membership of the +FM+PD group was predicted by higher FACIT-F total score and higher DAS28.

    Discussion

    This study shows that only 46% of unselected patients with RA in moderate to high composite disease activity states had inflammatory joint disease activity detected by an US PD signal. By combining comprehensive 44 joint US assessment to accurately define the inflammatory status of most joints, with detailed physical examination and multiple PROMs, we could examine the relationship of patients meeting criteria for FM to PDUS defined inflammatory disease. We had hypothesised that three groups, inflammatory RA (−FM+PD), fibromyalgic RA (+FM−PD) and a combined group (+PD+FM) would be found and were surprised by the (−FM−PD) group, given that all patients had active disease as defined by DAS28 scores. This group, accounting for 27% of patients, may have peripheral nociplastic pain,13 26 a group not commonly recognised in current rheumatology practice.

    Inflammatory pain in RA is mediated by inflammatory mediators activating peripheral pain nerves in the joints, with subsequent peripheral afferent pain signals processed by peripheral, spinal and central nervous system pain pathways, recently termed nociceptive pain.25–27 Peripheral sensitisation occurs when nociceptor neurons become more sensitive to afferent nerve stimuli.28 Mediators released during synovial inflammation can, not only directly stimulate peripheral nociceptors, but also act to reduce the activation threshold of these nociceptors to nerve stimuli. If nociceptor neurons are repeatedly stimulated, the recruitment threshold for secondary spinal cord neurons can be reduced, a process called wind up. This produces signs of pain sensitisation now termed nociplastic pain, of hyperalgesia and allodynia at the peripheral sites these nerves innervate.29 30 This concept is well established in the pain science literature.31–33

    Many studies show that pain sensitisation is common in patients with RA, using different questionnaires and physical examination, with this group often called fibromyalgic RA.10 12 34–36 However, the definition of the extent of inflammatory disease using a sensitive and specific technique such as US has been absent. Our study demonstrates that active inflammatory disease may be less frequent than previously thought in patients who are not in low disease states. One study suggested that a difference in tender more than swollen joints of seven may identify patients with pain sensitisation.36 Our previous finding using PDUS, that a significant number of patients with this score, also had inflammatory RA,37 has been confirmed in this larger study, demonstrating that active inflammatory RA and pain sensitisation co-exist in many patients.

    A strong trend through these data is the usefulness of the physician global score, which might be influenced by SJC/TJC difference, ESR/CRP, and FM tender count, and to a lesser extent SJC, to identify patients with inflammatory RA. However, while strongly associated, physician global alone is not sufficiently accurate to characterise patients reliably. We were unable to find predictive algorithms for the different groups, with high values of PROMs reflecting the FM aspect of patients in +FM+PD group, dominating signals suggesting inflammatory status in the regression analysis. In this analysis, the +FM+PD group was more like the +FM−PD group, reflecting the high levels of patient distress and fatigue that accompany central pain sensitisation/FM. The low sensitivity of clinical prediction of active inflammatory arthritis and the high PROM scores suggest that currently PDUS is the most reliable test for the presence or absence of active inflammatory RA in the presence of FM. In situations with limited access to US examination, integration of PROMS may help clinicians understand patient symptoms, with clinical signs being somewhat helpful. Our finding that patients with positive PDUS have more joint damage, confirms they need effective therapy for active RA as well as concurrent treatment for FM to improve quality of life.

    We identified two groups with tender joints without US inflammation, which differed markedly in PROMs relating to widespread pain and patient distress. The −FM−PD group correlated positively with physician global VAS and negatively to the FM tender point score and FACIT-F, opposite to those in the +FM−PD group who correlated positively with the FM tender point score, FACIT-F and PHQ-15, and negatively with physician global VAS score. We believe these two groups with minimal inflammation may represent different pain phenotypes. The −FM−PD group may have pain from non-inflammatory peripheral nociplastic pain28 and the +FM−PD group have widespread pain suggestive of central nociplastic pain.13 The alternative explanation that serious joint damage causes persistent peripheral pain without inflammation in the −PD−FM group is not supported by the radiographic scores. One other option is that this group has very mild FM, calculated by adding the widespread index and symptom severity index. However, the clear differences in many other measures such as fatigue and low mood suggest this might be a separate group, with peripheral sensitisation, a concept well established in pain literature,31–33 being an alternative explanation.

    Spinal pathways are normally subject to inhibitory signals originating in the brain stem which modulate the perception of pain.31 If these brainstem-derived inhibitory signals are reduced, so called central sensitisation occurs, with similar signs of hyperaesthesia/allodynia as seen in peripheral sensitisation, but usually in a widespread distribution. FM, often described as the prototypical central sensitivity syndrome,38 39 is characterised by high levels of non-pain symptoms captured by PROMs for multiple somatic and psychological measures.40 We believe the differences in PROMs in the −FM−PD compared with both the +FM−PD and +FM+PD groups suggest the −FM−PD group represents patients with predominant peripheral pain sensitisation.

    We used an US-related definition of inflammatory joint synovitis of one of the 44 joints scanned showing a doppler score of 1 on a 1–3 scale. GS US positive joints were present in all patients, including those without any PD positive joints, suggesting synovial membrane changes are present in all patients. In those patients without doppler positive synovial changes, persistent synovial cellular activity, for example, by fibroblasts, might mediate pain signalling, despite reduced synovial inflammation. This idea is discussed in more length in a recent publication from our centre41 and is now under investigation.

    This study has several important features. Enrolling unselected sequential patients with few exclusion criteria from routine clinics makes our findings generalisable to most patient populations. We scanned a large number of joints to provide a clear understanding of any joint inflammation.42 The score of one joint to select PD+ or PD− patient groups was chosen based on data showing that RA patients in remission with a PD signal in one or more joints were likely to lose remission status over time,43 suggesting it is a meaningful cut-off.

    The limitations of our study relate primarily to small patient numbers which are not large enough to generate predictive algorithms to identify and differentiate patients with FM and/or active inflammatory RA. Larger studies will be needed to confirm these preliminary findings and allow for training and testing datasets to improve prediction accuracy. Due to the burden of the assessments, we did not study pain mechanisms by quantitative sensory testing methods used in pain research and increasingly applied to rheumatology research.11 44 For this reason, we used FM as a proxy for pain caused by central mechanisms. We also used the 2010 criteria for FM, as in our preliminary study,37 rather than the 2016 update. We acknowledge that using the FM criteria may not identify every patient perceiving pain due to central mechanisms. Further research using these methods alongside joint US is needed to provide further insights into those with peripheral and/or central sensitisation.

    Our study highlights the challenges currently facing clinicians to identify the underlying mechanisms driving signs and symptoms seen in the clinic. We adopted the treat-to-target approach for all our patients in 2004 and achieved major improvements in disease activity in our population over the first few years.45 Subsequently, we recognised that some patients with moderate/high disease activity scores had dominant pain sensitisation.7 However, the extent of this group with very low inflammation was not recognised until we completed this study.

    Data availability statement

    Data are available upon reasonable request. Almost all data used in the analysis is included in the tables and supplementary files.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Dulwich Research Ethics Committee and the Health Research Authority (REC 14/LO/1869). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We thank all the patients who have taken part in this study. The authors acknowledge Professor Stephen McMahon, whose insights into pain mechanisms contributed to the interpretation of our results, who has sadly passed away.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • KC and EC are joint first authors.

    • SN and BWK are joint senior authors.

    • Presented at This work has previously been presented as an abstract at EULAR and published abstract available at: http://dx.doi.org/10.1136/annrheumdis-2021-eular.3509.

    • Contributors KC, TG, ZR-L, AV, JG, SM, BWK designed study protocol and analysis plan. KC, EC, TG, AV, BWK gathered data. KC, EC carried out ultrasound imaging. KC, TG scored ultrasound images. KC, TG, ZR-L, JG, SM, BWK analysed data and wrote manuscript. All authors reviewed the draft manuscript and contributed to the final manuscript. BWK will act as 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.

    • Patient and public involvement statement The research questions were designed as a result of discussions between researchers and patients, who highlighted that pain is a key research priority. Patient partners provided important feedback on the low attention paid to the causes of pain in patients with RA and how DAS-led therapy did not improve well-being in many patients, encouraging us the carry out this study. Patients also gave feedback on the PROMs used in this study. We have already discussed the results of our study with our patient partners.

    • 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.