INTRODUCTION

In the past two decades, major progress has been achieved in the treatment of rheumatoid arthritis (RA), leading to a new generation of patients who experience rapid disease control and are spared from critical joint destructions and disability.¹ Hence, patients treated in the current era could be expected to report feeling well. In contrast, it has been observed that the way patients with RA report about their health does not necessarily match with the biomedical evaluation of their disease. For example, patients continue to report moderate-to-high levels of pain and fatigue despite low levels of inflammation.^{2 3} Likewise, a literature review concluded that many patients with RA continue to report unacceptable levels of pain and fatigue and problems with physical and mental function despite ongoing RA treatment.⁴

This discrepancy was also demonstrated in the early stage of the disease. Steunebrink and colleagues showed that more than one-third of patients with early RA perceived their health as not improving at all after 1 year of treatment, even despite a good clinical response.⁵ How patients view and interpret their disease is, however, particularly important early in the disease course, as adequate illness beliefs might help patients in adjusting to their chronic illness.⁶ Additionally, it has been found that patients’ perceptions about their disease contribute more to their level of pain and functioning than the actual disease status in RA.⁷

Altogether, these prior observations show that controlling joint inflammation and improving patient-reported outcomes (PROs) are different concepts in RA, both requiring attention from care providers.⁸ In order to optimise the clinical course of newly diagnosed patients with early RA, we need to better understand why, after optimal pharmacological treatment, some of them still feel unwell, whereas their RA is clinically well controlled. We hypothesised that patients who report signs of poor well-being early in the disease course, despite a rapid and persistent clinical response to initial treatment, are at risk of feeling persistently unwell. This assumption was confirmed by our patient researcher. First, we aimed to identify among patients with early RA, with a well-controlled disease from 4 months of initial treatment onwards, subgroups reporting not feeling well after 1 year. Second, we aimed to investigate if these subgroups can be recognised already early in the disease course based on PRO parameters.

RESULTS

Within the group of patients eligible for this study (n=333), 140 (42%) could be categorised as early and persistent clinical responders. Among these 140 patients, Two-Step cluster analysis yielded three clusters of patients as the optimal cluster solution when looking at pain, fatigue, physical functioning, quality of life and sleep quality as clustering variables for well-being at year 1. Regarding these five PROs used to cluster patients, the proportion of missingness that was imputed at year 1 was 2.1% for pain, 2.9% for fatigue, 2.1% for physical functioning, 15.7% for RA quality of life and 21.4% for sleep quality. Cluster membership remained stable between imputed and not imputed datasets and between k-means clustering and hierarchical median clustering (Supplementary file 2).

The largest cluster (n=109) comprised patients with a low level of pain and fatigue, a good physical functioning and RA-related quality of life and a relatively good sleep quality (table 1). Since the PROs of these patients are in line with the clinical disease activity characteristics, we labelled this cluster the ‘concordant to disease activity’ cluster. Around 20% of the patients (n=31) were allocated to one of two ‘discordant’ clusters with diverging scores, mainly because of their pain and fatigue reporting. The first discordant cluster, comprising 13 patients, was labelled the ‘dominant fatigue’ cluster as these patients mainly reported a high fatigue level at year 1. The second discordant cluster, including 18 patients, was called the ‘dominant pain and fatigue’ cluster, because these patients reported both pain and fatigue at considerable levels at year 1. Compared with the ‘concordant to disease activity’ cluster, patients assigned to the ‘dominant fatigue’ and the ‘dominant pain and fatigue’ clusters reported a more functional loss and a worse RA-related quality of life. Sleep quality seemed less of a discriminating variable for cluster allocation. Table 1 presents the average scores at year 1 of the five PROs used to assign patients to a cluster. Baseline patient characteristics and PROs of the three clusters are shown in table 2.

The differences in self-reporting between patients in the ‘discordant’ clusters and those in the ‘concordant to disease activity’ cluster are depicted in figure 1: small (blue shading), medium (orange shading) and large (green shading) effect sizes (ESs) were found for PROs at baseline and week 16. First, the differences in reporting with patients in the ‘concordant’ cluster were small; however, patients in the ‘dominant fatigue’ cluster reported at week 16 more pain (ES=0.20), worse RA quality of life (ES=0.30), worse sleep quality (ES=0.27), more social support seeking (ES=0.49), more personal control (ES=0.20), more negative emotions about the disease (ES=0.28) and more negative social interactions (ES=0.26). Furthermore, their physical functioning was slightly better at baseline (ES=−0.30). A moderately higher fatigue at baseline (ES=0.54), more avoidant coping at week 16 (ES=0.56), a stronger belief that the symptoms are part of RA at week 16 (ES=0.61), a higher belief in chronicity of RA at week 16 (ES=0.50) and a lower belief in the effectiveness of treatment to control RA at week 16 (ES=−0.61) were observed in the ‘dominant fatigue’ cluster. A large difference in effect size was found for fatigue at week 16 (ES=1.38), with more fatigue reported by patients in the ‘dominant fatigue’ cluster compared with patients in the ‘concordant’ cluster.

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Figure 1

Effect sizes of patient-reported outcomes at baseline and week 16 when comparing the ‘dominant pain and fatigue’ cluster with the ‘concordant to disease activity’ cluster and the ‘dominant fatigue cluster’ cluster with the ‘concordant to disease activity’ cluster. The red line represents no effect: patients in the ‘discordant’ clusters gave the same score as patients in the ‘concordant to disease activity’ cluster. The area on the left of this line represents the negative ESs: patients in the ‘discordant’ clusters reported a lower score. The area on the right represents the positive ES: patients in the ‘discordant’ clusters reported a higher score. White area: no meaningful effect (Cohen’s d 0–0.2); blue area: small effects (Cohen’s d 0.2–0.5), orange area: medium effects (Cohen’s d 0.5–0.8), green area: large effects (Cohen’s d≥0.8). BL: Baseline; W16: week 16 of treatment.

Second, when comparing the ‘dominant pain and fatigue’ cluster with the ‘concordant to disease activity’ cluster, a slightly higher level of fatigue at baseline (ES=0.40), worse RA quality of life at baseline (ES=0.22), better sleep quality at week 16 (ES=−0.21), more social support seeking at week 16 (ES=0.38), more fostering of reassuring thoughts at week 16 (ES=0.33), more avoidant coping at week 16 (ES=0.41), a stronger belief that the symptoms are part of RA at week 16 (ES=0.25), more negative beliefs about the consequences of RA at week 16 (ES=0.34), a higher belief in a variable nature of the disease at week 16 (ES=0.40), a stronger belief in risk factors as disease cause at week 16 (ES=0.27) and less perceived excessive social support at week 16 (ES=−0.24) were seen. A moderate difference in reporting between clusters was found for patients’ belief in immunity as disease cause, with a stronger belief reported by patients in the ‘dominant pain and fatigue’ cluster at week 16 (ES=0.54). Large differences between clusters were found for pain and fatigue reporting at week 16, with higher pain (ES=1.38) and fatigue (ES=0.86) scores in the ‘dominant pain and fatigue cluster’ compared with the ‘concordant’ cluster.

The mean scores ±SD of PROs at week 16 are presented in Supplementary file 3.

DISCUSSION

We identified three distinct clusters in patients with early RA, who had a rapid and sustained first treatment response. Patients in the largest cluster reported PROs in concordance with the disease activity trajectory after 1 year of treatment. However, one in five patients continued to report signs of poor well-being, despite having enjoyed a favourable treatment response. One cluster showed excessive fatigue, and the other cluster had increased levels of both pain and fatigue. Patients of those two ‘discordant’ clusters reported higher pain and fatigue levels already early in the disease course. Apart from that, patients with a ‘discordant’ PRO profile after 1 year also seem to have different illness perceptions and coping strategies early in the disease course.

Patients reporting not feeling well were all affected by fatigue in our study. Fatigue has already been proposed as an important outcome for patients with RA.²⁰ However, it appears to be a challenging symptom to manage because of its multidimensionality.²¹ Basu et al found distinct fatigue subtypes among patients with RA reporting severe fatigue, demonstrating the complex nature of this symptom.²² As patients with RA experience different types of fatigue, and the optimal intervention targets are still to be established,²³ further research is needed to explore how fatigue evaluation and management could correspond better to patients’ experience of fatigue. Besides fatigue reporting in our study, also pain was reported at a relatively high level despite control of disease activity, in accordance with the current literature summarised by Taylor et al.⁴ A clinically relevant message of our study is to take patients reporting remaining pain and fatigue seriously already in the early stage of RA, as the results indicate that this can be associated with how patients perceive their RA later on. The perspective of these patients should be further explored using qualitative research methodology to get more insight into this symptom reporting and to identify clues for specific interventions that could prevent the occurrence of secondary fibromyalgia or depression in this patient group.

Patients who are feeling unwell despite good disease control should be identified earlier, to prevent both escalation of perceived disease impact as well as increased medical costs due to overtreatment of non-inflammatory symptoms by immunosuppressive drugs.²⁴ Our results suggest that this early detection might already be achievable in the first 4 months of treatment. Patients` illness perceptions and coping style at week 16, including an avoidant coping strategy and a stronger belief that the experienced symptoms were part of RA, were more prominent in the ‘discordant’ clusters compared with the ‘concordant’ cluster at these early time points. Additionally, the IPQ-R subscale ‘timeline cyclical’ was scored higher by these patients, indicating that they experienced the disease as more fluctuating, which can result in more uncertainty. Attention to such patient factors early in the disease could be a missing link to further optimize the clinical course both short and long term of newly diagnosed patients with RA.²⁵

Inadequate illness representations could be countered by investing in timely education and by reserving time to increase patients’ illness awareness throughout the first months after diagnosis, which is the task of healthcare professionals of different disciplines (eg, physicians, physiotherapists, occupational therapists, psychologists). Nurses could play a specific role in this field as patient education and health promotion are core aspects of their role in disease management.²⁶ Moreover, a recent systematic review in RA showed that psychological interventions can also have a significant effect on coping and self-management behaviours.²⁷ Dures et al found that patients perceive psychological support from rheumatology clinicians and general practitioners as a positive option.²⁸ Hence, it should be investigated whether non-psychologically trained health professionals could deliver such interventions.²⁷ It has been demonstrated that rheumatology clinicians were able to learn and implement interventions such as cognitive behavioural techniques.²⁹ Another option to influence patients` behaviour could be peer mentorship,³⁰ although in general most non-pharmacological interventions to support patients with RA need further study.

Some methodological considerations need to be addressed. First, a disadvantage of k-means clustering is that data should be normally distributed, and that data only contains numerical data. However, sensitivity analyses using hierarchical median clustering showed similar results as the k-means clustering which underlines the robustness of our analysis. However, we utilised HAQ and VAS as numerical variables, but research has shown that caution should be taken using these variables in such a way.³¹ Second, the number of clusters depended entirely on the variables in the analysis. However, we selected five PROs that reflect typical aspects being communicated by patients during a routine consultation as a reflection of their well-being, including pain, fatigue, sleep and functional problems. Patients’ health-related quality of life was added to further strengthen the face validity of the cluster analysis. As the selected instruments are frequently used in daily practice, our findings could also stimulate the integration of cluster definitions into practice. Third, PRO scores were clustered after 1 year of treatment, while another time point could have resulted in other cluster solutions. However, according to our patient researcher, newly diagnosed patients need time to ‘recover’ and find a new balance, and therefore, improvement in PROs could be delayed. The year 1 time point in the CareRA trial should reflect a more stable disease stage, with most clinically well-controlled patients on methotrexate monotherapy and already off glucocorticoids for 4 months. We also assumed that patients who report signs of poor well-being after 1 year despite a well-controlled disease from 4 months onwards are at risk of feeling persistently unwell. Therefore, we chose year 1 as our endpoint. Fourth, we considered the calculation of ESs more appropriate than p values because of the rather small sample size with risk of multiple testing in this explorative study. However, we acknowledge that our findings need validation in a larger patient population with early RA. Still, the clusters showed a high face validity. Finally, we cannot exclude that there might also have been participants who did not feel well but did not report this as such. Hence, patient questionnaires are a very useful tool, but cannot replace direct communication and interaction with patients. A major strength of this study is that patients were part of a pragmatic clinical trial with a standardised collection of both PROs and disease markers. Another strength is that in this study on the patient perspective, a patient researcher was involved in each research phase: setting up the research question, selection of measurements and evaluation points, interpretation of the cluster solution and differences between clusters, discussion of the results and manuscript writing.

In conclusion, this study identified three clusters of well-being in patients with early RA who enjoyed a rapid and persistent initial treatment response, based on five clinically relevant PROs reported after 1 year of treatment. Although most patients reported very low pain and fatigue levels in concordance with their well-controlled disease activity, one in five persistent responders displayed additional, non-pharmacological needs already in the early disease stage. Patients prone to persistently feeling unwell reported higher pain and fatigue levels already early in the disease course. Evaluated coping and illness perceptions provide opportunities for early intervention with appropriate education and counselling.