Changes and sex differences in patient reported outcomes in rheumatoid factor positive RA–results from a community based study

Rheumatoid arthritis (RA) is a chronic, inflammatory disorder, which is characterized by progressive joint damage and has a major impact on physical function and health related quality of life (HRQoL). There is evidence indicating that the disease has become less severe during the last decades, possibly due to better management with more extensive treatment, or secular changes in other factors influencing disease severity. For example, a lower disease activity and disability in 1995 compared to 1978 has been demonstrated in Swedish patients with RA[1], and a recent survey indicated that the incidence of total hip arthroplasties has decreased in RA patients over time[2]. Furthermore, severe extra-articular RA manifestations such as vasculitis have also become less frequent in recent years[3]. On the other hand, in poor countries many patients still have active, uncontrolled disease[4].

A patient-reported outcome (PRO) is a questionnaire used in a clinical trial or a clinical setting, where the responses are collected directly from the patient. A number of PROs are validated measures that are considered relevant outcomes in quantitative research[5] and feasible, quantitative measures for standard rheumatology clinical care[6]. RA is far more common in women, and sex specific factors may also influence various aspects of disease severity, including PROs. For example, there seem to be gender differences with worse reported HRQoL among female patients with early RA[7], and a fourfold increased risk of work disability in women with RA compared to men[8]. The impact of recent changes in management and recent secular changes on such differences is unknown.

Our aim was to investigate changes over time in PROs such as visual analogue scales (VAS) for patients’ global assessment of disease activity and pain, disability and HRQoL, as well as treatment in male and female patients in a population-based sample of patients with RA.

In this study, we found that treatment with biologics and corticosteroids increased over time, and there was improvement in all patient reported outcomes. Despite similar treatment, male patients reported better outcomes and more improvement, in particular for the impact of pain, compared to female patients.

Several previous studies have reported improved outcomes over time in comparisons of samples of patients with RA evaluated at different time points. Such improvements were observed in patients’ clinical status according to disease activity[1, 17], functional capacity[17–19], radiographic scores[17, 20], and other clinical measures[17]. This most likely at least partly reflects the fact that management and treatment of RA has become more efficient in recent years. Several clinical trials have shown that tight control of disease activity can be achieved in many patients with early RA by optimizing treatment with traditional DMARDs[21, 22]. Current guidelines emphasize the importance of a treat to-target approach[23], with addition of TNF-inhibitors and other biologics in refractory cases or as first line therapy in patients with a severe prognosis[24, 25]. Currently, decision making about treatment of RA in the studied population and in other parts of Sweden is largely based on national guidelines[25]. In Malmö, initiation of treatment with biologics is discussed at a scheduled meeting, to ensure uniform indications in clinical practice.

Triple therapy with methotrexate, sulphasalazine and antimalarials was rarely used in this cohort. The low use of triple therapy in 2009 was similar to that observed in 2010 in a cross sectional study from Kristiansand, Norway[26], but lower than that reported from Jyväskylä, Finland, where biologics were less extensively used[26]. The comparison between the cohorts from Kristiansand and Jyväskylä suggested that good functional status may be reached with combination of conventional DMARDs[26].

Improvement of PROs in patients with RA is of major clinical relevance. Not only are reduced disability and improved HRQoL important treatment goals in themselves, but such measures also predict long term outcomes. For example, disability, measured using HAQ, has been shown to predict mortality in several studies[4, 27, 28].

In the survey performed in 2009, patients with RA had significantly lower scores for physical as well as mental components of HRQoL compared to the expected based on normative data. This suggests that although patients with RA surveyed in 2009 were significantly improved compared to previous investigations in 1997, 2002 and 2005, there is still a major difference in HRQoL compared to the general population. Evidently, there is still need for further improvements in the management of RA.

Influence of gender on various aspects of disease severity has been described in several studies. One retrospective review of a community based sample revealed a higher proportion with erosive disease in male patients, but a greater number of orthopaedic procedures in women[29]. In studies of the Swedish multi-centre early RA BARFOT cohort, women had slightly higher disease activity, measured using the DAS28 score, compared to men already at baseline[30, 31], mainly due to higher numbers of tender joints and worse rating of general health[31]. The difference in DAS28 increased over time[31] and was still present after 8 years of follow-up[32]. However, male patients had higher CRP at baseline[30] and there was no difference in baseline radiographic joint damage or progression of joint damage over time[31], although other studies have suggested that female gender may be an independent predictor of radiographic progression[33]. In the BeST study, a randomized controlled trial of 4 response-driven treatment strategies, female patients were significantly less likely to achieve drug-free remission[34]. PROs, including the HAQ, have also been noted to be worse in female patients compared to males in a large multinational database[35].

One possible explanation for such differences could be lower muscle mass in women. However, in our study, there were major differences in SF-36 scores compared to the general population for both sexes, with greater numerical differences for women.

The results of the present study are compatible with the concept that a higher pain perception in women is part of the explanation for these findings. This may reflect patterns that are not specific for RA, since chronic widespread pain is twice as frequent in women as in men in the general population[36], and female sex may be a predictor of future chronic widespread pain in individuals with regional pain[37]. On the other hand, the relative impact of RA on co-morbidity and mortality may be at least as great in women as in men. In a survey that included part of the population of the present study, treatment with TNF inhibitors was associated with a lower mortality in women, but not in men[28]. These differences are of major clinical relevance, and the underlying mechanisms should be further studied.

The major strengths of this study include the use of a community-based register of patients with RA diagnosis from a well-defined area, with structured assessment using repeated questionnaires during a period of 11 years.

Limitations include the sample size, which affects the precision of some of the outcome estimates, the lack of longitudinal data for analysis of individual cases, and the lack of available objective measures of disease activity due to the study design.

In a well-defined population of patients with RA that received more aggressive treatment over time, we have demonstrated improvement in patient reported outcomes.

Despite similar treatment, male patients reported better outcomes and greater improvements over time, especially for pain and physical function. We suggest that patient reported outcomes should be reported separately in male and female patients with RA.