Disease Activity and Disability in Women and Men With Early Rheumatoid Arthritis (RA): An 8-Year Followup of a Swedish Early RA Project

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1 Arthritis Care & Research Vol. 64, No. 8, August 2012, pp DOI /acr , American College of Rheumatology ORIGINAL ARTICLE Disease Activity and Disability in Women and Men With Early Rheumatoid Arthritis (RA): An 8-Year Followup of a Swedish Early RA Project EVA HALLERT, 1 MATHILDA BJÖRK, 2 ÖRJAN DAHLSTRÖM, 3 THOMAS SKOGH, 4 AND INGRID THYBERG 4 Objective. To compare women and men regarding the course of disease activity and disability over 8 years from diagnosis of recent-onset rheumatoid arthritis (RA). Methods. A total of 149 patients were followed in the Swedish TIRA study (Early Intervention in RA) for 8 years from RA diagnosis ( ) regarding 28-joint count Disease Activity Score (DAS28), pain (visual analog scale), grip force, Grip Ability Test (GAT), Signals of Functional Impairment (SOFI; hand, upper/lower extremity), walking speed, activity limitation (Health Assessment Questionnaire [HAQ]), and prescribed disease-modifying antirheumatic drugs (DMARDs). Results. Disease activity pattern over time was similar in women and men, showing improvement during the first year and a stable situation during 6 years thereafter. However, at the 7- and 8-year followup times, deterioration was seen with a less favorable course in women. HAQ score did not differ between sexes at diagnosis, but at all followup times women had significantly higher scores than men. Women also had lower grip force and lower walking speed, but higher upper extremity mobility. DMARD prescription was similar for both sexes. Over 8 years, disease duration, sex, biologic agents, grip force, SOFI hand, and pain intensity together explained 43% of the variation in DAS28, whereas grip force, SOFI lower extremity, GAT, and pain intensity could together explain 55% of variations in HAQ score. Conclusion. Disease activity was fairly well managed, but disability gradually worsened. Despite similar medication, women had more disability than men. The discrepancy between disease activity and disability indicates unmet needs for multiprofessional interventions to prevent progressing disability, and patients at risk for disability need to be identified early in the process. INTRODUCTION Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. Insufficiently treated, it is associated with joint destruction and disability, and imposes a considerable burden for the patients and their families and for society (1 3). Disability related to RA can be described in terms of impairment, activity limitation, and participation Supported by the County Council in Östergötland Research Foundations, the Medical Research County Council of South-East Sweden, the Swedish Research Council ( ), King Gustaf V s 80-Year Fund, and the Swedish Rheumatism Association. 1 Eva Hallert, PhD: Linköping University and Linköping University Hospital, Linköping, Sweden; 2 Mathilda Björk, PhD: School of Health Sciences, Jönköping University, Jönköping, Sweden; 3 Örjan Dahlström, PhD: Linköping University, Linköping, Sweden; 4 Thomas Skogh, PhD, MD, Ingrid Thyberg, PhD: Linköping University Hospital, Linköping, Sweden. Dr. Skogh has received speaking fees (less than $10,000 each) from BMS and Novo Nordisk and has served as a member of the Roche Advisory Board. restriction (4). The main therapeutic goals for patients with RA are to suppress disease activity and to minimize disability. Previous studies have reported that disease activity is an important determinant of disability in all phases of RA (5,6). Disability at baseline has also proved to be the most consistent predictor of disability over time (7 9). Several studies have concluded that women have a more disabling disease compared to men, and that women have lower remission rates (10,11). It has also been suggested that the sex differences might depend on different pain perception or different muscular strength in men and women (12 14). During the last decade, tremendous progress has been made with respect to the understanding of etiopathogenic aspects of RA, early diagnostic markers of disease devel- Address correspondence to Eva Hallert, PhD, Center for Medical Technology Assessment, Department of Medical and Health Sciences, Linköping University, SE Linköping, Sweden. eva.hallert@liu.se. Submitted for publication October 25, 2011; accepted in revised form February 29,

2 1102 Hallert et al Significance & Innovations Disease activity decreased in women and men with early rheumatoid arthritis over 8 years, but disability worsened. Disability showed a less favorable course in women. Disease activity is predicted by disease-related variables and disability is predicted by disability variables. The discrepancy between disease activity and disability indicates unmet needs for interventions to prevent progressing disability. opment, disease progression, and outcome (15). Nevertheless, despite the introduction of novel efficacious pharmacotherapy regimens, deterioration may eventually continue in the long term, leading to progressive impairment and disability. Apart from early instituted potent antirheumatic pharmacotherapy, early targeted therapy by allied health professionals may give important contributions, and further developments along this line are needed (16,17). The Swedish TIRA project (Early Intervention in RA) was launched in 1996 in cooperation between 10 rheumatology units in Southeast and Middle Sweden, corresponding to a catchment area of 1 million inhabitants (18). The purpose of the TIRA project was to establish routines for early diagnosis and multiprofessional interventions and to collect data for multidisciplinary research. During , 320 patients with recent-onset ( 1 year) RA were included in the TIRA-1 cohort. We have previously reported that disease activity decreased significantly 3 months after inclusion and then remained essentially unchanged over 2 years (18). Disability, as measured by the Swedish version of the Health Assessment Questionnaire (HAQ), was initially significantly improved, but had a consistently less favorable course in women than in men (18). Hand function, as measured by Signals of Functional Impairment (SOFI) hand and walking time, slowly deteriorated and was almost back to inclusion levels at the 3-year followup (19). At inclusion, women and men had similar HAQ scores, but over the following years women had significantly more disability than men, as measured by the HAQ, the Evaluation of Daily Activities Questionnaire, and grip force (12,18,20). Women also reported more fatigue and lower mental health than men (21). HAQ scores at the 3-year followup were strongly related to grip force (12). After 5 years, HAQ scores were to some extent explained by baseline HAQ score and grip force, but not by disease activity (3). The aim of the present study was to evaluate possible differences between women and men regarding disease activity and disability over 8 years from the diagnosis of recent-onset RA. In addition, predictors of disease activity and disability during the 8 years were explored. PATIENTS AND METHODS Patients. The requirements to be included in the TIRA-1 study were that the first joint swelling had occurred 12 months before a diagnosis of RA was made, based either on fulfillment of at least 4 of the 7 American College of Rheumatology (ACR) 1987 classification criteria (22) or morning stiffness 60 minutes, symmetric arthritis (palpable synovitis), and small joint arthritis (metacarpophalangeal and/or metatarsophalangeal joints 2 4 and/or proximal interphalangeal joints). Two hundred fifty-one patients (164 women, mean SD age years at inclusion and 87 men, mean SD age at inclusion) constituted the group of patients eligible for the present study, which is based on cases recruited from 7 of the 10 rheumatology units still participating in the TIRA project at the 8-year followup. Ninety-five percent of the patients fulfilled the ACR 1987 classification criteria (22). Disease activity and disability were assessed at inclusion and yearly during the 8 years thereafter. Patients who dropped out over the 8 years (n 102) were significantly older compared to the 149 patients (68% women) in the final study group (mean age 61 versus 54 years; P 0.001). At inclusion, there were no significant differences between the dropouts and the study group concerning the 28-joint count Disease Activity Score (DAS28) (23), pain reported on a 100-mm visual analog scale (VAS), or disability reported by the HAQ (24). This study is based on data from inclusion and the yearly followup times during 8 years. The study protocol was approved by the local ethics committees associated with the participating units. All patients gave written informed consent to participate. Interventions. The patients were offered pharmacologic treatment, physiotherapy, occupational therapy, and social counseling, as judged appropriate. In addition, most patients participated in a patient education program between year 1 and year 2. Ongoing disease-modifying antirheumatic drugs (DMARDs) were registered at all visits. DMARD medication here refers to any single or combination therapy with methotrexate, sulfasalazine, antimalarials, gold salts, azathioprine, or cyclosporine, either ongoing or prescribed at the visit. Biologic agents refer to any biologic antirheumatic drug. Combination therapy refers to treatment with traditional DMARDs together with a biologic agent. Disease activity and disability. Disease activity was assessed according to the DAS28, based on erythrocyte sedimentation rate, swollen and tender joint count, and the patient s global assessment (VAS) of average disease activity during the last week (23). Disability was assessed by impairments and activity limitations as described below. Average pain intensity related to the rheumatic disease during the last week was reported by a VAS. Grip force was measured by the electronic device Grippit (Detektor), and average values for the right hand were achieved during a 10-second period (25). Grip ability was tested by the Grip Ability Test (GAT) (26). The GAT score (range 10

3 Disability and Disease in Early RA Over 8 Years 1103 Table 1. Mean SD values for disease and disability at inclusion, year 1, and year 8, and P values for tests of differences between visits for women and men* Inclusion Year 1 Year 8 Inclusion to year 1, P Year 1 to year 8, P Women (n 101) DAS28 (range 0 10) Pain (range mm) Grip force, N GAT (range ) SOFI hand (range 0 16) SOFI upper extremity (range 0 12) SOFI lower extremity (range 0 16) Walking time, seconds HAQ (range 0 3) Men (n 48) DAS28 (range 0 10) Pain (range mm) Grip force, N GAT (range ) SOFI hand (range 0 16) SOFI upper extremity (range 0 12) SOFI lower extremity (range 0 16) Walking time, seconds HAQ (range 0 3) * DAS28 28-joint count Disease Activity Score; GAT Grip Ability Test; SOFI Signals of Functional Impairment; HAQ Health Assessment Questionnaire. Deteriorations. 276) is based on the time needed to perform 3 tasks, with a high score corresponding to decreased hand function. Mobility was assessed by the SOFI in the hands (range 0 16), upper extremities (range 0 12), and lower extremities (range 0 16), and a score of 0 indicates full function (27). Walking speed was defined as the time to walk 20 meters as fast as possible. Activity limitation was reported with the Swedish version of the HAQ (score range 0 3), with 0 corresponding to no difficulty and 3 corresponding to unable to do (24). Statistical analyses. Mean SD values were calculated. Differences between the subgroups and differences between followups were tested by independent- and dependentsamples t-tests. Independent associations between the variables of interest were investigated by generalized estimating equations (GEEs) (28), similar to multiple linear regression analysis but with adjustment for within-patient correlations between different measurements, allowing investigation of longitudinal data. An independent correlation matrix was used and the analysis used a backward procedure, which means that all independent variables were, in the first step, forced into the analysis and in the next step, the least significant variable was excluded and a new analysis was run with the remaining variables. This procedure continued until only significant independent variables remained in a GEE model. To evaluate a GEE model, predicted values from the model were correlated with the measured values using Pearson s correlations. A P value less than 0.05 was considered significant. All analyses were performed using IBM SPSS, version RESULTS Time course. At inclusion, both women and men had high average disease activity (DAS28 scores of 5.3 and 5.4, respectively) and considerable disability, as reported in Table 1. Disease activity was significantly reduced between inclusion and the 1-year followup in both women and men, and a further highly significant reduction was found in Figure 1. Mean values and 95% confidence intervals for the 28- joint count Disease Activity Score (DAS28) in women and men over 8 years.

4 1104 Hallert et al Differences between women and men. Disease activity did not differ significantly between women and men during the 8-year followup (Figure 1). Disability, as measured by grip force, was lower in women at all followup times. The overall tendency was that mean values for pain, GAT, SOFI lower extremity, and walking time were less favorable in women than in men, although all differences did not reach statistical significance. HAQ scores were similar in women and men at inclusion, but women had a significantly higher HAQ score at all followup times (Figure 2). There were no significant differences in DMARD prescription between women and men during the followup period (Table 2). Figure 2. Mean values and 95% confidence intervals for disability in women and men over 8 years. GAT Grip Ability Test; SOFI Signals of Functional Impairment; HAQ Health Assessment Questionnaire. both groups when comparing year 1 to year 8. Also, disability was significantly reduced during the first year after inclusion, as reflected by the majority of variables in both women (grip force, GAT, SOFI hand, SOFI lower extremity, and HAQ) and men (pain, grip force, GAT, SOFI hand, walking time, and HAQ), but at 8-year followup, disability had worsened substantially, with some variables even worse than at the time of diagnosis. Prediction of disease activity and disability. Two separate GEE models explained disease activity (DAS28) and disability (HAQ) during the 8 years, with disease duration, sex, use of DMARDs, use of biologic agents, age, grip force, GAT, pain intensity, walking time, SOFI hand, SOFI upper extremity, and SOFI lower extremity as initial predictors in the full models. When modeling the DAS28 in a GEE analysis, the DAS28 was significantly predicted by disease duration, sex, use of biologic agents, grip force, SOFI hand, and pain intensity. HAQ score was significantly predicted by grip force, SOFI lower extremity, GAT, and pain intensity. The correlations between the predicted and measured values of the HAQ and DAS28 were 0.74 and 0.66, respectively, indicating that 55% of the variance in HAQ score and 43% of the variance in the DAS28 could be explained by the significant predictors in the GEE models (Table 3). Of the included predictors, sex and use of biologic agents had no significant correlations with the DAS28 at any followup time, but were nevertheless included in the final model. Exclusion of sex and use of biologic agents resulted in a model explaining 41% of the variance in the DAS28. A probable reason for the inclusion of these variables is that they act as suppressors; sex correlated significantly with grip force (ranging from over the followup times) and use of biologic agents correlated significantly with disease duration ( 0.21). Table 2. Number of patients prescribed any disease-modifying antirheumatic drugs (DMARDs) and/or biologic agents over 8 years Inclusion Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Women (n 101) DMARD monotherapy* DMARD combination therapy Biologic agents Men (n 48) DMARD monotherapy* DMARD combination therapy Biologic agents * One DMARD and no biologic agents. More than 1 DMARD and no biologic agents. Use of biologic agents (regardless of DMARDs).

5 Disability and Disease in Early RA Over 8 Years 1105 Table 3. Multivariate model with the DAS28 and HAQ as dependent variables based on the significant predictors in each model* DAS28 HAQ Predictors SE GEE 95% CI P SE GEE 95% CI P Intercept , , Disease duration , ns Age ns ns Sex ns Female , 0.06 Male Referent DMARD ns ns Using Not using Biologic agents ns Using , 0.97 Not using Referent Grip force , , SOFI hand , ns SOFI upper extremity ns ns SOFI lower extremity ns , GAT ns , Pain intensity , , Walking time ns ns * DAS28 28-joint count Disease Activity Score; HAQ Health Assessment Questionnaire; GEE generalized estimating equation coefficient; 95% CI 95% confidence interval; ns not significant; DMARD disease-modifying antirheumatic drug; SOFI Signals of Functional Impairment; GAT Grip Ability Test. DISCUSSION The present study shows that, in a routine Swedish clinical rheumatology setting during , disease activity decreased in both women and men during 8 years after the diagnosis of early RA. However, despite initial improvement, the mean disease activity remained rather high over the 8 years. This may be related both to the decreasing use of DMARDs over time and to the fact that, for patients not responding to traditional DMARDs, biologic therapy was not available until year 3. Disease activity did not differ significantly between sexes, and this may partly be explained by the rather high DAS28 levels. It has previously been shown that differences in disease activity between men and women are most pronounced at lower levels of the DAS28 (13). Activity limitations and functional impairments decreased during the first year, but were still affected and deteriorated further over the following years and had a less favorable course in women. HAQ scores were similar in men and women at inclusion, but had a worse course in women compared to men at all time points during 8 years of followup. This is consistent with previous reports. Welsing et al reported that female sex was a predictive factor for increasing disability in a cohort of early RA followed over 9 years (6). In the Swedish BARFOT (Better Anti- Rheumatic FarmacOTherapy) project, Tengstrand et al showed that, compared to male patients, women with early ( 12 months) RA had higher DAS28 and HAQ scores 2 years after inclusion, and that the rate of disease remission was higher in men than in women (29). In a study from Northern Sweden, Hörnberg et al reported that disability remained unchanged, although disease activity decreased during a 2-year followup period in patients with early RA (30), and a study from Southern Sweden reported that disease activity decreased while HAQ score deteriorated during a 10-year followup of early ( 2 years) RA (31). Ahlmén et al reported that men and women had similar degrees of radiographic joint destruction after 5 years and suggested that higher DAS28 levels and HAQ scores in women might depend on different pain perception and less muscular strength (14). This is also mentioned in the Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis study, which is a large multinational cross-sectional cohort of patients with RA. In this study, however, women had a higher frequency of erosions compared to men (13). Considering that men are physically stronger than women, this may, however, substantially affect measures of functional capacity (13). It has also been suggested that women may have a general tendency to report more symptoms than men (14). Previous studies have reported that disability in early RA is influenced by disease activity and later on, is more related to joint damage (1,32). In a Dutch 10-year followup study on early RA, Kroot et al reported that after an initial improvement from baseline, functional capacity remained rather unchanged during the first 6 years, but at 10-year followup, functional capacity had returned to baseline levels (33). Previous reports from the Swedish TIRA project have shown that disease activity improved, while disability slowly worsened (3,18,34). This discrepancy was maintained over the years and was even more pronounced at 8-year followup, as shown in the present study. Men had poorer function of the hands and upper extremities

6 1106 Hallert et al compared to women, but had higher grip force, reflecting that men are stronger, but have less mobility in the hands and upper extremities. Similar sex differences are, however, also seen in the general population (3). Approximately 50% of the variance in DAS28 and HAQ scores was explained by the variance in the other variables. HAQ score was predicted by disability variables and not by disease activity. This is in line with earlier followup times in the TIRA project (3,35). DAS28 levels over 8 years did not differ significantly between sexes. Sex was, however, a significant predictor of DAS28 in the GEE analysis, but was responsible for 1% of the 43% explained variance. Further analysis showed that the reason for inclusion of sex was an intercorrelation between sex and the disability variables, for example, grip force. The present study describes the clinical course of the disease in patients with early RA diagnosed between 1996 and 1998, reflecting the situation in Sweden in With the more aggressive early treatment approach and the introduction of new biologic antirheumatic treatment modalities, the strategies have changed dramatically and continue to do so (36). Patients in the Swedish TIRA project were recruited during a period just before anti tumor necrosis factor biologics became available on the market and the antirheumatic medication was not instituted according to a study protocol, but was prescribed as judged appropriate by the rheumatologists. At that time, approximately 2000, biologic agents were mainly prescribed to patients with severe disease. However, as shown in the GEE analysis, the use of biologic agents was important for reduced disease activity, even though they were prescribed to rather few patients. Despite the general intention in the Swedish TIRA project to institute DMARDs rapidly, surprisingly, only 34% of the patients were prescribed such medications at inclusion. Over the following years, the number of patients receiving DMARDs increased substantially, but after 8 years the DMARD prescription had decreased again and was back to 58%, and was similar in women and men. This was unexpected, but as treatment decisions were made by the physician s preference, this may reflect different treatment traditions between the participating units in In a previous report from TIRA-1, drug prescription was analyzed during the first 2 years, comprising 89% of the 320 patients included in the cohort, and at the 2-year followup, DMARD prescription was significantly higher in women compared to men (18). This difference was not, however, seen in the present study population of patients who completed the entire 8-year followup period. Accordingly, the increasing disability in women compared to men does not appear to be explained by differences in medication strategies. The patients in the present TIRA study had disease durations between 2 and 4 years before biologic treatment became available on the market. This historical cohort of patients can therefore be compared to our new cohort, TIRA-2, comprising 522 early RA patients recruited during and with access to biologic agents early on in the disease course. This offers a unique possibility to compare disease activity, disability, and medication in patients with early RA in a 10-year perspective. A number of patients were lost to followup over 8 years, and this is a limitation of the present study. Unfortunately, radiographs were not available in the TIRA cohort and this is a disadvantage, since radiographs provide a true measure of tissue damage and may also reflect the level of severity of the disease. No data on physical exercises were collected in the present study. This is a drawback, since physical activity is associated with better functional capacity, increased muscle strength, and better mental health (37). The majority of patients with RA do not participate in physical activity on a regular basis and, as reported by Sokka et al, female sex, older age, high disease activity, pain, and fatigue are associated with physical inactivity (37). This gives important implications to encourage patients (and especially women) to increase their level of physical activity. The strength of the present study is the well-characterized patient material and the longitudinal prospective design with regular followup times, allowing analyses of longterm outcomes of patients with recent-onset RA. To conclude, disease activity decreased in both women and men in the TIRA-1 cohort, but disability showed a less favorable course. This resulted in deterioration regarding activity limitation and functional impairment, and was most obvious in women. Disease activity and disability have different predictors. Disease activity is predicted by disease-related variables and disability by other disability variables. Despite the multiprofessional interventions at regular followup times, disability worsened, especially in women. This implies a need for further research to identify characteristics of patient subgroups at risk of progressing disability, not only in the early phase of disease, but also later on in the disease process, and in addition gives implications to encourage patients (and especially women) to increase their level of physical activity. ACKNOWLEDGMENTS We thank all of the patients and TIRA coworkers in Eskilstuna, Jönköping, Linköping, Motala, Norrköping, Västervik, and Oskarshamn, Sweden. We also thank Ms Ylva Billing for excellent cooperation. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Hallert had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Hallert, Thyberg. Acquisition of data. Hallert, Thyberg. Analysis and interpretation of data. Hallert, Björk, Dahlström, Skogh, Thyberg. REFERENCES 1. Scott DL, Smith C, Kingsley G. Joint damage and disability in rheumatoid arthritis: an updated systematic review. Clin Exp Rheumatol 2003;21 Suppl:S Hallert E, Husberg M, Jonsson D, Skogh T. Rheumatoid arthritis is already expensive during the first year of the disease

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