Abstract
Objectives: The aim of the study was to determine the prevalence of widespread pain (WP) in women with early rheumatoid arthritis (RA) and to compare physical function, activity limitations, health-related quality of life, mental distress, and disease activity between women with WP and non-widespread pain (NWP).
Method: This cross-sectional study included 102 women with early RA. Participants were provided with self-reported questionnaires quantifying activity limitations, physical activity, pain intensity, health-related quality of life, and fatigue. Hand-grip force, muscle function test of the lower extremities, erythrocyte sedimentation rate, and number of tender and swollen joints were assessed.
Results: One-third (35.9%) of the women fulfilled the American College of Rheumatology criteria for WP 20 months after disease onset. Women with RA + WP had significantly higher 28-joint Disease Activity Score (DAS28) (p = 0.004), number of tender joints (p = 0.001), pain intensity (p < 0.001), fatigue (p < 0.001), Health Assessment Questionnaire score (p < 0.001), and Hospital Anxiety and Depression Scale – Depression (p = 0.001). Furthermore, women with RA + WP showed significantly worse global health (p < 0.001) and physical health (36-item Short Form Health Survey – Physical Component Summary) (p < 0.001). The hand-grip force was found to be significantly reduced (p = 0.001), as was the muscle function of the lower extremities (p < 0.001), for women with RA + WP compared to women with RA + NWP. After adjustment for inflammatory joint disease, the significant differences between the groups remained.
Conclusion: A significant group of women with early RA experience WP with a high DAS28 and increased pain intensity level. These women display severe muscle function deficiency in clinical examinations, and report general activity limitations and low psychological and physical health, despite an absence of or low objective signs of inflammation.
Rheumatoid arthritis (RA) (Citation1) is a chronic autoimmune disease that affects approximately 0.5–1.1% of the adult population (Citation2). A characteristic of the disease is symmetrical inflammation of peripheral joints often resulting in progressive destruction of articular and peri-articular structures (Citation3, Citation4). The clinical features of RA are pain, stiffness, reduced range of motion, muscle weakness, and fatigue (Citation5), which often leads to a slow deterioration of function. Consequently, patients experience difficulties with daily activities, reduced health-related quality of life, and often impaired work ability (Citation6).
Pain in RA is associated with inflammation of the peripheral joints and is generally a sign of increased disease activity. However, some patients experience moderate to high levels of prolonged pain in the absence of objective signs of inflammation (Citation7). This may involve peripheral and central pain mechanisms as well as clinical factors (Citation8).
Remaining pain despite good clinical response to pharmacological treatment has been reported in patients with early RA (Citation9). One year after disease onset, a majority (58%) of patients report incomplete improvement of pain (Citation10). High baseline pain has been found to be a strong predictor of the future development of chronic widespread pain (CWP) in RA (Citation11). WP is commonly defined according to the following criteria: pain in both sides of the body, above and below the waist, and in the axial skeleton (Citation12). Pain duration for at least 3 months indicates CWP (Citation12). For classification of fibromyalgia (FM), manual palpation of tender points is required, showing 11 or more tender points (Citation12). Patients with RA and FM or CWP have poorer health, more limitations on activity, higher pain level (Citation11, Citation13, Citation14), and signs of increased disease activity assessed with the Disease Activity Score based on 28-joint count (DAS28) (Citation13) compared with patients with RA with no signs of FM or CWP. Pain is an important determinant of physical disability in RA and a strong predictor of decreased general health (Citation15) and CWP in RA (Citation11). In this study, we have chosen to use the criteria of WP, based on patients’ report of their pain distribution on a pain manikin. We were interested to study whether physical function and general health differed between women with early RA reporting WP and women reporting non-widespread pain (NWP).
This study aimed to estimate the prevalence of WP in women with new-onset RA. Furthermore, this study aimed to evaluate differences in physical function, activity limitations, health-related quality of life, mental distress, and disease activity between women with WP and NWP.
Method
Study design
This was a sub-study of a multicentre controlled cross-sectional study, which examined shoulder function in women with early RA compared to age-matched healthy women (Citation16). Written and oral study information was provided to all study participants and written consent was obtained. The study was approved by the Regional Ethical Review Board in Gothenburg, Sweden.
Selection of patient groups
Eligible patients were women who met the 1987 American College of Rheumatology (ACR) criteria for RA, with a disease duration ranging from 6 months to 3 years, aged 20–60 years. Exclusion criteria were other severe and chronic somatic or psychiatric diseases as well as the inability to read and speak Swedish. Patients were recruited from three rheumatology units in the Region of Västra Götaland, West Sweden (Sahlgrenska University Hospital, Skövde Hospital, and Uddevalla Hospital), following a search of the Swedish RA register and a review of the medical records of patients with RA from 2006 to 2008. In total, 143 women were identified and invited to participate in the study. However, 13 patients were disqualified because of the exclusion criteria. A further 27 patients could not be enrolled owing to time restrictions, lack of contact, or declining to participate, leaving a total of 103 patients. All women except for one belonging to the original cohort were included in the analysis in the present study. This woman failed to fill in the pain manikin and was therefore not included.
Information about demographic data and disease variables was obtained in interviews and from the patients’ medical records. Examinations and administration of the questionnaires were carried out by four experienced physical therapists. Examinations of joints for assessment of tender and swollen joints in the patients were conducted under the supervision of an experienced rheumatologist.
Assessments
The Grippit (AB Detektor, Gothenburg, Sweden), a digital electronic dynamometer that measures grip force in newtons (N), was used to assess hand-grip force (Citation17, Citation18). The mean grip force over a set period (10 s) was recorded. Ten of the patients reported left-handed dominance. No significant difference in grip force was found between the dominant and right hands for these women, and thus the mean grip force during 10 s for the right hand was used in the analysis. The reference value for mean hand-grip force for healthy women is suggested to be 228.6 ± 63 N (mean ± sd) (Citation18). The Chair Rising test was used for assessing muscle function of the lower extremities (Citation19). The number of stands from a normal high chair during 1 min was counted. The reference value for healthy women is suggested to be 30 rises (Citation19). The Leisure Time Physical Activity Instrument (LTPAI) was used to assess the amount of physical activity performed during a typical week (Citation20). The numbers of patients who reached the recommendations for health-enhancing physical activity of 150 min per week of moderate or 75 min of vigorous level was assessed (Citation21). The Health Assessment Questionnaire (HAQ) Index was used for assessment of general activity limitations (Citation22, Citation23). The HAQ is a RA disease-specific instrument that measures eight aspects of activity during the previous week, rated from 0 to 3 (severe difficulties). The total mean score is calculated from the eight aspects. The 36-item Short Form Health Survey (SF-36) was used for assessment of general quality of life (Citation24, Citation25). The SF-36 consists of eight dimensions of health. The total score varies from 0 to 100, where a higher score indicates better health. The Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores were used in the analysis. The Hospital Anxiety and Depression Scale (HADS) was used for the assessment of depression and anxiety (Citation26). HADS contains 14 statements, ranging from 0 to 3, where higher scores refer to a higher degree of distress. The scores of the 14 items build two subscales: HADSa (0–21) for anxiety and HADSd (0–21) for depression. A cut-off score of 8 is suggested to indicate possible anxiety or depression (Citation27).
Pain distribution on a pain manikin was used to assess the number of pain localizations (Citation28). The manikin consisted of check-boxes 0–18 with corresponding predefined regions on a body drawing. With regard to WP, patients were categorized as having RA + WP (i.e. pain registered on both sides of the body, above and below the waist, and in the axial skeleton) (Citation12) or RA + NWP (i.e. WP criteria not fulfilled) to identify the prevalence of WP in patients with RA based on the pain distribution manikin. A visual analogue scale (VAS) was used for the assessment of average pain intensity due to joint disease during the last week (0 = no pain, 100 = worst possible). A cut-off score of VAS > 40 mm is suggested to indicate clinically significant pain in RA (Citation29). A VAS for the assessment of fatigue related to RA during the last week was recorded. A cut-off score of VAS > 50 mm is suggested to indicate severe fatigue in patients with RA (Citation30). The Disease Activity Score based on 28-joint count (DAS28) (Citation31) for the assessment of disease activity was recorded; this is based on a calculation of the erythrocyte sedimentation rate (ESR, mm/h), the number of swollen and tender joints (28-joint index), and self-reported general health scored on a VAS (0–100). A higher value indicates more disease activity. Rheumatoid factor (RF) was assessed with standard laboratory tests at the accredited laboratories of Sahlgrenska University Hospital. The occurrence of erosions was assessed by radiographs of the hands, wrists, and feet. The prevalence of erosions is a marker of disease severity.
Statistics
Descriptive data are presented for continuous data as mean ± sd and for categorical variables as number and percentage. For comparisons between two groups, the Mann–Whitney U-test was used for continuous variables, Mantel–Haenszel chi-square test for ordered categorical variables, and Fisher’s exact test for dichotomous variables. All significance tests were two-sided and conducted at the 5% significance level. The comparison of outcome variables between RA + WP and RA + NWP was also adjusted for the number of swollen joints and ESR, representing inflammatory joint disease. The adjustment was performed with multivariable logistic regression with group (WP/NWP) as the dependent variable, outcome variable as the main independent variable, and possible confounders as additional independent variables.
Results
Characteristics of the study population
The mean age of the women was 47.1 ± 10.0 years. The mean duration of disease was 20.3 ± 8.5 months and the mean DAS28 was 3.8 ± 1.4. The large majority (78.6%) of the women were RF positive. Radiographs were taken at an average of 21.1 ± 10.1 months after diagnosis, showing erosive changes of the hands and/or feet in 37.9% of the patients. Radiographs were not taken in four patients owing to administration difficulties. The large majority (90.2%) of the women were receiving active treatment with disease-modifying anti-rheumatic drugs (DMARDs).
Prevalence of WP
WP was found to be present in 37 patients (35.9%) of the total study population when assessed with the ACR criteria for WP (Citation12).
Group differences between women with RA + WP and women with RA + NWP
Women with RA + WP were found to have significantly higher DAS28 (p = 0.004), number of tender joints (p = 0.001) and HAQ score (p < 0.001), and worse global health (p < 0.001) compared to patients with RA + NWP. They also reported significantly higher pain intensity (p < 0.001) and fatigue (p < 0.001) (). Substantial pain (VAS > 40) was reported in 57% and 17%, and severe fatigue (VAS > 50) in 68% and 37% of the women with RA + WP and RA + NWP, respectively. Moreover, women with RA + WP reported significantly (p < 0.001) lower SF-36 PCS score. Women with RA + WP reported significantly higher HADSd (p = 0.001) than women with RA + NWP (). When assessed with the HADS suggested cut-off score of > 8, 21.6% and 7.7% reported symptoms for depression and 32.4% and 21.0% for anxiety among the women with RA + WP and RA + NWP, respectively.
Table 1. Comparisons of demographic data, and disease assessments among women with rheumatoid arthritis with widespread pain (WP) and without widespread pain (NWP).
Table 2. Comparisons of clinical outcomes among women with rheumatoid arthritis with widespread pain (WP) and without widespread pain (NWP).
The muscle function in the women with RA + WP was found to be significantly reduced with regard to the hand-grip force (p = 0.001) and muscle endurance of the lower extremities (p < 0.001) compared to women with RA + NWP (). The mean hand-grip force was within the reference values for 14% and 26% of the women with RA + WP and RA + NWP, respectively. Muscle endurance of the lower extremities corresponded with healthy reference values in 11% of the women with RA + WP and 33% of the women with RA + NWP. General recommendations for health-enhancing levels of physical activity were attained in 54.1% of the women with RA + WP and 70.8% of the women with RA + NWP. The results of the adjusted outcome analyses between RA + WP and RA + NWP for swollen joints and ESR were very much the same as for the unadjusted analyses ().
Discussion
Approximately one-third of the study population was found to fulfil the ACR criteria for WP, which is in line with a previous study on patients with early RA in Sweden (Citation32). Other reports have found FM/CWP to be present in 6.2–18% of patients with early RA (Citation33, Citation34) and in 15–33% of patients with established RA (Citation11, Citation14, Citation35, Citation36). This indicates that our sample of patients with RA is representative of other study populations in terms of WP.
When WP was present, women with RA and WP reported more activity limitations, higher pain intensity and signs of depression, and lower general health and quality of life, and displayed more muscle function impairment in clinical examinations of the lower and upper extremities compared to women with RA with no WP.
The large majority, 90% of the study population, were receiving active treatment with DMARDs at the time of the examination and 20% of the women had additional treatment with oral corticosteroids. The disease activity assessed with DAS28 was found to be moderate for both groups. No significant difference was found for ESR or number of swollen joints, indicating equally inflammatory disease activity for the two groups. However, women with WP had significantly higher DAS28 score than women with NWP. It has been suggested that disease activity can be overestimated in patients with RA and CWP/FM when assessed by DAS28 owing to an increased number of tender joints, i.e. pain (Citation35, Citation37). In support of this statement, we found much higher numbers of tender joints among the women with WP, while the frequency of erosive changes was lower. Women with WP reported significantly worse global health, which may also have contributed to the higher DAS28 (Citation8, Citation37, Citation38).
The majority of the study population displayed reduced muscle function compared to reference values (Citation18, Citation19, Citation39). Our findings are in line with previous studies as impaired muscle function is common in RA (Citation40, Citation41). The impaired muscle function among the women may involve pain-related mechanisms such as increased pain sensitivity and dysfunctional pain inhibitory mechanisms, arthrogenic muscle inhibition, and hyperalgesia (Citation37, Citation42–Citation44). However, this cannot be explained by our study. Furthermore, low hand-grip force (< 114 N) has been found to be associated with substantial activity limitations in early RA (Citation45). In the present study, half (51%) of the women with WP had a hand-grip force below 114 N, compared to 20% in the group of women with NWP, while only 14% of the women with WP and 26% of the women with NWP had a hand-grip force corresponding to the healthy reference (Citation18). Moreover, previous studies have shown that hand-grip force and function of the lower extremities are strong predictors of general activity limitations (HAQ) 5 years after disease onset of RA (Citation46, Citation47). This indicates that the women with RA + WP in the present study risk prolonged problems with daily living as both the hand-grip force and the muscle function of the lower extremities were low.
Pain is one of the most important determinants of physical disability among patients with RA (Citation15). A pain VAS score above 40, female gender, and a HAQ score > 1 at disease onset have been found to predict CWP in RA (Citation32). Our findings of high self-reported pain and increased HAQ score 20 months after disease onset among the women with WP may indicate a similar trend. However, this warrants longitudinal studies to identify patients at risk of developing CWP and FM concomitant to their RA diagnosis.
RA together with WP has been found to be associated with poorer health (Citation13, Citation14). In the present study, decreased health-related quality of life assessed with SF-36 was reported in the total study population. Even though the SF-36 PCS score was reduced in both groups, women with WP reported significantly worse SF-36 PCS. This indicates that the physical dimension of health-related quality of life is negatively influenced in women with RA with WP.
Distress and decreased health are both individually associated with chronic pain and RA (Citation14, Citation48). In the present study, the SF-36 MCS was found to be low in both groups, indicating mental strain for the total study population. Furthermore, when assessed with the suggested cut-off score for depression and anxiety for HADS, 21.6% of the women with WP reported depression and 32.4% anxiety, while the corresponding numbers for the women with NWP were 7.7% and 21.0%. Remaining pain and fatigue have been suggested to be the dominant predictors of self-reported depression and anxiety in RA (Citation49). A high level of fatigue (Citation30) was present in 62.1% of women with WP, which was significantly higher than in those with NWP, 27.7%. The increased and high frequency of depression, anxiety, and fatigue indicates the severe consequences of WP and is likely to contribute to high global VAS and increased DAS28 among the women with WP.
Physical activity is often recommended for people suffering from prolonged pain. Physical activity improves muscle function and is suggested to promote angiogenesis (Citation50) and improve the function of the vascular endothelium (Citation51). This has several beneficial effects including reduced ischemia, which is postulated to contribute to peripheral sensitization (Citation52). In the present study, half of the women with WP reported > 150 min per week of moderate or 75 min of vigorous exercise, which is the recommendation for health-enhancing physical activity, while the corresponding number for the women with NWP was 74% (Citation53). Promotion of physical exercise is important in women with RA to reduce pain and for the promotion of general health (Citation54). Our results indicate that women with WP tend to be physically active on a health-enhancing level despite high levels of pain and muscle function deficiency. However, one- third of the total study population did not reach the recommended level of physical activity, which calls for intensified support and coaching for these patients to promote physical activity.
Limitations
The main strength of our study is the clinical assessment of muscle function in the upper and lower extremities, in addition to self-administered questionnaires assessing physical function and general health. Including only women in the study could be considered a limitation. However, RA and WP are more common in women; thus, only women were included in the study. Another limitation is the small study sample. However, the majority of the women were RF positive and almost 40% showed erosive changes within 2 years of disease onset. This indicates that the study population is representative of other early RA populations in Scandinavia with disease duration between 6 and 36 months (Citation55, Citation56). The definition of WP based on the pain manikin may reflect WP in connective tissues, widespread joint pain, or a combination of both. Our findings do not differentiate between these aspects of WP. When we adjusted for swollen joints and ESR, to indicate inflammatory joint disease, the significant differences between the two groups (WP and NWP) remained. Our results indicate that WP is associated with impaired muscle function, increased limitations on activity, and impaired health, independently of arthritis.
Another limitations is the cross-sectional study design, which meant that the causality for WP, disease activity, and muscle strength could not be stated in this study. In the future, prospective studies to follow the progress of pain in patients with RA reporting WP early in the disease course are warranted.
Conclusion
More than one-third of the women with RA fulfilled the ACR criteria for WP 20 months after disease onset. When WP was present, women reported higher pain intensity, more activity limitations, more fatigue, and lower psychological and physical health, and displayed more muscle function impairment in clinical examinations of the lower and upper extremities, compared to women with NWP. This study indicates that a significant group of women with early RA experience WP, with a high DAS28 and self-reported WP. These women have severe muscle function impairment, general activity limitations, and reduced health, despite an absence of or low objective signs of inflammation.
Acknowledgements
Anette Tellander and Jeanette Ahlgren helped with the examinations.
This work was supported by grants from the Norrbacka-Eugenia Foundation, the Swedish Rheumatism Association, Göteborg’s Association against Rheumatism (RIG), and the Health and Medical Care Executive Board of Västra Götalands Region (VGR).
Disclosure statement
No potential conflict of interest was reported by the authors.
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