Assessment of the Natural History of Forefoot Bursae Using Ultrasonography in Patients With Rheumatoid Arthritis: A Twelve-Month Investigation

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1 Arthritis Care & Research Vol. 62, No. 12, December 2010, pp DOI /acr , American College of Rheumatology ORIGINAL ARTICLE Assessment of the Natural History of Forefoot Bursae Using Ultrasonography in Patients With Rheumatoid Arthritis: A Twelve-Month Investigation CATHERINE J. BOWEN, 1 LINDSEY HOOPER, 2 DAVID CULLIFORD, 3 KEITH DEWBURY, 4 MADELEINE SAMPSON, 4 JANE BURRIDGE, 3 CHRISTOPHER J. EDWARDS, 4 AND NIGEL K. ARDEN 5 Objective. To determine the natural history and clinical significance of forefoot bursae over a 12-month period in patients with rheumatoid arthritis (RA). Methods. Patients with RA (n 149) attending rheumatology outpatient clinics were assessed at baseline. A total of 120 participants, mean SD age years and mean SD disease duration years, completed the 12-month followup (98 women, 22 men, 93 rheumatoid factor positive, 24 rheumatoid factor negative, and 3 unknown). Musculoskeletal ultrasound (US) was used to identify forefoot bursae in all of the participants. Clinical markers of disease activity (well-being visual analog scale [VAS], erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] level, and Disease Activity Score in 28 joints [DAS28]) and foot symptoms on the Leeds Foot Impact Scale (LFIS) Questionnaire were recorded on both occasions. Results. Presence of US-detectable forefoot bursae was identified in 93.3% of returnee (n 120) participants (individual mean 3.7, range 0 11) at baseline. Significant associations were identified between bursae presence and patient-reported foot impact for impairment/footwear (LFIS IF ; baseline: r 0.226, P and : r 0.236, P 0.009) and activity limitation/participation restriction (LFIS AP ; baseline: r 0.254, P and : r 0.235, P 0.010). After, 42.5% of participants had an increase in the number of US-detectable forefoot bursae and 45% of participants had a decrease. Changes in bursae number significantly correlated with changes in LFIS IF (r 0.216, P 0.018) and LFIS AP (r 0.193, P 0.036). No significant associations were identified between changes in bursae and changes in global well-being VAS, ESR, CRP level, or DAS28. Conclusion. The findings of this study suggest that forefoot bursae may regress or hypertrophy over time in patients with RA, and that these changes may be associated with self-reported foot impairment and activity restriction. INTRODUCTION Manifestations of rheumatoid arthritis (RA) disease in the forefoot detected radiologically and clinically in patients with RA have recently been highlighted as a cause of patient-reported foot disability and poor function (1). Plain film radiography has traditionally been the method through which the progression of RA disease has been 1 Catherine J. Bowen, PhD, FCPodMed: University of Southampton, Southampton, and University of Oxford, Oxford, UK; 2 Lindsey Hooper, BSc: University of Southampton and Southampton University Hospitals National Health Service Trust, Southampton, UK; 3 David Culliford, MSc, Jane Burridge, PhD: University of Southampton, Southampton, UK; 4 Keith Dewbury, FRCR, Madeleine Sampson, FRCR, Christopher J. Edwards, MD, FRCP: Southampton University Hospitals National Health Service Trust, Southampton, UK; 5 Nigel K. Arden, MD, FRCP: Southampton University assessed by demonstrating cartilage loss or bony erosion. As techniques in other imaging modalities such as musculoskeletal ultrasound (US) have advanced, new knowledge of the effect of RA on the metatarsophalangeal (MTP) joints has emerged. Consequently, approaches to treatment of MTP joint synovitis have improved (2 4). Disease progression in the forefoot, however, continues to be predominantly identified with MTP joint synovitis as either causative or symptomatic (5 8). Relatively little is Hospitals National Health Service Trust and University of Southampton, Southampton, and University of Oxford, Oxford, UK. Address correspondence to Catherine J. Bowen, PhD, FCPodMed, School of Health Sciences, Building 45, University of Southampton, Highfield Campus, Southampton, Hampshire, SO17 1BJ, UK. cjb5@soton.ac.uk. Submitted for publication March 8, 2010; accepted in revised form August 2,

2 Changes in Forefoot Bursae in RA Over Time 1757 known about the concomitant change, or impact of changes, in soft tissue structures such as bursae and rheumatoid nodules or soft tissue pathology such as tenosynovitis within the forefoot. Two types of bursae may occur within the plantar forefoot region. Intermetatarsal bursae are anatomic bursae that have synovial lining (9,10), and are often considered clinically significant due to their close cohesion with the intermetatarsal neurovascular bundle (11,12). Conversely, adventitial bursae are defined as fluid-filled spaces without a synovial lining, predominantly occurring within the plantar forefoot fat pad tissues (13). The adventitial bursae are considered mechanically derived, where abnormal shearing forces during gait result in collagen degradation and concomitant localized fluid collection at this site (14). When hypertrophied, anatomic intermetatarsal bursae appear on US as a well-defined fluid collection with hypoechoic or anechoic zones usually bulging more than 1 mm under the metatarsal head level (15,16). Submetatarsal, adventitial bursae are defined on US as anechoic or heterogeneous collections of fluid within the submetatarsal fat pad (15). We have previously reported that US-detectable forefoot bursae are highly prevalent in patients with RA (17). Our findings indicated a significantly higher prevalence of USdetectable bursae in patients with RA (92.6%) than detectable by clinical examination (23.5%), and significantly higher than in control subjects (38%) (17). Our crosssectional findings confirmed suggestions in previous reports that bursae in the forefoot are poorly documented, may be the cause of foot symptoms instead of, or as well as, MTP joint synovitis, and warranted additional clinical attention and further investigation (16,18). In order to optimize the management of foot symptoms associated with RA, it would be informative to confirm the prevalence of bursae, detectable by US, at different time points and to establish whether bursal hypertrophy is reversible. As such, the aims of this study were to compare the prevalence of US-detectable forefoot bursae in patients with RA at baseline and again at. A further aim was to explore the relationship between US-detectable forefoot bursae and patient-reported outcomes of foot impact over time. SUBJECTS AND METHODS Participant selection. A longitudinal 12-month cohort study design was used in which a consecutive sample of RA patients fulfilling the American College of Rheumatology (formerly the American Rheumatism Association) criteria (19) was selected from those attending routine rheumatology outpatient appointments at Southampton General Hospital. Patients were excluded from the study if they had a history of previous forefoot surgery, received a corticosteroid injection to the forefoot within the 3 months prior to this study, had an additional musculoskeletal disease (e.g., primary osteoarthritis, gout, Paget s disease, systemic lupus erythematosus), or had a serious medical (other than RA) or psychological disorder that would prevent completion of the study protocol. Informed consent and local research ethics committee approval was secured prior to data collection. Data collection. Data collection took place between August 2006 and September All data collection occurred within the Wellcome Trust Clinical Research Facility, Southampton General Hospital. A single investigator (CJB) who was blinded to the patient-reported outcome measures, blood tests, and disease scores undertook all of the clinical foot and US assessments. Assessment of demographic and clinical characteristics. Demographic data, including age, sex, weight, height, disease duration, and presence of rheumatoid factor, were recorded. Information regarding current medication, including disease-modifying antirheumatic drug use, was obtained from the patients notes. Last known C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values were obtained from the clinical/laboratory database. Clinical activity of RA disease was assessed by the Disease Activity Score 28 tender and swollen joint count (DAS28) (20). DAS28-ESR data were obtained from the clinical notes. Both subscales of the Leeds Foot Impact Scale (LFIS) Questionnaire, impairment/footwear (LFIS IF ) and activity limitation/participation restriction (LFIS AP ), previously validated for use in RA populations (21), were used to identify patient-reported foot impact. Clinical examination of the feet for this study focused on detection of plantar forefoot bursae by forefoot palpation and identification of bursae as fluctuant/capsulated swellings on the plantar aspect. Due to our previous finding that clinical examination was insensitive in detection of plantar forefoot bursae (17), no attempt was made to differentiate the location of bursae by clinical palpation. The same investigator (CJB) completed the foot assessments on all occasions. US imaging. All US scans were performed after the clinical foot examinations by the same investigator (CJB). We attempted to reduce the effect of investigator bias by maintaining a systematic order to the data collection and using experienced independent data handlers to double enter and clean all of the information onto the SPSS data sheet (SPSS). Good image acquisition and interpretation agreement ( 0.702, P 0.01) with an expert US radiologist (KD) was confirmed prior to data collection (22). The US scans were completed using a Diasus ultrasound system (Dynamic Imaging) that operates as a system with dual probes and was readily clinically accessible. In accordance with recommended standard reference values (23), we employed the 5 12-MHz linear probe, footprint 40 mm. At the time of this study there was no standard definition for imaging the area of clinical interest, clinically apparent plantar forefoot bursal swelling, by US. We were interested in determining the prevalence of bursal hypertrophy within the plantar forefoot region and therefore scanned the forefoot using a systematic protocol moving from the medial to the lateral aspect of the foot, scanning in both the transverse and longitudinal planes from the

3 1758 Bowen et al bursae, LFIS IF, LFIS AP, and clinical indicators of disease at both baseline and and associations for raw changes between the variables were identified using Pearson s correlation coefficient. Multiple linear regression was used to assess the relationship between total numbers of US-detectable bursae and impact of disease on the foot (LFIS IF and LFIS AP ) against other potentially confounding explanatory variables. RESULTS Figure 1. Ultrasound image of the left foot plantar metatarsal area of a study participant with rheumatoid arthritis demonstrating hypertrophied bursae as demarcated anechoic areas between the second and third metatarsal heads and the third and fourth metatarsal heads (arrows) (A). The image is seen from the plantar aspect and in the transverse plane as depicted by the inset photograph (B). M2 second metatarsal head; M3 third metatarsal head; M4 fourth metatarsal head; P plantar surface; D dorsal surface. plantar surface of the foot. US-detected bursae were identified from the plantar aspect of the forefoot according to previous definitions (13,16,24 26) (Figures 1 and 2). Following preliminary comparisons with higher-resolution US technology (Philips HDI 5000 System; Royal Philips Electronics), our US imaging protocol was confirmed as the best approach for detection of plantar forefoot bursae (22). Statistical analysis. Data evaluation and statistical analyses were performed using SPSS software, version 14.0 (SPSS). Participant demographic and clinical characteristic information is presented as the mean SD for continuous variables or as the range for ordinal data. Independent-sample t-tests and chi-square analyses were used to determine differences within cohort characteristics between baseline and. Associations between US Figure 2. Ultrasound image of the left foot plantar metatarsal area of a study participant with rheumatoid arthritis demonstrating adventitial bursa formation as a demarcated anechoic area within the fat pad under the second metatarsal head (arrow) (A). The image is seen from the plantar aspect and in the transverse plane as depicted by the inset photograph (B). M1 first metatarsal head; M2 second metatarsal head; P plantar surface; D dorsal surface. Of the 149 participants who were assessed at baseline, 120 (80.5%) attended the 12-month appointment. Nonresponder analyses suggested that at there were no significant differences between returnees and nonreturnees for any of the tested variables. Returnee demographics. A total of 120 participants with a mean SD age of years and a mean SD disease duration of years completed the 12-month appointment (98 women, 22 men, 93 rheumatoid factor positive, 24 rheumatoid factor negative, and 3 unknown). The participants regular treatment of RA included 65% (n 78) receiving methotrexate and 45.8% (n 55) taking anti tumor necrosis factor (anti-tnf ; adalimumab, infliximab, etanercept) therapy at baseline. At the numbers were higher, with 70.8% (n 85) receiving methotrexate and 45% (n 54) receiving anti-tnf therapy. At baseline, although 59.1% had recorded foot symptoms in their clinical notes, only 31.7% (n 38) were receiving clinical foot care (orthoses and/or podiatry) on a regular basis; however, this had improved to 45% (n 54) at. Mean SD baseline and 12-month values plus change values for weight, height, patient-reported global wellbeing, ESR, CRP level, and DAS28 are shown in Table 1. There were no statistical differences between baseline and for any of the variables. US-detectable bursae presence. At, 112 participants (93.3%) had US-detectable forefoot bursae present (mean SD number of bursae per individual , range 0 11), and of these, 96 participants (85.7%) had US-detectable bursae bilaterally. US-detectable bursae were most frequently identified in the intermetatarsal spaces (n 109 [90.8%]; mean SD number per individual , range 0 7). The sites of the most frequently reported bursae at in both the left and right feet were similar to those at baseline, i.e., intermetatarsal 4/5 (left: 61.1%, right: 55.7%), intermetatarsal 1/2 (left: 26.8%, right: 25.5%), intermetatarsal 3/4 (left: 28.2%, right: 20.1%), intermetatarsal 2/3 (left: 11.4%, right: 7.4%), submetatarsal head 5 (left: 7.4%, right: 10.7%), submetatarsal head 2 (left: 6.7%, right: 8.7%), submetatarsal head 3 (left: 4.7%, right: 8.1%), submetatarsal head 1 (left: 5.4%, right: 4.0%), and submetatarsal head 4 (left: 2.0%, right: 4.0%). Table 2 shows the correlations between US-detectable bursae and clinical markers of disease activity. The total number of US-detectable bursae per individual signifi-

4 Changes in Forefoot Bursae in RA Over Time 1759 Table 1. Demographic and clinical characteristics of the study cohort at baseline and * Baseline (n 120) (n 120) Change Weight, kg Height, cm Global well-being, 100-mm VAS ESR, mm/hour CRP level, mg/liter DAS US-detectable bursae Clinically palpable bursae Total LFIS, (0 51) LFIS IF, (0 21) LFIS AP, (0 30) * Values are the mean SD. VAS visual analog scale; ESR erythrocyte sedimentation rate; CRP C-reactive protein; DAS28 Disease Activity Score in 28 joints; US ultrasound; LFIS Leeds Foot Impact Score; LFIS IF LFIS impairment/footwear subscale; LFIS AP LFIS activity/participation limitation subscale. cantly correlated with LFIS IF and LFIS AP at baseline (LFIS IF r 0.226, P 0.013; LFIS AP r 0.254, P 0.005) and also at (LFIS IF r 0.236, P 0.009; LFIS AP r 0.235, P 0.010). No significant associations were identified between the presence of bursae and disease markers of the well-being visual analog scale, ESR, CRP level, and DAS28 at either baseline or ; however, a significant association existed with disease duration at baseline (r 0.404, P 0.001). Change in bursae and LFIS after. When individual person-specific data was analyzed, 51 participants (42.5%) demonstrated an increase in US-detectable bursae number, 54 participants (45%) decreased, and 15 participants (12.5%) had no change after. For those who had no change, 2 participants (1.7%) had no bursae at both time points and 13 participants (10.8%) had stable bursae presence. The most common locations for change in bursae presence in the forefeet were the intermetatarsal spaces (Table 3). Furthermore, analysis of changes within the locations at identified 211 new bursae, whereas 199 had resolved and 233 remained persistent. No significant associations were identified between the changes in US-detectable bursae and changes in disease activity of the ESR, CRP level, or DAS28. However, a significant positive correlation between the changes in the number of US-detectable bursae and changes in the LFIS IF and LFIS AP values was noted (LFIS IF r 0.216, P 0.018; LFIS AP r 0.193, P 0.036). After adjusting for age, well-being, and ESR (CRP level and DAS28 were not included due to their colinearity with the ESR and wellbeing), the changes in US-detectable bursae remained a significant independent factor at the 0.05 level associated with LFIS IF ( 0.276, P 0.012) and LFIS AP ( 0.450, P 0.028). Of note, no correlations were found between clinical Table 2. Correlations between ultrasound-detectable bursae and clinical markers of RA disease activity at baseline and * Baseline Pearson s correlation coefficient Significance (2-tailed) Pearson s correlation coefficient Significance (2-tailed) Age, years (n 120) Duration of RA, years (n 119) Weight, kg (n 120) Height, cm (n 119) Global well-being, 100-mm VAS (n 120) ESR, mm/hour (n 115) CRP level, mg/liter (n 113) DAS28 (n 97) LFIS IF (n 120) LFIS AP (n 12) *RA rheumatoid arthritis; VAS visual analog scale; ESR erythrocyte sedimentation rate; CRP C-reactive protein; DAS28 Disease Activity Score in 28 joints; LFIS IF Leeds Foot Impact Score impairment/footwear subscale; LFIS AP LFIS activity/participation limitation subscale. Significant at the 0.01 level. Significant at the 0.05 level.

5 1760 Bowen et al Table 3. Change in ultrasound-detectable bursae at given sites within the forefeet after No bursae presence at baseline and New bursae at Persistent bursae at baseline and Regressed bursae at Left foot, submetatarsal Right foot, submetatarsal Left foot, intermetatarsal 1/ Right foot, intermetatarsal 1/ Left foot, submetatarsal Right foot, submetatarsal Left foot, intermetatarsal 2/ Right foot, intermetatarsal 2/ Left foot, submetatarsal Right foot, submetatarsal Left foot, intermetatarsal 3/ Right foot, intermetatarsal 3/ Left foot, submetatarsal Right foot, submetatarsal Left foot, intermetatarsal 4/ Right foot, intermetatarsal 4/ Left foot, submetatarsal Right foot, submetatarsal Total 1, identification of forefoot bursae and the LFIS IF and LFIS AP values. DISCUSSION This study provides novel prospective longitudinal data regarding the prevalence and progression of bursae within the forefoot detectable by US in a cohort of patients with RA treated in secondary care. The results of this study suggest that the high prevalence of US-detectable bursae in RA patients may change over time and that such changes appear to be associated with patient-reported foot impact measures. With further insights gained from assessment of the forefoot using US, there is potential for better focus of treatment and preventative foot health. This would allow more targeted therapeutic approaches such as corticosteroid injection, where bursae within other anatomic areas have responded well to injection (27,28). The current evidence for clinical interventions for foot pathology in RA is consistently reported as insufficient, particularly with regard to soft tissue complications such as bursae (1,29,30). Our longitudinal findings do confirm suggestions from previous studies that regardless of type, bursae in the forefoot may be a cause of foot symptoms in RA patients (16 18). We additionally identified that the longitudinal association between foot impact scores and US-detectable bursae may be independent of well-being and ESR, highlighting the importance of the use of US and patient-reported measures as well as physical and chemical markers of disease activity. A possible explanation for the prior limited evidence regarding forefoot bursae may be the continued literary confusion regarding their definition. Further clarification of bursae type, i.e., anatomic/intermetatarsal or adventitial/submetatarsal, may be advantageous in answering this question; however, no additional insight can be gained based on the findings of this study. Our study also provides evidence that, although the overall mean prevalence of US-detectable bursae appears to remain stable over a 12-month period, the prevalence within individual patients varies substantially over time. Of note, 45% of our participants had regression of one or more bursae, although a similar number had new episodes of bursal hypertrophy identified by US. No one location within the forefoot could be established as having more new bursae or regression of bursal hypertrophy than any other, but the changes by location appear to be symmetric. This implies that the formation or regression of bursal hypertrophy over time is more of a dynamic process than previously suspected. It was surprising that there was a correlation between disease duration and the number of bursae at baseline but not at. Nonreturnee analyses demonstrated no significant differences within the returnee group, suggesting that the distribution of US-detectable bursae may have changed. Interestingly, we did not find any significant associations of the US-detectable bursae changes with changes in disease activity. The associations that we found between the changes in US-detectable bursae and the changes in patient-reported foot impact data, on the other hand, were justified as significant at both time points. This underscores the importance of US-detectable bursae in contributing to foot impairment and activity restriction in patients with RA. Therefore, it may be that as well as disease-related soft tissue inflammation, mechanical irritation to the soft tissues of the forefoot, either by increased activity or structural/functional change, may contribute to bursae formation (1,31). A recommendation for future work includes not only more detailed exploration of the

6 Changes in Forefoot Bursae in RA Over Time 1761 natural history of forefoot bursae but also consideration of their potential etiologic factors and clinical impact. To our knowledge, this is the first longitudinal study of US-detectable forefoot bursae, and it has a good rate of followup. The nature of the sample population being based in secondary care, however, may have overinflated the reported prevalence of US-detectable forefoot bursae. Further exploration of early and chronic arthritis subgroups independently may therefore be beneficial. Using the Diasus (Dynamic Imaging) US technology, we were unable to assess the exact size and anatomic features of the forefoot bursae. Newer US machines with enhanced probe technology and power Doppler features have excellent image quality and would more readily allow evaluation of the plantar forefoot structures in better detail (32). Arguably, the presence of MTP joint synovitis or tenosynovitis may also have related associations with foot symptoms as well as plantar forefoot bursal hypertrophy. A study also using magnetic resonance imaging would be more appropriate to delineate these soft tissue structures in detail and therefore would be beneficial in future research programs. Another limitation within this study is that the US measurements were not performed independently of the clinical foot assessments. It was not feasible to have numerous independent investigators and as such, investigator bias cannot be discounted. The effect of investigator bias is, however, related to the results of the clinical foot examinations and not the patient-reported outcome measures or blood tests and disease scores. LFIS scores remained blinded to the investigator and therefore, it is unlikely that the results from the study for the associations between LFIS scores and musculoskeletal US detectable bursae would be affected. Finally, this was a pragmatic clinical study in one center, and needs to be repeated in other settings. This makes the generalization of the prevalence data to all patients with RA difficult, because this group will represent the severe end of the disease activity spectrum. This is highlighted by the prevalence of patients receiving methotrexate, which is substantially higher than the populationbased estimate from the UK (33). In summary, the results of this study confirm a high prevalence of US-detectable forefoot bursae in patients with established RA that may change over time, either by increasing or decreasing in prevalence. Our findings also suggest that there is a relationship between the changes in US-detectable bursae and patient-reported outcomes of foot impact over time. Further investigation into the natural history, etiology, and clinical importance of forefoot bursae is recommended. 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 submitted for publication. Dr. Bowen 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. Bowen, Burridge, Edwards, Arden. Acquisition of data. Bowen, Dewbury, Sampson, Arden. Analysis and interpretation of data. Bowen, Hooper, Culliford, Arden. REFERENCES 1. Van der Leeden M, Steultjens MP, Terwee CB, Rosenbaum D, Turner D, Woodburn J, et al. A systematic review of instruments measuring foot function, foot pain, and foot-related disability in patients with rheumatoid arthritis. Arthritis Rheum 2008;59: Hau M, Kneitz C, Tony HP, Keberle M, Jahns R, Jenett M. 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