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Lack of beneficial effects of low-dose radiation therapy on hand osteoarthritis symptoms and inflammation: a randomised, blinded, sham-controlled trial
Address correspondence and reprint requests to: M.J.M. Minten, Department of Rheumatology, Sint Maartenskliniek Nijmegen, PO Box 9011, 6500 GM, Nijmegen, The Netherlands. Tel.: 31-24-327-2712.
Department of Rheumatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Department of Rheumatology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Rheumatology, Flevoziekenhuis, Almere, The Netherlands
Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The NetherlandsDepartment of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The NetherlandsDepartment of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The NetherlandsDepartment of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
Low-dose radiation therapy (LDRT) is widely used as treatment for osteoarthritis (OA) in some countries, while relatively unknown in others. Systematic literature review displayed a lack of high-level evidence for beneficial effects in clinical practice. The aim was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomised, blinded, sham-controlled trial, using validated outcome measures.
Design
Hand OA patients, ≥50 years, with pain ≥5 (scale 0–10) and non-responding to conservative therapy were included and randomised 1:1 to receive LDRT (6 × 1 Gy in 2 weeks) or sham (6 × 0 Gy in 2 weeks). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months post-intervention. Secondary outcomes were pain and functioning (Australian/Canadian Hand Osteoarthritis Index; AUSCAN), quality of life (Short Form Health Survey; SF36) and inflammatory outcomes: erythrocyte sedimentation rate and C-reactive protein serum levels, effusion, synovial thickening and power Doppler signal on ultrasound (range 0–3).
Results
Fifty-six patients were included. After 3 months, no significant difference in responders was observed between groups (LDRT: 8 (29%); sham: 10 (36%); difference −7% (95%CI −31–17%)). Also, differences in clinical and inflammatory outcomes between groups were small and not significant.
Conclusions
We were unable to demonstrate a substantial beneficial effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small effect can not be excluded, a treatment effect exceeding 20% is very unlikely, given the confidence interval. Therefore, in the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA.
. Hand OA is characterized by the involvement of multiple joints, in particular distal (DIP's) and proximal (PIP's) interphalangeal joints and first carpometacarpal joints (CMC1's)
Health-related quality of life in women with symptomatic hand osteoarthritis: a comparison with rheumatoid arthritis patients, healthy controls, and normative data.
. Inflammatory aspects such as effusion and synovitis, assessed by ultrasonography or MRI, are frequently observed in OA patients and are associated with pain and progression of structural damage
Inflammatory ultrasound features show independent associations with progression of structural damage after over 2 years of follow-up in patients with hand osteoarthritis.
Currently, no effective disease-modifying treatment options are available. Therefore, treatment of hand OA aims to relieve symptoms and to enhance patients' coping skills. Pharmacological (e.g., paracetamol, NSAID's), non-pharmacological (e.g., education, hand exercise) and surgical (e.g., trapeziectomy) treatment options are used, but with low to medium effect sizes, or not applicable in many hand OA patients
EULAR evidence based recommendations for the management of hand osteoarthritis: report of a task force of the EULAR standing committee for international clinical studies including therapeutics (ESCISIT).
. Therefore more effective hand OA treatment options are warranted.
Low-dose radiation therapy (LDRT) may fulfil this requirement. Although relatively unaddressed in medical literature, LDRT is a commonly used treatment modality for benign disorders, including OA, in some countries. For instance, in Germany and in Eastern parts of Europe, over 80% of the radiotherapy centres report to treat patients with OA using LDRT
Previous research using in vitro and animal models has shown that LDRT can decrease inflammatory responses, such as lowering leukocyte adhesion to endothelial cells in cell studies and decreasing joint swelling in animal models
. However, systematic review of the literature, including seven clinical studies, showed that there is a lack of sufficient evidence for beneficial effects of LDRT on OA symptoms in clinical practice
. Although beneficial effects were reported, these studies provided low-quality evidence as they utilized retrospective observational study designs without control groups, and non-validated outcome measures.
Therefore, the aim of the current study was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomized, blinded, sham-controlled trial, using validated outcome measures.
Methods
Study design
This is a blinded, double-arm, randomized, sham-controlled trial, investigating the effects of LDRT on symptoms and inflammation in patients with hand OA. The local Medical Ethics Committee approved the study (2014-275). All patients gave written informed consent. Patient screening and data collection took place at the department of Rheumatology of the Sint Maartenskliniek, Nijmegen, The Netherlands. The (sham) LDRT was given at the department of Radiation Oncology of the Radboud university medical center, Nijmegen, The Netherlands.
Participants
Patients previously enrolled in a multidisciplinary occupational therapy program for hand OA at the rheumatology outpatient clinic of the Sint Maartenskliniek, Nijmegen, The Netherlands, were screened for eligibility using their electronic medial records. Potential participants were received information and were contacted within 2 weeks and asked to participate. Furthermore, participants were recruited via advertisements in local newspapers and a Dutch Arthritis Foundation newsletter, inviting hand OA patients to contact the researchers. Inclusion and exclusion criteria are shown in Table I.
Predominant pain in the metacarpophalangeal joints (MCP's) and/or wrist
Age ≥50 years
Unilateral hand OA
Hand pain score ≥5 on a 0–10 numeric rating scale (NRS) for at least 15 of the last 30 days, despite analgesic use and occupational and/or physical therapy
Treatment for hand OA by an occupational or physical therapist in the last 6 months
The ability to read, write and communicate well in Dutch
Other rheumatic diseases with possible hand localisation
Previous or scheduled surgical treatment of the hand joints
Corticosteroid injections in the previous 4 weeks
Fibromyalgia according to 2011 modified ACR criteria
Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia.
Analgesic use was allowed, in which case we encouraged it not to be changed during the study. Corticosteroid injections or treatment by physical of occupational therapist during the study were discouraged. However, when needed, their use were allowed and monitored.
Randomization and intervention
Included patients were randomly allocated 1:1 to either the LDRT group or the sham group, using a computer-generated randomization list. Allocation was stratified for pain intensity at the screening visit (<8 vs ≥8 out of 10), using stratified block randomization with random block sizes ranging between 2, 4 and 6.
For the LDRT group, radiation therapy consisted of six fractions of 1 Gray (Gy), with a total dose of 6 Gy, delivered every other weekday over 2 weeks, according to the consensus guidelines for radiation therapy of benign diseases of the German Society for Radio-Oncology (DEGRO)
. The clinical target volume included DIP's 2–5, PIP's 2–5 and CMC1's of both hands. The full treatment protocol is available in the online Supplementary File. The sham group received six 0 Gy-fractions over the two-week period. During sham, a recorded audio fragment was played to mimic sounds of the linear accelerator during operation. Except for fraction dose, all instructions and proceedings were identical for both groups.
Assessments
Assessments were planned at baseline (T0, maximally 2 weeks before start intervention) and 1, 2 and 3 months (T1, T2 and T3) post-intervention. At T0 and T3, assessment visits were scheduled, while at T1 and T2, a set of questionnaires was sent and returned by mail. To reduce random error, questionnaires were administered twice at T0 and at T3 with 9 days in between on average. Mean scores were used in the analyses.
Clinical parameters
At T0, demographic and OA-related characteristics and the number and nature of comorbidities were collected. Furthermore, postero-anterior (PA) radiographs of both hands were taken
. Erosive hand OA was classified as the presence of at least one joint in the E phase or the R phase. At T0 and during all follow-up assessments, a set of questionnaires was completed, including:
1)
The Australian/Canadian Hand Osteoarthritis Index (AUSCAN)
Dimensionality and clinical importance of pain and disability in hand osteoarthritis: development of the Australian/Canadian (AUSCAN) osteoarthritis hand index.
. The Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were calculated and normalised to the general population, with a mean (SD) of 50 (10), where lower scores represent worse health status.
Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study.
Medication and health care use: type of drug (i.e., paracetamol, NSAID's, tramadol, other) and frequency (i.e., no, every day, some days per week, some days per month) of analgesic use, use of corticosteroid injections and visits to the general practitioner, health care professional or medical specialist, during the last month.
4)
Numeric rating scale (NRS) on pain, functioning, stiffness and patient global assessment (PGA), where 0 represents the best outcome and 10 the worst.
At T1-T3, the following questionnaires were added:
5)
Perceived adverse effects. These were reported by guidance of a self-composed list of potential adverse effects that might be expected after radiation therapy. Other adverse effects could also be reported.
6)
Transition questions about the change in general health status and pain, on a 7-point Likert scale. Response options were transformed to ‘worse’, ‘same’ and ‘better’, analogue to the score by Von Pannewitz
, which is often used to assess effects of LDRT in benign diseases.
Inflammatory outcomes
Inflammatory outcomes were assessed at T0 and T3. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured. Cut-off values for elevated levels were 20 mm/h for women and 15 mm/h for men for ESR, and ≥ 5 mg/l for CRP. DIP's 2–5, PIP's 2–5 and CMC1's were assessed for tenderness (0–3)
and swelling (0–1) by a trained researcher. A tender joint sum score was calculated. Finger joints were also assessed by ultrasound (US) for effusion, synovial thickening and power Doppler signal intensity (PDS; scale 0–3)
by a trained researcher. US training involved a basic ultrasound training course, a hands-on training session with an expert and individual training sessions with >20 hand OA patients. There was opportunity for secondary assessment of US images by another expert in case of doubt. A Philips iU22 with a 5–17 MHz linear array transducer was used. PDS gain was adjusted until background signal was removed. Settings were optimized by the application specialist of the machine manufacturer. A sum score was calculated for each US feature, and the number of joints with a score ≥1 for any of the three features was determined.
Primary outcome
The primary outcome was the proportion of responders according to the OMERACT-OARSI responder criteria at T3
. Responders are patients who improve in either pain or function with ≥50% (relative) and ≥20/100 (absolute); or if improvement is ≥20% (relative) and ≥10/100 (absolute) for 2 of the following 3: pain, functioning and PGA. AUSCAN pain and functioning subscales and NRS PGA were used for responder calculation.
Blinding
Patients and researchers involved in patient contact or assessments were blinded for randomization. The radiotherapy technologist who performed the (sham) treatment was not blinded, but was instructed not to communicate about randomization allocation with patients. Instruction of patients, baseline assessments and marking of target locations were performed before randomization. Statistical analyses were conducted before the randomization key was revealed. Blinding success was assessed by comparing patients’ perceived allocation with the actual intervention.
Sample size
Given the nature of the treatment (e.g., radiation exposure, multiple visits in a short period of time) we believe that LDRT can only be rightfully used in clinical practice when its effects are substantial. Therefore, this study was powered to detect a large effect of LDRT and the following assumptions were made: 1) an expected difference of 40% in the proportion of responders between the LDRT and sham group, 2) 80% power and 5% alpha, and 3) 40% responders in the sham group, as a substantial placebo effect was expected for this intervention
. Allowing 15% drop-outs, we aimed to include 27 patients per group, resulting in a total sample size of 54.
Statistics
Descriptive statistics are provided as mean (SD) or median [25–75%]. Differences between groups are presented as LDRT minus sham group. The difference between the LDRT and sham group, in proportion of responders at T3, was analysed using logistic regression. Differences at T3 were analysed using unpaired t-tests, Wilcoxon rank-sum (Mann–Whitney) tests, or chi-square tests where appropriate. Missing values for the primary outcome were substituted using the value of the previous assessment (last observation carried forward) or the following available value, when the previous was unavailable. All statistical analyses were adjusted for randomization stratification group (NRS pain <8 vs ≥8 out of 10)
. P-values <0.05 were regarded as statistically significant. STATA 13.1 statistical software was used to perform all analyses.
Results
Patients
Between February 2016 and May 2017, 56 patients were included; twenty-eight in either group (Fig. 1; Table II). Forty-four (79%) were female, mean age was 65 (7) years, median body mass index (BMI) was 27 [26–29] kg/m2. Patients were moderately to severely disabled by their disease, considering their scores for pain, functioning and PGA. Every patient had at least one joint with US inflammatory characteristics. Five (18%) in the LDRT and 6 (21%) patients in the sham group were randomized in the high-pain stratum. The majority of the patients (n = 39; 70%) was recruited in the rheumatology outpatient clinic. At baseline, groups differed on age, BMI and number of joints with KL-grade ≥2 and with swelling, and number of patients with erosive hand OA and with elevated CRP. Analyses adjusted for these factors yielded similar results as presented below (presented in online Supplementary file). All patients completed the experimental or sham treatment according to protocol. One patient withdrew from the study after T1, due to adverse reactions (change in nail colouring). Missing data were limited: 2.7–5.8% on questionnaire item level and 2.7–3.6% on questionnaire scale level. Thirty (55%) patients guessed the correct intervention, suggesting successful blinding.
At T3, we found 8 (29%) responders in the LDRT group and 10 (36%) in the sham group (OR 0.69; 95%CI 0.22 to 2.17), with a non-significant difference in proportions of −7% (95%CI −31 to 17%; Fig. 2). Sub-analyses among only erosive hand OA patients also revealed no difference in responders between groups (3 (21%) and 3 (33%) in the LDRT and sham group, respectively; OR 0.53; 95%CI 0.08 to 3.59). At T1, there were 5 (18%) responders in the LDRT group and 7 (25%) in the sham group (OR 0.65; 95%CI 0.18 to 2.35; difference in proportion −7%; 95%CI −29–14%). At T2 this was 8 (29%) for the LDRT group and 9 (32%) for the sham group (OR 0.82; 95%CI 0.26 to 2.60; difference in proportion −4%; 95%CI −28 to 20%).
Fig. 2Proportion of responders with 95%CI over time.
Both groups showed small mean improvements in all clinical outcomes between baseline and T3 (Table III). At T3, no significant differences were seen in clinical outcomes between groups, except for a better SF36 mental component scale in the LDRT group (56 vs 51); difference 5.7 (95%CI 0.6 to 10.1). Eleven patients in the LDRT group and 10 patients in the sham group reported less complaints on the general transition scale; 7 patients in the LDRT and 6 patients in the sham group reported improved pain on the pain transition scale.
Table IIIAbsolute changes (SD) of clinical and inflammatory outcomes per group between baseline and 3 months follow-up, and odds ratio (OR) or β-coefficient (95% CI) with the sham group as reference
Change (SD) in LDRT group n = 27
Change (SD) in sham group n = 28
β-coefficient or odds ratio (OR) (95%CI) for LDRT
Clinical parameters included in the primary outcome
AUSCAN pain (0–100)
−3.3 (12)
−7.8 (16)
4.5 (−3.4 to 12)
AUSCAN function (0–100)
−2.6 (12)
−9.9 (17)
7.4 (−0.8 to 16)
PGA (range 0–10)
−0.8 (2.3)
−1.1 (2.3)
0.4 (−0.9 to 1.6)
Clinical parameters not included in the primary outcome
AUSCAN stiffness (0–100)
−1.4 (17)
−7.6 (21)
6.0 (−4.5 to 17)
NRS pain (0–10)
−1.1 (1.6)
−0.9 (2.3)
−0.1 (−1.2 to 1.0)
SF36 MCS
1.6 (6.9)
1.0 (8.9)
0.6 (−3.9 to 5.0)
SF36 PCS
1.4 (6.8)
2.3 (6.0)
−1.1 (−4.6 to 2.4)
Ultrasound parameters
Effusion sum score (0–54)
−0.7 (2.6)
−1.0 (3.1)
0.2 (−1.3 to 1.8)
Synovial thickening sum score (0–54)
−1.0 (2.5)
−0.9 (2.3)
0.0 (−1.4 to 1.3)
Power Doppler sums score (0–54)
−0.4 (3.2)
−0.7 (2.3)
0.3 (−1.3 to 1.8)
number of joints with ≥1 US feature (0–18)
−0.7 (2.1)
−0.6 (2.9)
−0.1 (−1.4 to 1.3)
Tender and swollen joints
Tender joint sum score (0–54)
−2.8 (5.5)
−2.6 (6.2)
−0.1 (−3.3 to 3.1)
Swollen joint count (0–18)
−0.2 (3.0)
0 (3.2)
−0.2 (−1.9 to 1.5)
Change values are presented as mean changes.
Negative changes indicate less pain, better function, better PGA, decrease in joint counts and sum scores and SF-36 mental and physical health.
Both groups showed no significant changes in US inflammatory outcomes between baseline and T3. Changes were similar for both groups (Table III). The following changes in the number of patients with elevated ESR were observed: −1 (−3 percent points (p.p.)) and 1 (3 p.p.) for LDRT and sham, respectively. The number of patients with elevated CRP decreased with 1 (−4 p.p.) and 4 (−13 p.p.) for LDRT and sham group, respectively.
Medication and health care use
At baseline, medication use was comparable for both groups. Roughly 75% had used analgesics in the last month. At T3, medication use was lower in both groups, 16 (57%) in the LDRT group and 17 (61%) in the sham group (OR 0.9; 95%CI 0.3 to 2.8). This decrease was mainly due to lower paracetamol use. No corticosteroid injections were reported during follow-up. Three patients in the LDRT group visited the rheumatologist during follow-up. Two for a scheduled control visit, one for increased pain in thumb base and toe. No therapeutic adjustments were made during these visits.
Adverse reactions
The number of adverse reactions was comparable for both groups, except for nail reactions, which were reported more frequently in the LDRT group (8 (29%) in LDRT and 3 (11) in sham,; difference in proportions: 18 (95%CI −2 to 38); Table IV). One patient reported changes in lunulae colouring, others were unspecified.
This is the first study to assess the effects of LDRT on pain, functioning and inflammatory outcomes in hand OA patients, using a randomized, blinded, sham-controlled design and validated outcome measures, in a well-defined patient population. Our findings indicate that LDRT is not strongly effective in reducing hand OA symptoms over 3 months follow-up. Furthermore, LDRT is possibly related to changes in finger nails colouring.
The absence of LDRT treatment effects in the current study cannot be explained by an a priori suboptimal treatment strategy, as ours was in line with the 2015 DEGRO guidelines
. These guidelines recommend LDRT for patients failing to respond to conservative treatment, >40 years old, with a symptom duration exceeding 3 months. Target volumes should include joint cartilage, adjoining bony structures, synovial tissue, and adjoining muscles and connective tissues. The total dose should range between 3.0 Gy and 6.0 Gy, with fraction sizes of 0.5–1.0 Gy, applied 2 to 3 times per week, and evaluation of the treatment effect should be performed after 2–3 months. All these recommendations were followed in the current study.
Although patients were randomly assigned to either the LDRT or sham group, groups differed on a few aspects at baseline. Age, BMI, radiographic severity, swollen joint count and the number of patients with erosive hand OA or elevated CRP differed between groups. Analyses adjusted for these differences yielded similar results (Supplementary file). Therefore, we believe that these differences at baseline are of insignificant influence on our final results. However, confounding effects by unassessed variables can still play a role.
External validity of our study seems to be good. Our population can be characterised as patients with typical advanced hand OA and is comparable to other hand OA populations. Pain and impaired functioning are slightly higher in our population in relation to others
Subsets of symptomatic hand osteoarthritis in community-dwelling older adults in the United Kingdom: prevalence, inter-relationships, risk factor profiles and clinical characteristics at baseline and 3-years.
, probably caused by selection of patients with at least moderate pain severity. The US sum scores for synovial thickening and power Doppler signal were slightly lower in our population in relation to others
. An explanation for this difference is the lower number of joints that was assessed in our study; 18 vs 30. Therefore, possible inflammation in particularly PIP1's and MCP1's might have been missed in our study. Furthermore, PDS sensitivity is US machine-dependent and might be lower in our study compared to others.
In light of these negative results, it could be argued that LDRT is only effective in a certain OA subpopulation, such as erosive hand OA where inflammation is more common. However, sub-analyses among erosive hand OA patients in this study revealed no difference in responders between groups. Taking all this into account, we consider our results generalizable to all patients with advanced hand OA.
Our findings are in line with two low-quality RCTs, published in the 1970's, showing no beneficial effect of LDRT
. These studies had heterogeneous study populations including a variety of benign diseases and using poorly defined outcome measures. Other clinical studies did report beneficial effects of LDRT on pain and functioning
. However, these studies had inferior study designs (e.g., no control-arm, non-validated outcome measures, poorly defined study population), with high risk of bias.
Our study has some limitations. First, we had limited precision due to a relatively small sample size. We designed the study to detect a 40% difference in responders between LDRT and sham. The results therefore do not rule out a small beneficial effect of LDRT over sham. Nevertheless, considering the 95%CI of the difference in responders between the groups, an effect exceeding 20% in favour of LDRT seems unlikely. Secondly, hand grip strength was not included as outcome measures for functioning, although recommended for assessment in clinical trials in hand OA
. However, with our current results in mind, a significant effect of LDRT on hand grip strength seems unlikely. Thirdly, we used US to assess inflammation severity in this study. Although this method is considered equally sensitive as (contrast-enhanced) MRI, it is more operator dependent
Reliability and construct validity of ultrasonography of soft tissue and destructive changes in erosive osteoarthritis of the interphalangeal finger joints: a comparison with MRI.
. However, this was minimised by extensive US training before study start. Fourthly, effects of LDRT on inflammation were only evaluated 3 months after treatment. Therefore, potential short-time effects on inflammation could not be detected in our study. Nevertheless, we can at least conclude that LDRT has no relevant sustained effect on inflammation and that a possible short-lived anti-inflammatory effect is not clinically beneficial.
In conclusion, we were unable to demonstrate a substantial positive effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small beneficial effect could not be excluded, it is very unlikely to exceed a difference of 20% between the groups, given the 95% confidence interval of the difference. Based on these results, and the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA.
Contributions
MM, TL-H, JWL, FvdH, AdB and CvdE were involved in the conception and design of the study. MM, TL-H and MCK were involved in the acquisition of data. MM, MK, MCK, PP, FvdH, AdB and CvdE were involved in the analysis and interpretation of data. All authors were involved in the draft of this article and gave their final approval for its submission.
Competing interests
There are no competing interests. MK reports grants from Pfizer, and support of her institution from GlaxoSmithKline, Merck, Abbvie, and Levi-cept, outside the submitted work.
Funding
This study was financially supported by the Dutch Arthritis Foundation (15-1-201). The funder was not involved in the study design, collection, analyses and interpretation of the data, writing the manuscript and the decision to publish the data.
Acknowledgements
We thank all patients who participated in the study.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
Health-related quality of life in women with symptomatic hand osteoarthritis: a comparison with rheumatoid arthritis patients, healthy controls, and normative data.
Inflammatory ultrasound features show independent associations with progression of structural damage after over 2 years of follow-up in patients with hand osteoarthritis.
EULAR evidence based recommendations for the management of hand osteoarthritis: report of a task force of the EULAR standing committee for international clinical studies including therapeutics (ESCISIT).
Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia.
Dimensionality and clinical importance of pain and disability in hand osteoarthritis: development of the Australian/Canadian (AUSCAN) osteoarthritis hand index.
Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study.
Subsets of symptomatic hand osteoarthritis in community-dwelling older adults in the United Kingdom: prevalence, inter-relationships, risk factor profiles and clinical characteristics at baseline and 3-years.
Reliability and construct validity of ultrasonography of soft tissue and destructive changes in erosive osteoarthritis of the interphalangeal finger joints: a comparison with MRI.
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