Anthony Doyle

Mechanisms of bone erosion in gout; a quantitative analysis using plain radiography and computed tomography.

Objective: The underlying basis of bone erosion in gout remains speculative. The aim of this study was to understand the mechanisms of bone erosion in gout using non-invasive imaging techniques. Methods: Paired plain radiographs and computed tomography (CT) scans of 798 individual hand and wrist joints from 20 patients with gout were analysed. Radiographs were scored for erosion (0–5) using the Sharp/van der Heijde method. CT scans were scored for the presence and diameter of bone erosions and tophi. The presence of intraosseous tophus (tophus visualised within bone) was recorded. The relationships between radiographic erosion, CT erosion and tophus scores were analysed. Results: With increasing radiographic erosion scores, the percentage of joints with intraosseous tophus increased (p<0.001). For those joints with a radiographic erosion score of 4 or 5, 96/98 (98%) had CT evidence of intraosseous tophus. There was a significant relationship between the radiographic erosion scores and intraosseous tophus size (p<0.001). For those joints with CT erosion, 194/237 (81.8%) had visible intraosseous tophus. Of the joints with CT erosions greater than 5 mm, 106/112 (94.6%) had visible intraosseous tophus and all (56/56) erosions greater than 7.5 mm had intraosseous tophus. There was a strong correlation between CT erosion diameter and intraosseous tophus diameter (r  =  0.93, p<0.001). Intraosseous tophi were larger than non-intraosseous tophi, but had similar density and calcification. Conclusion: There is a strong relationship between bone erosion and the presence of intraosseous tophus. These results strongly implicate tophus infiltration into bone as the dominant mechanism for the development of bone erosion and joint damage in gout.

Cellular characterisation of magnetic resonance imaging bone oedema in rheumatoid arthritis; implications for pathogenesis of erosive disease

OBJECTIVES Magnetic resonance imaging (MRI) bone oedema is an important predictor of bone erosion in rheumatoid arthritis (RA). This study aimed to determine the cellular components of MRI bone oedema, and clarify the relationship between bone erosion and MRI bone oedema. METHODS Twenty-eight bones from 11 patients with RA undergoing orthopaedic surgery were analysed by quantitative and semi-quantitative immunohistochemistry. Pre-operative contrast-enhanced MRI scans were analysed for bone oedema. RESULTS The density of osteoclasts was higher in those samples with MRI bone oedema than those without MRI bone oedema (p = 0.01). Other cells identified within bone marrow included macrophages and plasma cells, and these were more numerous in samples with MRI bone oedema (p = 0.02 and 0.05 respectively). B cells were present in lower numbers, but B cell aggregates were identified in some samples with MRI bone oedema. There was a trend to increased RANKL expression in samples with MRI bone oedema (p = 0.09). Expression of RANKL correlated with the number of osteoclasts (r = 0.592, p = 0.004). CONCLUSIONS The increased number of osteoclasts and RANKL expression in samples with MRI bone oedema supports the hypothesis that bone erosion in RA occurs through activation of local bone resorption mechanisms within subchondral bone as well as through synovial invasion into bone.

Tendon involvement in the feet of patients with gout: a dual-energy CT study

Objectives To examine the frequency and patterns of monosodium urate (MSU) crystal deposition in tendons and ligaments in patients with gout using dual-energy CT (DECT). Methods Ninety-two patients with tophaceous gout had DECT scanning of both feet. Two readers scored the DECT scans for MSU crystal deposition at 20 tendon/ligament sites and 42 bone sites (total 1840 tendon/ligament sites and 3864 bone sites). Results MSU crystal deposition was observed by both readers in 199/1840 (10.8%) tendon/ligament sites and in 399/3864 (10.3%) bone sites (p=0.60). The Achilles tendon was the most commonly involved tendon/ligament site (39.1% of all Achilles tendons), followed by the peroneal tendons (18.1%). Tibialis anterior and the extensor tendons were involved less commonly (7.6–10.3%), and the other flexor tendons, plantar fascia and deltoid ligaments were rarely involved (<5%) (p<0.0001 between sites). Involvement of the enthesis alone was more common in the Achilles tendon (OR (95% CI) 74.5 (4.4 to 1264), p<0.0001), as was any involvement of the enthesis (OR (95% CI) 6.8 (3.6 to 13.0), p<0.0001). Conclusions Tendons are commonly affected by MSU crystal deposition in patients with tophaceous gout. The patterns of MSU crystal deposition suggest that biomechanical strain or other local factors may contribute to deposition of MSU crystals.

Methods of tophus assessment in clinical trials of chronic gout: a systematic literature review and pictorial reference guide

Objective To identify methods of tophus measurement for gout studies, summarise the properties of these methods and compile a detailed pictorial reference guide to demonstrate the methods. Methods A systematic search strategy for methods of tophus measurement was formulated. For each method, papers were assessed by two reviewers to summarise information according to the specific components of the Outcomes Measures in Rheumatology (OMERACT) filter: feasibility, truth and discrimination. Detailed images were obtained to construct the reference guide. Results Eight methods of tophus measurement were identified: counting the total number of tophi, physical measurement using tape measure, physical measurement using Vernier callipers, digital photography, ultrasonography (US), MRI, CT and dual energy CT. Feasibility aspects of the methods are well documented. Physical measurement techniques are more feasible than advanced imaging methods, but do not allow for assessment of intra-articular tophi or for data storage and central reading. The truth aspect of the filter has been documented for many methods, particularly Vernier callipers, US, MRI and CT. Reliability of most methods has been reported as very good or excellent. Sensitivity to change has been reported for all methods except MRI and CT. Conclusion A variety of methods of tophus assessment have been described for use in clinical trials of chronic gout. Physical measurement techniques (particularly the Vernier calliper method) and US measurement of tophus size appear to meet most aspects of the OMERACT filter.

Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study

Background The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout. Methods We analysed DECT scans of the feet from asymptomatic individuals with serum urate ≥540 µmol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33). Results DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ≤3 years) and 16/19 (84%) with late gout (p<0.001). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in those with gout (p≤0.001 for both joint and tendon sites). The volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia, compared with the early and the late gout groups (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups. Conclusions Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.

Imaging in gout - What can we learn from MRI, CT, DECT and US?

There are many exciting new applications for advanced imaging in gout. These modalities employ multiplanar imaging and allow computerized three-dimensional rendering of bone and joints (including tophi) and have the advantage of electronic data storage for later retrieval. High-resolution computed tomography has been particularly helpful in exploring the pathology of gout by investigating the relationship between bone erosions and tophi. Magnetic resonance imaging and ultrasonography can image the inflammatory nature of gouty arthropathy, revealing synovial and soft tissue inflammation, and can provide information about the composition and vascularity of tophi. Dual-energy computerized tomography is a new modality that is able to identify tophi by their chemical composition and reveal even small occult tophaceous deposits. All modalities are being investigated for their potential roles in diagnosis and could have important clinical applications in the patient for whom aspiration of monosodium urate crystals from the joint is not possible. Imaging can also provide outcome measures, such as change in tophus volume, for monitoring the response to urate-lowering therapy and this is an important application in the clinical trial setting.

MRI bone oedema scores are higher in the arthritis mutilans form of psoriatic arthritis and correlate with high radiographic scores for joint damage

IntroductionThe aim of this study was to investigate the magnetic resonance imaging (MRI) features of bone disease in the arthritis mutilans (AM) form of psoriatic arthritis (PsA).MethodsTwenty-eight patients with erosive PsA were enrolled (median disease duration of 14 years). Using x-rays of both hands and feet, 11 patients were classified as AM and 17 as non-AM (erosive psoriatic arthritis without bone lysis)by two observers. MRI scans (1.5T) of the dominant hand (wrist and fingers scanned separately) were obtained using standard contrast-enhanced T1-weighted and fat-saturated T2-weighted sequences. Scans were scored separately by two readers for bone erosion, oedema and proliferation using a PsA MRI scoring system. X-rays were scored for erosions and joint space narrowing.ResultsOn MRI, 1013 bones were scored by both readers. Reliability for scoring erosions and bone oedema was high (intraclass correlation coefficients = 0.80 and 0.77 respectively) but only fair for bone proliferation (intraclass correlation coefficient = 0.42). MRI erosion scores were higher in AM patients (53.0 versus 15.0, p = 0.004) as were bone oedema and proliferation scores (14.7 versus 10.0, p = 0.056 and 3.6 versus 0.7, p = 0.003 respectively). MRI bone oedema scores correlated with MRI erosion scores and X-ray erosion and joint space narrowing scores (r = 0.65, p = 0.0002 for all) but not the disease activity score 28-C reactive protein (DAS28CRP) or pain scores.ConclusionsIn this patient group with PsA, MRI bone oedema, erosion and proliferation were all more severe in the AM-form. Bone oedema scores did not correlate with disease activity measures but were closely associated with X-ray joint damage scores. These results suggest that MRI bone oedema may be a pre-erosive feature and that bone damage may not be coupled with joint inflammation in PsA.

Assessment of tophus size: a comparison between physical measurement methods and dual-energy computed tomography scanning.

BackgroundDual-energy computed tomography (DECT) has recently been described as a sensitive method to detect urate deposits in patients with gout. ObjectivesThe aim of this study was to compare the reproducibility of DECT with various physical measurement methods of tophus size assessment. MethodsSixty-four tophi from 25 patients were analyzed. Each tophus was assessed by 2 independent observers using Vernier calipers and tape measure. All patients proceeded to DECT scanning of both feet. Urate volume within index tophi was assessed by 2 independent observers using automated DECT volume assessment software (n = 55 tophi). Five patients returned within 1 week for repeat physical assessment of tophus size. Dual-energy computed tomography scans from the returning patients were scored twice by both observers. Intraobserver and interobserver reproducibility was assessed by intraclass correlation coefficient (ICC) and limits-of-agreement analysis. ResultsOverall, DECT was more reproducible than the physical methods with interobserver ICCs for DECT of 0.95, for calipers 0.78, and for tape measurement 0.88, and intraobserver ICCs for DECT of 1.00, for calipers 0.75, and for tape measurement 0.91. Vernier caliper and tape measurements correlated highly with each other (rs = 0.84, P < 0.0001) but less well with DECT (for index tophi, rs = 0.46, P = 0.004 for both). Large variation was observed in the amount of urate deposits documented by DECT in tophi of similar physical size. ConclusionsDual-energy computed tomography scanning is a highly reproducible method for measuring urate deposits within tophi. This imaging modality reveals the composition of tophi that contain variable urate deposits embedded within soft tissue.

Development of a computed tomography method of scoring bone erosion in patients with gout: validation and clinical implications

OBJECTIVES To develop a method of scoring bone erosion in the feet of patients with gout using CT as an outcome measure for chronic gout studies, consistent with the components of the OMERACT filter. METHODS Clinical assessment, plain radiographs and CT scans of both feet were obtained from 25 patients with chronic gout. CT scans were scored for bone erosion using a semi-quantitative method based on the Rheumatoid Arthritis MRI Scoring System (RAMRIS). CT bone erosion was assessed at 22 bones in each foot (total 1100 bones) by two independent radiologists. A number of different models were assessed to determine the optimal CT scoring system for bone erosion, incorporating the frequency of involvement and inter-reader reliability for individual bones. RESULTS An optimal model was identified with low number of bones required for scoring (seven bones/foot), inclusion of bones over the entire foot, high reliability and ability to capture a high proportion of disease. This model included the following bones in each foot: first metatarsal (MT) head, second to fourth MT base, cuboid, middle cuneiform and distal tibia (range 0-140). Scores from this model correlated with plain radiographic damage scores (r = 0.86, P < 0.0001) and disease duration (r = 0.42, P < 0.05). Scores were higher in those with clinically apparent tophaceous disease than in those without tophi (P < 0.0001). CONCLUSIONS We have developed a preliminary method of assessing bone erosion in gout using conventional CT. Further testing of this method is now required, ideally in prospective studies to allow analysis of the sensitivity to change of the measure.

Magnetic resonance imaging bone edema is not a major feature of gout unless there is concomitant osteomyelitis: 10-year findings from a high-prevalence population.

Objective. Magnetic resonance imaging (MRI) is commonly used in autoimmune inflammatory arthritis to define disease activity and damage, but its role in gout remains unclear. The aim of our study was to identify and describe the MRI features of gout. Methods. Over a 10-year period we identified patients with gout who underwent MRI scanning of the hands or feet. Scans were reviewed for erosions, synovitis, tenosynovitis, tendinosis, bone edema, and tophi by a musculoskeletal radiologist and 2 rheumatologists in a blinded manner. MRI features in patients with uncomplicated gout were compared with features where concomitant osteomyelitis was diagnosed. Results. A total of 47 patients with gout (51 scans) were included: 33 (70%) had uncomplicated gout and 14 (30%) had gout complicated by osteomyelitis. MRI features included tophi in 36 scans (71%), erosions in 35 (69%), bone edema in 27 (53%), synovitis in 15 (29%), tenosynovitis in 8 (16%), and tendinosis in 2 (4%). Uncomplicated gout and gout plus osteomyelitis did not differ for most MRI features. However, “severe bone marrow edema” was much more common in gout plus osteomyelitis, occurring in 14/15 scans (93%) compared with 3/36 scans (8%) in uncomplicated gout (OR 154.0, 95% CI 14.7–1612, p < 0.0001). Sensitivity and specificity of “severe bone edema” for concomitant osteomyelitis were 0.93 (95% CI 0.68–0.99) and 0.92 (95% CI 0.78–0.98), respectively. Conclusion. MRI reveals that gout affects the joints, bones, and tendons. Bone edema in patients with chronic tophaceous gout is frequently mild and this contrasts with the “severe bone edema” observed in patients with concomitant osteomyelitis.