Exploring cartilage damage in gout using 3-T MRI: distribution and associations with joint inflammation and tophus deposition.

OBJECTIVE: Few imaging studies have investigated cartilage in gout. Magnetic resonance imaging (MRI) can image cartilage damage and also reveals other features of gouty arthropathy. The objective was to develop and validate a system for quantifying cartilage damage in gout. METHODS: 3-T MRI scans of the wrist were obtained in 40 gout patients. MRI cartilage damage was quantified using an adaptation of the radiographic Sharp van der Heijde score. Two readers scored cartilage loss at 7 wrist joints: 0 (normal), 1 (partial narrowing), 2 (complete narrowing) and concomitant osteoarthritis was recorded. Bone erosion, bone oedema and synovitis were scored (RAMRIS) and tophi were assessed. Correlations between radiographic and MRI cartilage scores were investigated, as was the reliability of the MRI cartilage score and its associations. RESULTS: The GOut MRI Cartilage Score (GOMRICS) was highly correlated with the total Sharp van der Heijde (SvdH) score and the joint space narrowing component (R = 0.8 and 0.71 respectively, p < 0.001). Reliability was high (intraobserver, interobserver ICCs = 0.87 [0.57-0.97], 0.64 [0.41-0.79] respectively), and improved on unenhanced scans; interobserver ICC = 0.82 [0.49-0.95]. Cartilage damage was predominantly focal (82% of lesions) and identified in 40 out of 280 (14%) of joints. Cartilage scores correlated with bone erosion (R = 0.57), tophus size (R = 0.52), and synovitis (R = 0.55), but not bone oedema scores. CONCLUSIONS: Magnetic resonance imaging can be used to investigate cartilage in gout. Cartilage damage was relatively uncommon, focal, and associated with bone erosions, tophi and synovitis, but not bone oedema. This emphasises the unique pathophysiology of gout.

Effect of glacial acetic acid pre-treatment of cervical liquid-based cytology specimens on the molecular detection of human papillomavirus.

OBJECTIVE: Cytology laboratories routinely treat cervical liquid-based cytology (LBC) specimens that are heavily contaminated with blood with glacial acetic acid (GAA) in order to lyse red blood cells and facilitate assessment. However, the impact on downstream human papillomavirus (HPV) detection is not well understood. This study examines the effect of GAA pre-treatment of ThinPrep(®) Preservcyt(®) specimens on the molecular detection of HPV. METHODS: A panel of 150 routinely collected cervical LBC specimens was tested with two commercial HPV tests, the Abbott RealTime High Risk HPV test (rtHPV) and the Qiagen Hybrid Capture 2 High Risk HPV DNA test (HC2), as aliquots before and after GAA treatment. Statistical analysis was performed using McNemars test and Bland and Altman plots. RESULTS: Agreement between the results of the rtHPV test on GAA-untreated and GAA-treated specimens was 95.7%, with no evidence of a significant difference in the distribution of the discrepant results (P = 0.414). HC2 test agreement on GAA-untreated and GAA-treated specimens was 91% at a cut-off of 1 relative light unit index (RLUI) and 92% at a cut-off of 2 RLUI. There was no evidence of a difference in the distribution of discordant results at a cut-off of 1 (P = 0.405) and 2 RLUI (P = 0.564). CONCLUSIONS: GAA pre-treatment of cervical ThinPrep Preservcyt LBC specimens had little effect on the two commercial HPV tests used in this study. The impact of GAA treatment on HPV testing should, however, be validated for all HPV tests and all LBC collection media used in each particular diagnostic setting.

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.

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.

The Health Assessment Questionnaire Disability Index is a valid measure of physical function in gout.

OBJECTIVE: There are no disability instruments that have specifically been validated for gout. The aim of this study was to determine the construct validity of the Health Assessment Questionnaire Disability Index (HAQ-DI) in gout and the internal validity using Rasch analysis. METHODS: An observational cohort study of two groups of clinic patients with gout (n=20, n=53), in which clinical and functional measures were correlated with HAQ-DI scores. Rasch analysis was used to determine the internal validity of summated scores as a measure of physical disability. RESULTS: The HAQ-DI items fitted a Rasch measurement model, confirming internal validity of the scale, although there was evidence of disordered thresholds and rescoring items as a 3-option response rather than a 4-option response improved model fit and resolved the disordered thresholds. HAQ-DI scores showed a bimodal distribution and evidence of floor effects. Clinical indices correlated highly with HAQ-DI scores in gout patients, particularly other measures of physical function. A strong relationship between days of sick leave and HAQ-DI was observed in gout patients (r2=0.44, p<0.001). CONCLUSIONS: It is concluded that HAQ-DI has good construct and internal validity in gout but a modified scoring approach better fits a Rasch model.

Disease Activity Score 28-ESR bears a similar relationship to treatment decisions across different rheumatologists, but misclassification is too frequent to replace physician judgement.

OBJECTIVES: To determine whether physician factors are associated with disease activity status in RA, independently of 28-joint disease activity score (DAS28)-ESR and to re-evaluate DAS28-ESR misclassification rates for identifying active disease in usual practice. METHODS: A prospective observational study of outpatients with RA seen by 17 rheumatologists across New Zealand. Active disease was defined by an increase in therapy together with a reason of 'active disease'; very low disease activity was defined by a decrease in therapy together with a reason of 'patient well'. The independent physician effect was assessed using logistic regression. Sensitivity and specificity of current DAS28-ESR thresholds were calculated. RESULTS: In 511 patients, 178 had active disease, 220 had low disease activity, 37 had very low disease activity and 76 had uncertain disease activity status. There was no independent effect of physician upon active disease status (P = 0.16) with DAS28-ESR [(OR) 3.7] explaining around 50% of the variability in active disease status. There was a trend towards an independent effect of physician upon very low disease activity status (P = 0.06) and greater variability in the distribution of DAS28-ESR for patients in very low disease activity. DAS28-ESR thresholds showed a significant risk of misclassification for active disease. CONCLUSIONS: DAS28-ESR discriminates satisfactorily between groups of patients with active and non-active disease, with no evidence of additional physician-specific factors to explain disease activity status. However, DAS28-ESR is not as good for discriminating remission from non-remission status. There are appreciable probabilities of misclassification error, which make DAS28-ESR inappropriate as a sole guide for treatment decisions.

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout.

OBJECTIVES: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). METHODS: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. RESULTS: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except "total body urate pool". Additional domains were suggested and clarification sought for defining "joint inflammation" and "musculoskeletal function". Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1-2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. CONCLUSIONS: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

Functional MRI in NPSLE patients reveals increased parietal and frontal brain activation during a working memory task compared with controls.

OBJECTIVES: Anatomical MRI brain scans may not reflect neurological dysfunction in patients with NPSLE. We used blood-oxygen-level-dependent functional MRI (BOLD-fMRI) to investigate working memory function in NPSLE patients. METHODS: Twenty-seven females took part: nine NPSLE patients (mean age 40 yrs; SLEDAI 10.9); nine RA patients and nine healthy controls. Subjects were tested using the n-back paradigm for working memory, where patients indicate when a stimulus matches one presented n trials previously. Functional scans used 3 mm slices x 30, repetition time 2570 ms, echo time 50 ms. Echo planar images were superimposed onto T1w anatomical images (Siemens 1.5 T). Data analysis used Brain Voyager QX Version 1.7. RESULTS: During the memory task, there was activation in areas serving working memory, executive function and attention in all groups. Nine regions of interest were selected for activation during working memory (N-back task vs fixation, P < or = 0.005). In six out of nine regions, there was greater activation in the NPSLE group. This reached significance in three regions: the posterior inferior parietal lobules of both hemispheres [Brodmann area (BA) 7] separately and combined (P = 0.014, 0.016 and 0.004, respectively), and the supplementary motor area (mid-line frontal lobe) (BA32/6; P = 0.032). CONCLUSIONS: NPSLE patients showed greater frontoparietal activation than the other groups during the memory task, suggesting a greater need to recruit extra cortical pathways, possibly to supplement impaired function of standard pathways.

Tophaceous joint disease strongly predicts hand function in patients with gout.

OBJECTIVES: The functional impact of gout is poorly understood. The aim of this study was to determine predictors of hand function in gout. METHODS: Twenty unselected patients with gout were recruited from rheumatology clinics. No patient had an acute gout flare at assessment. Participants were assessed for clinical characteristics of gout, including the site and number of tophi. Hand function was assessed by the Sollerman hand function test. Fingertip to palm (FTP) distance measurement, grip strength and the Disability Assessment of Shoulder and Hand (DASH) questionnaire scores were also recorded. Data were analysed by simple and multiple linear regression models. RESULTS: The median Sollerman score was 75.5 (range 31-80). The median hand FTP distance was 2.91 (0.88-6.69) cm, grip strength was 31 (4-71) kg, and DASH score was 28.77 (0-76.47). Of the clinical characteristics measured, the number of joints of the hand with overlying tophi (hand tophus joint count) was the strongest single predictor of the Sollerman score (r2 = 0.59), and also predicted the other measures of hand mobility and function. A multiple regression model including hand tophus joint count, sex, number of gout flares in the preceding 6 months, gout disease duration and hand tender joint count was a better predictor of the Sollerman score than hand tophus joint count alone (r2 = 0.81, F(4,14) = 3.94, P = 0.024). CONCLUSIONS: Measures of chronic and poorly controlled disease predict hand function in patients with gout. In particular, tophaceous joint disease has a major impact on functional capacity in gout.

High-grade MRI bone oedema is common within the surgical field in rheumatoid arthritis patients undergoing joint replacement and is associated with osteitis in subchondral bone.

OBJECTIVES: MRI bone oedema has been observed in early and advanced RA and may represent a cellular infiltrate (osteitis) in subchondral bone. We studied MRI scans from RA patients undergoing surgery, seeking to identify regions of bone oedema and examine its histopathological equivalent in resected bone. METHODS: Preoperative contrast-enhanced MRI scans were obtained in 11 RA patients scheduled for orthopaedic surgery to the hands/wrists or feet. In 9, MRI scans were scored by 2 readers for bone oedema (RAMRIS system). Its distribution with respect to surgical site was investigated. In 4 patients, 7 bone samples were examined for a cellular infiltrate, and this was compared with MRI bone oedema, scored for spatial extent and intensity. RESULTS: Inter-reader intraclass correlation coefficients for bone oedema were 0.51 (all sites) and 0.98 (bone samples for histology). Bone oedema was observed at 60% of surgical sites vs 38% of non-surgical sites. High-grade bone oedema (score >/=50% maximum) was strongly associated with the surgical field (OR 9.3 (3.5 to 24.2), p<0.0001). Bone oedema scores correlated with pain (r = 0.67, p = 0.048) and CRP (r = 0.86, p = 0.01). In 4 of the 7 bone samples, there was concordance between bone oedema and subchondral osteitis. In 3, there was no MRI bone oedema, and osteitis was "slight". CONCLUSION: High-grade MRI bone oedema was common within the field of intended surgery and associated with pain. There was concordance between the presence and severity of MRI bone oedema and osteitis on histology, with an MRI threshold effect due to differences in image resolution.

Using a quality control approach to define an 'adequately cellular' liquid-based cervical cytology specimen.

OBJECTIVE: To define a minimum acceptable total squamous cellularity for (ThinPrep) liquid-based cervical cytology (LBC) specimens using quality control techniques. METHODS: Two hundred LBC preparations were made containing varying numbers (<200) of severely dyskaryotic squamous cells and with varying total cellularities. RESULTS: Ninety-eight per cent of the LBC preparations that were missed by one or more of three cytoscreeners had fewer than 16 abnormal objects (single dyskaryotic cells or clumps of cells) and 87 dyskaryotic cells. The minimum ratio of dyskaryotic to total squamous cells that, in a preparation of 5000 squamous cells has a probability of at least 0.98 that 87 or more dyskaryotic cells will be present is 1:47. Twenty-three preparations diagnosed as abnormal had ratios of dyskaryotic to total squamous cells of between 1:2.5 and 1:4596. There is thus no feasible minimum acceptable squamous cellularity that will give an acceptable probability of detection of all specimen vials containing abnormal cells in the observed proportions. CONCLUSIONS: It is suggested that the minimum acceptable cellularity for LBC specimens is set pragmatically by the screening programme to give a feasible percentage of repeat tests.

MRI bone oedema predicts eight year tendon function at the wrist but not the requirement for orthopaedic surgery in rheumatoid arthritis.

OBJECTIVE: To investigate the role of early magnetic resonance imaging (MRI) of the wrist in predicting functional outcome in rheumatoid arthritis. METHODS: MRI scans of the dominant wrist were scored for synovitis, tendon inflammation, bone oedema, and erosion at first presentation (n = 42), at 1 year (n = 42), and at 6 years (n = 31). At 8 years, clinical reassessment (n = 28) was undertaken. Tendon function was graded 0-3 for movement, tendon sheath swelling, and pain on resistance at nine flexor and extensor tendons of the hand. Hand function was also assessed using the Sollerman grip test. The requirement for joint or tendon surgery by 8 years was determined by telephone survey in 39 of the original 42 patients. RESULTS: At 8 years, tendon function was highly correlated with hand function (Sollerman score, R = -0.51, p = 0.005) and global function (health assessment questionnaire score, R = 0.53, p = 0.004). Using a model incorporating baseline and 1 year MRI scores, the MRI bone oedema score was strongly predictive of tendon function at 8 years (chi(2)(2) = 15.3, p = 0.0005), as was the MRI bone erosion score (chi(2)(2) = 9.23, p = 0.01). Hand function was also predicted by the baseline MRI erosion score (p = 0.02). MRI variables did not predict the requirement for surgery, but patients who had surgery were more likely to show progression of MRI bone erosion scores between baseline and 1 year (p = 0.008). CONCLUSIONS: Extensive MRI bone oedema and erosions at the wrist in early rheumatoid arthritis predict tendon dysfunction and impaired hand function in the medium term but not the requirement for joint or tendon surgery.

The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the metacarpophalangeal joints.

This paper presents the metacarpophalangeal (MCP) joint magnetic resonance images of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. The illustrations include synovitis in the MCP joints (OMERACT RA magnetic resonance imaging scoring system (RAMRIS), grades 0-3), bone oedema in the metacarpal head and the phalangeal base (grades 0-3), and bone erosion in the metacarpal head and the phalangeal base (grades 0-3, and examples of higher grades). The presented reference images can be used to guide scoring of MCP joints according to the OMERACT RA MRI scoring system.

The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the wrist joint.

This paper presents the wrist joint MR images of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. Reference images for scoring synovitis, bone oedema, and bone erosions according to the OMERACT RA MRI scoring (RAMRIS) system are provided. All grades (0-3) of synovitis are illustrated in each of the three wrist joint areas defined in the scoring system--that is, the distal radioulnar joint, the radiocarpal joint, and the intercarpal-carpometacarpal joints. For reasons of feasibility, examples of bone abnormalities are limited to five selected bones: the radius, scaphoid, lunate, capitate, and a metacarpal base. In these bones, grades 0-3 of bone oedema are illustrated, and for bone erosion, grades 0-3 and examples of higher grades are presented. The presented reference images can be used to guide scoring of wrist joints according to the OMERACT RA MRI scoring system.