Diagnostic Considerations of Intermetatarsal Bursitis: A Systematic Review.

Intermetatarsal bursitis (IMB) is an inflammation of the intermetatarsal bursas. The condition causes forefoot pain with symptoms similar to those of Morton's neuroma (MN). Some studies suggest that IMB is a contributing factor to the development of MN, while others describe the condition as a differential diagnosis. Among patients with rheumatic diseases, IMB is frequent, but the scope is yet to be understood. The aim of this paper was to investigate the diagnostic considerations of IMB and its role in metatarsalgia by a systematic review approach. We identified studies about IMB by searching the electronic databases Pubmed, Embase, Cochrane Library, and Web of Science in September 2022. Of 1362 titles, 28 met the inclusion criteria. They were subdivided according to topic: anatomical studies (n = 3), studies of patients with metatarsalgia (n = 10), and studies of patients with rheumatic diseases (n = 15). We conclude that IMB should be considered a cause of pain in patients with metatarsalgia and patients with rheumatic diseases. For patients presenting with spreading toes/V-sign, IMB should be a diagnostic consideration. Future diagnostic studies about MN should take care to apply a protocol that is able to differ IMB from MN, to achieve a better understanding of their respective role in forefoot pain.

Association between IL-6 production in synovial explants from rheumatoid arthritis patients and clinical and imaging response to biologic treatment: A pilot study.

INTRODUCTION: The need for biomarkers which can predict disease course and treatment response in rheumatoid arthritis (RA) is evident. We explored whether clinical and imaging responses to biologic disease modifying anti-rheumatic drug treatment (bDMARD) were associated with the individual's mediator production in explants obtained at baseline. METHODS: RA Patients were evaluated by disease activity score 28 joint C-reactive protein (DAS 28-)), colour Doppler ultrasound (CDUS) and 3 Tesla RA magnetic resonance imaging scores (RAMRIS). Explants were established from synovectomies from a needle arthroscopic procedure prior to initiation of bDMARD. Explants were incubated with the bDMARD in question, and the productions of interleukin-6 (IL-6), monocyte chemo-attractive protein-1 (MCP-1) and macrophage inflammatory protein-1-beta (MIP-1b) were measured by multiplex immunoassays. The changes in clinical and imaging variables following a minimum of 3 months bDMARD treatment were compared to the baseline explant results. Mixed models and Spearman's rank correlations were performed. P-values below 0.05 were considered statistically significant. RESULTS: 16 patients were included. IL-6 production in bDMARD-treated explants was significantly higher among clinical non-responders compared to responders (P = 0.04), and a lack of suppression of IL-6 by the bDMARDS correlated to a high DAS-28 (ρ = 0.57, P = 0.03), CDUS (ρ = 0.53, P = 0.04) and bone marrow oedema (ρ = 0.56, P = 0.03) at follow-up. No clinical association was found with explant MCP-1 production. MIP-1b could not be assessed due to a large number of samples below the detection limit. CONCLUSIONS: Synovial explants appear to deliver a disease-relevant output testing which when carried out in advance of bDMARD treatment can potentially pave the road for a more patient tailored treatment approach with better treatment effects.

Synovial explant inflammatory mediator production corresponds to rheumatoid arthritis imaging hallmarks: a cross-sectional study.

INTRODUCTION: Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans. METHODS: RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1ß (MIP-1ß) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model. RESULTS: Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman's ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman's ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman's ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman's ρ = 0.50), BME score (P = 0.04, approximate Spearman's ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman's ρ = 0.35). MIP-1ß was associated with CDUS activity (P = 0.02, approximate Spearman's ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman's ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance. CONCLUSIONS: The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1ß, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.

Comparison of discrimination and prognostic value of two US Doppler scoring systems in rheumatoid arthritis patients: a prospective cohort study.

OBJECTIVES: The aim of this paper is to investigate sensitivity to change (SRM), predictive validity and discriminative ability of a quantitative (QS) and a semi-quantitative (SQS) Doppler ultrasound scoring systems in patients with rheumatoid arthritis (RA) treated with anti-TNF-α therapy. METHODS: RA patients with wrist joint affection treated with TNF-α inhibitor were followed for one year. The wrist was examined with Doppler before initiating therapy and after one year. DAS28 was determined at both visits. One person trained in the SQS system and one in the QS system evaluated the anonymised images. The SRM, predictive validity and discriminative ability for both systems were calculated using DAS28 as the measure of disease improvement. RESULTS: Fourty-six patients with RA (80% females) were included. The mean Doppler activity at baseline was QS:24.4% (SD=17.7%) and SQS:2.0 (SD=0.6). A decrease in Doppler activity was seen for both systems after anti-TNF-α therapy. Sensitivity to change was seen, SRM=-0.52 (95%CI; -0.83 to -0.21; QS) and -0.24 (-0.53 to -0.05; SQS). Predictive value was poor (QS rs=-0.24; SQS rs=-0.05). Construct validity was; QS: rs=0.29, SQS: rs=0.23. CONCLUSIONS: Both systems were to some extent sensitive to change. Predictive validity and discriminate capacity of both systems showed only a weak association to DAS 28 in the study population. The QS was a little superior to the SQS. The results do not necessarily reflect Doppler evaluation as being ineffective, but may be caused by DAS28 not being a perfect marker of inflammation.

Ultrasound colour Doppler is associated with synovial pathology in biopsies from hand joints in rheumatoid arthritis patients: a cross-sectional study.

OBJECTIVES: Little is known regarding the association between ultrasound-determined pathological synovial blood flow and synovial pathology in rheumatoid arthritis (RA). We therefore examined the association between colour Doppler ultrasound imaging and synovitis assessed by histopathology and specific cell markers by immunohistochemistry in patients with RA. METHODS: 81 synovial sites from wrist and finger joints from 29 RA patients were evaluated by ultrasound colour Doppler and subsequently biopsied by needle arthroscopy. The association between ultrasound colour fraction and an overall synovitis score and immunohistochemical staining for CD3, CD68, Ki67 and von Willebrand factor was investigated, including repeated samples from the same patients. The overall synovitis score (total 0-9) assessed synovial lining hyperplasia (0-3), stromal activation (0-3) and inflammatory infiltration (0-3). Data were clustered within patients, thus a linear mixed model was applied for the statistical tests. Parsimony in the statistical models was achieved omitting covariates from the model in the case of what was judged no statistical significance (p>0.1). RESULTS: Doppler colour fraction showed an association with the overall synovitis score (approximated Spearman, approximately r=0.43, p=0.003). The density of all immunohistochemical stainings showed a significant association with Doppler colour fraction: von Willebrand factor (approximately r=0.44, p=0.01), CD68 (approximately r=0.53, p=0.02), Ki67 (approximately r=0.57, p=0.05) and CD3 (approximately r=0.57, p=0.0003). CONCLUSIONS: Colour Doppler activity is associated with the extent of inflammation present in the synovial biopsies from RA patients. However, synovial pathology was also seen in biopsies taken from Doppler negative sites.

Evidence of accumulated stress in Achilles and anterior knee tendons in elite badminton players.

Tendon-related injuries are a major problem, but the aetiology of tendinopathies is unknown. In tendinopathies as well as during unaccustomed loading, intra-tendinous flow can be detected indicating that extensive loading can provoke intra-tendinous flow. The aim of present study is to evaluate the vascular response as indicated by colour Doppler (CD) activity in both the Achilles and patella tendon after loading during high-level badminton matches. The Achilles tendon was subdivided into a mid-tendon, pre-insertional, and insertional region and the anterior knee tendons into a quadriceps-, patella- and tuberositas region. Intra-tendinous flow was measured using both a semi-quantitative grading system (CD grading) and a quantitative scoring system (CF) on colour Doppler. Intra-tendinous flow in the Achilles and anterior knee tendons was examined in fourteen single players before tournament and after 1st and 2nd match, respectively on both the dominant and non-dominant side. All players had abnormal intra-tendinous flow (Colour Doppler ≥ grade 2) in at least one tendon in at least one scan during the tournament. At baseline, only two of the 14 players had normal flow in all the tendons examined. After 1st match, tendencies to higher intra-tendinous flow were observed in both the dominant patella tendon and non-dominant quadriceps tendon (P-values n.s.). After 2nd match, intra-tendinous flow was significant increased in the dominant patella tendon (P = 0.009). In all other locations, there was a trend towards a stepwise increase in intra-tendinous flow. The preliminary results indicate that high amount of intra-tendinous flow was found in elite badminton players at baseline and was increased after repetitive loading, especially in the patella tendon (dominant leg). The colour Doppler measurement can be used to determine changes in intra-tendinous flow after repetitive loading.

Ultrasound Doppler measurements predict success of treatment with anti-TNF-α drug in patients with rheumatoid arthritis: a prospective cohort study.

OBJECTIVE: To investigate the predictive ability of core outcomes applied in RA trials, including ultrasound (US) Doppler (USD) measurements differentiating patients who remain on anti-TNF-α therapy following 1 year. METHODS: Patients with RA in anti-TNF-α therapy were followed 1 year after therapy initiation. All patients had wrist involvement. At baseline, 2 weeks, 26 weeks and 1 year a USD examination, clinical examination including tender and swollen joint count, visual analogue scale (VAS) global and HAQ, biochemical measures and 28-joint DAS (DAS28) were collected for all patients. The amount of USD signal in the synovium was quantified by measuring the percentage of colour pixels-the colour fraction (CF). Predictive validity for patients who remain on anti-TNF-α therapy after 1 year was assessed for both USD measurements and other disease measures. Baseline values of disease measures of patients who remained on treatment after 1 year was compared with those who stopped therapy. RESULTS: The study cohort consisted of 109 patients. In this study, the baseline CF was the only measure predicting which patients would stay on the initial anti-TNF-α therapy for 1 year, evaluated using the square-root of CF (P = 0.024). The other disease markers could not significantly differentiate between the two groups of patients, with P-values of 0.86 and 0.98 for tender and swollen joint count, respectively, 0.86 for CRP, 0.24 for VAS, 0.10 for HAQ and 0.38 for DAS28. CONCLUSION: There is now evidence to support that baseline USD, in contrast to clinical measures, can predict which patients will remain on anti-TNF-α 1 year after initiating therapy.

Signal intensity of normal breast tissue at MR mammography on midfield: applying a random coefficient model evaluating the effect of doubling the contrast dose.

PURPOSE: To prospectively investigate the effect on signal intensity (SI) of healthy breast parenchyma on magnetic resonance mammography (MRM) when doubling the contrast dose from 0.1 to 0.2 mmol/kg bodyweight. MATERIALS AND METHODS: Informed consent and institutional review board approval were obtained. Twenty-five healthy female volunteers (median age: 24 years (range: 21-37 years) and median bodyweight: 65 kg (51-80 kg)) completed two dynamic MRM examinations on a 0.6T open scanner. The inter-examination time was 24 h (23.5-25 h). The following sequences were applied: axial T2W TSE and an axial dynamic T1W FFED, with a total of seven frames. At day 1, an i.v. gadolinium (Gd) bolus injection of 0.1 mmol/kg bodyweight (Omniscan) (low) was administered. On day 2, the contrast dose was increased to 0.2 mmol/kg (high). Injection rate was 2 mL/s (day 1) and 4 mL/s (day 2). Any use of estrogen containing oral contraceptives (ECOC) was recorded. Post-processing with automated subtraction, manually traced ROI (region of interest) and recording of the SI was performed. A random coefficient model was applied. RESULTS: We found an SI increase of 24.2% and 40% following the low and high dose, respectively (P<0.0001); corresponding to a 65% (95% CI: 37-99%) SI increase, indicating a moderate saturation. Although not statistically significant (P=0.06), the results indicated a tendency, towards lower maximal SI in the breast parenchyma of ECOC users compared to non-ECOC users. CONCLUSION: We conclude that the contrast dose can be increased from 0.1 to 0.2 mmol/kg bodyweight, if a better contrast/noise relation is desired but increasing the contrast dose above 0.2 mmol/kg bodyweight is not likely to improve the enhancement substantially due to the moderate saturation observed. Further research is needed to determine the impact of ECOC on the relative enhancement ratio, and further studies are needed to determine if a possible use of ECOC should be considered a compromising factor, if an MRM is indicated in a young woman.

Biopsy guided by real-time sonography fused with MRI: a phantom study.

OBJECTIVE: The purpose of our study was to test the accuracy of sonographically guided biopsies in a phantom of structures not visible on sonography but shown on MRI by using commercially available sonography systems with image fusion software. MATERIALS AND METHODS: A previously recorded MRI examination from a custom-made phantom was loaded into the sonography system. The phantom contained spheres that were invisible to sonography and contained red dye. The red dye was visible in the biopsy if it was successful. The images were coregistered using structures visible on both sonography and MRI, and biopsies were taken. The biopsy procedure was continued until a biopsy was successful, and the number of needle passes and time spent were registered. RESULTS: A total of 130 targets were hit. Ten minutes was used for loading the MRI data set and the coregistration; 94 of the 130 biopsies (72.3%) were successful at the first needle pass. The median number of needle passes until a successful biopsy was obtained was one (range, 1-7). CONCLUSION: The described method was successful in obtaining an adequate sample in a phantom.

Clinical outcome and imaging changes after intraarticular (IA) application of etanercept or methylprednisolone in rheumatoid arthritis: magnetic resonance imaging and ultrasound-Doppler show no effect of IA injections in the wrist after 4 weeks.

OBJECTIVE: To assess the magnetic resonance imaging (MRI) and ultrasound (US) changes in the wrist of patients with rheumatoid arthritis (RA) 4 weeks after an US guided intraarticular (IA) injection. METHODS: Contrast enhanced MRI and US-Doppler were performed at baseline and 4 weeks after IA injection of either 40 mg methylprednisolone (n = 12) or 25 mg etanercept (n = 13) in 25 patients with RA taking disease modifying antirheumatic drugs with a therapy-resistant wrist joint. All injections were US guided. RESULTS: There was an improvement in swollen target joint score (p < 0.001), tender target joint score (p < 0.002), and physician visual analog scale score (p < 0.001) after 4 weeks. Baseline MRI synovitis score was mean 5.08 (range 3-9) and was unchanged at followup in the whole group (p = 0.52) and between treatment groups (p = 0.43). MRI edema score (mean 4.46, range 0-29) in the total group was unchanged after 4 weeks (p = 0.13), whereas MRI erosion score increased in the total group from baseline, 17.88 (range 7-40), to 4 weeks, 18.25 (range 7-40) (p < 0.001). Neither US-Doppler color fraction (0.07) nor Resistive Index (RI) (p = 0.36) changed from baseline to 4 week followup. CONCLUSION: In contrast to the clinical evaluation, imaging measures of relevance for the estimation of inflammation, US-Doppler, US RI, MRI synovitis, and bone-marrow edema did not change 4 weeks after a single IA injection of either methylprednisolone or etanercept in the wrist. Within the same period, erosive progression in some patients suggested that joints with active disease may deteriorate within as little as 1 month, and that this development is not arrested by 1 injection. Given the small sample size of our study further studies are required to confirm our results.

Contrast kinetics of the malignant breast tumour--border versus centre enhancement on dynamic midfield MRI.

PURPOSE: To quantify the border versus centre enhancement of malignant breast tumours on dynamic magnetic resonance mammography. MATERIALS AND METHODS: Fifty-two women diagnosed with primary breast cancer underwent dynamic magnetic resonance mammography (Omniscan 0.2 mmol/kg bodyweight) on a midfield scanner (0.6 T), prior to surgery. The following five variables were recorded from the border and centre regions of the tumours: Early Enhancement, Time to Peak, Wash-in rate, Wash-out rate and Area under Curve. Information on histology type, oestrogen and progesterone receptor status was collected. Statistical analysis was performed in SAS 9.1 as paired samples t-tests. RESULTS: Fifty of 52 malignant tumours displayed a faster Early Enhancement in the border region compared to the centre (p<0.0001). Significant differences between the border and centre values were found for Time to Peak, Wash-in rate, Wash-out rate and Area under Curve. Hormone receptor positive tumours displayed an over-all highly significant difference between border and centre enhancement, whereas no significant differences for any of the five variables were recorded in neither oestrogen nor progesterone hormone receptor negative tumours. CONCLUSION: The border/centre enhancement difference in malignant breast tumours is easily visualized on midfield dynamic magnetic resonance mammography. The dynamic behaviour is significantly correlated to histological features and receptor status of the tumours.

Colour doppler ultrasonography and sclerosing therapy in diagnosis and treatment of tendinopathy in horses-a research model for human medicine.

Sclerosing therapy has in recent studies showed promising results in patients with clinically and ultrasonographically diagnosed tendinosis in Achilles and patellar tendons. The aim of this investigation was to study the presence of intratendinous colour Doppler (CD) flow in horses with clinically diagnosed chronic tendinopathy and to test if experience from human studies could be extrapolated to horses. Special interest was focused on the treatment with sclerosing therapy and whether we could obtain the same successful peroperative findings as in humans. Four horses with clinically diagnosed unilateral chronic tendinosis in the forelimbs were examinated with both grey-scale ultrasonography (US) and CD. The horses were to be euthanised according to standard procedure is such cases. The US findings were used for guidance of sclerosing therapy. All horses showed abnormal findings on US, especially intratendinous neovascularisation in the affected limb but not in the contralateral limb. The CD findings had the same appearance as seen in human Achilles tendons with chronic tendinopathy. In all cases the intratendinous neovascularisation was successfully "shut down" peroperatively. The horses showed no signs of discomfort or worsening of symptoms during the short follow-up period after the procedure. The results indicate that the promising results from human medicine might be transferred to treatment of horses with chronic tendinopathy. In the future it will hopefully be possible to use the model from overused tendons in the horse to determine the best treatment of overuse injuries in humans as well. The animal model will allow experimental studies including substantial tissue sampling for mechanical and molecular biological analysis.

Acute rotator cuff tear: do we miss the early diagnosis? A prospective study showing a high incidence of rotator cuff tears after shoulder trauma.

The aim of this study was to evaluate the epidemiologic data of patients with an acute soft-tissue injury to the shoulder, with an emphasis on improving the early diagnosis of acute rotator cuff tears. This study included 104 patients, with a median age of 49 years (range, 19-75 years). The patients were evaluated clinically and with ultrasonography at a median of 13 days (range, 3-49 days) after the injury. A total of 60 patients (58%) had some degree of cuff lesion on the ultrasonographic examination. Of these patients, 33 (32%) had a full-thickness rotator cuff tear, 14 (13%) had a partial-thickness cuff tear in the tendon substance, and 13 (13%) had a partial cuff tear at the insertion site on the major tubercle. The injury mechanism or activity at the moment of injury did not correlate with the presence of a rotator cuff lesion, but we found a strong age correlation, with a prevalence of any rotator cuff tear, above 50%, for patients aged above 50 years and with a prevalence of full-thickness tears of 50% in the groups aged 50 to 59 years and aged 60 to 69 years. In conclusion, this study found a high incidence of rotator cuff lesions by further evaluation of patients undergoing consultation at the emergency department, with an inability to perform active abduction above 90 degrees and normal radiographs, after an acute shoulder trauma.

Safety of intra-articular injection of etanercept in small-joint arthritis: an uncontrolled, pilot-study with independent imaging assessment.

This study was conducted to test the safety of intra-articular tumor necrosis factor alpha (TNF-alpha) antagonists in small joints with arthritis. A dose of 2-8 mg etanercept was given intra-articularly guided by ultrasonography (US) in 26 patients with a flare of arthritis in a particular joint (16 wrists, two elbows, two ankles, six finger joints). Primary end points were imaging analyses by independent investigators: US-Doppler measurements were performed in all patients before and after the injection and MRI before and after were obtained in nine patients. The only adverse event was a case of swelling of the hand lasting 2 days after a wrist injection. Two patients had a supplementary glucocorticoid injection and were excluded from efficacy analysis after 4 days and 3 weeks, respectively. VAS for pain decreased after 1 week in 23 of 25 patients (median 0.62), and after 1 month in 14 of 24 patients (median 0.60). No significant changes were seen in erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). On MRI, all nine cases tested had a reduction in synovial thickness (P=0.008) and US Doppler signals diminished after treatment (resistance index (RI) P=0.02, pixels P=0.09). In conclusion, intra-articular injection of etanercept gave no noticeable adverse events.

Ultrasonography and articular cartilage defects in the knee: an in vitro evaluation of the accuracy of cartilage thickness and defect size assessment.

The purpose of this cadaver study was to test the accuracy of ultrasonography in measuring cartilage thickness, and the extent and depth of induced cartilage defects on the medial and lateral femoral condyles of the knee in a clinically relevant setting. With the knees maximally flexed, cartilage thickness was measured at 24 marked sites in four knees with a 10 MHz probe. The areas of measurement were then excised and the thickness measured with a calliper gauge. In another seven cadaver knees, 21 cartilage defects were produced. The defect diameter varied from 4 to 8 mm. The depths of the defects were either a partial cartilage defect (grade 2), a defect to intact subchondral bone (grade 3), or a defect involving subchondral bone (grade 4) (classification by ICRS). The limits of agreement between ultrasonography and calliper gauge measurement for cartilage thickness were chi(diff)+/-2SD(diff)=0.0+/-0.4 mm. For cartilage defect diameter, the limits of agreement between ultrasonography and the slide ruler measurement were chi(diff)+/-2SD(diff)=-0.2+/-1.0 mm. For the depths of the lesions there was a 100% agreement between radiologist and actual lesion depth for the classification into International Cartilage Repair Society (ICRS) grades 2, 3, and 4. Our conclusion is that ultrasonography is capable of measuring accurately both cartilage thickness and the extent and depth of induced cartilage defects in a cadaver model.