Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia.

INTRODUCTION: Interstitial, cartilage, and bone collagens have been proposed as biomarkers of joint deterioration in hemophilic arthropathy. The role of basement membrane (type IV and VIII) collagens as biomarkers of endothelial turnover in relation to acute joint bleeding is not understood. METHODS: Thirty-one adult patients with hemophilia were studied prospectively for 3 years with musculoskeletal ultrasound/power Doppler (MSKUS/PD) during pain-free intervals and painful events for joint bleed status, synovial vascular flow, and 10 plasma markers of collagen turnover. Joint health was determined using Hemophilia Joint Health Scores and Pettersson scores. In animal studies, bleeding was induced in factor VIII-/- mice by knee joint injury. Synovial vascular remodeling was assessed using MSKUS/PD and histology. Murine plasma samples were analyzed for type IV collagen turnover markers. RESULTS: Ninety-one patient visits were compiled. Twenty-five were due to acute painful episodes, with 16 confirmed hemarthroses. Type IV collagen turnover markers (PRO-C4 and C4M), and a type VIII collagen synthesis marker (PRO-C8), were transiently elevated during acute hemarthrosis. Hemarthrosis was accompanied by increased synovial microvascular flow (MSKUS/PD), and levels of type IV collagen markers correlated with PD signals in the joint. In factor VIII-deficient mice, plasma levels of type IV collagen turnover markers correlated negatively with synovial αSMA staining, indicating that reduced type IV collagen turnover was associated with thicker vessels. CONCLUSIONS: Our findings suggest that basement membrane turnover markers, closely linked to synovial vascular remodeling, may be systemic biomarkers of acute hemarthrosis. Vascular instability during neovascularization may be involved in the dynamics of hemarthrosis.

Dysbaric osteonecrosis (DON) among the artisanal diving fishermen of Yucatán, Mexico.

INTRODUCTION: Artisanal diving fishermen in Yucatán, Mexico have high rates of decompression sickness as a result of frequently unsafe diving practices with surface supplied compressed air. In this study, we investigated the prevalence of dysbaric osteonecrosis (DON), a type of avascular necrosis, in the most susceptible joints in a cohort of these fishermen. METHODS: We performed radiographs of bilateral shoulders, hips, and knees of 39 fishermen in Mexico and surveyed them about their medical and diving histories. We performed pairwise correlations to examine if the fishermen's diving behaviours affected the numbers of joints with DON. RESULTS: The radiographs revealed Grade II or higher DON in 30/39 (76.9%) of the fishermen. Twenty-two of 39 fishermen (56.4%) had at least two affected joints. The number of joints with DON positively correlates with the lifetime maximum diving depth and average bottom time. CONCLUSIONS: These findings represent among the highest prevalence rates of DON in divers and reflect the wide-spread scale of decompression sickness among these fishermen. Through this work, we hope to further educate the fishermen on the sequelae of their diving with the aim of improving their diving safety.

Rebound Vertebral Fractures in a Patient With Lung Cancer After Oncology-Dose Denosumab Discontinuation: A Cautionary Tale.

We describe a 55-year-old woman with lung cancer complicated by bone metastases. Treatment with denosumab (120 mg monthly) was interrupted after 9 doses because of concern for potential osteonecrosis of the jaw during upcoming dental work. Fifteen months after receiving the last dose of denosumab, the patient presented with 7 atraumatic spinal compression fractures requiring kyphoplasty for symptom relief. No malignancy was found in pathology specimens. Evaluation for secondary causes of osteoporosis was negative. This phenomenon of rebound fractures after discontinuing the use of denosumab, an inhibitor of RANK ligand, has been well described in patients with osteoporosis, who receive much lower doses than do patients with cancer. However, this has not been previously reported in oncology patients, likely because most succumb to their disease before denosumab therapy is stopped.

Development and Reliability of the Joint Tissue Activity and Damage Examination for Quantitation of Structural Abnormalities by Musculoskeletal Ultrasound in Hemophilic Joints.

OBJECTIVES: Musculoskeletal ultrasound (US) is used increasingly to examine hemophilic arthropathy. However, quantitative algorithms to document findings are lacking. We developed and sought to validate a protocol quantifying hemophilic joint abnormalities. METHODS: Thirty-one patients with hemophilia were examined serially for 2 years with musculoskeletal US (≈600 joint examinations and ≈6000 images). Based on the spectrum of pathologies, a quantitative algorithm, named Joint Tissue Activity and Damage Examination (JADE), was developed for soft tissue and osteochondral measurements, including power Doppler, using nominal group techniques. To study intra- and inter-rater reliability, 8 musculoskeletal US-experienced hemophilia providers performed anatomic landmark recognition and tissue measurements on 86 images with arthropathic changes, with repetition 1 month later. Twenty-three musculoskeletal US-inexperienced providers performed similar assessments. Inter-operator reliability was established by 6 musculoskeletal US-experienced hemophilia providers, each acquiring images and JADE assessments of 3 hemophilic arthropathic joints. A radiologist and musculoskeletal sonographer functioned as adjudicators. The statistical analysis was performed with the intraclass correlation coefficient (ICC), Fleiss κ, and Cohen κ where appropriate. RESULTS: The musculoskeletal US-experienced providers showed excellent intra-and inter-rater reliability for tissue measurements (ICCs, 0.94-0.96). Agreement was good to excellent for landmark recognition (Fleiss κ, 0.87-0.94). Inter-operator reliability was excellent for measurements and landmark recognition (ICC, 0.90; Fleiss κ, 1.0). Agreement with adjudicators was mostly good to excellent. Musculoskeletal US-inexperienced providers showed excellent inter-rater reliability for measurements (ICC, 0.96) and moderate agreement for landmark recognition (Fleiss κ, 0.58). CONCLUSIONS: The JADE protocol appears feasible for quantifying hemophilic intra-articular abnormalities. Musculoskeletal US-trained hemophilia providers showed high intra-rater, inter-rater, and inter-operator reliability, supporting JADE as a protocol for clinical management and research.

Advanced Hemophilic Arthropathy: Sensitivity of Soft Tissue Discrimination With Musculoskeletal Ultrasound.

OBJECTIVES: Point-of-care musculoskeletal ultrasound (US) is increasingly used by hemophilia providers to guide management; however, pathologic tissue differentiation with US is uncertain. We sought to determine the extent to which point-of-care musculoskeletal US can identify and discriminate pathologic soft tissue changes in hemophilic arthropathy. METHODS: Thirty-six adult patients with hemophilia A/B were prospectively enrolled. Point-of-care musculoskeletal US examinations were performed on arthropathic joints (16 knees, 10 ankles, and 10 elbows) using standard views by a musculoskeletal US-trained and certified hematologist, who recorded abnormal intra-articular soft tissue accumulation. Within 3 days, magnetic resonance imaging was performed using conventional and multiecho ultrashort echo time sequences. Soft tissue identification (synovial proliferation with or without hemosiderin, fat, and/or blood products) was performed by a musculoskeletal radiologist. Findings obtained with both imaging modalities were compared and correlated in a blinded fashion. RESULTS: There was perfect agreement between the modalities on the presence of abnormal soft tissue (34 of 36 cases). However, musculoskeletal US was unable to discriminate between coagulated blood, synovium, intrasynovial or extrasynovial fat tissue, or hemosiderin deposits because of wide variations in echogenicity. CONCLUSIONS: Musculoskeletal US is valuable for point-of-care imaging to determine the presence of soft tissue accumulation in discrete areas. However, because of limitations of musculoskeletal US in discriminating the nature of pathologic soft tissues and detecting hemosiderin, magnetic resonance imaging will be required if such discrimination is clinically important.

Post-biopsy MRI changes in the size and enhancement of intramuscular myxomas: A report of two cases.

Intramuscular myxomas are benign soft-tissue tumors, characterized by bland spindle-shaped cells and fibroblasts within an abundant mucoid matrix on histologic examination. Classically, these are slowly enlarging masses which may occasionally cause pain, paresthesia, and muscle weakness secondary to mass effect. We present an interesting phenomenon of two histologically confirmed cases of intramuscular myxomas that exhibited size and enhancement changes on follow-up imaging after image-guided biopsy. To our knowledge, this is the first report to describe size and enhancement changes of intramuscular myxomas after biopsy.

The hypertension of hemophilia is associated with vascular remodeling in the joint.

OBJECTIVE: Hemophilic arthropathy is associated with pronounced vascular joint remodeling. Also, compared to the general population, PWH have a higher prevalence of hypertension not explained by usual risk factors. As vascular remodeling in various vascular beds is a hallmark of hypertension, we hypothesized that vascular joint remodeling is associated with elevated blood pressures and hypertension. METHODS: Elbows, knees, and ankles of 28 adult PWH were evaluated for vascular abnormalities with MSKUS/PD, as well as for radiographic and clinical status and pain. Logistic and linear regression models were fitted to examine associations between hypertension, blood pressure, and PD score. RESULTS: The extent of vascular abnormalities was associated with hypertension and blood pressures. Hypertensive patients had a higher PD score compared to nonhypertensive patients, and the risk of hypertension increased steeply with PD score. SBP was also strongly associated with PD score, while DBP was only weakly associated. CONCLUSIONS: Vascular remodeling in hemophilic joints is associated with hypertension and elevated blood pressures. As hypertension is a grave risk factor for intracranial hemorrhage, a prominent cause of mortality in hemophilia patients, future studies are needed to address the causal pathways between vascular joint remodeling and blood pressure.

Erdheim-Chester disease with novel gene mutations discovered as an incidental finding in explanted liver of a patient with hepatitis C cirrhosis: A case report and literature review.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by xanthogranulomatous infiltration of foamy histiocytes frequently involving bone and other organ systems. We herein report a unique case of ECD discovered incidentally in an explanted liver in a 65-year-old male with end-stage liver disease secondary to hepatitis C cirrhosis. Histological examination and immunohistochemical studies in the explanted liver revealed prominent foamy histiocytes that were CD68 positive, but CD1a and S100 negative. Mutational hotspot analysis of the explanted liver using a panel of 47 most common cancer-related genes performed by next generation sequencing (NGS) revealed likely somatic mutations in the PDGFRA, PTEN, and HNF1A genes, but no BRAF codon 600 mutations were detected. The bone marrow showed similar findings as in the liver. Whole body PET and bone scans demonstrated increased heterogeneous uptake in bilateral humeral and femoral diaphysis, most compatible with ECD. To our knowledge, this is the first case report of ECD that involves mainly bone marrow and liver with novel genomic alterations. Our case highlights the diversity and complexity of this disease entity and the importance of multi-modality approach integrating clinical and radiologic features with histopathologic and molecular/genomic findings.

Vascular remodeling underlies rebleeding in hemophilic arthropathy.

Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.

Hypertrophy of the anterior arch of the atlas associated with congenital nonunion of the posterior arch: a retrospective case-control study.

BACKGROUND CONTEXT: Nonunion of the posterior arch of the atlas is an uncommon but normal developmental variant. It is usually asymptomatic in the patient but may be associated with greater incidence of fracture because of increased stress on the anterior arch. PURPOSE: We sought to determine whether anterior arch hypertrophy is present in cases of congenital nonunion of the posterior arch of the atlas. STUDY DESIGN/SETTING: A retrospective analysis of 1 year (February 2005-January 2006) of computed tomography cervical spine studies requested by the University of California San Diego Medical Center Trauma Department was undertaken. PATIENT SAMPLE: All patients matching the search criteria (see Study design) were included. OUTCOME MEASURES: Area density product, defined as the midline cross-sectional area of the anterior arch on sagittal reformat multiplied by the average areal radiodensity in Hounsfield units (HU) as measured by two raters, was calculated for cases and controls. METHODS: Cases of posterior arch nonunion were identified and matched to controls. The significance of differences in area density product between cases and controls were established by the Student t test. Interrater correlation was calculated. RESULTS: Posterior arch nonunion was identified in 26 individuals (3.1% of 839 studies reviewed). Compared with age- and sex-matched controls, a 21% increase in area density product of the midline anterior arch was observed in posterior arch nonunion cases (773 HU-cm2 in cases vs. 637 HU-cm2 in controls; p<.001). This increase was attributable to a 21% increase in cross-sectional area (1.05 cm2 in cases vs. 0.87 cm2 in controls; p<.002). In contrast, there was no significant difference with regard to increased average radiodensity. CONCLUSIONS: It has long been subjectively recognized but not objectively quantified, until the present study, that the anterior arch of the atlas is hypertrophied in cases of posterior arch nonunion. Anterior arch hypertrophy may represent an adaptive response to chronically elevated mechanical stress and loss of hoop strength in cases of posterior nonunion.

Computed tomography (CT) of fractures of the ankle and foot: correlating fracture patterns with the presence of tenosynovial fat: Tenosynovial fat in ankle and foot fractures.

PURPOSE: To correlate ankle and foot fracture patterns with the presence of tenosynovial fat on computed tomography (CT). MATERIALS AND METHODS: In this retrospective, cross-sectional, observation study, two blinded musculoskeletal radiologists independently reviewed 89 CT scans of patients with ankle or foot fractures and recorded the presence of fat about Henry's knot, tibialis posterior tendon, and peroneus longus tendon. RESULTS: The agreement between the two readers ranged from excellent to substantial. Sixteen to 23 percent of fractures were associated with tenosynovial fat. CONCLUSIONS: The finding of tenosynovial fat following ankle or foot trauma warrants a closer search for a fracture.

Footprint of the lateral ligament complex of the ankle.

BACKGROUND: We describe the topographic anatomy of the lateral ligament complex of the ankle using 3-dimensional (3D) computed tomography (CT) imaging. METHODS: Dissection of the anterior talofibular ligament (ATFL) and the calcaneofibular ligament (CFL) was performed on 8 unpaired fresh-frozen cadaver feet. Ligaments were sharply dissected from bone, and the footprint was outlined with radio-opaque paint. The specimen underwent a 0.625-mm slice CT scan of the ankle with 3D reconstructions. Software was used to determine the surface area of the ligament footprint as well as measure the distance from the peroneal tubercle to the center of the CFL footprint. Data are presented as mean ± standard error. RESULTS: Six specimens had a bifid ATFL. Seven ankles had a bifid ATFL footprint on the talus. All specimens had intact CFL fibers. The intact superior and inferior limbs of the ATFL measured 19.7 ± 1.2 mm and 16.7 ± 1.1 mm. The CFL measured 24.8 ± 2.4 mm. The area of the footprints of the superior ATFL and inferior ATFL on the talus measured 1.5 ± 0.26 cm(2) and 0.90 ± 0.07 cm(2). The CFL and ATFL origins on the fibula were continuous and measured 3.48 ± 0.39 cm(2). The CFL insertion on the calcaneus measured 2.68 ± 0.20 cm(2). The CFL was found 27.1 ± 1.0 mm posterior and superior from the peroneal tubercle. CONCLUSIONS: In presumably uninjured specimens, both the ATFL and its footprint on the talus were bifid. The CFL and ATFL origins have a single confluent footprint on the anterior border of the distal fibula. The CFL footprint on the calcaneus is almost 3 cm posterior and superior to the peroneal tubercle. CLINICAL RELEVANCE: This study may assist surgeons in anatomically reconstructing the lateral ligament complex of the ankle.

Imaging of the rotator cuff.

The imaging evaluation of the rotator cuff augments the clinical evaluation. Radiography, computed tomography, and magnetic resonance imaging all have various roles in the assessment of the rotator cuff, which can be combined with arthrography for added detail. Furthermore, ultrasound is a very useful technique that provides functional information that is not offered by simple anatomic imaging.

Inflammatory characteristics on ultrasound predict poorer longterm response to intraarticular corticosteroid injections in knee osteoarthritis.

OBJECTIVE: To assess whether inflammation on ultrasound is predictive of clinical response to intraarticular (IA) corticosteroid injections in patients with knee osteoarthritis (OA). METHODS: Patients with symptomatic knee OA were randomized to receive either an IA injection of 40 mg triamcinolone acetonide in the treatment group or 1 cc 0.9% saline in the placebo group. Clinical response was assessed by changes in baseline Western Ontario and McMaster Universities (WOMAC) index scores and physician global assessment at 4 and 12 weeks. Ultrasounds were performed at each visit. Patients and assessors were blinded to treatment status. RESULTS: Seventy-nine patients were enrolled into the study. Four-week data were available for 67 patients in the primary analysis comparing change in WOMAC pain score from baseline to 4 weeks. There was almost no change in the WOMAC pain subscale score from baseline to 4 weeks in the control group, but there was a significant improvement in WOMAC pain subscale score from 10.8 (SD +/- 3.2) at baseline to 8.75 (SD +/- 4.0) at 4 weeks in the treatment group (adjusted p = 0.001). Of the 34 patients in the treatment group; 16 (47%) had inflammatory disease and 18 (53%) had noninflammatory disease as determined by ultrasound. There was no difference in the change in WOMAC pain score between the inflammatory and noninflammatory patients in the treatment group at 4 weeks. There was a statistically significant greater improvement in pain subscale scores among noninflammatory patients than among inflammatory patients at 12 weeks. CONCLUSION: Intraarticular corticosteroid injections are an effective short-term treatment for symptomatic knee OA compared to placebo. Patients with noninflammatory characteristics on ultrasound had a more prolonged benefit from IA corticosteroids compared to inflammatory patients.

Anatomical features of metacarpal heads that simulate bone erosions: cadaveric study using computed tomography scanning and sectional radiography.

OBJECTIVE: The objective of this study was to demonstrate the anatomical features of metacarpal heads that can simulate bone erosions. MATERIALS AND METHODS: After performing computed tomography scanning of 6 cadaveric hand specimens, normal anatomy was identified; the maximum depth, height, and area of the osseous concavities in the ulnar, radial, and intersesamoid aspects of the metacarpal heads were measured. An average value was determined for each of the measurements of the 5 fingers, and statistical analysis was done. RESULTS: Three concavities were identified in the first metacarpal head (intersesamoid, ulnar, and radial) and 2 in the others fingers (ulnar and radial). All of them had sharp regular margins without sclerotic reaction. The measurements of these concavities were done. CONCLUSIONS: We analyzed the normal osseous anatomy of the metacarpal heads. Knowledge of this normal anatomy enables the radiologist to differentiate normal concave regions from bone erosions that accompany a variety of synovial inflammatory diseases.

Anatomic features of metatarsal heads that simulate erosive disease: cadaveric study using CT, radiography, and dissection with special emphasis on cross-sectional characterization of osseous anatomy.

OBJECTIVE: The purpose of our study was to characterize and describe normal osseous contours of the metatarsal heads that may simulate erosive changes. MATERIALS AND METHODS: CT of the metatarsal heads was performed in six human cadaveric feet, and 3D reformatted images were analyzed. Subsequently, five feet were sectioned in planes corresponding to those at imaging for anatomic correlation, and one foot was anatomically dissected for correlation. The normal anatomic osseous contours of the metatarsal heads were analyzed and described. RESULTS: Normal osseous anatomy of the greater (first) and lesser (second through fifth) metatarsal heads was identified. The normal osseous landmarks that simulate erosive changes were identified. Variations in the normal anatomic osseous contours, including those related to the medial and lateral condyles, were present in all specimens. The lateral condyle of the first metatarsal head was found to be more prominent than the medial condyle. In addition, anatomic variations in the normal osseous concavities of the lateral and medial aspects of each metatarsal head were measured. An intersesamoidal ridge, present on the plantar surface of the first metatarsal head, was identified in all specimens. CONCLUSION: The normal anatomic contours of the metatarsal head are a potential major source for diagnostic error when viewing sectional CT and MR images in patients with suspected erosive arthritis. These normal variations, although common and varied, produce characteristic findings that can be differentiated from bone erosions.