Edwin H. G. Oei

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2–24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.

Phenotypic spectrum of the SMAD3-related aneurysms–osteoarthritis syndrome

Background Aneurysms–osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene. Methods A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed. Results Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome. Conclusion The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.

High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control: The Rotterdam Study

OBJECTIVE Individuals with type 2 diabetes have increased fracture risk despite higher bone mineral density (BMD). Our aim was to examine the influence of glucose control on skeletal complications. RESEARCH DESIGN AND METHODS Data of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA1c <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA1c ≥7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]). RESULTS The ICD group had 1.1–5.6% higher BMD, 4.6–5.6% thicker cortices, and −1.2 to −1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47–62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12–1.92]) and ACD (1.62 [1.09–2.40]), whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67–1.23]). CONCLUSIONS Poor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently “strong” bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.

Review of radiological scoring methods of osteoporotic vertebral fractures for clinical and research settings

AbstractBackgroundOsteoporosis is the most common metabolic bone disease; vertebral fractures are the most common osteoporotic fractures.MethodsSeveral radiological scoring methods using different criteria for osteoporotic vertebral fractures exist. Quantitative morphometry (QM) uses ratios derived from direct vertebral body height measurements to define fractures. Semi-quantitative (SQ) visual grading is performed according to height and area reduction. The algorithm-based qualitative (ABQ) method introduced a scheme to systematically rule out non-fracture deformities and diagnoses osteoporotic vertebral fractures based on endplate depression. The concordance across methods is currently a matter of debate.ResultsThis article reviews the most commonly applied standardised radiographic scoring methods for osteoporotic vertebral fractures, attaining an impartial perspective of benefits and limitations. It provides image examples and discusses aspects that facilitate large-scale application, such as automated image analysis software and different imaging investigations. It also reviews the implications of different fracture definitions for scientific research and clinical practice.ConclusionAccurate standardised scoring methods for assessing osteoporotic vertebral fractures are crucial, considering that differences in definition will have implications for patient care and scientific research. Evaluation of the feasibility and concordance among methods will allow establishing their benefits and limitations, and most importantly, optimise their effectiveness for widespread application.Key Points• Several scoring methods using different criteria for assessing osteoporotic vertebral fractures exist. • Standardised osteoporotic vertebral fracture assessment should be applicable to different radiological investigations. • Accurate assessment of osteoporotic vertebral fractures is essential for proper patient management. • Optimising feasibility of scoring methods enables widespread use in scientific research. • Assessment of concordance between methods is important for application in patient care.

Value of information analysis used to determine the necessity of additional research: MR imaging in acute knee trauma as an example

PURPOSE To help guide future outcomes research regarding the use of magnetic resonance (MR) imaging in patients with acute knee trauma in an emergency department setting, with use of prospective data from a randomized clinical trial and value of information analysis. MATERIALS AND METHODS A total of 189 patients (123 male, 66 female; mean age, 33.4 years) were randomly assigned to undergo radiography alone (n = 93) or radiography and MR imaging (n = 96). Institutional review board approval and informed consent (parental consent for minors) were obtained. During 6 months of follow-up, data on quality of life and 39 cost parameters were collected. Value-of-information analysis was used to estimate the expected benefit of future research to eliminate the decision uncertainty that remained after trial completion. In addition, the parameters that were responsible for most of the decision uncertainty were identified, the expected benefits of various study designs were evaluated, and the optimal sample size was estimated. RESULTS Only three parameters were responsible for most of the decision uncertainty: number of quality-adjusted life-years, cost of an overnight hospital stay, and friction costs. A study in which data on these three parameters are gathered would have an optimal sample size of 3500 patients per arm and would be expected to result in a societal benefit of euro 5.6 million or 70 quality-adjusted life-years. CONCLUSION The optimal study design for use of MR imaging to evaluate acute knee trauma involves a trial in which there are 3500 patients per trial arm, and data on the number of quality-adjusted life-years, cost of an overnight hospital stay, and friction costs are collected.

Quantitative MRI techniques of cartilage composition

Due to aging populations and increasing rates of obesity in the developed world, the prevalence of osteoarthritis (OA) is continually increasing. Decreasing the societal and patient burden of this disease motivates research in prevention, early detection of OA, and novel treatment strategies against OA. One key facet of this effort is the need to track the degradation of tissues within joints, especially cartilage. Currently, conventional imaging techniques provide accurate means to detect morphological deterioration of cartilage in the later stages of OA, but these methods are not sensitive to the subtle biochemical changes during early disease stages. Novel quantitative techniques with magnetic resonance imaging (MRI) provide direct and indirect assessments of cartilage composition, and thus allow for earlier detection and tracking of OA. This review describes the most prominent quantitative MRI techniques to date-dGEMRIC, T2 mapping, T1rho mapping, and sodium imaging. Other, less-validated methods for quantifying cartilage composition are also described-Ultrashort echo time (UTE), gagCEST, and diffusion-weighted imaging (DWI). For each technique, this article discusses the proposed biochemical correlates, as well its advantages and limitations for clinical and research use. The article concludes with a detailed discussion of how the field of quantitative MRI has progressed to provide information regarding two specific patient populations through clinical research-patients with anterior cruciate ligament rupture and patients with impingement in the hip. While quantitative imaging techniques continue to rapidly evolve, specific challenges for each technique as well as challenges to clinical applications remain.

Diabetes, Diabetic Complications, and Fracture Risk

Diabetes and osteoporosis are both common diseases with increasing prevalences in the aging population. There is increasing evidence corroborating an association between diabetes mellitus and bone. This review will discuss the disease complications of diabetes on the skeleton, highlighting findings from epidemiological, molecular, and imaging studies in animal models and humans. Compared to control subjects, decreased bone mineral density (BMD) has been observed in type 1 diabetes mellitus, while on average, higher BMD has been found in type 2 diabetes; nonetheless, patients with both types of diabetes are seemingly at increased risk of fractures. Conventional diagnostics such as DXA measurements and the current fracture risk assessment tool (FRAX) risk prediction algorithm for estimating risk of osteoporotic fractures are not sufficient in the case of diabetes. A deterioration in bone microarchitecture and an inefficient distribution of bone mass with insufficiency of repair and adaptation mechanisms appear to be factors of relevance. A highly complex and heterogeneous molecular pathophysiology underlies diabetes-related bone disease, involving hormonal, immune, and perhaps genetic pathways. The detrimental effects of chronically elevated glucose levels on bone should be added to the more well-known complications of diabetes.

Diagnosis of Lumbar Spinal Stenosis An Updated Systematic Review of the Accuracy of Diagnostic Tests

Study Design. Systematic review of diagnostic studies. Objective. To update our previous systematic review on the diagnostic accuracy of tests used to diagnose lumbar spinal stenosis. Summary of Background Data. A wide range of clinical, radiological, and electrodiagnostic tests are used to diagnose lumbar spinal stenosis. An accurate diagnosis is vital, because lumbar spinal stenosis may require specific medical advice and treatment. Therefore, it is important to know the accuracy of these diagnostic tests currently available. Methods. A comprehensive literature search was conducted for original diagnostic studies on lumbar spinal stenosis, in which one or more diagnostic tests were evaluated with a reference standard, and diagnostic accuracy was reported or could be calculated. Our previous systematic review included studies up to March 2004; this review is current up to March 2011. Included studies were assessed for their methodological quality using the QUADAS tool. Study characteristics and reported diagnostic accuracy were extracted. Results. Twenty-two additional articles in addition to the 24 included in the previous review met the inclusion criteria. Combined, this resulted in 20 articles concerning imaging tests, 11 articles evaluating electrodiagnostic tests, and 15 articles evaluating clinical tests. Estimates of the diagnostic accuracy of the tests differed considerably. Conclusion. There is a need for a consensus on criteria to define and classify lumbar spinal stenosis. At present, the most promising imaging test for lumbar spinal stenosis is magnetic resonance imaging, avoiding myelography because of its invasiveness and lack of superior accuracy. Electrodiagnostic studies showed no superior accuracy for conventional electrodiagnostic testing compared with magnetic resonance imaging. These tests should be considered in the context of those presenting symptoms with the highest diagnostic value, including radiating leg pain that is exacerbated while standing up, the absence of pain when seated, the improvement of symptoms when bending forward, and a wide-based gait. Level of Evidence: 1

Quantifying osteoarthritic cartilage changes accurately using in vivo microCT arthrography in three etiologically distinct rat models

In vivo microCT arthrography (µCTa) can be used to measure both quantity (volumetric) and quality (glycosaminoglycan content) of cartilage. This study investigated the accuracy of four segmentation techniques to isolate cartilage from µCTa datasets and then used the most accurate one to investigate if the µCTa method could show osteoarthritic changes in rat models during longitudinal follow‐up. Volumetric measurements and glycosaminoglycan contents of patellar cartilage from in vivo µCTa‐scans were compared with an ex vivo gold standard µCT‐scan. Cartilage was segmented with three global thresholds and one local threshold algorithm. Comparisons were made for healthy and osteoarthritic cartilage. Next, three rat models were investigated for 24 weeks using µCTa. Osteoarthritis was induced by injection with a chemical (mono‐iodoacetate), a surgical intervention (grooves applied in articular cartilage), and via exercise (strenuous running). After euthanasia, all knee joints were isolated for histology. Local thresholds accurately segmented cartilage from in vivo µCTa scans and best measured cartilage quantity and glycosaminoglycan content. Each of the three osteoarthritic rat models showed a specific pattern of osteoarthritis progression. All µCTa results were comparable to histology. In vivo µCTa is a sensitive technique for imaging cartilage degradation. Local thresholds enhanced the sensitivity of this method and will probably more accurately detect disease‐modulating effects from interventional strategies. The data from rat models may serve as a reference for the time sequence of cartilage degeneration during in vivo testing of new strategies in osteoarthritis treatment. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1788–1794, 2011

Recommendations of the ESSR Arthritis Subcommittee for the Use of Magnetic Resonance Imaging in Musculoskeletal Rheumatic Diseases.

This article presents the recommendations of the European Society of Musculoskeletal Radiology Arthritis Subcommittee regarding the standards of the use of MRI in the diagnosis of musculoskeletal rheumatic diseases. The recommendations discuss (1) the role of MRI in current classification criteria of musculoskeletal rheumatic diseases (including early diagnosis of inflammation, disease follow-up, and identification of disease complications); (2) the impact of MRI on the diagnosis of axial and peripheral spondyloarthritis, rheumatoid arthritis, and juvenile spondyloarthritis; (3) MRI protocols for the axial and peripheral joints; (4) MRI interpretation and reporting for axial and peripheral joints; and finally, (5) methods for assessing MR images including quantitative, semiquantitative, and dynamic contrast-enhanced MRI studies.