Citations

ABSTRACT Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m2) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25 kg/m2, the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m2 was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research.

ObjectiveTo evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA).MethodsThe Rituximab in AAV trial was a randomized, double‐blind, placebo‐controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other).ResultsAlthough remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty‐four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety‐one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)–ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3‐ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare.ConclusionCurrent treatment regimens are largely successful in controlling AAV, but in approximately one‐fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3‐ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Abstract Lymphangiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex (TSC). Because only a minority of women with TSC develops symptomatic LAM, we hypothesized that a relationship might exist between the type of germline TSC1 or TSC2 gene mutation and the risk of developing LAM. We examined all 41 exons of the TSC2 gene and 21 coding exons of the TSC1 gene for mutations in a group of 14 women with both TSC and LAM using single-strand conformation polymorphism analysis. Seven mutations were found in TSC2 and one in TSC1. Of the seven patients with TSC2 mutations, two had the same in-frame exon 40 deletion and one had an exon 41 missense change. We conclude that germline mutations in the extreme carboxy-terminus of tuberin can result in LAM. Further studies will be required to determine whether mutations in exons 40 and 41 are associated with an increased incidence and/or severity of LAM in women with TSC.

Objective To evaluate carbonic anhydrase IX ( CAIX ) expression as an independent prognostic marker for clear cell renal cell carcinoma ( ccRCC ). With recent smaller studies showing conflicting results, we aimed to update our initial analysis in 2007 with an additional 5‐year follow‐up. Patients and Methods We provided long‐term follow‐up of the same cohort used in our 2007 study (730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999). Associations of CAIX expression with RCC death and distant metastases were evaluated using C ox proportional hazards regression models. Results CAIX was expressed in 708 (97.0%) of the specimens; 163 tumours (22.3%) had low (≤85%) expression and 567 (77.7%) high (>85%) expression. There were 483 deaths and 265 RCC ‐specific deaths. The median follow‐up for the 247 patients still under observation was 13.8 years. Univariately, low CAIX expression was associated with an increased risk of RCC death vs high expression (hazard ratio 1.62; P < 0.001). Low CAIX expression was not statistically significantly associated with RCC death or distant metastases after adjusting for nuclear grade or coagulative tumour necrosis. Conclusion After additional long‐term follow‐up of our large cohort, our results continue to suggest that CAIX is not an independent prognostic marker for ccRCC .