Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks ...validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans.
A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring.
36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments.
Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.
Context: Although the majority of pituitary macroadenomas are clinically nonfunctioning, treatments as well as follow-up strategy for this condition lack evidence from randomized studies.
Evidence ...Acquisition: We evaluated the evidence of treatment and follow-up strategies for clinically nonfunctioning adenomas. PubMed was searched for articles on nonfunctioning adenomas in November 2007, and references of selected articles were assessed for potentially relevant articles.
Evidence Synthesis: All evidence for treatment and follow-up for nonfunctioning adenomas is based on observational studies. The most effective treatment is transsphenoidal surgery, indicated in patients with visual field defects. A wait-and-see approach may be considered in nonfunctioning macroadenomas not reaching to the optic chiasm. Some of these tumors (∼10%) will show spontaneous regression, whereas in approximately 50% there will be progression within 5 yr observation. Postoperative radiotherapy should not be applied to all patients after surgery but can be considered in patients with large postoperative remnants of the tumor. During follow-up careful assessment and replacement of pituitary insufficiencies should be performed. Magnetic resonance imaging is advised with intervals of 1–3 yr and evaluation of visual fields when appropriate. Recurrence rates are reported to be 6–46% after transsphenoidal surgery, whereas after postoperative radiotherapy, recurrence rates of 0–36% are reported. Long-term sequelae of nonfunctioning macroadenomas are hypopituitarism, persistent visual field defects, and decreased quality of life. Whether nonfunctioning macroadenomas are associated with an increased mortality is still a matter of debate.
Conclusion: Clinically nonfunctioning pituitary macroadenomas, although benign in nature, need individualized treatment and lifelong radiological and endocrinological follow-up.
Summary
Introduction
New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated ...comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta‐analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE.
Methods
We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase 3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random‐effects models.
Results
Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24 455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval CI 0.74–1.05), 1.02 (95% CI 0.39–5.96), and 0.97 (95% CI 0.83–1.14), respectively. The RR for major bleeding was 0.60 (95% CI 0.41–0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95% CI 0.15–0.87) and 1111. A fixed‐effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban.
Conclusions
NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high.
Introduction The association between type 1 diabetes (T1D) and other auto-immune diseases is well known. However, a quantitative overview of all associated auto-immune diseases and their prevalence ...in T1D is lacking. Methods We searched PubMed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalence using a random-effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration. Results One hundred eighty articles were eligible including a total of 293 889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8% (95% CI: 7.5-12.3) of patients. Meta-regression showed that for every 10-year age increase, hypothyroidism prevalence increased 4.6% (95% CI: 2.6-6.6, P < 0.000, 54 studies). Weighted prevalence of celiac disease was 4.5% (95% CI: 4.0-5.5, 87 studies). Gastric autoimmunity was found in 4.3% of patients (95% CI: 1.6-8.2, 8 studies) and vitiligo in 2.4% (95% CI: 1.2-3.9, 14 studies) of patients. The prevalence of adrenal insufficiency was 0.2% (95% CI: 0.0-0.4, 14 studies) and hyperthyroidism was found in 1.3 percent (95% CI: 0.9-1.8, 45 studies) of type 1 diabetes patients. For all analyses, statistical heterogeneity between studies was moderate to high. Conclusions The prevalence of antibody-mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.
Cushing's syndrome (CS) is associated with an hypercoagulable state and an increased risk of venous thromboembolism (VTE). Evidence-based guidelines on thromboprophylaxis strategies in patients with ...CS are currently lacking. We aimed to map the current clinical practice for thromboprophylaxis management in patients with CS across reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN), which are endorsed specifically for the diagnosis and treatment of CS. Using the EU survey tool, a primary screening survey, and subsequently a secondary, more in-depth survey were developed.
The majority of the RCs provided thromboprophylaxis to patients with CS (n = 23/25), although only one center had a standardized thromboprophylaxis protocol (n = 1/23). RCs most frequently started thromboprophylaxis from CS diagnosis onwards (n = 11/23), and the majority stopped thromboprophylaxis based on individual patient characteristics, rather than standardized treatment duration (n = 15/23). Factors influencing the initiation of thromboprophylaxis were 'medical history of VTE' (n = 15/23) and 'severity of hypercortisolism' (n = 15/23). Low-Molecular-Weight-Heparin was selected as the first-choice anticoagulant drug for thromboprophylaxis by all RCs (n = 23/23). Postoperatively, the majority of RCs reported 'severe immobilization' as an indication to start thromboprophylaxis in patients with CS (n = 15/25). Most RCs (n = 19/25) did not provide standardized testing for variables of hemostasis in the postoperative care of CS. Furthermore, the majority of the RCs provided preoperative medical treatment to patients with CS (n = 23/25). About half of these RCs (n = 12/23) took a previous VTE into account when starting preoperative medical treatment, and about two-thirds (n = 15/23) included 'reduction of VTE risk' as a goal of treatment.
There is a large practice variation regarding thromboprophylaxis management and perioperative medical treatment in patients with CS, even in Endo-ERN RCs. Randomized controlled trials are needed to establish the optimal prophylactic anticoagulant regimen, carefully balancing the increased risk of (perioperative) bleeding, and the presence of additional risk factors for thrombosis.
Abstract Background Uterine serous carcinoma (USC) shows greater morphological, clinical and molecular similarities to high-grade ovarian tubal serous carcinoma than to other types of endometrial ...cancer. As high-grade ovarian tubal serous carcinoma is known to be associated with BRCA1/ 2 pathogenic germline mutations (PMs), we aimed to explore whether USC is also a constituent of hereditary breast and ovarian cancer syndrome. Methods Pubmed, EMBASE and Web of Science were searched in July 2016 for articles assessing the association between USC and germline BRCA1/2 -PMs. Pooled analysis and comparisons were performed using a random effects logistic model, stratifying for ethnicity (Ashkenazi versus non-Ashkenazi). In addition, tumour tissue from an USC case with a hereditary BRCA1 -PM was analysed for loss of heterozygosity at the BRCA1 locus and was functionally analysed for homologous recombination proficiency. Results The search yielded 1893 citations, 10 studies were included describing 345 USC patients. For Ashkenazi Jews, the pooled odds ratio of having a germline BRCA1/2 -PM was increased in USC patients compared with the general Ashkenazi population: odds ratio 5.4 (95%confidence interval: 2.2–13.1). In the patient with USC, we identified the known germline BRCA1 -PM in the tumour DNA. Furthermore, we showed both loss of heterozygosity of the wild-type allele and a deficiency of homologous recombination. Conclusion This study suggests that USC may be an overlooked component of BRCA1/2 -associated hereditary breast and ovarian cancer syndrome. Screening for germline BRCA1/2 -PMs should be considered in patients diagnosed with USC, especially in cases with a positive first-degree family history for breast and/or ovarian cancer.
Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non‐randomized studies ...suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. Patients and Methods: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24 h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow‐up. Results: Of 297 included patients, who all completed the follow‐up, six (2.0%; 95% confidence interval CI 0.8–4.3) had recurrent VTE (five PE 1.7% and one DVT 0.3%). Three patients (1.0%, 95% CI 0.2–2.9) died during the 3 months of follow‐up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08–2.4). Conclusion: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319; http://www.trialregister.nl/trialreg/index.asp).
Obesity is an emerging condition, with a prevalence of ~20%. Although the simple measurement of BMI is likely a simplistic approach to obesity, BMI is easily calculated, and there are currently no ...data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity. An increased BMI leads to a number of hormonal changes. Additionally, concomitant hormonal diseases can be present in obesity and have to be properly diagnosed - which in turn might be more difficult due to alterations caused by body fatness itself. The present European Society of Endocrinology Clinical Guideline on the Endocrine Work-up in Obesity acknowledges the increased prevalence of many endocrine conditions in obesity. It is recommended to test all patients with obesity for thyroid function, given the high prevalence of hypothyroidism in obesity. For hypercortisolism, male hypogonadism and female gonadal dysfunction, hormonal testing is only recommended if case of clinical suspicion of an underlying endocrine disorder. The guideline underlines that weight loss in obesity should be emphasized as key to restoration of hormonal imbalances and that treatment and that the effect of treating endocrine disorders on weight loss is only modest.
Summary
Background
Data on statins' effect on venous thromboembolism (VTE) recurrence are conflicting.
Objectives
We examined whether statin use was associated with reduced risk of recurrent VTE in a ...nationwide population‐based setting.
Patients/Methods
Using the Danish National Patient Registry, we identified first‐time and recurrent VTEs between 1 July 2004 and 31 December 2012 (n = 27 862). VTE diagnoses were validated by medical record review of a subsample of patients. We ascertained nationwide prescription data and categorized statin use as current (further divided into new and long‐term use), former and no use. We identified statin use at baseline (mimicking an intention‐to‐treat analysis) and in a time‐varying manner during follow‐up (mimicking per‐protocol analysis) and computed hazard ratios (HRs) for recurrent VTE using Cox regression. In a supplementary nested case–control study, we identified statin use at time of VTE recurrence and computed odds ratios as unbiased estimates of the incidence rate ratios (IRRs) using conditional logistic regression. We adjusted for age, sex, year of diagnosis, provoking factors, co‐morbidities and co‐medications, including time‐varying use of aspirin and anticoagulant drugs.
Results
The adjusted HR comparing current use with no use was 0.72 (95% confidence interval CI, 0.59–0.88) for recurrent VTE, with a stronger effect of high (0.40; 95% CI, 0.21–0.78) vs. low potency statins (0.77; 95% CI, 0.63–0.94). Consistently, the recurrence rate was reduced in both the time‐varying analysis (HR=0.64; 95% CI, 0.54–0.77) and nested case–control analysis (IRR=0.55; 95% CI, 0.45–0.67). The effect was largest for recurrent deep venous thrombosis.
Conclusions
Statin use was associated with reduced VTE recurrence.
An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was ...endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.
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