[Paget's disease of bone: 1877-2023. Etiology, and management of a disease on epidemiologic transition]. / Enfermedad ósea de Paget: 1877-2023. Etiología y abordaje de una enfermedad en transición epidemiológica.

Paget's disease of bone is characterized by the alteration, in one or several bone locations, of the equilibrium between bone formation and bone resorption. This imbalance results in a disorganized, widened bone, in many cases with increased bone density, although more fragile. A genetic predisposition for Paget's disease of bone could explain between 5% and 40% of the cases. Different environmental factors should explain the rest of the cases. Paget's disease of bone was classically considered the second most common metabolic bone disease. However, in recent decades there has been a marked decrease in both incidence and clinical severity. These changes have led to believe that the influence of some environmental factor may have diminished or even disappeared. This decrease in incidence should not be an excuse for abandoning Paget's disease of bone research, but rather it should be the reason to remain searching to try to understand better its pathogenesis.

The complexity of classifying ANCA-associated small-vessel vasculitis in actual clinical practice: data from a multicenter retrospective survey.

The different sets of criteria for diagnosis or classification of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) lead to numerous overlapping and reclassified diagnoses in clinical practice. We designed this study to assess the difficulties in classifying patients with AAV. As a secondary objective, different variables were tested to predict prognosis. We conducted a retrospective chart review in a Western Spain multicentre survey. A total of 115 adult patients diagnosed with AAV from 2002 to 2013 and followed for at least 3 years were included. They were classified according to (1) Chapel Hill Consensus Conference (CHCC), (2) European Medicines Agency algorithm and (3) French Vasculitis Study Group/European Vasculitis Society phenotypes. Fifty-three patients (46%) had neither distinctive histopathological data of a single AAV definition nor any surrogate markers for granulomatous inflammation and thus did not fulfill any diagnostic criteria. Ocular, ear, nose, throat, skin, and lung involvement were more frequent with proteinase 3 (PR3) antibodies, whereas peripheral neuropathy was more frequent with myeloperoxidase (MPO) antibodies. When the disease was severe at diagnosis, the HR for mortality was 10.44. When induction treatment was not given in accordance with the guidelines, the HR for mortality was 4.00. For maintenance treatment, the HR was 5.49 for mortality and 2.48 for relapse. AAV classification is difficult because many patients had neither specific clinical data nor distinctive histological features of a single CHCC definition. A structured clinical assessment of patient severity is the best tool to guide the management of AAV.

Does my patient really need this at admission? Seven opportunities for improving value in patient care during their hospitalization.

INTRODUCTION: Besides the main treatment for their disease, hospital patients receive multiple care measures which include venous lines (VL), urinary catheters (UC), dietary restrictions (DR), mandatory bed rest (BR), deep venous thrombosis prophylaxis (VTP), stress ulcer prophylaxis (SUP) and anticoagulation bridge therapy for atrial fibrillation (BAF). In many cases these practices are of low value. METHODS: We analysed patients admitted to Internal Medicine wards throughout 2018 (2714 inpatients). We used different methodologies to identify low-value clinical practices. RESULTS: BR or DR at admission were recommended in 37% (32-44) and 24% (19-30) of the patients respectively. In 81% (71-87) and 33% (21-45) of the cases this restriction was deemed unnecessary. Ninety-six percent (92-98) had VL and 25% (19-32) UC. VL were not used in 10% (6-12), UC had no indications for insertion in 21% (11-35) and for maintenance in 31% (12-46) patients. Fifty-seven percent (49-64) of the patients were administered VTP and 69% (62-76) were prescribed SUP. Twenty-two percent (15-31) of patients with VTP and 52% (43-60) with SUP had no indication. Chronic anticoagulation for AF was interrupted in 65% (53-75) with BAF was prescribed in 38% (25-52) of them. An intervention to reduce low-value care supporting clinical practices addressed only to the Internal Medicine Wards showed very poor results. CONCLUSION: These results demonstrate that there is ample room for reduction of low-value care. Interventions to implement clinical guidelines at admissions should be addressed to cover the entire admission process, from the emergency room to the ward. Partial approaches are discouraged.

Bisphosphonates for Paget's disease of bone in adults.

BACKGROUND: Bisphosphonates are considered to be the treatment of choice for people with Paget's disease of bone. However, the effects of bisphosphonates on patient-centred outcomes have not been extensively studied. There are insufficient data to determine whether reducing and maintaining biochemical markers of bone turnover to within the normal range improves quality of life and reduces the risk of complications. OBJECTIVES: To assess the benefits and harms of bisphosphonates for adult patients with Paget's disease of bone. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ISI Web of Knowledge and trials registers up to March 2017. We searched regulatory agency published information for rare adverse events. SELECTION CRITERIA: Randomised controlled trials (RCTs) of bisphosphonates as treatment for Paget's disease in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data and assessed studies for risk of bias. We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 20 trials (25 reports, 3168 participants). Of these, 10 trials (801 participants) compared bisphosphonates (etidronate, tiludronate, ibandronate, pamidronate, olpadronate, alendronate, risedronate, zoledronate) versus placebo, seven compared two bisphosphonates (992 participants), one trial compared a bisphosphonates with a bisphosphonate plus calcitonin (44 participants), and two studies, the largest trial (1331 participants) and its interventional extension study (502 participants), compared symptomatic treatment and intensive treatment where the goal was to normalise alkaline phosphatase.Most studies were assessed at low or unclear risk of bias. Six of 10 studies comparing bisphosphonates versus placebo were assessed at high risk of bias, mainly around incomplete outcome data and selective outcome reporting.Participant populations were reasonably homogeneous in terms of age (mean age 66 to 74 years) and sex (51% to 74% male). Most studies included participants who had elevated alkaline phosphatase levels whether or not bone pain was present. Mean follow-up was six months.Bisphosphonates versus placeboBisphosphonates tripled the proportion (31% versus 9%) of participants whose bone pain disappeared (RR 3.42, 95% confidence interval (CI) 1.31 to 8.90; 2 studies, 205 participants; NNT 5, 95% CI 1 to 31; moderate-quality evidence). This result is clinically important. Data were consistent when pain change was measured as any reduction (RR 1.97, 95% CI 1.29 to 3.01; 7 studies, 481 participants).There was uncertainty about differences in incident fractures: 1.4% fractures occurred in the bisphosphonates group and none in the placebo group (RR 0.89, 95% CI 0.18 to 4.31; 4 studies, 356 participants; very low-quality evidence).None of the studies reported data on orthopaedic surgery, quality of life or hearing thresholds.Results regarding adverse effects and treatment discontinuation were uncertain. There was a 64% risk of mild gastrointestinal adverse events in intervention group participants and 48% in the control group (RR 1.32, 95% CI 0.91 to 1.92; 6 studies, 376 participants; low-quality evidence). The likelihood of study participants discontinuing due to adverse effects was slightly higher in intervention group participants (4.4%) than the control group (4.1%) (RR 1.01, 95% CI 0.41 to 2.52; 6 studies, 517 participants; low-quality evidence). Zoledronate was associated with an increased risk of transient fever or fatigue (RR 2.57, 95% CI 1.21 to 5.44; 1 study, 176 participants; moderate-quality evidence).Bisphosphonates versus active comparatorMore participants reported pain relief with zoledronate than pamidronate (RR 1.30, 95% CI 1.10 to 1.53; 1 study, 89 participants; NNT 5, 95% CI 3 to 11) or risedronate (RR 1.36, 95% CI 1.06 to 1.74; 1 study, 347 participants; NNT 7, 95% CI 4 to 24; very low quality evidence). This result is clinically important.There was insufficient evidence to confirm or exclude differences in adverse effects of bisphosphonates (RR 1.05, 95% CI 0.95 to 1.76; 2 studies, 437 participants; low-quality evidence) and treatment discontinuation (2 studies, 437 participants) (RR 2.04, 95% CI 0.43 to 9.59; 2 studies, 437 participants; very low-quality evidence).Intensive versus symptomatic treatmentThere was no consistent evidence of difference to response in bone pain, bodily pain or quality of life in participants who received intensive versus symptomatic treatment.Inconclusive results were observed regarding fractures and orthopaedic procedures for intensive versus symptomatic treatment (intensive treatment for fracture: RR 1.84, 95% CI 0.76 to 4.44; absolute risk 8.1% versus 5.2%; orthopaedic procedures: RR 1.58, 95% CI 0.80 to 3.11; absolute risk 5.6% versus 3.0%; 1 study, 502 participants; low-quality evidence).There was insufficient evidence to confirm or exclude an important difference in adverse effects between intensive and symptomatic treatment (RR 1.05, 95% CI 0.79 to 1.41; low-quality evidence).There was insufficient evidence to confirm or exclude an important difference of risk of rare adverse events (including osteonecrosis of the jaw) from the regulatory agencies databases. AUTHORS' CONCLUSIONS: We found moderate-quality evidence that bisphosphonates improved pain in people with Paget's disease of bone when compared with placebo. We are uncertain about the results of head-to-head studies investigating bisphosphonates. We found insufficient evidence of benefit in terms of pain or quality of life from intensive treatment. Information about adverse effects was limited, but serious side effects were rare, and rate of withdrawals due to side effects was low.

Development and Validation of the COMPLES Score for Differentiating Between Tuberculous Effusions with Low Pleural pH or Glucose and Complicated Parapneumonic Effusions.

BACKGROUND: The frequency of "complicated" pleural effusions (CPE) (i.e., pleural fluid pH ≤ 7.2 and/or glucose ≤60 mg/dL) of tuberculous origin (CTPE) is not well reported. This study aims to quantify their prevalence, and develop a score to differentiate CTPE from complicated parapneumonic effusions (CPPE). METHODS: Retrospective analysis of databases from three Spanish hospitals which included patients with CTPE and CPPE. Forty percent of the study population served to generate a scoring system (COMPLES, COMplicated PLeural Effusion Score) that was further validated in the remaining 60 %. RESULTS: During the study period (1992-2015) 549 patients were diagnosed with tuberculous effusions and 434 parapneumonic effusions, of whom 25 and 64 %, respectively, had CPE. COMPLES was based on the combination of pleural fluid adenosine deaminase (ADA), the percentage of mononuclear cells (MNC %), pH, and age. The cutoff values and assigned scores were: ADA (<46 IU/L [0 points], 46-100 IU/L [4 points], ≥100 IU/L [6 points]), MNC % (<10 % [0 points], 10-50 [3 points], >50 [8 points]), pH (<7.07 [0 points], 7.07-7.20 [3 points], >7.20 [5 points]), and age (≥30 [0 points], <30 years [3 points]). A sum of 12 or more points had 97 % sensitivity, 92 % specificity, likelihood ratio positive 12.3, likelihood ratio negative 0.03, and area under the curve of 0.947 for identifying CTPE versus CPPE in the validation set. CONCLUSIONS: CPE is not an unusual presentation of tuberculosis. A simple new scoring system provides a reliable tool for differentiating between CTPE and CPPE.

VAV3 Gene Polymorphism Is Associated with Paget's Disease of Bone.

BACKGROUND AND AIMS: Paget's disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The disease affects osteoclasts which increase in size, number, and activity. One of the etiopathogenic hypotheses is that the disease is genetic. It has been reported that Rho GEF Vav3 is an essential factor in the regulation of osteoclast function, and alteration of the VAV3 gene could influence the development of the disease. The aim of our study was to perform an association study between variants of the VAV3 gene and the risk of developing Paget's disease of bone. PATIENTS AND METHODS: The genotypic and allelic distribution of the VAV3 c.892A>T/p.T298S (rs7528153) polymorphism was compared between a cohort of 238 Spanish subjects with PDB and a cohort of 253 healthy subjects. RESULTS: Our results indicated that individuals carrying the VAV3 rs7528153 TT genotype were at a significantly increased risk of developing PDB (p < 0.001, odds ratio [OR] = 3.15, 95% confidence interval [95% CI] = 1.77-5.61). CONCLUSIONS: These results suggest that inheriting the VAV3 rs7528153 polymorphism is a likely susceptibility factor for developing Paget's disease of bone.

Overall survival, renal survival and relapse in patients with microscopic polyangiitis: a systematic review of current evidence.

OBJECTIVE: There are limited data on the long-term prognosis of microscopic polyangiitis (MPA). A systematic review was performed to estimate the survival, renal survival and relapse rates in patients with MPA. METHODS: Articles included in MEDLINE and EMBASE databases were reviewed. Randomized or non-randomized trials, cohort, case-control and cases-series studies of patients with MPA diagnosed according to Chapel Hill Consensus Conference definitions, a high rate of biopsy-confirmed diagnosis, follow-up >1 year and follow-up losses <10%. Two independent authors using a predefined questionnaire for evaluating the quality and risk of bias for each study extracted data. RESULTS: Eighteen studies for MPA prognosis (n = 940) and six for MPA outcomes after transplantation (n = 65) were included. Survival rates were 77-100% at 1 year, 46-80% at 5 years and 60-80% at 10 years. Higher mortality density occurred within the first months after diagnosis. Vasculitis was the cause of death in 32-50% of patients. Relapses were detected in 19-39% of cases (median time to relapse 15-43 months). Renal graft survival was 85-94% at 1 year and 51-87% at 5 years. Age, renal involvement and immunosuppressive treatment were related to mortality. Lower relapse rate was achieved with 12 vs 6 CYC pulses. CONCLUSION: Evidence regarding MPA prognosis is weak. MPA mortality is mainly concentrated in the first months after diagnosis. Fewer than 50% of deaths are related to MPA activity. MPA long-term prognosis is less severe, although relapses are frequent. End-stage renal failure is a frequent complication of MPA, and renal transplantation could be an effective therapy in these patients. Early diagnosis, early initiation of a tailored therapy according to risk factors and a longer follow-up of the patients are needed.

Use of noninvasive ventilation on internal wards for elderly patients with limitations to respiratory care: a cohort study.

BACKGROUND: The use of noninvasive positive pressure ventilation (NPPV) outside the intensive wards has been evaluated in patients with no limitation on life-sustaining support. Our aim was to evaluate its usefulness in general wards for patients with NPPV as the ceiling of ventilator care when admission to the intensive care unit (ICU) has been withheld. MATERIALS AND METHODS: Noninvasive positive pressure ventilation was used in 44 patients with acute respiratory failure (ARF) and limitations to respiratory care- 22 with chronic obstructive pulmonary disease (COPD) exacerbations and 22 with acute cardiogenic pulmonary oedema (CPE). Survival at hospital discharge, and survival and readmission rate at 12 months were assessed. RESULTS: Sixty-three per cent of COPD and 55% of CPE patients survived hospital discharge; and 50% and 37% respectively, were alive after 1 year. The cause of the in-hospital mortality was related to the admission diagnosis in 88% of cases. Cancer in COPD patients [P = 0·040, odds ratio (OR) = 15, 95% CI = 1·14-198] and the completion of NPPV treatment in both diseases (P = 0·008, OR = 0·03, 95% CI = 0·00-0·39 for COPD and P = 0·010, OR = 0·04, 95% CI = 0·00-0·45 for CPE) were related to in-hospital mortality. Fifty-six per cent of COPD and 33% of CPE patients that survived hospital admission were readmitted. CONCLUSIONS: Our study suggests that the use of NPPV in general wards could be a safe and effective option, as a last choice treatment, in patients with NPPV as the ceiling of ventilator care when admission to ICU has been withheld.

Long-term follow-up of microscopic polyangiitis, 17-year experience at a single center.

BACKGROUND: Long-term prognoses of Wegener granulomatosis (WG) and Churg-Strauss syndrome (CSS) are known; however, few data exist on long-term prognoses for microscopic polyangiitis (MPA). Our aim was to analyse the prognoses of MPA. METHODS: Cohort study with retrospective selection of patients. Twenty-two patients admitted to our Hospital (1990-2006) with biopsy-proven MPA were studied. The start date for entry into the study was the date of diagnosis. Statistical analysis was performed to look for prognostic factors for survival. RESULTS: MPA patients were followed-up for a median of 78 (5-131) months. MPA patients were treated with cyclophosphamide (Cy) plus corticosteroid (Cs) (59%) or Cs alone (41%). Seven MPA patients died. Cumulative MPA patient survival at 1, 5, and 10 years were 85% (75-95%), 85% (75-95%), and 74% (60-88%) in those treated with Cy plus Cs and 50% (32-68%), 36% (14-58%), and 0% (0-30%) in those treated with Cs alone, respectively (P=0.04). Disease extent index <5 (P=0.02) and age <65 years (P=0.02) were associated with improved survival rates in MPA patients treated with Cy. Five MPA (23%) patients relapsed after a median of 54 months (35-93). No variables were related to relapses. Despite treatment, 11MPA (50%) patients developed end-stage renal disease after a median of 9 months (0-53). CONCLUSIONS: Most MPA patients had life-threatening renal or lung involvement at diagnosis. Patients not treated with immunosuppressants had a poorer prognosis. The long-term prognosis of MPA patients who survived 6 months post diagnosis was good, although renal survival rates are low.

Paget's disease of bone is not associated with common polymorphisms in interleukin-6, interleukin-8 and tumor necrosis factor alpha genes.

BACKGROUND: Cytokines, specially interleukin (IL)-6, play an important role in the differentiation and activation of osteoclasts and might be involved in osteoblast stimulation in Paget's disease of bone (PDB). OBJECTIVES: The aim of this study was to investigate the association of polymorphisms in IL-6, IL-8 and tumor necrosis factors-alpha (TNFA) genes among Spanish patients with PDB. METHODS: We studied four single nucleotide polymorphisms (-174 G>C IL-6, -251 T>A IL-8, -238 G>A TNFA and -308 G>A TNFA) in 172 PDB patients and 150 healthy controls. Distribution of alleles and pro-inflammatory genotypes were studied for association with the presence of the disease and with clinical and laboratory data, as well as the response to bisphosphonate treatment in PDB patients. RESULTS: We found no statistically significant association between genotype and allele distribution of any of the cytokines polymorphism studied and PDB. No association between the clinical and therapeutic characteristics of PDB and the investigated polymorphism were found. CONCLUSIONS: This study does not support the hypothesis that the analyzed IL6, IL8 and TNFA polymorphism are associated with PDB.

La sospecha clínica inicial como elemento clave para el diagnóstico del tromboembolismo pulmonar / Initial clinical suspicion as a key element when deciding the diagnosis of pulmonary embolism

Introduction: The initial suspicion for pulmonary embolism (PE) and its quantification by the estimation of the pre-test probability are basic to design the diagnostic algorithm that enables us to assess the presence or absence of PE in our patients. Methods: We made a search in Medline of PE diagnosis articles. We selected articles that describe the clinical characteristic that allows the diagnosis of PE and articles that study the accuracy of pre testprobability assessment of PE using clinical gestalt or clinical predictions rules. Results: Dyspnoea (64%-84%) and chest pain (40%-52%) are the principal symptoms of PE. Nearly half of the patients have risk factor for PE. Chest radiograph, electrocardiographyc signs and arterial blood gas measurement are not specific for PE. Clinical gestalt has a sensitivity of 78%-92% and a specificity of 16%-71%. The likelihood ratio for the high probability estimation group is from 1.9 to 5.7 and for the low probability estimation group from 0.3 to 0.5. Clinical rules do not improve significantly the accuracy of clinical gestalt. Conclusion: The determination of the pre-test probability is basic for PE diagnosis. Clinical gestalt and prediction rules have a similar accuracy for PE diagnosis. Prediction rules could be recommended for medical training and also recommended when PE diagnosis needs to be standardized

Introducción: La sospecha clínica inicial de tromboembolia pulmonar (TEP) y su cuantificación mediante la estimación de la probabilidad de padecer una TEP son clave para el desarrollo del algoritmo que nos permita confirmar o descartar la enfermedad en nuestros pacientes. Métodos: Realizamos una búsqueda en Medline de los artículos relacionados con el diagnóstico de la TEP. Seleccionamos aquellos que describían las manifestaciones clínicas que permiten diagnosticar una TEP así como los artículos que estudiaban la utilidad del establecimiento ­empírico o mediante reglas de predicción­ de la probabilidad de padecer TEP. Resultados: La disnea (64% a 84%) y el dolor torácico (40% a 52%) son las principales manifestaciones clínicas de la TEP. La mitad de los pacientes tienen antecedentes clínicos sugerentes de TEP. Los resultados de la radiografía torácica, el electrocardiograma y la gasometría no son específicos. La sensibilidad de la estimación clínica de la TEP es del 78% al 92% y la especificidad del 16% al 71%. La razón de verosimilitud para el grupo de pacientes con probabilidad alta de padecer TEP está entre 1.9 y 5.7 y entre 0.3 y 0.5 para los de baja probabilidad. Los modelos clínicos no mejoran la estimación clínica empírica. Conclusión: La determinación de la probabilidad de padecer una TEP es clave para su diagnóstico. La determinación de forma empírica y las reglas de predicción tienen una fiabilidad similar. El uso de estas últimas podría recomendarse para médicos en formación o cuando es preciso estandarizar el diagnóstico de la enfermedad.

[Pulmonary embolism: analysis of cases without initial suspicion and sensitivity of three clinical models]. / Tromboembolia pulmonar: análisis de los casos sin sospecha inicial y sensibilidad de tres modelos clínicos.

BACKGROUND AND OBJECTIVE: Pulmonary embolism (PE) is a frequent and severe condition. Although clinical models do exist, many patients are wrongly diagnosed. Our objective was to evaluate the clinical characteristics of patients with PE who are admitted at a hospital without initial clinical suspicion of it. We also evaluated the sensitivity of three clinical models in order to categorize the pre-test probability of PE. PATIENTS AND METHOD: Retrospective review of clinical cases of PE diagnosed in a teaching hospital during one year. We compared the clinical features of patients whose PE was not initially suspected with those of patients in whom PE was a first diagnosis. The three clinical models were applied in all cases. RESULTS: 58 patients were identified. In 15 out of them (26%), PE was not an initial diagnosis. Patients without an initial PE suspicion were older, and previous surgery was less frequent among them. The clinical models exhibited sensitivities (60, 85, 89%) which were lower than those previously reported but higher than the doctor's initial clinical suspicion (74%). The models showed bad agreement between them (kappa = 0.06-0.1). CONCLUSIONS: An initial misdiagnosis of PE is not justified by atypical clinical characteristics. The use of clinical models would improve the clinical suspicion.