Pilar Aguado’s research while affiliated with University of La Rioja and other places

We analyzed the incidence of fractures and changes in bone mineral density and bone turnover markers in 264 patients who discontinued bisphosphonates. Fractures were recorded in 12.3%. Half were clinical vertebral fractures. We identified patients with a high-risk profile who should not discontinue treatment. The optimal length of bisphosphonate discontinuation is unknown, as is the type of patient who could benefit from this approach. The objectives of the study were to analyze, in clinical practice, the incidence of fractures and associated risk factors, changes in bone mineral density (BMD) and bone turnover markers (BTMs) after discontinuation of bisphosphonates. This observational retrospective study included 264 patients from 14 Spanish rheumatology departments. Postmenopausal women or men with osteoporosis received alendronate or risedronate for ≥ 5 years or zoledronate for ≥ 3 years and had discontinued treatment for ≥ 1 year or ≥ 2 years, respectively. Spinal X-rays were obtained before discontinuation and in suspected clinical vertebral fracture during follow-up. BMD and BTMs were determined before discontinuation and at different time points. The mean discontinuation time was 2.7 (± 6.7) years. Thirty-two patients (12.3%) had 36 fractures, mainly clinical vertebral fractures. The main risk factor for fracture was a high-risk profile (femoral neck T-score ≤ –2.5 and/or a history of fracture and/or multiple fractures [≥ 5 years]) before discontinuation. At 12 months, 10.41% of patients with high-risk profile experienced a fracture, being 0.8% and 1.08% in moderate- and low-risk patients, respectively. Significant BMD loss at the femoral neck and total hip was detected, with duration of discontinuation being the key factor. PINP was the marker with the greatest changes. We identified a profile of patients with osteoporosis who should not discontinue bisphosphonates, owing to the possibility of fractures, especially vertebral, which are already evident the first year after discontinuation.

Objectives To estimate the prevalence of chondrocalcinosis and calcium pyrophosphate dihydrate deposition disease (CPPD) in patients with low alkaline phosphatase (ALP) levels and a positive ALPL genetic study (+GT) for hypophosphatasia (HPP) compared to those with the same biochemical abnormality and a negative genetic test (−GT). As a secondary objective, to analyze the biochemical factors associated with its presence in subjects with ALPL variants. Methods Seventy-eight subjects with persistently low ALP levels and ALPL genetic test were included. Baseline and 24-mo knee ultrasounds were performed in 42 + GT and 36 −GT subjects, in whom the fibrocartilage, hyaline cartilage of menisci, tendons, and synovial fluid were scanned to detect calcium pyrophosphate deposits. A MyLabTwice ultrasound machine (Esaote) with a multifrequency linear array transducer (4–13 MHz) was used. Results A higher percentage of chondrocalcinosis was observed in the +GT group [9/42 (21.4%)] compared to the −GT group [2/36 (5.6%), p=.045)]. Two patients (4.76%), both in the +GT group, had arthritis secondary to CPPD. No new cases were identified at the 24-mo control. When comparing +GT patients with and without chondrocalcinosis, ALP levels were lower, and pyridoxal-5′-phosphate (PLP) and phosphate levels were higher in the former group (p<.05). Logistic regression analysis revealed that higher PLP levels are associated with the presence of chondrocalcinosis (OR: 1.1; 95% confidence interval, CI, 1.001–1.012). Conclusions Chondrocalcinosis was a frequent ultrasonographic finding in HPP. Arthritis secondary to calcium pyrophosphate deposits, however, proved less prevalent. Genetic causes, such as HPP, should be considered when evaluating patients with chondrocalcinosis in clinical practice.

Background: Hypophosphatasia (HPP) is a rare and underdiagnosed condition characterized by deficient bone and teeth mineralization. The aim of this study was first, to evaluate the diagnostic utility of employing alkaline phosphatase (ALP) threshold levels to identify adults with variants in ALPL among individuals with persistently low ALP levels and second, to determine the value of also including its substrates (serum pyridoxal-5'-phosphate-PLP-and urinary phosphoetanolamine-PEA) for this purpose in order to create a biochemical algorithm that could facilitate the diagnostic work-up of HPP. Results: The study population comprised 77 subjects with persistent hypophosphatasaemia. They were divided into two groups according to the presence (+GT) or absence (-GT) of pathogenic ALPL variants: 40 +GT and 37 -GT. Diagnostic utility measures were calculated for different ALP thresholds and Receiver Operating Characteristic (ROC) curves were employed to determine PLP and PEA optimal cut-off levels to predict the presence of variants. The optimal threshold for ALP was 25 IU/L; for PLP, 180 nmol/L and for PEA, 30 µmol/g creatinine. Biochemical predictive models were assessed using binary logistic regression analysis and bootstrapping machine learning technique and results were then validated. For ALP < 25 UI/L (model 1), the area under curve (AUC) and the 95% confidence intervals (CI) was 0.68 (95% CI 0.63-0.72) and it improved to 0.87 (95% CI 0.8-0.9), when PEA or PLP threshold levels were added (models 2 and 3), reaching 0.94 (0.91-0.97) when both substrates were included (model 4). The internal validation showed that the addition of serum PLP threshold levels to the model just including ALP improved significantly sensitivity (S) and negative predictive value (NPV) - 100%, respectively- with an accuracy (AC) of 93% in comparison to the inclusion of urinary PEA (S: 71%; NPV 75% and AC: 79%) and similar diagnostic utility measures as those observed in model 3 were detected when both substrates were added. Conclusions: In this study, we propose a biochemical predictive model based on the threshold levels of the main biochemical markers of HPP (ALP < 25 IU/L and PLP > 180 nmol/L) that when combined, seem to be very useful to identify individuals with ALPL variants.

p>Introduction: In Spain, few data have been reported on mortality and survival in rheumatoid arthritis with diffuse interstitial lung disease. Objectives: To estimate mortality and survival for patients with symptomatic diffuse interstitial lung disease and rheumatoid arthritis and to analyze the effect of clinical factors. Methods: We performed an observational study between 2007 and 2018 at the Interdisciplinary Rheumatology and Pulmonology Clinic, from a tertiary Hospital. Patients with rheumatoid arthritis and symptomatic of diffuse interstitial lung disease confirmed by high-resolution computed tomography were included. Causes of death and clinical factors were reported. Results: We identified 90 patients with rheumatoid arthritis and symptomatic interstitial lung disease. Twenty-six patients died and diffuse interstitial lung disease was the most frequent cause (50%). The overall mortality rate was 19.7 per 1000 patient-years (95% CI: 13.4 - 29). The multivariate model revealed the predictors of mortality to be a long time between diagnosis of rheumatoid arthritis and lung involvement (HR = 1.17; p = 0.003) and low forced vital capacity (HR = 0.02; p = 0.018). The probability of survival was 50% at 10.2 years from diagnosis of interstitial lung disease. Comparison of survival did not reveal significant differences by type of radiologic pattern (p = 0.823). Conclusions: The fact that almost one-third of patients died and that survival is 50% at 10 years highlights the important role of diffuse interstitial lung disease in rheumatoid arthritis. The radiologic pattern does not seem to be as important for survival as forced vital capacity at diagnosis and the time between diagnosis of rheumatoid arthritis and lung involvement. Key points 1. DILD is associated with shorter survival in patients with RA. 2. The radiologic pattern does not seem to influence the survival in patients with RA and DILD. 3. The FVC at diagnosis is an important factor that influences the prognosis of patients with RA and DILD.</p

Objective To determine and analyse the organisational approach adopted by Spanish rheumatologists to osteoporosis (OP) to define strategic priorities. Material and method A group of experts designed a questionnaire on OP in the rheumatologist practice. The survey was sent to the Spanish Society of Rheumatology (SER) members. Through the Delphi round, strategic priorities were agreed upon in OP. Results The priorities are: 1) The SER should promote the inclusion of OP in 100% of the services and expand the training offer; 2) Rheumatology services should promote the role of the nurse in OP, promote quality indicators and referral protocols agreed with primary care in addition to promoting their training in this area; 3) The SER and Rheumatology services should promote electronic consultation, OP monographic clinics and participation in Fracture Liaison Service units. Conclusions Strategic priorities in OP help identify areas of improvement at organisational, structural and quality standards level in this pathology.

Abstract Background Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase–ALP–measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. Results Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9–30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9–13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p

Background The etiology of bone loss in Rheumatoid Arthritis (RA) is multifactorial and systemic inflammation plays a relevant role. Recently, a relationship between autoimmunity and bone mineral density (BMD) has been described in patients with RA. Objectives To study BMD and biochemical parameters of bone metabolism in a cohort of patients with early rheumatoid arthritis, and assess the relationship between them and autoimmunity and other markers of inflammation. Methods A prospective longitudinal study was performed. 128 patients from an early Rheumatoid Arthritis Unit (ERAU) were included. All of them fullfilled ACR 2010 classification criteria for RA. Demographic, clinical, biochemical, immunological, radiological and densitometric data, and also inflammatory activity index DAS 28, HAQ functional index, were collected. Any value >20 IU/mL for RF and >30 IU/mL for ACPA was defined as positive. Results Between January 2009 and June 2017, 801 patients were evaluated in our ERAU. After two years of follow-up, the most frequent definitive diagnoses were: Early RA 221 (27.6%), Undifferentiated Arthritis 97 (12.1%), Psoriatic Arthritis 62 (7.7%), Spondyloarthritis 54 (6.7%) and autoimmune Diseases 28 (3.4%). From the 128 patients with early rheumatoid arthritis evaluated, 104 (81.9%) were ACPA positive and 98 (77.2%) FR positive. The mean BMD in the total column was 0.96 ±0.14 g/cm2 and in the femoral neck was 0.76 ±0.12 g/cm2. No correlation of BMD with autoimmunity markers was found in either of the two locations studied, while a negative relationship between BMD and the PCR inflammation marker (BMD femoral neck: rho-0.203, p = 0.027 and BMD lumbar spine rho =-0.27, p 0.003) was found. The BMD did not correlate with DAS28 nor the HAQ index. The mean baseline serum calcidiol value was 20.7±8 ng/ml, and a negative correlation of basal serum calcidiol with the functional HAQ index was observed (rho=-0.23, p= 0.008). No correlation between other autoimmunity (FR and ACPA) and inflammation (VSG, PCR and DAS 28) markers and vitamin D was found. Conclusion The BMD in patients with early rheumatoid arthritis of our cohort correlates with the PCR inflammation marker. Unlike other studies shows, in our cohort, serological autoimmunity factors do not have shown to have an independent effect on BMD. References [1]Llorente I, Merino M, Ortiz AM, et al. Anti-citrullinated protein antibodies are associated with decreased bone mineral density: baseline data from a register of early arthritis patients. Rheumatol Int (2017) 37:799–806 Disclosure of Interests Sara Garcia Carazo: None declared, Diana Peiteado: None declared, Alejandro Villalva: None declared, Laura Nuño: None declared, Mariana Diaz: None declared, Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz, Pilar Aguado: None declared

Background The use of a specific and widely used type of intravenous ferrotherapy, ferric carboxymaltose (FCM), has been linked to the development of an asymptomatic and transient hypophosphataemia. However, in recent years it has been published that it can generate a severe hypophosphataemic osteomalacia (HPO) mediated by fibroblast growth factor 23 (FGF23) that is associated with high morbidity¹. It is a potentially serious adverse effect whose prevalence is unknown and that clinicians may know little about. Objectives To know the clinical and biochemical characteristics of this adverse effect and make it visible in the medical community. Methods Observational descriptive study of three cases of patients assessed in the Rheumatology department of our hospital who were referred for study of recurrent fractures and diagnosed of FGF23-mediated HPO due to FCM. Demographic, clinical and laboratory data of the patients are described. Results The clinical and laboratory characteristics of the patients are shown in table 1. All patients presented clinical and biochemical features compatible with FGF23-mediated HPO (mean of FGF levels 240 kRU/L, NR 0-145). All had multiple insufficiency fractures (Fx) and/or avascular necrosis (AN), with hip involvement in all 3 cases. Other causes of HPO were ruled out in all of them using PET ¹⁸F-FDG, octreotide scintigraphy, abdominal magnetic resonance and PET ⁶⁸Ga-DOTATOC, and a genetic study of hypophosphataemic rickets was also performed in case 1. In all patients FCM was discontinued and phosphate levels were progressively normalized allowing the withdrawal of oral phosphate and calcitriol replacement therapy. After metabolic normalization, none presented new Fx or AN.View this table: • View inline • View popup Table 1. Clinical and biochemical characteristics of the patients Conclusion Treatment with FCM can cause severe FGF23-mediated HPO, multiple fractures and a great decrease in the quality of life. Since it can be potentially serious and easily reversible, it is important to favor the dissemination of these new cases and the knowledge of this disease. The need to monitor phosphate and/or FGF23 levels in patients receiving this intravenous iron therapy should be evaluated. References [1]Bishay RH, Ganda K, Seibel MJ. Long-term iron polymaltose infusions associated with hypophosphataemic osteomalacia: a report of two cases and review of the literature. Ther Adv Endocrinol Metab. 2017;8(1-2):14–19. doi:10.1177/2042018816678363 Disclosure of Interests Elisa Fernández: None declared, Carolina Tornero: None declared, Victoria Navarro-Compán Consultant of: Abbvie, Lilly, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Lilly, Novartis, Pfizer, UCB, Gemma Bonilla: None declared, Chamaida Plasencia: None declared, Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz, Pilar Aguado: None declared