Implementation of a hybrid healthcare model in rheumatic musculoskeletal diseases: 6-months results of the multicenter Digireuma study.

OBJECTIVES: Rheumatic and musculoskeletal diseases (RMDs) require a tailored follow-up that can be enhanced by the implementation of innovative tools. The Digireuma study aimed to test the feasibility of a hybrid follow-up utilizing an electronic patient reported outcomes (ePROs)-based monitoring strategy in patients with RMDs. METHODS: Adult patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) were recruited for a 6-month bicentric prospective follow-up consisting of face-to-face and digital assessments. Patients were asked to report disease-specific ePROs on a pre-established basis, and could also report flares, medication changes, and recent infections at any time. Four rheumatologists monitored these outcomes and contacted patients for interventions when deemed necessary. Results from face-to-face and digital assessments were described. RESULTS: Of 56 recruited patients, 47 (84%) submitted any ePROs to the digital platform. Most patients with RA were female (74%, median age of 47 years), while 48% of patients with SpA were female (median age 40.4 years). A total of 3,800 platform visits were completed, with a median of 57 and 29 visits in patients with RA and SpA, respectively. Among 52 reported alerts, 47 (90%) needed contact, of which 36 (77%) were managed remotely. Adherence rates declined throughout the study, with around half of patients dropping out during the 6 months follow-up. CONCLUSION: The implementation of a hybrid follow-up in clinical practice is feasible. Digital health solutions can provide granular knowledge of disease evolution and enable more informed clinical decision making, leading to improved patient outcomes. Further research is needed to identify target patient populations and engagement strategies.

Diagnostic validity of ultrasound including extra-cranial arteries in giant cell arteritis.

OBJECTIVES: Color Doppler ultrasound (CDUS) of the temporal arteries (TA) is becoming the first test to be performed for suspected giant cell arteritis (GCA). Our aim was to assess the added value of including CDUS of large vessels (LV) in the diagnosis of GCA. METHODS: We performed an observational and retrospective study of consecutive patients with suspected GCA. Baseline CDUS of the TA and LV (axillary, subclavian, and carotid) were conducted. We defined the CDUS finding as positive if the halo sign was present. RESULTS: Of 198 patients with suspected GCA, 87 were eventually diagnosed with GCA: 45 (51.7%) had a cranial pattern exclusively, 31 (35.6%) had both a cranial and an LV pattern, and 11 (12.6%) had an isolated LV pattern. CDUS of the TA had a sensitivity of 83.9%, specificity of 97.3%, and positive and negative predictive values (PPV, NPV) of 96.1% and 88.5%, respectively. When LV was added, sensitivity increased to 96.6% and NPV to 98.2%. Specificity was 97.3% and PPV was 96.6%. As for LVs, the axillary, subclavian, and carotid arteries were involved in 87.8%, 77.4%, and 34.4%, respectively. Isolated axillary examination resulted in a loss of 12.2% of patients with LV involvement; however, inclusion of the axillary and subclavian arteries retained 100% of patients with LV involvement. CONCLUSIONS: Detection of GCA by ultrasound should routinely include examinations of the TA and LV (at least the axillary and subclavian arteries) to improve diagnostic accuracy. More than 12% of patients in our cohort had isolated LV involvement. Key Points • Extracranial involvement in GCA is very common: half of patients have extracranial vasculitis and more than 12% isolated LV involvement that can be demonstrated with CDUS. • Adding a CDUS examination of LV to TA increased sensitivity (from 83.9 to 96.6%) and the negative predictive value (from 88.5 to 98.2%) for diagnosis of GCA. • In our cohort, if we only examined the axillary arteries, 12.2% of the CGA with LV involvement would not have been diagnosed. • We propose a CDUS protocol that includes examination of the TA and LV (at least the axillary and subclavian arteries) routinely in cases of suspected GCA.

Outdoor exposure in children from Buenos Aires Province, Argentina.

OBJECTIVES: To evaluate myopia risk factors, mainly outdoor exposure and reading habits, in a country with low prevalence of myopia (Buenos Aires Province, Argentina). METHODS: Consecutive children interviewed in a clinical private practice setting were autorefracted under cycloplegia with cyclopentolate 1%. Their parents consented to fill a questionnaire about schooling, tutorial classes, outdoor exposure, reading habits, and cellphone use, both on weekdays and weekends. The Spanish questionnaire was based on past English questionnaires of myopia clinical trials. The spherical equivalent of the right eye was used for the refractive distribution. The average daily hours spent for each activity were calculated. RESULTS: This study involved 115 children aged 10.48 ±â€¯3.65 years (range 5-18 years), with 56.5% being girls. Children had 8 h of schooling per day in 62.6% of cases, and only 14.8 % had tutorial classes after school. There were 38.3% myopes (<-0.50 D), 24.3% hyperopes (>+2.00 D) and the rest were emmetropes. The mean time that these children spent outdoors per day was 3.94 ±â€¯1.45 h (27.60 ±â€¯10.16 h per week). The total mean time spent reading and writing per day was 1.50 ±â€¯0.98 h, and that spent using cellphones and tablets was 2.43 ±â€¯1.66 h. CONCLUSION: In an environment with low myopia prevalence, children spend almoast 4 h per day outdoors, much more than the usual recommendation of 2 h a day for myopia prevention.

Exposición al aire libre en niños de la Provincia de Buenos Aires, Argentina / Outdoor exposure in children from Buenos Aires Province, Argentina

Objetivos Evaluar los factores de riesgo de la miopía, principalmente la exposición al aire libre y los hábitos de lectura, en una región con baja prevalencia de miopía (Provincia de Buenos Aires, Argentina). étodos Los niños entrevistados consecutivamente entre febrero y marzo de 2020 fueron refraccionados bajo cicloplejía con ciclopentolato al 1%. Sus padres consintieron llenar un cuestionario sobre escolaridad, clases extracurriculares, exposición al aire libre, hábitos de lectura y uso del teléfono móvil, tanto entre semana como los fines de semana. Se utilizó el equivalente esférico del ojo derecho para la distribución refractiva. Se calculó el promedio de horas diarias dedicadas a cada actividad. Resultados En este estudio participaron 115 niños de 10,48±3,65 años y el 56,5% eran niñas. Los niños tenían 8h de escolaridad al día en el 62,6% de los casos y solo el 14,8% tenía clases de extracurriculares después de la escuela. Había 38,3% miopes (<−0,50 D), el 24,3% hipermétropes (>+2,00 D) y el resto eran emétropes. El tiempo medio pasado al aire libre por día fue de 3,94±1,45h (27,60±10,16h por semana). El tiempo medio total dedicado a la lectura y a la escritura por día fue de 1,50±0,98h, y el de uso de teléfonos móviles y tabletas fue de 2,43±1,66h. Conclusión En un entorno con baja prevalencia de miopía, los niños pasan al menos 4h diarias al aire libre, mucho más que la recomendación habitual de 2h diarias para la prevención de la miopía (AU)

Objectives To evaluate myopia risk factors, mainly outdoor exposure and reading habits, in a country with low prevalence of myopia (Buenos Aires Province, Argentina). Methods Consecutive children interviewed in a clinical private practice setting were autorefracted under cycloplegia with cyclopentolate 1%. Their parents consented to fill a questionnaire about schooling, tutorial classes, outdoor exposure, reading habits, and cellphone use, both on weekdays and weekends. The Spanish questionnaire was based on past English questionnaires of myopia clinical trials. The spherical equivalent of the right eye was used for the refractive distribution. The average daily hours spent for each activity were calculated. Result This study involved 115 children aged 10.48±3.65 years (range 5 to 18 years), with 56.5% being girls. Children had 8h of schooling per day in 62.6% of cases, and only 14.8% had tutorial classes after school. There were 38.3% myopes (<−0.50 D), 24.3% hyperopes (>+2.00 D) and the rest were emmetropes. The mean time that these children spent outdoors per day was 3.94±1.45 hs. (27.60±10.16 hs. per week). The total mean time spent reading and writing per day was 1.50±0.98h, and that spent using cellphones and tablets was 2.43±1.66h. Conclusion In an environment with low myopia prevalence, children spend almoast 4hours per day outdoors, much more than the usual recommendation of 2hours a day for myopia prevention (AU)

Prevalencia y características clínicas de la enfermedad pulmonar intersticial difusa sintomática en la artritis reumatoide en una población española / Prevalence and clinical characteristics of symptomatic diffuse interstitial lung disease in rheumatoid arthritis in a Spanish population

Antecedentes y objetivos: En España, los estudios epidemiológicos de prevalencia de enfermedad pulmonar intersticial difusa (EPID) en artritis reumatoide (AR) son escasos y limitados. Nuestro objetivo fue estimar la prevalencia de EPID sintomática en AR y sus características en nuestra área. Materiales y métodos: Se diseñó un estudio observacional longitudinal prospectivo en la consulta interdisciplinar de Reumatología y Neumología, en el que incluimos AR con síntomas respiratorios y EPID confirmada por tomografía computarizada de alta resolución. Resultados: De las 2.729 personas con AR de nuestra área, 47 presentaban EPID sintomática, estimándose una prevalencia de EPID sintomática en AR del 1,72% (intervalo de confianza del 95%: 1,26-2,29) con una edad al diagnóstico de AR de 57,3±13,3 años. Fue más frecuente en hombres, el 60,6% tenía antecedente de tabaquismo y el 84,3 y el 84,7% factor reumatoide y anticuerpos antipéptidos cíclicos citrulinados, respectivamente. El patrón más frecuente fue neumonía intersticial usual (NIU) en 28 (31,1%), la neumonía intersticial no específica (NINE) fue más frecuente en mujeres y el síndrome combinado enfisema-fibrosis (SCEF) exclusivamente en hombres. Conclusiones: En este estudio hemos analizado la prevalencia de AR-EPID sintomática en nuestra área, la cual está por debajo de lo esperado, probablemente en relación con las definiciones utilizadas. Así mismo, hemos descrito que el patrón NIU es el más frecuente en la AR, seguido del NINE y analizado por primera vez la prevalencia de SCEF en la AR, que alcanza el 13% (AU)

Background and objectives: In Spain, epidemiological studies of the prevalence of diffuse interstitial lung disease (ILD) in rheumatoid arthritis (RA) are limited. Our objective was to estimate the prevalence of symptomatic ILD in RA and its characteristics in our area. Materials and methods: In our hospital's interdisciplinary rheumatology and pulmonology clinic, a prospective longitudinal observational study was designed in which we included RA with respiratory symptoms and ILD confirmed by high resolution computed tomography. Results: Of the 2,729 people with RA in our area, 47 had symptomatic ILD, estimating a prevalence of symptomatic ILD in RA of 1.72% (95% CI 1.26 - 2.29) with an age at diagnosis of RA of 57.3±13.3 years. It was more frequent in men, 60.6% had a history of smoking, and 84.3% and 84.7% had rheumatoid factor (RF) and anti-cyclic citrullinated peptide (Anti-CCP) antibodies, respectively. The most frequent pattern was usual interstitial pneumonitis (UIP), appearing in 28 (31.1%). Nonspecific interstitial pneumonia (NSIP) was more frequent in women, while the combined pulmonary fibrosis-emphysema (CPFE) syndrome presented exclusively in men. Conclusions: We have analysed the prevalence of symptomatic RA-ILD in our area, which is lower than expected, probably in relation to the definitions used. We have also described that the UIP pattern is the most frequent in RA in our environment, followed by the NSIP. Lastly, we have analysed the prevalence of CPFE in RA, which reaches 13%, for the first time (AU)

Biochemical algorithm to identify individuals with ALPL variants among subjects with persistent hypophosphatasaemia.

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.

Early monitoring of infliximab serum trough levels predicts long-term therapy failure in patients with axial spondyloarthritis.

OBJECTIVE: To evaluate whether serum infliximab trough levels (ITL) during the early stages of treatment are predictive of long-term clinical failure in patients with axial spondyloarthritis (axSpA). METHODS: Longitudinal observational study involving 81 patients with axSpA monitored during infliximab therapy. Serum ITL were measured before starting infliximab treatment and at weeks 2 (W2), W6 and W12 of treatment. Disease activity was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline, W24 and W52, and every 6 months thereafter until treatment discontinuation, regardless of the reason. Non-clinically important improvement was defined by ΔASDAS<1.1. The association between serum levels during the early stages and clinical outcomes (non-clinically important improvement at W52, drug survival and drop-out due to secondary inefficacy) was investigated through logistic regression models and Kaplan Meier curves. Receiver operating characteristic (ROC) curves were employed to determine the best cut-off for serum ITL. RESULTS: Out of the 81 patients, 45 (56%) did not achieve clinical improvement at W52. These patients had lower serum ITL at W12 compared to those who improved: ITL [median (IQR)]: 4.1(0.9-8.3) µg/mL vs 7.1 (4.3-11.3) µg/mL, respectively;p = 0.007). ITL<6.7 µg/mL at W12 was significantly associated with: i) not achieving clinical improvement at W52 (OR: 2.3; 95%CI: 1.3-3.9); ii) shorter drug survival (5.0 years (95% CI 3.8-6.2) vs 7.0 years (95% CI 4.8-6.9; p = 0.04), and iii) higher drop-out rates due to secondary inefficacy (OR: 3.5; 95% CI: 1.2-10.2). CONCLUSION: Low serum ITL at W12 were associated with long-term clinical failure in patients with axSpA, due to secondary inefficacy.

Prevalence and clinical characteristics of symptomatic diffuse interstitial lung disease in rheumatoid arthritis in a Spanish population.

BACKGROUND AND OBJECTIVES: In Spain, epidemiological studies of the prevalence of diffuse interstitial lung disease (ILD) in rheumatoid arthritis (RA) are limited. Our objective was to estimate the prevalence of symptomatic ILD in RA and its characteristics in our area. MATERIALS AND METHODS: In our hospital's interdisciplinary rheumatology and pulmonology clinic, a prospective longitudinal observational study was designed in which we included RA with respiratory symptoms and ILD confirmed by high resolution computed tomography. RESULTS: Of the 2729 people with RA in our area, 47 had symptomatic ILD, estimating a prevalence of symptomatic ILD in RA of 1.72% (95% CI 1.26-2.29) with an age at diagnosis of RA of 57.3 ±â€¯13.3 years. It was more frequent in men, 60.6% had a history of smoking, and 84.3% and 84.7% had rheumatoid factor (RF) and anti-cyclic citrullinated peptide (Anti-CCP) antibodies, respectively. The most frequent pattern was usual interstitial pneumonitis (UIP), appearing in 28 (31.1%). Nonspecific interstitial pneumonia (NSIP) was more frequent in women, while the combined pulmonary fibrosis-emphysema (CPFE) syndrome presented exclusively in men. CONCLUSIONS: We have analysed the prevalence of symptomatic RA-ILD in our area, which is lower than expected, probably in relation to the definitions used. We have also described that the UIP pattern is the most frequent in RA in our environment, followed by the NSIP. Lastly, we have analysed the prevalence of CPFE in RA, which reaches 13%, for the first time.

Evaluación de la densidad mineral ósea y de los parámetros de 3D-Shaper en la hipofosfatasia congénita del adulto / Agitated/inattentive children: explanatory models

Objetivo: Evaluar la densidad mineral ósea (DMO) y parámetros de 3D-Shaper a nivel de fémur proximal (FP) en adultos con hipofosfatasia (HPP) confirmada genéticamente y compararlos en aquellos sujetos con y sin fracturas. Material y métodos: Análisis transversal de datos densitométricos y de arquitectura ósea de la visita basal de un estudio longitudinal en el que se incluyeron pacientes con HPP. Se realizó un estudio densitométrico (Lunar Prodigy, GE iDXA) en FP y se empleó el software 3D-Shaper (version 2,7. Galgo Medical). Resultados: Se incluyeron 33 adultos con HPP con mutaciones en heterocigosis. Un 63,6% (21/33) fueron mujeres (42,9% postmenopáusicas), y 8 de los varones (66,6%) fueron mayores de 50 años. La media de edad fue 50,56±15,08 años, el 30,3% (10/33) tuvieron fracturas previas traumáticas, y un 15,2% (5/33), de estrés. La prevalencia de osteoporosis en CF fue del 11,8% (2/17) y de osteopenia, 82,4% (14/17). En premenopáusicas y varones jóvenes se detectó baja masa ósea para la edad en un 12,5% (2/16). Al comparar sujetos con fracturas de estrés y sin ellas, así como con traumáticas, no hubo diferencias en DMO. El 3D-Shaper mostró disminución del grosor cortical (mm) en pacientes con fracturas de estrés [1,8 (1,77-1,89)] frente a sujetos sin ellas [1,94 (1,87-2,03, p=0,03)] y en comparación con los que tuvieron fracturas traumáticas [1,97 (1,88-2,04), p=0,03]. Conclusión: Estos datos reflejan una discreta repercusión densitométrica en formas más leves del adulto. Estudios de arquitectura ósea pudieran resultar de interés para determinar pacientes susceptibles de presentar fracturas de estrés. (AU)

Objetivo: To evaluate bone mineral density (BMD) and 3D-Shaper parameters at the proximal femur (FP) level in adults with genetically confirmed hypophosphatasia (HPP) and to compare them in those subjects with and without fractures. Material and methods: Crosssectional analysis of densitometric data and bone architecture from the baseline visit of a longitudinal study in which patients with HPP were included. A densitometric study (Lunar Prodigy, GE iDXA) was carried out in FP using 3D-Shaper software (version 2.7. Galgo Medical). Results: 33 adults with HPP with heterozygous mutations were included. 63.6% (21/33) were women (42.9% postmenopausal), and 8 of the men (66.6%) were older than 50 years. The mean age was 50.56±15.08 years, 30.3% (10/33) had previous traumatic fractures and 15.2% (5/33) presented stress fractures. The prevalence of osteoporosis in CF was 11.8% (2/17) and of osteopenia, 82.4% (14/17). In premenopausal women and young men, low bone mass was detected for age in 12.5% (2/16). When comparing subjects with and without stress fractures, as well as traumatic ones, there were no differences in BMD. The 3D-Shaper showed a decrease in cortical thickness (mm) in patients with stress fractures [1.8 (1.77-1.89)] compared to subjects without them [1.94 (1.87-2.03, p=0.03)] and compared to those with traumatic fractures [1.97 (1.88-2.04), p=0.03]. Conclusions: These data reflect a discrete densitometric impact in milder forms of the adult. Bone architecture studies could be of interest in determining patients susceptible to stress fractures. (AU)

Cost-effectiveness analysis of treatment sequences containing tofacitinib for the treatment of rheumatoid arthritis in Spain.

OBJECTIVE: To assess the cost-effectiveness of tofacitinib-containing treatment sequences versus sequences containing only standard biological therapies in patients with moderate-to-severe rheumatoid arthritis (RA) after the failure of conventional synthetic disease-modifying antirheumatic drugs (csDMARD-IR population) and in patients previously treated with methotrexate (MTX) who show an inadequate response to second-line therapy with any tumour necrosis factor inhibitor (TNFi-IR population). METHODS: A patient-level microsimulation model estimated, from the perspective of the Spanish Public NHS, lifetime costs and quality-adjusted life years (QALY) for treatment sequences starting with tofacitinib (5 mg twice daily) followed by biological therapies versus sequences of biological treatments only. Concomitant treatment with MTX was considered. Model's parameters comprised demographic and clinical inputs (initial Health Assessment Questionnaire [HAQ] score and clinical response to short- and long-term treatment). Efficacy was measured by means of HAQ score changes using mixed treatment comparisons and data from long-term extension (LTE) trials. Serious adverse events (SAEs) data were derived from the literature. Total cost estimation (€, 2018) included drug acquisition, parenteral administration, disease progression and SAE management. RESULTS: In the csDMARD-IR population, sequences starting with tofacitinib proved dominant options (more QALYs and lower costs) versus the corresponding sequences without tofacitinib. In the TNFi-IR population, first-line treatment with tofacitinib+MTX followed by scAbatacept+MTX➔rituximab+MTX➔certolizumab+MTX proved dominant versus scTocilizumab+MTX➔scAbatacept+MTX➔rituximab+MTX➔certolizumab+MTX; and tofacitinib+MTX➔scTocilizumab+MTX➔scAbatacept+MTX➔rituximab+MTX versus scTocilizumab+MTX➔scAbatacept+MTX➔rituximab+MTX➔certolizumab+MTX was less effective but remained a cost-saving option. CONCLUSIONS: Inclusion of tofacitinib seems a dominant strategy in moderate-to-severe RA patients after csDMARDs failure. Tofacitinib, as initial third-line therapy, proved a cost-saving strategy (€- 337,489/QALY foregone) in moderate-to-severe TNFi-IR RA patients. Key points • Therapeutical approach in rheumatoid arthritis (RA) consisted in sequences of several therapies during patient lifetime. • Treatment sequences initiating with tofacitinib followed by biological drugs provided higher health effects in csDMARDs-IR population, compared with sequences containing only biological drugs. • In both csDMARD-IR and TNFi-IR RA populations, initiating treatment with tofacitinib was associated to lower treatment costs for the Spanish National Health System.

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

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 < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively. CONCLUSIONS: In subjects with persistent hypophosphatasaemia -secondary causes excluded- one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.

Serum tocilizumab trough concentration can be used to monitor systemic IL-6 receptor blockade in patients with rheumatoid arthritis: a prospective observational cohort study.

OBJECTIVES: To investigate the pharmacokinetics (PK) and dynamics of tocilizumab (TCZ) in daily practice. METHOD: An observational study of 66 consecutive RA patients treated with TCZ 8 mg/kg once every 4 weeks intravenously, monitored for 24 weeks. Spearman's rank test was used to investigate the correlation between TCZ concentration and C-reactive protein (CRP). Clinical improvement was assessed at week 24 using the Disease Activity Score in 28 joints (DAS28) compared to baseline, and its relationship with TCZ concentration was investigated using linear regression analyses. TCZ trough concentrations and anti-drug antibodies were measured using an enzyme-linked immunosorbent assay (ELISA) and antigen binding test, respectively. RESULTS: At baseline, 26 patients (39.4%) had a CRP level above 10 mg/L with a median (interquartile range, IQR) of 37.7 (21.9-49.7) mg/L. A TCZ concentration above 1 mg/L was sufficient to normalize CRP levels. Spearman's rank test showed a correlation coefficient of -0.460 (p < 0.0001). The TCZ concentration varied widely, with concentrations < 1 mg/L in 17-31% of patients, depending on the time point of measurement. Anti-TCZ antibodies were detected in one sample. Linear regression analyses showed a coefficient of 0.080 with a 95% confidence interval (CI) of 0.039-0.113 (p < 0.001) for the association between TCZ concentration and ΔDAS28. No confounders were identified. CONCLUSIONS: The TCZ standard regimen results in a wide variety of serum TCZ trough concentrations; this is mostly due to target binding and to a lesser extent to immunogenicity. The majority of patients obtained TCZ concentrations > 1 mg/L, which is sufficient for CRP normalization. Therefore, dose taper strategies might be possible in a substantial proportion of patients.

Safety of antitumour necrosis factor treatments in chronic rheumatic diseases: therapy discontinuations related to side effects.

WHAT IS KNOWN AND OBJECTIVE: The appearance of antitumor necrosis factor drugs (ATDs) has been a major advance in the management of these patients. However, due to the immunosuppressive effect of these therapies, side effects that require treatment discontinuations can appear. The purpose of this study was to evaluate the frequency of ATD discontinuation due to adverse drug effects (ADEs) and the influence of different factors such as diagnosis, ATD prescribed and concomitant disease-modifying antirheumatic drugs (DMARDs). METHODS: Observational study from a prospective cohort conducted in a tertiary hospital (1350 beds) in Spain. Data were obtained from the database of the Rheumatology Outpatient Unit of the hospital and patients' clinical files. Included patients had a diagnosis of RA or peripheral or axial SpA (ankylosing spondylitis, psoriatic SpA, non-radiographic SpA, SpA associated with inflammatory bowel disease or reactive arthritis) treated between November 2000 and March 2014 with infliximab (IFX), etanercept (ETN) or adalimumab (ADA). RESULTS AND DISCUSSION: Study cohort included 531 rheumatic patients (282 patients with RA, 53·1%, and 249 patients with SpA, 46·9%). ATDs were discontinued in 62 cases (11·7%) because of ADEs, mainly inmunogenicity and infections (mainly due to infusion reactions, 58·1%, and infections, 19·3%). ATD discontinuation was higher in the group of RA patients compared with SpA (44/282 (15·6%) in RA vs. 18/249 (7·23%) in SpA). The appearance of ADEs that led to drop out was more frequent in patients under IFX therapy (45 (18·6%) with IFX vs. 12 (7·59%) with ETN and 5 (3·81%) with ADA). We observed a significantly increased risk of ADEs when patients received IFX than when ETN or ADA were used (P < 0·001); 444 patients (83·6%) received DMARDs in combination with ATDs. The risk of ATD withdrawal was significantly higher in patients treated with leflunomide as compared to those who do not (OR = 1·984, P < 0·05). WHAT IS NEW AND CONCLUSION: Discontinuation of ATD due to ADEs is relatively frequent and it depends on the diagnosis and ATD administered. The risk of treatment discontinuation is higher in patients diagnosed with RA vs. SpA or treated with IFX (rather than with ETN or ADA). The addition of DMARDs to ATDs increased the frequency of treatment discontinuation, up to three concomitant medications. Leflunomide in combination with an ATD significantly increased the probability of treatment discontinuation due to adverse reactions.

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

Relationship between SNPs and expression level for candidate genes in rheumatoid arthritis.

OBJECTIVES: The study of polymorphisms of genes differentially expressed may lead to the identification of putative causal genetic variants in multifactorial diseases such as rheumatoid arthritis (RA). Based on preceding transcriptomic results, we genotyped 10 single nucleotide polymorphisms (SNPs) belonging to six genes (S100A8, RNASE2, PGLYRP1, RUNX3, IL2RB, and LY96) showing the highest fold change (> 1.9) when level of expression was compared between RA patients and controls. These SNPs were then analysed to evaluate their role in RA. METHOD: The relationship between gene expression and genotypes of SNPs was first investigated by Kruskal-Wallis and Mann-Whitney tests in RA patients and controls. The genetic association of these SNPs with RA were then analysed using family-based association tests in trio families. RESULTS: We found that RNASE2 gene expression was related to rs2013109 genotypes in 14 RA patients (p = 0.030). The association study in a discovery sample of 200 French trio families revealed a significant association with RA for one SNP, PGLYRP1-rs2041992 (p = 0.019); this association was stronger in trios where RA patients carried the HLA-DRB1 shared epitope (SE) (p = 0.003). However, this association was not found in a replication sample of 240 European trio families (p = 0.6). CONCLUSIONS: Family-based association tests did not reveal an association between RA and any SNP of the candidate genes tested. However, RNASE2 gene expression was differentially expressed in RA patients considering a sequence polymorphism. This result led us to highlight the potential disease-specific regulation for this candidate gene in RA.

The 11q23.3 genomic region-rs964184-is associated with cardiovascular disease in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory disease associated with high risk of cardiovascular (CV) events. Recently, the rs964184 polymorphism has been associated with coronary artery disease in nonrheumatic Caucasian individuals. 2160 Spanish RA patients were genotyped for the rs964184 polymorphism. Sex, age at diagnosis and traditional CV risk factors (diabetes mellitus, dyslipidemia and smoking habit) were associated with increased risk of CV events. Interestingly, RA patients carrying the rs964184 GG genotype had significantly higher risk of CV events than those with CC genotype [hazard ratio (HR) = 2.91, 95% confidence interval (CI): 1.36-6.26, P = 0.006] after adjusting the results for sex, age at diagnosis and traditional CV risk factors. Our results indicate that rs964184 polymorphism is associated with CV disease in RA.

Single-nucleotide polymorphisms at the 9p21.3 genomic region not associated with the risk of cardiovascular disease in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic polygenic inflammatory disease associated with accelerated atherosclerosis and high risk of cardiovascular disease (CVD). In this study, we evaluated the potential association of 9p21.3 single-nucleotide polymorphisms (SNPs) - previously linked to coronary artery disease - and CVD risk in 2001 Spanish RA patients genotyped for 9p21.3 SNPs using TaqMan™ assays. Carotid intima media thickness (cIMT) and presence of carotid plaques were also analyzed. Cox regression model did not disclose significant differences between patients who experienced CVD and those who did not. Neither association was found between cIMT or carotid plaques and SNPs allele distribution. In conclusion, results do not support a role of rs10116277 or rs1537375 SNPs in CVD risk in Spanish RA patients.

Manejo perioperatorio de los fármacos modificadores de la enfermedad en Reumatología: recomendaciones basadas en un metaanálisis / Peri-operative management of disease modifying anti-rheumatic drugs: Recommendations based on a meta-analysis

Con el objetivo de proponer recomendaciones para el manejo perioperatorio de los fármacos modificadores de la enfermedad (FAME) en pacientes con enfermedades reumáticas que van a ser sometidos a cirugía, se ha realizado una revisión sistemática de la literatura. Se realizó una búsqueda de todos los estudios publicados y de los resúmenes de congresos, recopilando 5.285 documentos, de los que finalmente se incluyeron 27 estudios que proporcionan información de 5.268 pacientes y 7.933 cirugías. La mayoría eran mujeres (edad media: 55 años), estaban diagnosticados de artritis reumatoide y el fármaco más estudiado fue el metotrexate (MTX). Las recomendaciones finales son las siguientes: mantener el tratamiento con MTX o leflunomida en el período perioperatorio en ausencia de otros factores de riesgo de complicaciones posquirúrgicas (Nivel de evidencia 1c; Grado de recomendación D) y con respecto a los FAME biológicos, suspenderlos momentáneamente o programar la cirugía lo más alejada posible a la última dosis, espaciando al menos 2 dosis si existieran otros factores de riesgo (Nivel de evidencia 2c; Grado de recomendación D) (AU)

The objective of this paper is make recommendations for the perioperative management of antirheumatic treatment based on the best available evidence. A systematic review was performed including studies in which patients with rheumatic diseases treated with biological and non-biological disease-modifying antirheumatic drugs (DMARDs) had undergone surgery. A total of 5,285 studies were recorded, of which 27 were finally included. These contained information on 5,268 patients and 7,933 surgeries. The majority were women (mean age 55 years) were diagnosed with rheumatoid arthritis, and the most studied drug was methotrexate (MTX). The final recommendations include: maintaining treatment with MTX or leflunomide in the perioperative period in the absence of other risk factors for postoperative complications (Level of Evidence 1c, Grade D recommendation). Biological DMARDs should be temporarily suspended, or the surgery scheduled as far as possible from the last dose, and, if there were other risk factors a space at least two doses (Level of Evidence 2c; Grade D recommendation) (AU)