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.

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.

The ASAS-OMERACT core domain set for axial spondyloarthritis.

BACKGROUND: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary. OBJECTIVE: To update the ASAS-OMERACT core outcome set for AS into the ASAS-OMERACT core outcome set for axial spondyloarthritis (axSpA). METHODS: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two scenarios are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies. RESULTS: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extra-musculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials. CONCLUSION: The ASAS-OMERACT core domain set for AS has been updated into the ASAS-OMERACT core domain set for axSpA. The next step is the selection of instruments for each domain.

Unveiling axial involvement in psoriatic arthritis: An ancillary analysis of the ASAS-perSpA study.

OBJECTIVE: To determine the clinical profile of axial psoriatic arthritis (PsA) in a worldwide setting. Secondly, to identify factors associated with the development of axial involvement in patients with PsA. METHODS: Data from 3684 patients with axial spondyloarthritis (axSpA) or PsA from the ASAS-perSpA study were analysed. The ASAS-perSpA is a cross-sectional study that recruited consecutive patients with SpA (as diagnosed by their rheumatologist) from 68 centers worldwide and collected patient and disease data. First, 2651 axSpA patients and 367 PsA patients with any history of axial involvement (axPsA) were compared using logistic regression to later identify predictive factors for rheumatologist diagnosis of axPsA. Secondly, 367 axPsA patients were compared with 666 PsA patients lacking axial involvement (peripheral PsA [pPsA]) and the characteristics associated with axial manifestations were explored by logistic regression analysis. RESULTS: Patients with axPsA were older and less frequently males or HLA*B27 positive in comparison with axSpA patients. Additionally, while patients with axPsA had more peripheral manifestations and psoriasis, other extra-musculoskeletal manifestations (IBD and uveitis) were more frequent in those with axSpA. In the multivariable analysis, older age at diagnosis (OR = 1.04), peripheral arthritis (OR = 7.32) and dactylitis (OR = 2.82) were significantly associated with the diagnosis of axPsA. However, uveitis (OR = 0.22), IBD (OR = 0.12), HLA*B27 carriership (OR = 0.26) or sacroiliitis on imaging (OR = 0.5) were inversely associated with axPsA diagnosis as compared to axSpA. Axial involvement in patients with PsA was significantly associated with male gender (OR = 1.68), elevated CRP (OR = 2.87) and the absence of psoriasis (OR = 0.33). CONCLUSION: In this worldwide setting axPsA was defined by rheumatologists as a unique phenotype, with disease features lying between axSpA and pure pPsA.

Influence of smoking and obesity on treatment response in patients with axial spondyloarthritis: a systematic literature review.

To assess whether smoking and obesity are predictors of poor treatment response in patients with axial spondyloarthritis (axSpA). A systematic literature review was performed by searching in MEDLINE and EMBASE up to June 2019 with a strategy based on the PICO approach: Population: patients with axSpA; Intervention or exposure: smoking or obesity; Comparison: non-smokers (for smoking) and normal-weight individuals (for obesity); and Outcome: any response criteria currently validated for axSpA. The 2009 Oxford Centre for Evidence-based Medicine levels were used for assessing the studies quality. Out of 1873 references retrieved, 46 studies were selected for full-text review and 12 for data extraction: six stratified patients by smoking and six by obesity. All were longitudinal observational studies, except one, which was cross-sectional. Overall, these studies included 5291 patients (3917 for smoking and 1333 for obesity), and all these patients were on anti-tumor necrosis factor (anti-TNF) therapy. The quality of evidence was graded as level 2b except that from the cross-sectional study which was graded level 4. For smoking, the evidence found is inconsistent: two studies finding negative effects in response to anti-TNF while the other four found no differences in clinical response to this therapy. Regarding obesity, the evidence is more consistent: five of the six studies describing a negative influence in response to anti-TNF. According to the scientific evidence in patients with axSpA, obesity is associated with a more unsatisfactory response to anti-TNF therapy. A poorer response in smokers has yet to be demonstrated. Key Points • Identifying predictors of treatment response in axSpA, especially those that are modifiable, is relevant. • Obesity increases the risk of poorer response to anti-TNF agents in patients with axSpA. • Scientific evidence for smoking habit as a predictor of treatment response in axSpA is inconclusive.

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)

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.

The Effect of Axial Spondyloarthritis on Mental Health: Results from the Atlas.

OBJECTIVE: To assess the risk of mental disorders in patients with axial spondyloarthritis (axSpA) and to examine the factors associated with this. METHODS: In 2016, a sample of 680 patients with axSpA were interviewed as part of the development process for the Atlas of Axial Spondyloarthritis in Spain. The risk of mental disorders in these patients was assessed using the 12-item General Health Questionnaire scale. Additionally, the variables associated with the risk of mental disorders were investigated, including sociodemographic characteristics (age, sex, relationship, patient association membership, job status, and educational level), disease status (Bath Ankylosing Spondylitis Disease Activity Index, spinal stiffness, and functional limitation), and previous diagnosis of mental disorders (depression and anxiety). Bivariate correlation analyses were performed, followed by multiple hierarchical and stepwise regression analysis. RESULTS: A total of 45.6% patients were at risk of mental disorders. All variables except educational level and thoracic stiffness significantly correlated with risk of mental disorders. Nevertheless, disease activity, functional limitation, and age showed the highest coefficient (r = 0.543, p ≤ 0.001; r = 0.378, p ≤ 0.001; r = -0.174, p ≤ 0.001, respectively). In the stepwise regression analysis, 4 variables (disease activity, functional limitation, patient association membership, and cervical stiffness) explained the majority of the variance for the risk of mental disorders. Disease activity displayed the highest explanatory degree (R2 = 0.875, p < 0.001). CONCLUSION: In patients with axSpA, the prevalence of risk of mental disorders is high. Combined with a certain sociodemographic profile, high disease activity is a good indicator of the risk for mental disorders.

Measuring impairments of functioning and health in patients with axial spondyloarthritis by using the ASAS Health Index and the Environmental Item Set: translation and cross-cultural adaptation into 15 languages.

INTRODUCTION: The Assessments of SpondyloArthritis international society Health Index (ASAS HI) measures functioning and health in patients with spondyloarthritis (SpA) across 17 aspects of health and 9 environmental factors (EF). The objective was to translate and adapt the original English version of the ASAS HI, including the EF Item Set, cross-culturally into 15 languages. METHODS: Translation and cross-cultural adaptation has been carried out following the forward-backward procedure. In the cognitive debriefing, 10 patients/country across a broad spectrum of sociodemographic background, were included. RESULTS: The ASAS HI and the EF Item Set were translated into Arabic, Chinese, Croatian, Dutch, French, German, Greek, Hungarian, Italian, Korean, Portuguese, Russian, Spanish, Thai and Turkish. Some difficulties were experienced with translation of the contextual factors indicating that these concepts may be more culturally-dependent. A total of 215 patients with axial SpA across 23 countries (62.3% men, mean (SD) age 42.4 (13.9) years) participated in the field test. Cognitive debriefing showed that items of the ASAS HI and EF Item Set are clear, relevant and comprehensive. All versions were accepted with minor modifications with respect to item wording and response option. The wording of three items had to be adapted to improve clarity. As a result of cognitive debriefing, a new response option 'not applicable' was added to two items of the ASAS HI to improve appropriateness. DISCUSSION: This study showed that the items of the ASAS HI including the EFs were readily adaptable throughout all countries, indicating that the concepts covered were comprehensive, clear and meaningful in different cultures.

Is entheses ultrasound reliable? A reading Latin American exercise.

The objective of this study is to evaluate inter-reader entheses ultrasound (US) reliability and the influence of the type of image or degree of sonographer experience on US reliability in patients with spondyloarthritis (SpA). Eighteen Latin American ultrasonographers with different experience took part in an US reading exercise evaluating 60 entheseal images (50 % static images and 50 % videos) from healthy controls and SpA patients. The following sonographic lesions were assessed: structure, thickness, bone proliferation/tendon calcification, erosions, bursitis, and Doppler signal. Another group of three experts with significant experience in entheses US read all images too. Inter-reader reliability among participants and experts was calculated by the Cohen's kappa coefficient. Thresholds for kappa values were <0.2 poor, 0.21-0.4 fair, 0.41-0.6 moderate, 0.61-0.8 good, and 0.81-1 excellent. Furthermore, the results for the expert group were stratified based on the type of image. Kappa correlation coefficients among participants, showed variability depending on the type of lesion, being fair for structure and thickness, moderate for calcifications, erosions, and bursitis, and excellent for Doppler signal. Inter-reader reliability among experts was higher, being moderate for structure and thickness, good for calcifications and bursitis, and excellent for erosions and Doppler. Inter-reader reliability for assessing calcification and structure using static images was significantly higher than for videos. Overall inter-reader reliability for assessing entheses by US in SpA is moderate to excellent for most of the lesions. However, special training seems fundamental to achieve better inter-reader reliability. Moreover, the type of image influenced these results, where evaluation of entheses by videos was more difficult than by static images.

EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice.

A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.

Measurement error in the assessment of radiographic progression in rheumatoid arthritis (RA) clinical trials: the smallest detectable change (SDC) revisited.

OBJECTIVES: To evaluate if the mean smallest detectable change (SDC) of multiple time intervals using the Bland & Altman (B&A) levels of agreement (LoA) method is an appropriate surrogate for the generalisability analysis method for estimating the overall SDC of radiological progression in rheumatoid arthritis (RA) trials. Secondly, to compare the SDC based on 95% LoA with the SDC based on 80% LoA, and to investigate the association between SDC and baseline damage and progression. METHODS: Fifteen datasets from randomised controlled trials in RA were scored by 13 experienced readers as pairs according to the modified Sharp/van der Heijde method. The SDC using the 95% and 80% LoA and the generalisability methods was calculated. RESULTS: 21 295 radiographic time points from 7643 patients were included. The mean (range) SDC for the LoA and the generalisability methods was 3.1 (2.3-4.3) and 3.2 (2.3-4.6) units, respectively. The mean ± SD difference between the two methods was -0.13 ± 0.28. The mean SDC including all intervals (n=31) was 3.0 ± 0.7 for 95% LoA and 2.0 ± 0.4 for 80% LoA. No relationship was observed between baseline damage and the SDC, whereas the SDC increased with increasing radiological progression. CONCLUSIONS: The mean of the interval SDCs obtained by the simple LoA method is a valid surrogate for the SDC obtained by complex generalisability methods. The SDC depends on the level of radiographic progression rather than on the level of absolute damage. In addition, the use of an SDC based on 80% rather than on 95% LoA is proposed.

Dose escalation of the anti-TNF-alpha agents in patients with rheumatoid arthritis. A systematic review.

OBJECTIVE: To estimate the proportion of rheumatoid arthritis (RA) patients on anti-tumour necrosis factor (anti-TNF) who require dose escalation. METHODS: Systematic review of the scientific literature. Infliximab, etanercept and adalimumab studies in RA were considered. Primary outcome was the proportion of patients requiring dose escalation. American College Rheumatology (ACR) and Disease activity score (DAS) responses post-escalation were assessed when available. RESULTS: From 1801 references, 16 studies with 8510 patients were included. Of all the infliximab patients, 53.7% underwent dose escalation. Fourty-four per cent of the infliximab patients experienced dose increase and 8.3%, frequency increase. The ACR20 response to dose escalation ranged from 27 to 36% and DAS28 improved from 5.2 to 4.5 in one study and from 4.1 to 3.7 in another. Of the etanercept patients, 17.5% experienced a dose increase but changes on the mean dose were not statistically significant. CONCLUSIONS: Dose escalation is common in patients treated with infliximab, and less frequent with etanercept. In a proportion of patients, the dose escalation seems effective. The design and evidence level of the available studies limit the strength of the conclusions.