Bone marrow edema in the sacroiliac joints is associated with the development of structural lesions at the same anatomical location over time in patients with axial spondyloarthritis.

OBJECTIVE: To assess whether the presence of bone marrow edema (BME) leads to the development of structural lesions at the same anatomical location of the sacroiliac joints (SIJ), and to investigate the association between BME patterns over time and structural lesions in patients with early axial spondyloarthritis (axSpA). METHODS: Patients with axSpA from the DESIR cohort with ≥2 consecutive magnetic resonance imaging (MRI)-SIJ were assessed at baseline, 2 and 5 years. MRI-SIJ images were divided into 8 quadrants. The association between BME and subsequent structural lesions (sclerosis, erosions, fatty lesions, and ankylosis) on MRI in the same quadrant was tested longitudinally. Additionally, patients were grouped according to the pattern of BME evolution across quadrants over time (no BME, sporadic, fluctuating, and persistent). The association between these patterns and 5-year imaging outcomes (eg: ≥5 erosions and/or fatty lesions on MRI-SIJ) was tested. RESULTS: In total, 196 patients were included. BME in each quadrant was associated with sclerosis (OR:1.9 (95%CI: 1.1;3.4)), erosions (1.9 (1.5;2.5)) and fatty lesions (1.9 (1.4;2.6)). Ankylosis was uncommon. There was a gradient between increased level of inflammation and subsequent damage: compared to the 'no BME' pattern, the sporadic (OR (95% CI): 2.1 (1.0;4.5)), fluctuating (OR:5.6(2.2;14.4)) and persistent (OR:7.5(2.8;19.6)) patterns were associated with higher structural damage on MRI-SIJ at 5-years. CONCLUSIONS: In early axSpA, inflammation on MRI-SIJ leads to damage at the quadrant level. The higher the exposure to inflammation across quadrants in the SIJs over time the higher the likelihood of subsequent structural damage, suggesting a cumulative effect.

Can numerical rating scales of disease impact be used as targets for patient-centred management in rheumatoid arthritis?

OBJECTIVES: Patient centred care is an increasingly important paradigm. Applying a treat-to-target strategy to the impact of the disease in patients' lives seems a very promising tool to serve this purpose. We aimed to evaluate if maximum acceptable impact scores (target-values) defined at the population level provide an appropriate representation for most individual patients. To determine if the individually established target values of impact are consistent enough to be used in a treat-to-target strategy. METHODS: Consecutive patients with rheumatoid arthritis were asked to indicate, in two consecutive visits, the maximum severity of impact they considered acceptable to live with for the rest of their lives, in the seven domains of Rheumatoid Arthritis Impact of Disease score. The individual adequacy of population-based reference values was assessed by measures of dispersion. Stability of individual target-values were evaluated through intraclass correlation coefficient. Socio-demographic, clinical and psychological features were tested as co-factors of stability. RESULTS: 299 patients were included. The dispersion of targets was wide (CV>0.68), thus limiting the use of any population-based single values as targets for the individual patients. Although the mean target values were very similar in both visits for all domains, reliability was poor in all cases (ICCs: 0.37-0.47). Only 25-30% of the patients selected the same target value in the 2 visits. No explanatory factors for (non-)stability were identified. CONCLUSIONS: Quantified impact targets defined at population level are not appropriate for individual patient care. Research on alternative tools to support patient-centred, target-oriented management strategies is warranted.

Muscle dysfunction in axial spondylarthritis: the MyoSpA study.

OBJECTIVES: We aimed to investigate muscle physical properties, strength, mass, physical performance, and the prevalence of sarcopenia in patients with axial spondylarthritis (axSpA) compared to the healthy controls (HC). METHODS: We performed a cross-sectional study on 54 participants: 27 patients with axSpA and 27 HC, matched by age, gender, and level of physical activity. Muscle physical properties (stiffness, tone and elasticity), muscle strength (five-times sit-to-stand [5STS] test), muscle mass, physical performance (measured through gait speed) and sarcopenia were compared between the groups. Linear regression models were conducted allowing adjustment for relevant variables. RESULTS: Patients with axSpA (mean age 36.5 (SD 7.5) years, 67% males, mean disease duration 6.5 (3.2) years) had no significant difference in segmental muscle stiffness, tone or elasticity, compared with the HC, despite showing a slight numerically higher lower lumbar (L3-L4) stiffness [median 246.5 (IQR 230.5-286.5) vs. 232.5 (211.0-293.5), p=0.38]. No participants presented sarcopenia. Patients with axSpA, compared to the HC, had lower total strength [B=1.88 (95% CI 0.43;3.33)], as well as lower strength in the upper (B=-17.02 (-27.33;-6.70)] and lower limbs [B=-11.14 (-18.25;-4.04)], independently of muscle physical properties. Patients had also significantly lower gait speed than the HC [B=-0.11 (-0.21;-0.01)], adjusted for muscle mass, strength and muscle physical properties. CONCLUSIONS: Young axSpA patients with a relatively short disease duration presented similar segmental muscle physical properties as the HC and had no sarcopenia. Patients with axSpA had reduced physical performance and lower strength compared to the HC, despite normal muscle mass, suggesting a possible muscle dysfunction. Gait characteristics may be a potential biomarker of interest in axSpA.

The role of muscle in the susceptibility and progression of axial Spondyloarthritis: The MyoSpA Study Protocol.

BACKGROUND: Axial Spondyloarthritis (axSpA) is a chronic, inflammatory rheumatic disease that affects the axial skeleton, causing pain, stiffness, and fatigue. Genetics and environmental factors such as microbiota and microtrauma are known causes of disease susceptibility and progression. Murine models of axSpA found a decisive role for biomechanical stress as an inducer of enthesitis and new bone formation. Here, we hypothesize that muscle properties in axSpA patients are compromised and influenced by genetic background. OBJECTIVES: To improve our current knowledge of axSpA physiopathology, we aim to characterize axial and peripheral muscle properties and identify genetic and protein biomarker that might explain such properties. METHODS: A cross-sectional study will be conducted on 48 participants aged 18-50 years old, involving patients with axSpA (according to ASAS classification criteria, symptoms duration < 10 years) and healthy controls matched by gender, age, and levels of physical activity. We will collect epidemiological and clinical data and perform a detailed, whole body and segmental, myofascial characterization (focusing on multifidus, brachioradialis and the gastrocnemius lateralis) concerning: a) Physical Properties (stiffness, tone and elasticity), assessed by MyotonPRO®; b) Strength, by a dynamometer; c) Mass, by bioimpedance; d) Performance through gait speed and 60-second sit-to-stand test; e) Histological and cellular/ molecular characterization through ultrasound-guided biopsies of multifidus muscle; f) Magnetic Resonance Imaging (MRI) characterization of paravertebral muscles. Furthermore, we will perform an integrated transcriptomics and proteomics analysis of peripheral blood samples. DISCUSSION: The innovative and multidisciplinary approaches of this project rely on the elucidation of myofascial physical properties in axSpA and also on the establishment of a biological signature that relates to specific muscle properties. This hitherto unstudied link between gene/protein signatures and muscle properties may enhance our understanding of axSpA physiopathology and reveal new and useful diagnostic and therapeutic targets.

Direct tissue-sensing reprograms TLR4+ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients.

CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program.

The Effect of ACTN3 and VDR Polymorphisms on Skeletal Muscle Performance in Axial Spondyloarthropathies.

BACKGROUND: Spondyloarthritis (SpA) are the most common group of chronic inflammatory rheumatic diseases affecting about 1.5% of the adult Caucasian population. Low back pain is the most common symptom. The aetiopathogenesis of SpA is multifactorial, with well-known genetic and environmental contributions. Furthermore, muscle properties might also be involved in the pathophysiological process and these could be modulated by the genetic background. Alpha-actinin-3 (ACTN3) and Vitamin D receptor (VDR) genes are well-known genes related with muscle performance. Our aim was to analyze four SNPs of these genes and to evaluate their influence in axial SpA (axSpA) susceptibility, phenotype and muscle properties. METHODS: We performed a pilot study based on case-control approach involving 56 participants: 28 axSpA patients and 28 healthy controls matched by age, gender and levels of physical activity. Clinical, epidemiological and muscle characterization data-muscle physical properties (stiffness, tone, and elasticity), strength, mass, and performance, were collected. Two different muscles were considered for analysis, the Multifidus and Gastrocnemius. Four SNPs of ACTN3 (rs1815739) and VDR (rs2228570, rs731236, and rs7975232), were selected, analyzed and correlated with clinical, epidemiological and muscle characterization data. RESULTS: In total, 51 individuals (27 axSpA patients and 24 matched controls) were eligible for further genetic analysis, 66.7% being male and with a mean age of 36 years. Muscle physical properties, muscle strength and muscle mass were similar in both groups; however, axSpA patients showed a decrease in muscle performance. None of the studied SNPs were associated with disease susceptibility/phenotype, muscle physical properties, muscle strength or muscle mass. However, ACTN3 rs1815739 and VDR rs2228570 were shown to be associated with muscle performance. CONCLUSION: Our results suggest an association between ACTN3 and VDR polymorphisms and muscle performance in axSpA.

Lumbar myofascial physical properties in healthy adults: myotonometry vs. shear wave elastography measurements.

OBJECTIVE: The human resting myofascial tone maintains the body tone in a neutral posture, the assessment of this and other muscle physical properties (MPP) is relevant, since, it is altered in many pathological states. PATIENTS AND METHODS: Seventeen healthy subjects (8 males), between 18-50 years old, were assessed. The MPP of lower lumbar muscles was evaluated on right and left sides during prone resting position using two devices; myotonometry (stiffness, elasticity and tone) and ultrasound-based shear-wave elastography (SWE) (shear modulus). MTM measurements were performed at two anatomic points (ANp), selected by an experienced reader and at an adjacent ultra-sound determined point (USp). Myotonometry measurements of the erector spinae and SWE measurements of multifidus muscles at the L3-4 level were compared between genders and sides. The intra-reader reliability (IRR) for each device and correlations between techniques were analysed. MTM measurements performed at ANp and USp were compared. The intraclass correlation coefficient (ICC) was assessed for both devices. Correlations between stiffness (myotonometry) and shear modulus (SWE) at the respective muscle depths were assessed with Spearman correlation. RESULTS: Males had greater stiffness and tone than females, particularly on the dominant side. MPP assessed by myotonometry were not different between ANp and USp. Good/Excellent IRR was documented for measurements by MTM (ICC≥0.90) and SWE (ICC≥0.85). No correlation in myotonometry stiffness and SWE shear modulus was found. For myotonometry assessments, the addition of ultrasonography was not different from anatomic localizations. No correlation of measurements was found between devices assessing respective L3-4 level muscles. CONCLUSIONS: Gender and side differences must be considered when assessing MPP in axial muscles. For MTM assessments, the addition of ultrasonography was not different to anatomic references. No correlation was found between devices.

Biologic disease-modifying anti-rheumatic drugs and patient-reported outcomes in axial SpA: a systematic review and a call for action.

This paper is to assess the efficacy of different biologic DMARDs (bDMARDs) on several patient-reported outcomes (PROs) in randomized controlled trials (RCT) in axial spondyloarthritis (axSpA). A systematic literature review (SLR) was performed. MEDLINE (May 1, 2018) was used with the filters "published in the last 10 years" and "humans." The PICO criteria used were Patients: adults with radiographic axSpA (r-axSpA) or non-radiographic axSpA (nr-axSpA); Intervention: any bDMARD; Compararator: placebo (PBO)/any different drug; Outcome: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL), the EuroQol-5D (EQ-5D), the Short Form 36 Health Survey physical component summary (SF36-PCS), the Short Form 36 Health Survey mental component summary (SF36-MCS), and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). After screening 84 initial references and manually selecting other 9, 24 publications, assessing TNF inhibitors (TNFi) or IL17A inhibitors (IL17Ai) were selected. Four RCTs quantified the minimal clinical important difference (MCID) between treatment arms. Most of the RCTs compared the mean difference of PROs between different timepoints. Overall, the treatment arm was superior to the comparator. PROs were often underreported or highly heterogeneously presented. MCID was seldom mentioned. There is a need to raise the standard of care on SpA by aiming at remission and PRO associated improvements. In order to achieve this goal, the target must be clearly defined, reported, and tested.

Effectiveness of switching between TNF inhibitors in patients with axial spondyloarthritis: is the reason to switch relevant?

BACKGROUND: To investigate whether the reason to discontinue the first TNF inhibitor (TNFi) affects the response to the second TNFi in axial spondyloarthritis (axSpA). METHODS: Patients with axSpA from the Rheumatic Diseases Portuguese Register (ReumaPt), who discontinued their first TNFi and started the second TNFi between June 2008 and May 2018, were included. Response was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement (ASDAS-CII), major important improvement (ASDAS-MI), low disease activity (ASDAS-LDA), and inactive disease (ASDAS-ID). The reason for discontinuation of the first TNFi was defined, according to ASDAS-CII as primary failure (no response ≤ 6 months), secondary failure (response ≤ 6 months but lost thereafter), adverse events, and others. The association between the reason for discontinuation of the first TNFi and response to the second TNFi over time was assessed in multivariable generalized equation (GEE) models. RESULTS: In total, 193 patients were included. The reason for discontinuation of the first TNFi did not influence the response to the second TNFi, according to the ASDAS-CII. However, a difference was found with more stringent outcomes, e.g., there was a higher likelihood to achieve ASDAS-ID with the second TNFi for patients discontinuing the first TNFi due to secondary failure (OR 7.3 [95%CI 1.9; 27.7]), adverse events (OR 9.1 [2.5; 33.3]), or other reasons (OR 7.7 [1.6; 37.9]) compared to primary failure. CONCLUSION: Patients with axSpA with secondary failure to their first TNFi, compared to those with primary failure, have a better response to the second TNFi according to stringent outcomes.

Effect of biologic disease-modifying anti-rheumatic drugs targeting remission in axial spondyloarthritis: systematic review and meta-analysis.

OBJECTIVES: To assess the efficacy of biologic DMARDs (bDMARDs) in achieving Assessment of Spondyloarthritis International Society partial remission (ASAS-PR) and/or Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS-ID), as remission-like surrogates, in axial SpA (axSpA). METHODS: Data from randomized controlled trials (RCTs), including long-term extensions, were included. A systematic literature review was performed using the MEDLINE database (first search May 2018, updated February 2020) and PICO criteria according to Patients-adults with radiographic or non-radiographic axSpA; Intervention-any bDMARD; Comparator-placebo and/or any different drug; Outcomes-ASAS-PR and/or ASDAS-ID as primary or secondary endpoints. Meta-analysis was performed after assessment of the homogeneity of study designs, populations and outcomes. RESULTS: After screening 155 references, a total of 22 RCTs and 28 long-term extensions were retrieved. ASAS-PR was the dominant remission-like definition used. Concerning TNF inhibitors, 14/17 RCTs provided evidence of efficacy in reaching remission at different time points: 12, 16, 24 and 28 weeks (ASAS-PR in 16-62% of patients and ASDAS-ID in 24-40% of patients). With a limited number of studies available, IL-17A inhibitors exhibited remission rates of 15-21% for ASAS-PR and 11-16% for ASDAS-ID at week 16. A meta-analysis regarding ASAS-PR was performed considering RCTs with a similar duration (12, 16 or 24 weeks). The relative risk for achieving remission was 3.864 (95% CI 2.937, 5.085). CONCLUSION: bDMARDs have a clear impact in axSpA remission evaluated by ASAS-PR. Nevertheless, these data show an unmet need for improved reporting of remission-like outcomes.

The European Portuguese version of the ASAS Health Index for Patients with Spondyloarthritis: Measurement properties.

OBJECTIVE: The Assessments of SpondyloArthritis international Society Health Index (ASAS HI), estimates the impact of Spondyloarthritis (SpA) on global functioning and health. This article assesses the construct validity, reliability and responsiveness of the Portuguese version of the ASAS HI. PATIENTS AND METHODS: Patients fulfilling ASAS classification criteria for axial (axSpA) or peripheral SpA (pSpA) were included. Construct validity was assessed through Spearman's correlation analysis with other health outcomes. Discriminant validity was tested comparing the ASAS HI across disease activity and functional states using the Kruskal-Wallis test. Internal consistency was assessed by Cronbach's α, and test-retest reliability by intraclass correlation coefficients (ICC). Responsiveness was evaluated by the standardized response mean (SRM) in patients with active disease who required therapy escalation. RESULTS: Among the 91 patients included, 67% were male, mean (SD) age 47.2 (12.9) years, 63 patients with axSpA and 28 patients with pSpA. The hypothesis defined a priori to test construct validity were confirmed. The ASAS HI showed ability to discriminate between patients with different disease activity and functional states (p<0.001). Internal consistency (Cronbach's α: 0.88) and test-retest reliability [ICC=0.76 (95%CI 0.09-0.91)] were good. Responsiveness was moderate (SRM=-0.53). The smallest detectable change was 3.0. CONCLUSIONS: The Portuguese version of the ASAS HI is a comprehensible questionnaire that is valid, reliable and responsive. It can be used to assess the impact of SpA and its treatment on functioning and health, in clinical practice and for research purposes.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update.

OBJECTIVE: To update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA). METHODS: According to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined. RESULTS: The updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed. CONCLUSION: These recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.

Eligibility criteria for biologic disease-modifying antirheumatic drugs in axial spondyloarthritis: going beyond BASDAI.

OBJECTIVES: To compare definitions of high disease activity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in selecting patients for treatment with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: Patients from Rheumatic Diseases Portuguese Register (Reuma.pt) with a clinical diagnosis of axial spondyloarthritis (axSpA) were included. Four subgroups (cross-tabulation between ASDAS (≥2.1) and BASDAI (≥4) definitions of high disease activity) were compared regarding baseline characteristics and response to bDMARDs at 3 and 6 months estimated in multivariable regression models. RESULTS: Of the 594 patients included, the majority (82%) had both BASDAI≥4 and ASDAS ≥2.1. The frequency of ASDAS ≥2.1, if BASDAI<4 was much larger than the opposite (ie, ASDAS <2.1, if BASDAI≥4): 62% vs 0.8%. Compared to patients fulfilling both definitions, those with ASDAS ≥2.1 only were more likely to be male (77% vs 51%), human leucocyte antigen B27 positive (79% vs 65%) and have a higher C reactive protein (2.9 (SD 3.5) vs 2.1 (2.9)). Among bDMARD-treated patients (n=359), responses across subgroups were globally overlapping, except for the most 'stringent' outcomes. Patients captured only by ASDAS responded better compared to patients fulfilling both definitions (eg, ASDAS inactive disease at 3 months: 61% vs 25% and at 6 months: 42% vs 25%). CONCLUSION: The ASDAS definition of high disease activity is more inclusive than the BASDAI definition in selecting patients with axSpA for bDMARD treatment. The additionally 'captured' patients respond better and have higher likelihood of predictors thereof. These results support using ASDAS≥2.1 as a criterion for treatment decisions.

Translation, cross-cultural adaptation and validation of the Osteoarthritis Quality of Life (OAQoL) questionnaire for use in Portugal.

Osteoarthritis (OA) is the most prevalent rheumatic disease and is a leading cause of decreased quality of life (QoL). The OA Quality of Life questionnaire (OAQoL) is an OA-specific patient-reported outcome measures. The aim of this study was to translate and validate the original UK English version of the Osteoarthritis Quality of Life (OAQoL) questionnaire into European Portuguese. The translation of the questionnaire was carried out according to a dual panel methodology (bilingual panel followed by lay panel). This was followed by cognitive debriefing interviews (CDIs) with OA patients to assess comprehension and relevance of the translated questionnaire. Finally, a validation survey was conducted to assess its psychometric properties. The Portuguese OAQoL, a comparator scale (the Nottingham Health Profile-NHP) as well as questions relating to demographic and disease information were administered to OA patients. A sub-sample of patients also completed the Portuguese OAQoL two weeks later, to assess test-retest reliability. The internal consistency, construct validity and known group validity (according to perceived OA severity) of the scale was also assessed. Both the bilingual and lay panels consisted of five individuals and no major difficulties relating to the translation process were identified. A total of ten patients with OA participated in the CDIs. The mean time to complete the questionnaire was 5 min. These interviews revealed that the Portuguese version of the OAQoL was clear, relevant and easy to complete. Finally, 53 OA patients (44 females; mean age of 67.6 years) completed the validation survey. Cronbach's alpha coefficient was 0.87, demonstrating high internal consistency. Test-retest reliability, assessed by Spearman's rank correlation coefficient, was 0.86. Moderate correlations were found with the majority of the NHP sections, providing evidence of construct validity. Significant differences in OAQoL scores were found between patients who differed according to their perceived OA severity, providing evidence of known group validity. The Portuguese version of the OAQoL is a valid and reliable questionnaire that can be used to assess QoL in OA, both in clinical practice and for research purposes.

Prognostic factors for recovery and non-recovery in patients with non-specific neck pain: a protocol for a systematic literature review.

INTRODUCTION: Neck pain is a common musculoskeletal disorder worldwide. It can result in significant disability and impaired quality of life. More than 50% of patients with neck pain still report symptoms 1 year later despite receiving different forms of non-pharmacological and pharmacological treatment. Identifying patient characteristics that are modifiable or predict recovery and non-recovery for an individual patient might identify ways of improving outcomes. This systematic review aims to comprehensively summarise the existing evidence regarding baseline patient characteristics associated with recovery and non-recovery, as defined by measures of pain intensity, disability and global perceived improvement. METHODS AND ANALYSIS: Six electronic databases, PubMed, CINAHL, PEDro Database, EMBASE, Cochrane Library and Web of Science, will be searched, with terms related to the review question such as neck pain, prognostic or predictive research, from inception to 28 September of 2018. Studies will be included if they have investigated an association between patient characteristics and outcomes, with at least one follow-up time point. Two independent reviewers will screen the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. Data from included papers will be extracted using standardised forms, including study and participants' characteristics, outcomes, prognostic factors and effect size of the association. The risk of bias of each study will be assessed using the Quality in Prognostic Studies tool. A narrative synthesis will be conducted considering the strength, consistency of results and the methodological quality. ETHICS AND DISSEMINATION: This systematic review does not require ethical approval. The results will be disseminated through publication in a peer-review journal, as a chapter of a doctoral thesis and through presentations at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42018091183.

[Ozone Therapy in Knee Osteoarthritis: A Systematic Review]. / Ozonoterapia na Osteoartrose do Joelho: Revisão Sistemática.

INTRODUCTION: The aim of this study was to conduct a systematic review in order to examine the effectiveness of ozone therapy on knee osteoarthritis. The objectives were to evaluate the effect over time of ozone therapy in terms of knee pain, functional improvement and radiographic progression. MATERIAL AND METHODS: A search was carried out on PubMed, Embase, Cochrane Library, Scopus and Web of Science databases to identify randomized and controlled studies focusing on this association. The following descriptors were used in English: ozone therapy, knee osteoarthritis. A descriptive summary and quality assessment was made of all studies included for analysis. RESULTS: Six randomized and controlled studies were identified. The risk of bias assessment demonstrated that one study was considered as having a moderate risk of bias and the remainder a high risk of bias. No quantitative analysis of the data was performed, as the studies included were not sufficiently homogeneous. The participants in the studies were generally elderly patients with mild to moderate knee osteoarthritis. DISCUSSION: The variability of ozone therapy and the comparators demonstrates that there is no standardized therapy. Few studies reported adverse effects, and where they occurred, they were mild and associated with the procedure. CONCLUSION: Ozone therapy proved effective in the short-term in relation to placebo and when combined with hyaluronic acid, but it was not superior to other current treatments. More randomised and controlled studies are needed to evaluate the risks/benefits of ozone therapy, both in the short term and the medium/long term.

Introdução: O presente estudo teve por objetivo realizar uma revisão sistemática de forma a analisar a eficácia da ozonoterapia na osteoartrose do joelho. Os objetivos visaram avaliar o efeito temporal da ozonoterapia na dor no joelho, na melhoria funcional e na progressão radiográfica.Material e Métodos: Realizou-se uma pesquisa nas bases de dados PubMed, Embase, Cochrane Library, Scopus e Web of Science a fim de identificar estudos aleatorizados e controlados que tratassem dessa associação. Utilizaram-se os seguintes descritores em língua inglesa: 'ozone therapy', 'knee osteoarthritis'. Realizou-se um resumo descritivo e avaliação de qualidade de todos os estudos incluídos para análise.Resultados: Identificaram-se seis estudos aleatorizados e controlados relacionados com o objetivo deste trabalho. A avaliação do risco de viés mostrou que um estudo foi considerado como risco moderado de viés e os restantes como risco alto de viés. Não se realizou a análise quantitativa dos dados pois os estudos incluídos não foram suficientemente homogéneos. Os participantes dos estudos eram em geral doentes idosos com osteoartrose do joelho leve a moderada.Discussão: A variabilidade nas intervenções de ozonoterapia e comparadores, demonstra que não existe uma terapêutica estandardizada. Foram poucos os estudos que relataram os efeitos adversos, e quando aconteceu, estes eram ligeiros e associados ao procedimento.Conclusão: A ozonoterapia mostrou eficácia a curto prazo, em relação ao placebo e quando combinada com ácido hialurónico, sem ser promissora em relação aos restantes tratamentos vigentes. É importante que novos estudos aleatorizados e controlados avaliem os benefícios/riscos da ozonoterapia tanto a curto como a médio/longo prazo.

Work participation in spondyloarthritis across countries: analysis from the ASAS-COMOSPA study.

OBJECTIVES: To explore the role of individual and country level socioeconomic (SE) factors on employment, absenteeism and presenteeism in patients with spondyloarthritis (SpA) across 22 countries worldwide. METHODS: Patients with a clinical diagnosis of SpA fulfilling the ASAS classification criteria and in working age (≤65 years) from COMOSPA were included. Outcomes of interest were employment status, absenteeism and presenteeism, assessed by the Work Productivity and Activity Impairment Specific General Health questionnaire. Three multivariable models were built (one per outcome) using mixed-effects binomial (for work status) or ordinal regressions (for absenteeism and presenteeism), with country as random effect. The contribution of SE factors at the individual-level (eg, gender, education, marital status) and country-level (healthcare expenditure (HCE) per capita, Human Development Index (HDI) and gross domestic product per capita) SE factors, independent of clinical factors, was assessed. RESULTS: In total, 3114 patients with SpA were included of which 1943 (62%) were employed. Physical function and comorbidities were related to all work outcomes in expected directions and disease activity also with absenteeism and presenteeism. Higher education (OR 4.2 (95% CI 3.1 to 5.6)) or living in a country with higher HCE (OR 2.3 (1.5 to 3.6)) or HDI (OR 1.9 (1.2 to 3.3)) was positively associated with being employed. Higher disease activity was associated with higher odds for absenteeism (OR 1.5 (1.3 to 1.7)) and presenteeism (OR 2.1 (1.8 to 2.4)). No significant association between individual-level and country-level SE factors and absenteeism or presenteeism was found. CONCLUSIONS: Higher education level and higher country SE welfare are associated with a higher likelihood of keeping patients with SpA employed. Absenteeism and presenteeism are only associated with clinical but not with individual-level or country-level SE factors.

Translation and cross-cultural adaptation of the ASAS Health Index and ASAS Environmental Factors Item Set into European Portuguese Language.

OBJECTIVE: There is a lack of outcome measures to assess the impact of axial spondyloarthritis (axSpA) on health, function and quality of life. The Assessment of SpondyloArthritis International Society (ASAS) group developed the ASAS Health Index (ASAS-HI) and the ASAS Environmental Factors Item Set (ASAS-EF) to measure functioning and health across all aspects of health that are typically affected and relevant for patients with axSpA, based on the International Classification of Functioning, Disability and Health (ICF). The aim of this paper was to describe the translation and cross-cultural adaptation of both questionnaires into European Portuguese among patients with radiographic and non-radiographic axial SpA (nr-axSpA) and test the conceptual equivalence of the translated version in the Portuguese context. MATERIAL AND METHODS: The ASAS-HI and ASAS-EF were firstly translated into European Portuguese and then back-translated into English, following forward-backward procedure. After the review of the Portuguese version by an expert committee, the field test with cognitive debriefing involved a sample of 10 axSpA patients with different gender, age, disease duration, and educational background. RESULTS: Minor difficulties arose from the translation process of the ASAS-HI. The EF Item Set offered more difficulties indicating that concepts underlying the contextual factors may be more culture-dependent. A total of 10 patients with axSpA [8 males, mean age of 41.4 (±13.7)] participated in the field test. Cognitive debriefing showed that items of the ASAS-HI and EF Item Set of the Portuguese version are clear, relevant, understandable and easy to complete. As a result of cognitive debriefing, the wording of four items had to be changed to avoid misunderstandings or unintended interpretations, and a new response option "not applicable" was added to two items of the ASAS-HI to improve appropriateness. CONCLUSIONS: The resulting Portuguese version of the ASAS-HI and ASAS-EF showed acceptable linguistic validity and has potential for use in both clinical practice and research settings. Nevertheless, before European Portuguese versions can be fully implemented, its psychometric properties (validity and reliability) need to be evaluated.