Molecular Profiling of Axial Spondyloarthritis Patients Reveals an Association between Innate and Adaptive Cell Populations and Therapeutic Response to Tumor Necrosis Factor Inhibitors.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.

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.

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.

Is a combined programme of manual therapy and exercise more effective than usual care in patients with non-specific chronic neck pain? A randomized controlled trial.

OBJECTIVE: The aim of this study was to compare the effectiveness of a combined intervention of manual therapy and exercise (MET) versus usual care (UC), on disability, pain intensity and global perceived recovery, in patients with non-specific chronic neck pain (CNP). DESIGN: Randomized controlled trial. SETTING: Outpatient care units. SUBJECTS: Sixty-four non-specific CNP patients were randomly allocated to MET (n = 32) or UC (n = 32) groups. INTERVENTIONS: Participants in the MET group received 12 sessions of mobilization and exercise, whereas the UC group received 15 sessions of usual care in physiotherapy. MAIN MEASURES: The primary outcome was disability (Neck Disability Index). The secondary outcomes were pain intensity (Numeric Pain Rating Scale) and global perceived recovery (Patient Global Impression Change). Patients were assessed at baseline, three weeks, six weeks (end of treatment) and at a three-month follow-up. RESULTS: Fifty-eight participants completed the study. No significant between-group difference was observed on disability and pain intensity at baseline. A significant between-group difference was observed on disability at three-week, six-week and three-month follow-up (median (P25-P75): 6 (3.25-9.81) vs. 15.5 (11.28-20.75); P < 0.001), favouring the MET group. Regarding pain intensity, a significant between-group difference was observed at six-week and three-month follow-up (median (P25-P75): 2 (1-2.51) vs. 5 (3.33-6); P < 0.001), with superiority of effect in MET group. Concerning the global perceived recovery, a significant between-group difference was observed only at the three-month follow-up (P = 0.001), favouring the MET group. CONCLUSION: This study's findings suggest that a combination of manual therapy and exercise is more effective than usual care on disability, pain intensity and global perceived recovery.

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.

Responsiveness and Interpretability of the Portuguese Version of the Neck Disability Index in Patients With Chronic Neck Pain Undergoing Physiotherapy.

STUDY DESIGN: A prospective cohort study with a 7-week follow-up of 113 patients with chronic neck pain undergoing physiotherapy. OBJECTIVE: To examine the responsiveness of the Portuguese Version of the Neck Disability Index (NDI-PT), and to determine the minimal clinically important difference (MCID), minimal detectable change (MDC), and floor/ceiling effects. SUMMARY OF BACKGROUND DATA: Studies that determine MDC and MCID are needed to provide more accurate outcome evaluation and critically assess potential relevant sources for differences in the minimal important change values for the NDI. METHODS: The NDI-PT was administered twice: at the baseline and after 7 weeks of physiotherapy treatment. A Global Transition Scale was used as an external criterion measure to distinguish between improved and nonimproved patients' scores between baseline and follow-up. The responsiveness of the NDI-PT was assessed through anchor-based methods (correlation coefficient and receiver operating characteristics curves-ROC curves). The MCID was estimated by the ROC curve method, and the MDC through the standard Error of Measurement (SEM). RESULTS: The NDI-PT revealed moderate responsiveness when applied to patients with chronic neck pain undergoing physiotherapy (ρ = 0.328 and area under the curve of 0.595, 95% confidence interval: 0.484-0.706). The MDC achieved 12 points, whereas the MCID was found to be 5.5 points. A complementary ROC analysis based on percentage differences in NDI-PT scores from baseline revealed an optimal cutoff point of 27%. The optimal cutoff point was found to be dependent of disability baseline scores. CONCLUSION: The NDI-PT demonstrated moderate levels of responsiveness. The amount of change in questionnaire scores perceived by the patient to be meaningful is smaller than the amount of change required to be statistically 95% confident that score change is not just measurement error. LEVEL OF EVIDENCE: N/A.

Cross-cultural adaptation and validation of the neck disability index to European Portuguese language.

STUDY DESIGN: Cross-cultural adaptation and psychometric testing. OBJECTIVE: To complete the cultural adaptation of the European Portuguese version of the neck disability index (NDI-PT) and to investigate its reliability and validity in patients with chronic neck pain (CNP). SUMMARY OF BACKGROUND DATA: The NDI is the most widely used instrument for self-reporting of disability due to neck pain. Although the NDI has demonstrated both good reliability and validity, a recent systematic review called attention for the poor methodological quality of the translation processes and psychometric studies. METHODS: The NDI-PT was first piloted in a sample of 40 patients with CNP. Then, 113 patients with CNP completed the numeric pain rating scale and twice the NPI-PT with an interval of 4 to 7 days. Factor structure of the NDI was explored through principal component factor analysis. The internal consistency was estimated using the Cronbach α coefficient. Reliability was determined by repeatability using intraclass correlation coefficient (2,1) for the total sample and for the subsample of participants who remained stable in CNP status between the initial and follow-up assessment based upon the global rating of change scale, and agreement using the concept of "limits of agreement." Construct validity was assessed with correlations between the NDI-PT and the numeric pain rating scale for convergent validity, using Pearson correlation analysis. RESULTS: Exploratory factor analysis revealed the existence of 1 major factor that explained 54.7% of the variance. Test-retest reliability was 0.9 and internal consistency was 0.95. No systematic trend was observed in the Bland and Altman method. The NDI-PT showed a good correlation with pain intensity (r = 0.525, P < 0.01). CONCLUSION: The NDI-PT demonstrated excellent reliability and good construct validity and it may be useful for assessing functional status of Portuguese-speaking patients with CNP.

Analise de funcao: um modelo de elaboracao

O nosso objetivo foi elaborar u modelo de analise de funcao que respondesse as necessidades especificas da problematica de atendimento da reabilitacao profissional no INPS. Para cumprir com esta finalidade, foi necessaria uma abordagem particular e minuciosa dos itens da analise de funcao. Necessario, tambem, foi definir conceitual e operacionalmente cada uma das variaveis que compoem esses itens, tanto para possibilitar uma objetividade maior para o grupo de psicologos dos tecnicos de diversas categorias profissionais que a consultam. Ao lado desse carater particular, dado que as informacoes a respeito de analise de funcao se encontram extremamente dispersas na bibliografia afim, julgamos ser este modelo de utilidade para quem tambem lida com a materia.