Association between IL-6 production in synovial explants from rheumatoid arthritis patients and clinical and imaging response to biologic treatment: A pilot study.

INTRODUCTION: The need for biomarkers which can predict disease course and treatment response in rheumatoid arthritis (RA) is evident. We explored whether clinical and imaging responses to biologic disease modifying anti-rheumatic drug treatment (bDMARD) were associated with the individual's mediator production in explants obtained at baseline. METHODS: RA Patients were evaluated by disease activity score 28 joint C-reactive protein (DAS 28-)), colour Doppler ultrasound (CDUS) and 3 Tesla RA magnetic resonance imaging scores (RAMRIS). Explants were established from synovectomies from a needle arthroscopic procedure prior to initiation of bDMARD. Explants were incubated with the bDMARD in question, and the productions of interleukin-6 (IL-6), monocyte chemo-attractive protein-1 (MCP-1) and macrophage inflammatory protein-1-beta (MIP-1b) were measured by multiplex immunoassays. The changes in clinical and imaging variables following a minimum of 3 months bDMARD treatment were compared to the baseline explant results. Mixed models and Spearman's rank correlations were performed. P-values below 0.05 were considered statistically significant. RESULTS: 16 patients were included. IL-6 production in bDMARD-treated explants was significantly higher among clinical non-responders compared to responders (P = 0.04), and a lack of suppression of IL-6 by the bDMARDS correlated to a high DAS-28 (ρ = 0.57, P = 0.03), CDUS (ρ = 0.53, P = 0.04) and bone marrow oedema (ρ = 0.56, P = 0.03) at follow-up. No clinical association was found with explant MCP-1 production. MIP-1b could not be assessed due to a large number of samples below the detection limit. CONCLUSIONS: Synovial explants appear to deliver a disease-relevant output testing which when carried out in advance of bDMARD treatment can potentially pave the road for a more patient tailored treatment approach with better treatment effects.

Effects of Lifestyle on Muscle Strength in a Healthy Danish Population.

BACKGROUND: Lifestyle is expected to influence muscle strength. This study aimed at assessing a possible relationship between smoking, alcohol intake and physical activity, and muscle strength in a healthy Danish population aged 20-79 years. Population study based on data collected from The Copenhagen City Heart Study (CCHS) and measurements of Isokinetic muscle strength from a sub-study of randomly selected healthy participants from CCHS. METHODS: 126 women and 63 men were studied. All participants completed a questionnaire regarding their lifestyle, including physical activity, alcohol intake and smoking habits. Isokinetic muscle strength was measured over the upper extremities (UE), trunk, and lower extremities (LE). Multivariate analyses including all of the variables were carried out. RESULTS: The level of daily physical activity during leisure was positively correlated to muscle strength in the lower extremities (p = 0.03) for women, and lower extremities (p = 0.03) and trunk (p = 0.007) for men. Alcohol Intake was in general not correlated to muscle strength. No clear effect of smoking was seen on muscle strength. CONCLUSION: Our results show that physical activity during leisure is associated with a positive effect on muscle strength in both sexes. When keeping alcohol intake within the recommended limits, alcohol does not seem to affect muscle strength negatively. No effect of smoking on muscle strength was found in our group of healthy subjects. The findings are of importance when considering recommendation on life style when wishing to keeping fit with age to be able to carry out daily activities.

Psychometric properties of the painDETECT questionnaire in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: Rasch analysis and test-retest reliability.

BACKGROUND: Pain is inherent in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA) and traditionally considered to be of nociceptive origin. Emerging data suggest a potential role of augmented central pain mechanisms in subsets of patients, thus, valid instruments that can identify underlying pain mechanisms are needed. The painDETECT questionnaire (PDQ) was originally designed to differentiate between pain phenotypes. The objectives were to evaluate the psychometric properties of the PDQ in patients with inflammatory arthritis by applying Rasch analysis and to explore the reliability of pain classification by test-retest. METHODS: For the Rasch analysis 900 questionnaires from patients with RA, PsA and SpA (300 per diagnosis) were extracted from 'the DANBIO painDETECT study'. The analysis was directed at the seven items assessing somatosensory symptoms and included: 1) the performance of the six-category Likert scale; 2) whether a unidimensional construct was defined; 3) the reliability and precision of estimates. Another group of 30 patients diagnosed with RA, PsA or SpA participated in a test-retest study. Intraclass Correlation Coefficients (ICC) and classification consistency were calculated. RESULTS: The Rasch analysis revealed: (1) Acceptable psychometric rating scale properties; the frequency distribution peaked in category 0 except for item 5, threshold calibration >10 observations per category, no disorder in the category measures for all items, scale category outfit Mnsq <2.0, small distances (<1.4 logits) between thresholds for category 1, 2 and 3 for all items. (2) The principal component analysis supported unidimensionality; the standardized residuals showed that 53.7% of total variance was explained by the measure and the magnitude of first contrast had an eigenvalue of 1.5, no misfitting items, clinical insignificant different item hierarchies across diagnoses (DIF < 0.5 logits). (3) A targeted item-person map, person and item separation indices of 1.88(reliability = 0.78), and 13.04 (reliability = 0.99). The test-retest revealed: ICC: RA 0.86(0.56-0.96), PsA 0.96(0.74-0.99), SpA 0.93(0.76-98), overall 0.94(0.84-0.98). Classification consistency was: RA 70%, PsA 80%, SpA 90%, overall 80%. CONCLUSION: The results support that the PDQ can be used as a classification instrument and assist identification of underlying pain-mechanisms in patients suffering from inflammatory arthritis.

Improving activities of daily living ability in women with fibromyalgia: An exploratory, quasi-randomized, phase-two study, IMPROvE trial.

OBJECTIVE: To explore and compare the outcomes of adaptation and physical activity programmes regarding activities of daily living (ADL) ability following interdisciplinary rehabilitation in women with fibromyalgia. METHODS: Participants (n = 85) were quasi-randomized to 16-week adaptation (ADAPT) or physical activity (ACTIVE) programmes following 2-week interdisciplinary rehabilitation. Primary outcomes were ADL motor and ADL process ability, measured with the Assessment of Motor and Process Skills (AMPS) at 4-week follow-up. Data were analysed per protocol. RESULTS: Participants (ADAPT, n = 21; ACTIVE, n = 27) did not differ from withdrawers (n = 37). Improvements in ADL ability in the ADAPT (ADL motor mean change = 0.43 logits (95% confidence interval (95% CI) = 0.31-0.56); ADL process mean change = 0.34 logits (95% CI = 0.17-0.52)) and ACTIVE (ADL motor mean change = 0.33 logits (95% CI = 0.22-0.43); ADL process mean change = 0.25 logits (95% CI = 0.12-0.38)) groups were statistically significant, with no differences between groups. Responder analyses revealed that 63% of all participants obtained clinically relevant improvements in ADL motor ability and 48% in ADL process ability. CONCLUSION: Although limited by a large drop-out, this exploratory study showed that both adaptation and physical activity programmes following interdisciplinary rehabilitation improved ADL ability in the majority of participants. ADL ability outcomes were independent of group allocation (ADAPT vs ACTIVE), suggesting efficacy of both programmes.

Are the changes in observed functioning after multi-disciplinary rehabilitation of patients with fibromyalgia associated with changes in pain self-efficacy?

OBJECTIVE: To examine the hypothesis that change in pain self-efficacy is associated with observed and self-reported activity, pain intensity, catastrophizing, and quality of life after multi-disciplinary rehabilitation of fibromyalgia patients. DESIGN: In-depth analyses of secondary outcomes of a randomized-controlled trial. SUBJECTS: Women (N = 187) with fibromyalgia. METHODS: Outcomes were Pain Self-Efficacy, Assessment of Motor and Process Skills (AMPS), SF-36 Physical Function (SF-36-PF), pain intensity, and SF-36 Mental Composite Score (SF-36-MCS) to assess quality of life and pain catastrophizing. Individual and group associations between outcomes were examined. RESULTS: Individual changes in pain self-efficacy were not associated with changes in observed activity: AMPS motor (rs = 0.08, p = 0.27) and process (rs = 0.12, p = 0.11), not even in those patients with a clinically relevant improvement in observed functioning (38.5%), and only weakly or moderatly with changes in SF-36-PF; (rs = 0.31, p < 0.0001), SF-36-MSC; (rs = 0.41, p < 0.0001), and pain catastrophizing (rs = -0.31, p < 0.0001). No differences in pain self-efficacy were observed between the rehabilitated group and controls (difference: 1.61; 95% CI: -0.84 to 4.06; p = 0.24). However, a subgroup (34%) had a clinically relevant improvement in pain self-efficacy. This group was younger (mean age 41.4 vs. 45.8, p = 0.01), more recently diagnosed (1.8 vs. 2.8 years, p = 0.003), but had an unresolved welfare situation (59% vs. 40%, p = 0.02). CONCLUSION: The main hypothesis was falsified, as there was no association between pain self-efficacy and actual performance of activity. The relation to functioning may be limited to perceived, cognitive-emotional aspects, as indicated by the weak to moderate correlations to the self-reported measures. Implications for Rehabilitation Improvement in observed activity post multi-disciplinary rehabilitation was not associated with change in pain self-efficacy. Patients performed better after rehabilitation, but did not perceive to have improved their capacity. The relationship between pain self-efficacy and functioning may be limited to cognitive-emotional aspects rather than actual activity. Both observational and self-reported measures should be included in evaluating outcomes of rehabilitation for patients with fibromyalgia.

Aquatic exercise for the treatment of knee and hip osteoarthritis.

BACKGROUND: Osteoarthritis is a chronic disease characterized by joint pain, tenderness, and limitation of movement. At present, no cure is available. Thus only treatment of the person's symptoms and treatment to prevent further development of the disease are possible. Clinical trials indicate that aquatic exercise may have advantages for people with osteoarthritis. This is an update of a published Cochrane review. OBJECTIVES: To evaluate the effects of aquatic exercise for people with knee or hip osteoarthritis, or both, compared to no intervention. SEARCH METHODS: We searched the following databases up to 28 April 2015: the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library Issue 1, 2014), MEDLINE (from 1949), EMBASE (from 1980), CINAHL (from 1982), PEDro (Physiotherapy Evidence Database), and Web of Science (from 1945). There was no language restriction. SELECTION CRITERIA: Randomized controlled clinical trials of aquatic exercise compared to a control group (e.g. usual care, education, social attention, telephone call, waiting list for surgery) of participants with knee or hip osteoarthritis. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias of the included trials. We analysed the pooled results using standardized mean difference (SMD) values. MAIN RESULTS: Nine new trials met the inclusion criteria and we excluded two earlier included trials. Thus the number of participants increased from 800 to 1190 and the number of included trials increased from six to 13. Most participants were female (75%), with an average age of 68 years and a body mass index (BMI) of 29.4. Osteoarthritis duration was 6.7 years, with a great variation of the included participants. The mean aquatic exercise duration was 12 weeks. We found 12 trials at low to unclear risk of bias for all domains except blinding of participants and personnel. They showed that aquatic exercise caused a small short term improvement compared to control in pain (SMD -0.31, 95% CI -0.47 to -0.15; 12 trials, 1076 participants) and disability (SMD -0.32, 95% CI -0.47 to -0.17; 12 trials, 1059 participants). Ten trials showed a small effect on quality of life (QoL) (SMD -0.25, 95% CI -0.49 to -0.01; 10 trials, 971 participants). These effects on pain and disability correspond to a five point lower (95% CI three to eight points lower) score on mean pain and mean disability compared to the control group (scale 0 to 100), and a seven point higher (95% CI 0 to 13 points higher) score on mean QoL compared with control group (scale 0 to 100). No included trials performed a radiographic evaluation. No serious adverse events were reported in the included trials with relation to aquatic exercise. AUTHORS' CONCLUSIONS: There is moderate quality evidence that aquatic exercise may have small, short-term, and clinically relevant effects on patient-reported pain, disability, and QoL in people with knee and hip OA. The conclusions of this review update does not change those of the previous published version of this Cochrane review.

Predictors of improvement in observed functional ability in patients with fibromyalgia as an outcome of rehabilitation.

OBJECTIVE: To investigate predictors of improvement in observed ability to manage activities of daily living as an outcome of rehabilitation in fibromyalgia. METHODS: Exploratory analyses used data from the Interdisciplinary Rehabilitation and Evaluation Programme for Patients with Chronic Widespread Pain (the IMPROvE study); a randomized controlled trial including 191 females with fibromyalgia randomized (1:1) to rehabilitation or a waiting list. The primary outcome was observed activities of daily living ability evaluated with the Assessment of Motor and Process Skills (AMPS) 6 months post-intervention. RESULTS: Overall, 38.7% of subjects were AMPS responders, i.e. having a clinically meaningful improvement in AMPS activities of daily living ability measures at 6 months post-intervention. In the exploratory analysis, only 4 baseline variables out of the 52 analysed showed a statistically significant interaction with treatment allocation (at the 0.05 level) indicating possible predictive value. Statistical analyses that used continuous variables dichotomized at the median suggested a predictive value of a low intake of weak and strong analgesics, and a high score of current pain and total score on the Pain Detect Questionnaire. CONCLUSION: The results of this exploratory study suggest that several subgroups of patients, specifically those with a low baseline intake of weak and strong analgesics, and more pronounced clinical signs of central sensitization, may gain most clinical benefit from specialized rehabilitation when the outcome of interest is improvement in observed activity of daily living ability.

Ineffective ADL skills in women with fibromyalgia: a cross-sectional study.

BACKGROUND: Subgroups of women with fibromyalgia likely show different activity of daily living (ADL) skill deficits. Identifying ineffective ADL skills of significance in the 'typical' woman with fibromyalgia will promote the planning of targeted occupational therapy interventions aiming at improving ADL ability. OBJECTIVE: To identify frequently reported ADL skill deficits of significance in subgroups of women with fibromyalgia who have decreased ADL motor ability in combination with decreased or competent ADL process ability. METHOD: Women with fibromyalgia were evaluated with the Assessment of Motor and Process Skills (AMPS). If they demonstrated decreased ADL motor ability, the calibrated AMPS raters identified and reported ineffective ADL skills of significance. Descriptive comparisons were made between subgroups displaying either decreased or competent ADL process ability. RESULTS: Moves, calibrates, bends, reaches, and paces were identified as the most frequently reported ineffective ADL skills of significance within the total sample (n = 188). The ADL process skills items organise and accommodate were identified as ineffective only in the subgroup with decreased ADL process ability (n = 105). CONCLUSION: It is suggested that clinicians modify the individual's tasks and environments to compensate for identified ineffective ADL skills and to use the AMPS to differentiate interventions in women with fibromyalgia.

Differences in ability to perform activities of daily living among women with fibromyalgia: A cross-sectional study.

OBJECTIVE: To investigate whether the Assessment of Motor and Process Skills (AMPS), the physical function subscales of the Fibromyalgia Impact Questionnaire (FIQ PF) and the 36-item Short Form (SF-36 PF) can identify subgroups of women with fibromyalgia with clinically relevant differences in ability to perform activities of daily living. DESIGN: Cross-sectional study. SUBJECTS: A total of 257 women with fibromyalgia. METHODS: Participants were evaluated with the AMPS (measuring activities of daily living motor and activities of daily living process ability), FIQ and SF-36. AMPS independence cut-offs were used to divide the participants into 4 subgroups. Clinically relevant differences between subgroups were investigated based on the AMPS, FIQ PF and SF-36 PF. RESULT: Participants in the 4 AMPS-derived subgroups demon-strated clinically relevant differences in observed activities of daily living motor and process ability. Neither the FIQ PF nor the SF-36 PF could differentiate between subgroups with clinically relevant differences in AMPS activities of daily living process ability. CONCLUSION: Activities of daily living process skills reflect underlying organizational and adaptive capacities of the individual and are relevant targets for interventions aiming at improving activities of daily living ability. Since self-report instruments do not capture differences in activities of daily living process ability, clinicians should include observations-based assessment of activities of daily living ability in order to individualize interventions offered.

Synovial explant inflammatory mediator production corresponds to rheumatoid arthritis imaging hallmarks: a cross-sectional study.

INTRODUCTION: Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans. METHODS: RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1ß (MIP-1ß) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model. RESULTS: Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman's ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman's ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman's ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman's ρ = 0.50), BME score (P = 0.04, approximate Spearman's ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman's ρ = 0.35). MIP-1ß was associated with CDUS activity (P = 0.02, approximate Spearman's ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman's ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance. CONCLUSIONS: The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1ß, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.

Interdisciplinary rehabilitation of patients with chronic widespread pain: primary endpoint of the randomized, nonblinded, parallel-group IMPROvE trial.

This study examined the functional and psychological outcomes of a 2-week, group-based multicomponent treatment course that targeted patients with chronic widespread pain. Patients (192 included in the intention-to-treat population), all fulfilling the 1990 American College of Rheumatology classification criteria for fibromyalgia, were consecutively recruited from a tertiary care setting and randomized (1:1) to either the treatment course or a waiting list control group. Co-primary outcomes were the Assessment of Motor and Process Skills (AMPS) and SF-36 Mental Composite Score (MCS) evaluated at 6-month follow-up. Primary endpoints were partly achieved with a statistically significant improvement in AMPS activities of daily living motor (group mean difference: 0.20 [95% confidence interval (CI): 0.09 to 0.31] logits; P=.0003) and AMPS activities of daily living process (0.20 [95% CI: 0.12 to 0.27] logits, P<.0001) ability measures, whereas no difference in the SF-36 MCS (1.14 [95% CI: -1.52 to 3.81], P=.40) was observed. Individual patient responses varied, and the proportion of patients achieving a clinically meaningful change of at least 0.3 logits on the AMPS seemed influenced by the reporting of a pending social welfare application at the time of enrollment. We conclude that even in fibromyalgia patients presenting with a substantial disability established over many years, the 2-week multicomponent treatment course resulted in observable improvement of functional ability in a subgroup of patients at 6-month follow-up. This improvement, however, was not reflected in secondary patient reported outcomes, including scores of self-reported functional ability on standardized questionnaires. We suggest including observation-based assessments in future clinical trials focusing on functional outcomes in patients with fibromyalgia.

Ultrasound colour Doppler is associated with synovial pathology in biopsies from hand joints in rheumatoid arthritis patients: a cross-sectional study.

OBJECTIVES: Little is known regarding the association between ultrasound-determined pathological synovial blood flow and synovial pathology in rheumatoid arthritis (RA). We therefore examined the association between colour Doppler ultrasound imaging and synovitis assessed by histopathology and specific cell markers by immunohistochemistry in patients with RA. METHODS: 81 synovial sites from wrist and finger joints from 29 RA patients were evaluated by ultrasound colour Doppler and subsequently biopsied by needle arthroscopy. The association between ultrasound colour fraction and an overall synovitis score and immunohistochemical staining for CD3, CD68, Ki67 and von Willebrand factor was investigated, including repeated samples from the same patients. The overall synovitis score (total 0-9) assessed synovial lining hyperplasia (0-3), stromal activation (0-3) and inflammatory infiltration (0-3). Data were clustered within patients, thus a linear mixed model was applied for the statistical tests. Parsimony in the statistical models was achieved omitting covariates from the model in the case of what was judged no statistical significance (p>0.1). RESULTS: Doppler colour fraction showed an association with the overall synovitis score (approximated Spearman, approximately r=0.43, p=0.003). The density of all immunohistochemical stainings showed a significant association with Doppler colour fraction: von Willebrand factor (approximately r=0.44, p=0.01), CD68 (approximately r=0.53, p=0.02), Ki67 (approximately r=0.57, p=0.05) and CD3 (approximately r=0.57, p=0.0003). CONCLUSIONS: Colour Doppler activity is associated with the extent of inflammation present in the synovial biopsies from RA patients. However, synovial pathology was also seen in biopsies taken from Doppler negative sites.

Changes in bone marrow lesions in response to weight-loss in obese knee osteoarthritis patients: a prospective cohort study.

BACKGROUND: Patients are susceptible for knee osteoarthritis (KOA) with increasing age and obesity and KOA is expected to become a major disabling disease in the future. An important feature of KOA on magnetic resonance imaging (MRI) is changes in the subchondral bone, bone marrow lesions (BMLs), which are related to the future degeneration of the knee joint as well as prevalent clinical symptoms. The aim of this study was to investigate the changes in BMLs after a 16-week weight-loss period in obese subjects with KOA and relate changes in BMLs to the effects of weight-loss on clinical symptoms. METHODS: This prospective cohort study included patients with a body mass index ≥ 30 kg/m2, an age ≥ 50 years and primary KOA. Patients underwent a 16 weeks supervised diet program which included formula products and dietetic counselling (ClinicalTrials.gov: NCT00655941). BMLs in tibia and femur were assessed on MRI before and after the weight-loss using the Boston-Leeds Osteoarthritis Knee Score. Response to weight-loss in BML scores was dichotomised to patients experiencing a decrease in BML scores (responders) and patients who did not (non-responders). The association of BMLs to weight-loss was assessed by logistic regressions and correlation analyses. RESULTS: 39 patients (23%) were classified as responders in the sum of all BML size scores whereas 130 patients (77%) deteriorated or remained stable and were categorized as non-responders. Logistic regression analyses revealed no association between weight-loss < or ≥ 10% and response in BMLs in the most affected compartment (OR 1.86 [CI 0.66 to 5.26, p=0.24]). There was no association between weight-loss and response in maximum BML score (OR 1.13 [CI 0.39 to 3.28, p=0.81]). The relationship between changes in BMLs and clinical symptoms revealed that an equal proportion of patients classified as BML responders and non-responders experienced an OMERACT-OARSI response (69 vs. 71%, p=0.86). CONCLUSIONS: Weight-loss did not improve the sum of tibiofemoral BML size scores or the maximum tibiofemoral BML score, suggesting that BMLs do not respond to a rapidly decreased body weight. The missing relationship between clinical symptoms and BMLs calls for further investigation.

Differential effects of decoy receptor- and antibody-mediated tumour necrosis factor blockage on FoxP3 expression in responsive arthritis patients.

Our aim was to clarify if anti-tumour necrosis factor (TNF) drugs have effect on expression of three splice forms of FoxP3 mRNA in blood CD4+ T cells from rheumatoid arthritis (RA) patients compared with healthy controls. Forty-five rheumatoid arthritis patients treated with anti-TNF therapy were investigated in a 12-week prospective cohort study. FoxP3 isoforms, CD25 and CTLA-4 mRNA in blood CD4+ T cells were measured with quantitative real-time PCR. Patients benefitting from the treatment, based on changes in DAS28 scores, revealed a significant decrease in expression of full-length FoxP3 following 12 weeks treatment with TNF receptor 2 fusion protein (Etanercept), but not following treatment with anti-TNF antibodies (Adalimumab or Infliximab). A partial normalization of the CTLA-4/FoxP3fl ratio and a correlation between clinical improvement and change in FoxP3 mRNA expression were also seen in Etanercept responders. These changes were not observed in responsive patients treated with the antibody therapies. Our data suggest that TNF decoy receptor and anti-TNF antibodies differ in their effect on FoxP3 expression in responsive patients. As Etanercept binds both TNF-α and Lymphotoxin-α (LT-α), whereas the antibodies only target TNF-α, LT-α may regulate FoxP3 expression in a subset of RA patients. Our findings support the view that anti-TNF treatment is mainly symptomatic.

Muscle fatigue in fibromyalgia is in the brain, not in the muscles: a case-control study of perceived versus objective muscle fatigue.

OBJECTIVE: To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC). METHODS: Women with FM and HC completed an isometric muscle exhaustion task at 90° shoulder abduction. Surface electromyographic (EMG) activity in the deltoid muscle was recorded together with self-reported level of muscle fatigue. RESULTS: 25 participants with FM and 23 HC were included. Average time to exhaustion was 254 s shorter in participants with FM than in HC. Participants with FM did not exhibit the same level of objective signs of muscle fatigue, seen as fewer changes in the EMG activity, as the HC during the exhaustion task. The task did not provoke pain in the HC, while participants with FM reported a doubling of pain. CONCLUSIONS: Women with FM had shorter exhaustion times and showed fewer objective signs of muscle fatigue during an exhausting isometric shoulder abduction compared with younger HC. This indicates that perceived muscle fatigue may be of central origin and supports the notion of central nervous dysfunction as basic pathological changes in FM.

FoxP3 mRNA splice forms in synovial CD4+ T cells in rheumatoid arthritis and psoriatic arthritis.

Our aim was to elucidate the relative amount of the different splice forms of FoxP3 mRNA in CD4+ T cells in peripheral blood (PB) compared to synovial fluid (SF) in RA and PsA patients. FoxP3 mRNA was measured using a quantitative real-time PCR method. CD4+ T cells were isolated from 17 paired samples of PB and SF from RA and PsA patients, and PB from 10 controls. FoxP3fl and FoxP3Δ2 mRNA was significantly increased (6.7 and 2.1-fold, respectively) in PB CD4+ T cells from RA patients compared to controls. FoxP3fl and Δ2 mRNA in SF CD4+ T cells was increased compared to controls in sero-negative RA and PsA, but not in sero-positive RA patients, who had a high FoxP3 expression in both PB and SF. The FoxP3Δ2Δ7 mRNA was barely detectable in patient samples, and not at all in healthy individuals. We provide evidence of an increased expression of FoxP3 splice forms in synovial CD4+ T cells from RA patients. A skewed, high expression profile of FoxP3, but not CTLA-4, in sero-negative RA and PsA, indicates that synovial CD4+ T cells may represent unique subsets of T cells which have been induced locally or selectively recruited to the joint.

Correlation between computer-aided dynamic gadolinium-enhanced MRI assessment of inflammation and semi-quantitative synovitis and bone marrow oedema scores of the wrist in patients with rheumatoid arthritis--a cohort study.

OBJECTIVE: To test the correlation between assessment of inflammation using dynamic contrast-enhanced MRI (DCE-MRI) analysed by a novel computer-aided approach and semi-quantitative scores of synovitis and bone marrow oedema (BME) using the OMERACT-RA MRI Scoring (RAMRIS) system, in the wrist of patients with RA. METHODS: Fifty-four RA patients had conventional and DCE-MRI of a symptomatic wrist using a low-field 0.2T extremity scanner. RAMRIS synovitis and BME of the wrist joint were done. DCE-MRI data were analysed in three ways: (i) in all images (fully automated approach), (ii) within a large extended region of interest (ROI) placed around the wrist joint (semi-automated approach) and (iii) within a small ROI placed in the area with most visual enhancement (semi-automated approach). Time spent on each procedure was noted. Spearman's rank correlation test was applied to assess the correlation between RAMRIS and the computer-generated dynamic parameters. RESULTS: RAMRIS synovitis (range 2-9), BME (range 0-39) and the dynamic parameters reflecting the number of enhancing voxels were significantly correlated, especially when an extended ROI around the wrist was used (ρ = 0.74; P < 0.01 for synovitis and ρ = 0.82; P < 0.01 for BME). The observer spent on average 20 min (range 12-25 min) to perform RAMRIS, including acquisition of the results in the database, and 8 min (range 7-10 min) to perform all above-mentioned computer-aided analyses. CONCLUSION: Computer-aided analysis of DCE-MRI data correlated with RAMRIS synovitis and BME and was twice as fast to perform. This technique may be useful for quick semi-automated assessment of joint inflammation, but needs further validation.

Observation-based assessment of functional ability in patients with chronic widespread pain: a cross-sectional study.

Knowledge about functional ability, including activities of daily living (ADL), in patients with chronic widespread pain (CWP) and fibromyalgia (FMS) is largely based on self-report. The purpose of this study was to assess functional ability by using standardised, observation-based assessment of ADL performance and to examine the relationship between self-reported and observation-based measures of disability. A total of 257 women with CWP, 199 (77%) fulfilling the American College of Rheumatology tender point criteria for FMS, were evaluated with the Assessment of Motor and Process Skills (AMPS), an observation-based assessment providing linear measures of ADL motor and ADL process skill ability (unit: logits). A cutoff for effortless and independent ADL task performance is set at 2.0 for the motor scale and 1.0 for the process scale. A total of 248 (96.5%) had ability measures below the 2.00 ADL motor cutoff and 107 (41.6%) below the 1.00 ADL process cutoff, indicating increased effort and/or inefficiency during task performance as well as a potential need of assistance for community living. Mean ADL motor ability measure was 1.07 and was significantly lower in patients diagnosed with FMS than plain CWP (1.02 vs 1.27 logits, P=.001). Mean ADL process ability measure was 1.09 logits and was without difference between FMS and plain CWP (1.07 vs 1.16 logits, P=.064). Only weak to moderate correlations between self-reported functional ability and observation-based AMPS ability measures were observed. The results of the study support the notion of considerable performance difficulties in women with CWP. The everyday life problems are substantial and place the individual at risk of need of support for community living.

Reproduction of overall spontaneous pain pattern by manual stimulation of active myofascial trigger points in fibromyalgia patients.

INTRODUCTION: It has previously been reported that local and referred pain from active myofascial trigger points (MTPs) in the neck and shoulder region contribute to fibromyalgia (FM) pain and that the pain pattern induced from active MTPs can reproduce parts of the spontaneous clinical FM pain pattern. The current study investigated whether the overall spontaneous FM pain pattern can be reproduced by local and referred pain from active MTPs located in different muscles. METHODS: A spontaneous pain pattern in FM was recorded in 30 FM patients and 30 healthy subjects served as controls. Local and referred pain patterns induced from active (patients) and latent (controls) MTPs were recorded following manual stimulation. The existence of MTPs was confirmed by intramuscular electromyographical registration of spontaneous electrical activity. RESULTS: Local and referred pain areas induced from key active MTPs in FM were larger than pain areas from latent MTPs in healthy controls (P < 0.001), but were similar to the overall spontaneous FM pain area in FM (P > 0.05). The induced pain area was positively associated with current spontaneous pain intensity in FM (P < 0.01). The locations of key active MTPs in FM patients were found to have latent MTPs in healthy subjects. The muscles containing key active MTPs in FM are often observed in the muscles of extensor digitorum, trapezius, infraspinatus in the upper part of the body and of quadratus lumborum, gluteus medius in the lower part of the body. CONCLUSIONS: The overall spontaneous FM pain pattern can be reproduced by mechanical stimulation of active MTPs located in different muscles, suggesting that fibromyalgia pain is largely composed of pain arising from muscle pain and spasm. Targeting active MTPs and related perpetuating factors may be an important strategy in FM pain control. TRIAL REGISTRATION: ISRCTN ISRCTN43167547.

Ultrasound Doppler measurements predict success of treatment with anti-TNF-α drug in patients with rheumatoid arthritis: a prospective cohort study.

OBJECTIVE: To investigate the predictive ability of core outcomes applied in RA trials, including ultrasound (US) Doppler (USD) measurements differentiating patients who remain on anti-TNF-α therapy following 1 year. METHODS: Patients with RA in anti-TNF-α therapy were followed 1 year after therapy initiation. All patients had wrist involvement. At baseline, 2 weeks, 26 weeks and 1 year a USD examination, clinical examination including tender and swollen joint count, visual analogue scale (VAS) global and HAQ, biochemical measures and 28-joint DAS (DAS28) were collected for all patients. The amount of USD signal in the synovium was quantified by measuring the percentage of colour pixels-the colour fraction (CF). Predictive validity for patients who remain on anti-TNF-α therapy after 1 year was assessed for both USD measurements and other disease measures. Baseline values of disease measures of patients who remained on treatment after 1 year was compared with those who stopped therapy. RESULTS: The study cohort consisted of 109 patients. In this study, the baseline CF was the only measure predicting which patients would stay on the initial anti-TNF-α therapy for 1 year, evaluated using the square-root of CF (P = 0.024). The other disease markers could not significantly differentiate between the two groups of patients, with P-values of 0.86 and 0.98 for tender and swollen joint count, respectively, 0.86 for CRP, 0.24 for VAS, 0.10 for HAQ and 0.38 for DAS28. CONCLUSION: There is now evidence to support that baseline USD, in contrast to clinical measures, can predict which patients will remain on anti-TNF-α 1 year after initiating therapy.