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In healthy subjects repeated tactile stimulation in a conditioning test stimulation paradigm yields attenuation of primary (S1) and secondary (S2) somatosensory cortical activation, whereas a preceding painful stimulus results in facilitation. Since previous data suggest that cognitive processes might affect somatosensory processing in S1, the present study aims at investigating to what extent cortical reactivity is altered by the subjective estimation of pain. To this end, the effect of painful and tactile stimulation on processing of subsequently applied tactile stimuli was investigated in patients with fibromyalgia syndrome (FMS) and in subjects with masochistic behaviour (MB) by means of a 122-channel whole-head magnetoencephalography (MEG) system. Ten patients fulfilling the criteria for the diagnosis of FMS, 10 subjects with MB and 20 control subjects matched with respect to age, gender and handedness participated in the present study. Tactile or brief painful cutaneous laser stimuli were applied as conditioning stimulus (CS) followed by a tactile test stimulus (TS) 500 ms later. While in FMS patients significant attenuation following conditioning tactile stimulation was evident, no facilitation following painful stimulation was found. By contrast, in subjects with MB no attenuation but significant facilitation occurred. Attenuation as well as facilitation applied to cortical responses occurring at about 70 ms but not to early S1 or S2 responses. Additionally, in FMS patients the amount of attenuation was inversely correlated with catastrophizing tendency.

The present results imply altered cortical reactivity of the primary somatosensory cortex in FMS patients and MB possibly reflecting differences of individual pain experience.

Osteoarthritis is a chronic rheumatoid disease mediated by metalloproteinases and inflammatory cytokines. Methylsulfonylmethane (MSM) and boswellic acids (BA) each show promise in the treatment of inflammatory processes, but the efficacy of combined treatment with these substances in the treatment of arthritis has not yet been studied. In this prospective randomized clinical trial, MESACA (for "methylsulfonylmethane and boswellic acids in the treatment of knee arthritis"), 60 subjects affected by arthritis of the knee were randomly assigned to an experimental group treated for 60 days with 5 g of MSM and 7.2 mg of BA daily, or a control group which was administered a placebo. At 2 and 6 months follow-up (FU), the efficacy of combined treatment with these two dietary supplements was assessed using the visual analog pain scale (VAS) and the Lequesne index (LI) for joint function, as well as monitoring the use of anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs and anti-cyclooxygenase-2). Pain, assessed with the VAS scale, was worse in the group treated with MSM and BA as compared with the placebo group at 2 months FU (3.8 vs. 2.7; P=0.04), whereas no difference between the two groups was observed at 6 months FU (2.7 vs. 3.6; P=0.2). No statistically significant differences were found in the LI between the two groups at either FU (2 months: 4.8 vs. 4.2; P=0.51; 6 months: 4.4 vs. 4.5; P=0.91). By contrast, a statistically significant difference in patients need for anti-inflammatory drugs was seen in the experimental as compared to the placebo group, even by 2 months FU (0.2 vs. 0.6 tablets/day; P<0.0001), that persisted up to the end of the study (0.1 vs. 0.6 tablets/day; P<0.0001).

Although the combined administration of MSM and BA in the treatment of gonarthrosis was not shown to be more efficacious than placebo in the management of the clinical and functional picture, it significantly reduced patients need for anti-inflammatory drugs.

To evaluate the association between smoking and clinical parameters and structural damage in axial spondyloarthritis (axSpA). We systematically searched MEDLINE, EMBASE and Cochrane Library till November 2015. We selected articles that analysed the smoking impact on disease activity, functional status, structural damage, physical mobility and life quality. Independent extraction of articles by 2 authors using predefined data fields was performed. Studies quality was graded according to the Oxford Level of Evidence scale. A total of 17 articles were selected for inclusion: 2 case-control, 11 cross-sectional and 4 prospective cohort studies, which analysed 4694 patients. Weak evidence suggested a smoking effect on pain, overall assessment of health, disease activity, physical mobility and life quality in ankylosing spondylitis (AS). Moderate-good evidence revealed higher HAQ-AS among smokers (0.025units/y; 95% CI: 0.0071-0.0429; p = 0.007). Every additional unit of ASDAS resulted in an increase of 1.9 vs. 0.4 mSASSS units/2y in AS smokers vs. non-smokers. Good evidence revealed that cigarette smoking and smoking intensity was associated with spinal radiographic progression in axSpA [mSASSS ≥2 units/2y: OR = 2.75, 95% CI: 1.25-6.05, p=0.012; mSASSS progression in heavy smokers (>10 cigarettes/d): OR = 3.57, 95% IC: 1.33-9.60, p = 0.012].

Published data indicate that smoking has a dose-dependent impact on structural damage progression in axSpA. There is worse HAQ among AS smokers compared to non-smokers. Respect to pain, overall assessment of health, disease activity, physical mobility and life quality, although the evidence level is poor, all evidence points in the same direction: smoking AS patients are worse than non-smoking.

To evaluate effects of an orally administered mixture of chondroitin sulfate, glucosamine hydrochloride and manganese ascorbate (CS-G-M) on articular cartilage metabolism in dogs with cranial cruciate ligament (CCL) deficient and reconstructed knees, as reflected by concentrations of synovial fluid 3B3, 7D4 and total sulfated glycosaminoglycan (GAG). Sixteen adult dogs that underwent unilateral CCL transection were randomized into four groups. Thereafter, group I (N=3) had a sham CCL reconstruction, group II (N=3) had CS-G-M and sham CCL reconstruction, group III (N=5) had CCL reconstruction, and group IV (N=5) had CS-G-M and CCL reconstruction. Synovial fluid collected at 0, 1, 3 and 5 months was examined by ELISA for 3B3 and 7D4 epitope, and by DMMB assay for total GAG. Synovial fluid from CCL transected knees of CS-G-M treated dogs contained significantly elevated concentrations of 3B3 (P=0.029), 7D4 (P=0.036) and 7D4/GAG (P=0.007) in comparison to controls, in a cross-sectional analysis at 3 months. Furthermore, 7D4 and 7D4/GAG concentrations remained significantly elevated (P=0.012) in CCL transected knees of CS-G-M treated dogs over the 5 month period. However, when epitope concentrations were expressed as a ratio of CCL-transected to contralateral non-operated knee, treatment effect of CS-G-M was no longer significant. Reconstruction of the CCL had no significant effect on synovial fluid epitope.

Administration of CS-G-M was associated with altered concentrations of 3B3 and 7D4 epitope in synovial fluid, suggesting that these compounds may act to modulate articular cartilage matrix metabolism in vivo.

Vitamin D One hundred RA patients and 50 healthy controls, sex- and age-matched, were recruited. Disease Activity Score of 28 joints and Health Assessment Questionnaire scores were assessed. Baseline serum 25(OH)D Vitamin D deficiency (<50 nmol/L) was found in 63% of RA patients and 76% of healthy controls. Chinese RA patients and healthy controls had significantly more sufficient 25(OH)D

Vitamin D deficiency is prevalent in Malaysian RA patients. This study suggests that vitamin D is not associated with disease activity or serum IL-6 levels but it may have a role in functional disability in RA patients.

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality. In the current prospective study, we addressed the impact of RA on left atrial (LA) function and electrical remodelling. Further, we tried to demonstrate the effects of infliximab, an anti-TNF-alpha agent, on echocardiographical LA abnormality in RA patients with preserved left ventricular (LV) ejection fraction. We compared 38 female RA patients without clinical evidence of heart disease and 30 female controls without RA and clinical evidence of heart disease. Further, we compared RA patients receiving infliximab and increasing doses of prednisolone over a three-month period. At baseline and post treatment, this study assessed (1) LA and LV parameters using conventional and speckle tracking echocardiography (STE), and (2) electrocardiographic P-wave changes. The values of C-reactive protein (CRP), isovolumic relaxation time (IVRT), A wave, and deceleration time (DT) were significantly higher in RA patients compared to the control group (p < 0.05), whereas E/E' and E/A values were found to be lower (p < 0.05) in RA patients. E/E' values were lower in prednisolone- compared to infliximab-treated patients (p < 0.05). After three months of infliximab and prednisolone treatment, CRP and disease activity score (DAS 28) values decreased in both groups (p < 0.05), and Duke activity status index (DASI) increased (p < 0.05). Maximal left atrial volume index (LAVImax), pre-contraction left atrial volume index (LAVIpreA) and maximum P wave (Pmax) of the RA patients were higher compared to the control group (p < 0.05), whereas LA global strain was found to be lower (p < 0.05). There was no difference in Pmax values between groups before and after the treatment period. E/E', LAVImax and LAVIpreA values of infliximab-treated patients decreased and LA global strain increased after three months of therapy compared to baseline (p < 0.05). At baseline in both treatment groups, E/E' and LA global late diastolic strain rate were lower in prednisolone-compared to infliximab-treated patients (p < 0.05).

There was echocardiographic LA abnormality in these RA patients. In this patient group there was also a meaningful increase in maximum P wave assessed by electrocardiography. Infliximab therapy for a period of three months improved LA abnormality.

Systemic autoimmune diseases, in particular systemic lupus erythematosus and rheumatoid arthritis, are characterized by a high risk of premature cardiovascular (CV) events. Disease-related characteristics and traditional CV disease risk factors may contribute to atherosclerotic damage. However, there are limited data on the risk of overt CV events in primary Sjögren's syndrome (pSS). We retrospectively analysed a cohort of patients with 1343 pSS. Disease-related clinical and laboratory data, traditional CV disease risk factors and overt CV events were recorded. Prevalence of traditional CV disease risk factors and of major CV events was compared between a subgroup of 788 female patients with pSS aged from 35 to 74 years and 4774 age-matched healthy women. Hypertension and hypercholesterolaemia were more prevalent, whereas smoking, obesity and diabetes mellitus were less prevalent, in women with pSS than in control subjects. Cerebrovascular events (2.5% vs. 1.4%, P = 0.005) and myocardial infarction (MI) (1.0% vs. 0.4%, P = 0.002) were more common in patients with pSS. In the whole population, central nervous system involvement (odds ratio (OR) 5.6, 95% confidence interval (CI) 1.35-23.7, P = 0.02) and use of immunosuppressive therapy (OR 1.9, 95% CI 1.04-3.70, P = 0.04) were associated with a higher risk of CV events. Patients with leucopenia had a higher risk of angina (P = 0.01).

pSS is associated with an increased risk of cerebrovascular events and MI. Disease-related clinical and immunological markers may have a role in promoting CV events.

Data on sustained remission of granulomatosis with polyangiitis (GPA) after discontinuation of therapy (referred to as GPA with sustained remission off-therapy [SROT]) are scarce. In the present study, SROT among GPA patients from the French Vasculitis Study Group Registry was evaluated to identify factors associated with its occurrence and durability. For inclusion of patients in the study, the diagnosis of GPA had to meet the GPA classification criteria defined by the American College of Rheumatology and/or the revised Chapel Hill Consensus Conference nomenclature for vasculitis. SROT was defined as achievement of remission (a Birmingham Vasculitis Activity Score of 0) that was sustained for ≥6 consecutive months after having discontinued glucocorticoid (GC) and immunosuppressant treatments. The characteristics of the patients at baseline and treatments received were compared at 3, 5, and 10 years postdiagnosis according to whether or not SROT had been reached and maintained. Among 795 patients with GPA, 92 GPA patients with SROT at 3 years postdiagnosis were compared to 342 control subjects who had experienced disease relapse and/or were still receiving GCs or immunosuppressants. No baseline differences were found, but patients with SROT at 3 years postdiagnosis had more frequently received intravenous cyclophosphamide as induction therapy compared to control subjects (P = 0.01), with a higher median number of infusions (P = 0.05). At 5 years postdiagnosis, no baseline differences were observed between groups, but patients with SROT at 5 years postdiagnosis had received more cyclophosphamide infusions compared to control subjects (P = 0.03). More patients with SROT had received rituximab as maintenance therapy than control subjects at 3 years and 5 years postdiagnosis (P = 0.09 and P < 0.001, respectively). Of the 74 patients enrolled in the GPA Registry with 10-year follow-up data after having received conventional maintenance therapy, 15 (20%) had reached SROT at 3 years, and 5 (7%) maintained SROT at 10 years postdiagnosis.

After conventional therapies, 7% of GPA patients had reached SROT at 10 years postdiagnosis. No baseline vasculitis characteristics distinguished patients who achieved/maintained SROT from those who experienced disease relapse and/or those who continued to receive GCs or immunosuppressant therapy, but patients with SROT had received more intensive induction therapy and rituximab as maintenance therapy more frequently.

Clinical measurement study with a longitudinal design. Estimate Patient Acceptable Symptom State (PASS) thresholds in six shoulder outcome measures and two pain scales. Patients with rheumatic diseases undergoing shoulder surgery were assessed at baseline and one-year follow-up (with Bostrom Shoulder Movement Impairment Scale, Constant, Disability of the Arm, Shoulder and Hand [DASH], Oxford Shoulder Score [Oxford], Shoulder Function Assessment Scale, Shoulder Pain and Disability Index [Spadi], and two visual analog pain scales [VAS]). PASS thresholds were estimated using the 75th percentile and the receiver operating characteristic curve approach. One hundred patients were included; 74 (74%) patients considered their shoulder function to be acceptable (PASS+), which was significantly associated with being female, odds ratio (OR) 4.54, and having better functional status (Health Assessment Questionnaire), OR 0.17 (p<0.05). Activity-related pain (VAS), the Oxford, and the Spadi showed best discriminative accuracy for PASS. All measures estimated changes exceeding the minimal clinical important difference. 3. Diagnostic study.

The Oxford and the Spadi showed better discriminant ability for PASS than the more commonly used Constant score and the DASH. The PASS thresholds for pain showed that patients accepted less pain at rest than during activity, underlining the importance of assessing both aspects of pain.

To write a systematic review on the etiology and pathophysiology of the fibromyalgia syndrome (FMS) and of chronic widespread pain (CWP). An interdisciplinary level-3 guideline (i.e. systematic literature search and assessment, logic analysis, formal consensus procedure) for the diagnosis and therapy of FMS was created in cooperation with 10 medical and psychological societies and 2 patient self-help organizations. A literature search was performed covering all available review articles on the etiology and pathophysiology of FMS and CWP using the Cochrane Collaboration Reviews (1993-12/2006), Medline (1980-2006), PsychInfo (1966-12/2006), and Scopus (1980-12/2006). For the assignment of evidence classes the system of the Oxford Centre for Evidence-Based Medicine was applied. Consensus was achieved by a multi-step nominal group procedure. FMS aggregates in families (evidence level 2c). Physical and psychological stress at the workplace are risk factors for the development of CWP and FMS. Affective disorders are risk factors for the development and maintenance of FMS. Operant learning mechanisms and sensitization are risk factors for the chronification of FMS (evidence levels 2b). Several factors are associated with the pathophysiology of FMS, but the causal relationship is unclear. This includes alterations of central pain pathways, hyporeactivity of the hypothalamus-pituitary-adrenal axis, increased systemic pro-inflammatory and reduced anti-inflammatory cytokine profiles and disturbances in the dopaminergic and serotonergic systems.

FMS is the common final product of various etiological factors and pathophysiological mechanisms.

To improve treatment for rheumatoid arthritis (RA), rheumatologists have embraced patient-reported outcomes; however, limited data are available on patient perceptions of treatment. Our objective was to assess the use and perceptions of methotrexate (MTX) by patients with RA (primary objective) and their rheumatologists, patient-reported adverse events (AEs) related to MTX, and patient-reported use of alcohol, folic acid and biologic agents. Each rheumatologist completed a rheumatologist questionnaire and then asked patients with RA to complete a patient questionnaire. Questionnaires were completed by 46/50 rheumatologists and 1313/1313 patients. Patients (72% female, 38% > 10 years RA) took oral MTX regularly (72% never miss a dose) and at therapeutic doses. Most patients (79%) were currently taking MTX, but 36% of patients were on low doses (≤ 10 mg/week) and 8% intentionally and regularly did not take MTX. Most patients had a positive perception of MTX; 82% of patients considered MTX to be important; 60% preferred to continue taking MTX. Although AEs (generally mild and gastrointestinal) occurred regularly (38%) and in some patients continuously (13%), 41% of patients did not experience an AE. Patients abstained from alcohol (46%) and took folic acid (91%, but with variable dosage regimens and doses). There were 29% of patients taking biologic agent therapy; only 70% of these patients were also taking MTX.

MTX was well used, well tolerated and well perceived. However, to ensure that MTX therapy is as effective as possible, rheumatologists should discuss MTX use with their patients and consider alternative strategies for some patients.

To estimate prevalences of rheumatic diseases in Aboriginal Australians. The methodology of the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) was followed. Everyone aged 15 years or older in Yarrabah, North Queensland, was invited to complete a COPCORD Core Questionnaire. Aboriginal health workers carried out a house-to-house survey during January 2002. People reporting current musculoskeletal symptoms and 56 others (controls) were examined at the community health center. Eighty percent of the target population was covered during the survey. Eight hundred and forty-seven questionnaires were completed (47% men) and 135 people refused, a response of 86%. Rheumatic symptoms within the previous 7 days were reported by 33% and past symptoms by 22%. The most common sites of current pain were low back (12.5%), knee (11.2%), and shoulder (8.9%). Sixty-seven people (7.7%) said activities were limited by their symptoms. Two hundred and sixty-three people were examined, and the most common diagnoses were soft tissue pain (point prevalence 7.4%), osteoarthritis (5.5%), and low back pain (4.3%). The cumulative prevalence of gout was 7.0% in men and 0.9% in women over the age of 15 years. The relative risk of gout associated with drinking regularly was 2.5, and with body mass index > 25 was 3.3. No rheumatoid arthritis or systemic lupus erythematosus cases were identified, but there were 4 cases of psoriatic arthritis (point prevalence 0.5%).

This is the first unselected population study of rheumatic diseases in Australian Aboriginals. There was a high prevalence of gout among men, with modifiable factors of weight and alcohol identified.

To investigate the fluctuation in serum levels of anti-cyclic citrullinated peptide antibody (anti-CCP) retrospectively in patients with rheumatoid arthritis (RA). Serum levels of anti-CCP were measured retrospectively in 131 patients with RA and 90 patients with non-RA rheumatic diseases using a commercially available kit. All sera were collected from patients during the 22-year period, 1982-2004. To analyze the fluctuation in anti-CCP levels, 17 RA patients were selected on the basis of showing a significantly higher anti-CCP level in a serum sample taken at the first visit (> 80 U/ml), and availability of preserved serum samples that had been taken from each patient at 10 time points. The test gave a sensitivity of 88% (115/131) and a specificity of 81% (73/90). The longitudinal study of 17 RA patients showed that anti-CCP levels were elevated at the first visit in 12 (71%) patients and then decreased gradually, whereas those in the other five (29%) patients fluctuated substantially. In both cases, anti-CCP levels tended to fluctuate in parallel with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, reflecting the spontaneous aggravation of arthritis and the efficacy of anti-rheumatic drugs. The courses of three representative RA patients are illustrated in detail along with their therapeutic regimens, and these further confirm the correlation of anti-CCP levels with laboratory parameters (ESR and CRP) as well as the activity of arthritis.

Measurement of serum anti-CCP levels was found to be useful for not only the diagnosis but also the management of RA.

This study aims to evaluate the nitinol (X-Fuse®) implant in arthrodesis of the distal interphalangeal and the thumb joints with respect to bone fusion and clinical efficiency. This prospective study included 24 consecutive patients (7 males, 17 females; mean age 56.8 years; range 27 to 79 years) with nitinol (X-Fuse®) implants in their 41 joints. All patients were followed-up clinically and radiographically with respect to fusion, complications and outcome at a minimum of 14 months postoperatively (mean 28±6 months). X-rays, Disabilities of the Arm, Shoulder and Hand, and visual analog scale scores were recorded preoperatively and at postoperative fifth week, third month, first year, and subsequent visits. The Disabilities of the Arm, Shoulder and Hand score improved significantly from preoperative 37.7 points to postoperative 14.5 points at first year. The visual analog scale score improved significantly from preoperative 5.5 to postoperative 0.85 points at first year. Failure to fuse only occurred in two joints (5%), resulting in fusion after reoperation. No other severe complications such as deep infection, intraoperative fracture, wound healing problems or regional dystrophy were observed.

The X-Fuse® implant may be a reliable alternative method for finger joint arthrodesis.

To determine the differences in carotid intima-media thickness (CIMT) between patients with psoriatic diseases with and without metabolic syndrome. Eligible patients from the Cardiometabolic Outcome Measures in Psoriatic Arthritis Study database, which is comprised of both psoriasis and psoriatic arthritis (PsA) patients enrolled at 2 academic medical centers, were included. Detailed cardiovascular (CV) risk factors, including metabolic syndrome profiles, medication use, disease activity, and CIMT, were examined. A total of 343 patients with psoriatic disease were evaluated (42.28% with psoriasis and 57.72% with PsA). PsA patients were significantly older, with longer disease duration and higher blood pressure, body mass index, and C-reactive protein (CRP) level. PsA patients took more disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and underwent more CV procedures. There were no differences in prior CV events, family history of CV risk, and Framingham/Adult Treatment Panel III Risk Score. PsA patients had a higher risk of metabolic syndrome (univariate odds ratio [OR] 1.78 [95% confidence interval (95% CI) 1.08-2.95], P = 0.025). Even after adjusting for age, CRP level, and diastolic blood pressure, PsA patients not taking DMARDs were twice as likely to have metabolic syndrome compared to psoriasis patients (adjusted OR 2.09 [95% CI 0.78-5.59], P = 0.049). PsA patients with metabolic syndrome had the thickest CIMT compared to any other group (P < 0.001).

PsA patients had an increased prevalence of metabolic syndrome with significantly greater CIMT measurements compared to patients with psoriasis. Furthermore, PsA patients with metabolic syndrome had the greatest CIMT measurements compared to PsA patients without metabolic syndrome and psoriasis patients with or without metabolic syndrome. Incremental increases in inflammatory pathways in PsA may contribute to a higher CV risk as compared to psoriasis patients.

To describe the outcomes of MTX and biologic DMARD (bDMARD) treatment in patients with RA and assess unmet needs in patients who fail treatment, using real-world data from the Norwegian DMARD (NOR-DMARD) registry. Data included RA treatment courses from January 2007 until July 2016. Patients received MTX monotherapy (in MTX-naïve patients), bDMARD monotherapy, bDMARDs + MTX, or bDMARDs + other conventional synthetic DMARDs (csDMARDs). DAS28-4(ESR) was used to measure remission (<2.6) and inadequate response (>3.2) across all groups at Months 6 and 12. Estimated ACR20/50/70 and EULAR good and good/moderate response rates (based on DAS28-4[ESR] score) for bDMARDs were modelled at Months 6 and 12 using logistic mixed regression. DAS28-4(ESR) scores and changes from baseline, and rates and reasons for discontinuation, were evaluated for all groups over 24 months. The 2778 treatment courses in this analysis included 714 MTX monotherapy, 396 bDMARD monotherapy, 1460 bDMARDs + MTX and 208 bDMARDs + other csDMARDs. Of patients with DAS28-4(ESR) data at Months 6 and 12 (25.0-34.1%), 33.9-47.2% did not switch treatment and were inadequate-responders at Month 12. There were no significant differences in efficacy between bDMARD groups (bDMARD monotherapy, or bDMARDs + MTX or other csDMARDs). Lack of efficacy was the most common reason for stopping treatment across all groups (13.7-22.1% over 24 months). ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01581294.

An unmet treatment need exists for patients still experiencing inadequate response to MTX monotherapy and bDMARDs as monotherapy or in combination with MTX/other csDMARDs after 12 months.

Magnetic resonance imaging (MRI) is increasingly used in patients with rheumatoid arthritis (RA) to determine residual inflammation after treatment and as a predictor of structural damage progression. Establishing an optimal threshold of inflammatory activity that predicts lower risk of structural damage progression may inform treatment decisions. This post hoc analysis investigated whether patients with RA at low risk of structural damage progression can be identified based on MRI inflammation thresholds. Hand and wrist MRI was performed at baseline, and at months 6 and 12 in a phase 3b, randomized, active-controlled, double-blind trial of abatacept in early RA (AVERT). Pathologies were scored using the OMERACT RA MRI Score. Data were stratified into two risk subgroups (less and more severe inflammation) for structural damage progression (erosion change > 0.5) based on baseline inflammation. In this post hoc analysis, log odds ratios of probability of progression {adjusted for baseline Disease Activity Score in 28 joints [C-reactive protein; DAS28 (CRP)]} were compared between subgroups to test the performance of inflammation thresholds. There were 351 randomized and treated patients with baseline MRIs, of whom 276 (78.6%) and 235 (67.0%) had MRIs available at months 6 and 12, respectively. The DAS28 (CRP)-adjusted probabilities of progression from baseline to month 12 based on scores at baseline, and from months 6 to 12 based on month 6 scores, were significantly lower among patients with less inflammation (P < 0.0001-0.0459), independent of clinical disease activity. Predefined thresholds of synovitis ≤ 3 (total score 21), osteitis ≤ 3 (total score 69) and total inflammation score (osteitis double-weighted) ≤ 9 were associated with a lower likelihood of structural damage progression in unadjusted analyses. ClinicalTrials.gov identifier, NCT01142726. Bristol-Myers Squibb.

Levels of MRI-determined inflammatory activity below defined thresholds were independently associated with a lower risk of structural damage progression in early RA, providing a potential trial endpoint for levels of inflammation not associated with progression.

Femoral head impaction defects are observed with variable severity, as a result of traumatic hip dislocations which can be caused by traffic accidents or seen in professional athletes amongst other mechanisms. Compression of the articular cartilage and the subchondral bone into the femoral head results in irregular articular surfaces influencing the outcome with predisposition to osteoarthritis, and being predictive for the need for delayed total hip replacement. This study reports the outcome after a minimum follow-up (FU) of five years in a consecutive series treated with transfer of osteochondral shell autografts in hips (TOSAH) from the head-neck junction into the defect using surgical hip dislocation. Between 06/2007 and 03/2014 a series of twelve consecutive patients (mean age: 35yrs, range 18-53; median Injury Severity Score: 12, range 9-27) sustained a traumatic posterior hip dislocation in combination with acetabular and/or Pipkin fractures and were inter alia treated using TOSAH using surgical hip dislocation. Conversion to total hip replacement (THR) during FU was noted as failure. Patients were clinically (Merle d'Aubigné score) and radiographically assessed for occurrence of osteoarthritis (OA), avascular necrosis (AVN) and/or heterotopic ossification (HO) at a minimal follow-up of five years. Mean follow-up was 6.9 years (5.0-11.6). At five-year follow-up, we found a survivorship of 57.1% (95% Confidence interval {CI}, 46.7-100%). Four patients required conversion to a total hip replacement at 11, 16, 28 and 44 months respectively after the TOSAH procedure due to osteoarthritis progression. One patient required conversion to a total hip replacement 12 months after TOSAH procedure due to AVN. One patient was lost to follow-up after 2.7 years. The remaining six patients with preserved hips presented with a median Merle-d'Aubigné score of 16 points (range: 14-18) and no AVN. Two patients showed asymptomatic grade I osteoarthritis according to Tönnis at latest follow-up and three patients showed mild asymptomatic HO according to Brooker (Grade I-II).

The presented technique can be used as a salvage procedure for severely injured hip joints and to preserve the hip joint at midterm with satisfying clinical and radiological outcomes.

Biomarkers of cartilage metabolism have prognostic potential. To examine whether serum cartilage biomarkers, cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA procollagen (PIIANP), type II collagen breakdown product (collagen type-II cleavage (C2C)) predict cartilage volume loss and knee joint replacement. 117 subjects with knee osteoarthritis (OA) had MRI at baseline and 2 years. Cartilage biomarkers were measured at baseline. Change in knee cartilage volume over 2 years and knee joint replacement over 4 years was determined. The population was divided into subgroups with high or low cartilage biomarkers (based on biomarker levels greater than or equal to, or less than, the mean, respectively). The relationships between biomarkers and outcome measures were examined in the whole population, and separately in marker subgroups. The relationship between cartilage biomarkers and cartilage volume loss was not linear across the whole population. In the low (regression coefficient B=-9.7, 95% CI -0.01 to 0.003, p=0.01), but not high (B=-0.46, 95% CI -8.9 to 8.0, p=0.92) COMP subgroup, COMP was significantly associated with a reduced rate of medial cartilage volume loss (p for difference between groups=0.05). Similarly, in the low (B=-8.2, 95% CI -12.9 to -3.5, p=0.001) but not high (B=2.6, 95% CI -3.3 to 8.5, p=0.38) PIIANP subgroup, PIIANP was associated with a significantly reduced rate of medial volume cartilage loss (p for difference=0.003). C2C was not significantly associated with rate of cartilage volume loss. PIIANP was associated with a reduced risk of joint replacement (odds ratio (OR)=0.28, 95% CI 0.10 to 0.93, p=0.04).

Cartilage biomarkers may be used to identify subgroups among those with clinical knee OA in whom disease progresses at different rates. This may facilitate our understanding of the pathogenesis of disease and allow us to differentiate phenotypes of disease within a heterogeneous knee OA population.

Obesity is over-represented in patients with psoriatic arthritis (PsA) and associated with higher disease activity, poorer effect of treatment and increased cardiovascular morbidity. Studies on the effects of weight loss are however needed. This study aimed to prospectively study the effects of weight loss treatment with very low energy diet (VLED) on disease activity in patients with PsA (CASPAR criteria) and obesity (body mass index BMI ≥ 33 kg/m VLED (640 kcal/day) was taken during 12-16 weeks, depending on pre-treatment BMI. Afterwards, an energy-restricted diet was gradually reintroduced. Weight loss treatment was given within a structured framework for support and medical follow-up. Treatment with conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs was held constant from 3 months before, until 6 months after baseline. Patients were assessed with BMI, 66/68 joints count, Leeds enthesitis index, psoriasis body surface area (BSA), questionnaires and CRP at baseline, 3 and 6 months. Primary outcome was the percentage of patients reaching minimal disease activity (MDA) and secondary outcomes were reaching Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) response criteria. Totally 41/46 patients completed the study, 63% women, median age 54 years (IQR 48-62). At baseline increased BMI was associated with higher disease activity and poorer function. The median weight loss was 18.7 kg (IQR 14.6-26.5) or 18.6% (IQR 14.7-26.3) of the baseline weight. A majority of the disease activity parameters improved significantly after weight loss, including 68/66 tender/swollen joints count, CRP, BSA, Leeds enthesitis index, HAQ and patient VAS for global health, pain and fatigue. A larger weight loss resulted in more improvement in a dose-response manner. The percentage of patients with MDA increased from 29 to 54%, (p = 0.002). PsARC was reached by 46.3%. The ACR 20, 50 and 70 responses were 51.2%, 34.1% and 7.3% respectively. ClinicalTrials.gov identifier: NCT02917434 , registered on September 21, 2016-retrospectively registered.

Short-term weight loss treatment with VLED was associated with significant positive effects on disease activity in joints, entheses and skin in patients with PsA and obesity. The study supports the hypothesis of obesity as a promotor of disease activity in PsA.

The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) is a validated instrument for assessing organ damage in systemic lupus erythematosus (SLE). Trained physicians must complete it, thus limiting utility where this is impossible. We developed and pilot tested a self-assessed organ damage instrument, the Lupus Damage Index Questionnaire (LDIQ), in 37 SLE subjects and 7 physicians. After refinement, 569 English-speaking SLE subjects and 14 rheumatologists from 11 international SLE clinics participated in validation. Subjects and physicians completed the instruments separately. We calculated sensitivity, specificity, Spearman's correlations, and agreement using the SDI as the gold standard. Six hundred five SLE participants in the community-based National Data Bank for Rheumatic Diseases (NDB) study completed the LDIQ and we assessed correlations with outcome and disability measures. The mean LDIQ score was 3.3 (range 0-16) and the mean SDI score was 1.5 (range 0-9). The LDIQ had a moderately high correlation with the SDI (Spearman's r = 0.50, P < 0.001). Specificities of individual LDIQ items were >80%, except for neuropathy. Sensitivities were variable and lowest for damage, with <1% prevalence. Agreement between the SDI and LDIQ was >85% for all but neuropathy, reduced renal function, deforming arthritis, and alopecia. In the NDB, the LDIQ correlated well with the comorbidity index (r = 0.45), the Short Form 36 physical component scale (r = 0.43), the Medical Research Council dyspnea scale (r = 0.40), disability (r = 0.37), and the Systemic Lupus Erythematosus Activity Questionnaire score (r = 0.37).

The metric properties of the LDIQ are good compared with the SDI. It has construct validity and correlations with health assessments similar to the SDI. The LDIQ should allow expansion of SLE research. Its ultimate value will be determined in longitudinal studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the efficacy and safety of tofacitinib 5 or 10 mg twice daily (BID), in patients with moderate to severe RA, aged ≥65 and <65 years. Data were pooled from five Phase 3 trials and, separately, from two open-label long-term extension (LTE) studies (data cut-off April, 2012). Patients received tofacitinib, or placebo (Phase 3 only), with/without conventional synthetic DMARDs (mainly methotrexate). Clinical efficacy outcomes from Phase 3 studies were evaluated at Month 3. Safety evaluations using pooled Phase 3 data (Month 12) and pooled LTE data (Month 24) compared exposure-adjusted incidence rates (IRs; with 95% confidence intervals [CIs]), in older versus younger patients. In Phase 3 and LTE studies, 15.3% (475/3111) and 16.1% (661/4102) of patients, respectively, were aged ≥65 years. Consequently, exposure to tofacitinib was lower in older versus younger patients in Phase 3 (259.2 vs. 1554.9 patient years [pt-yrs]) and LTE (962.1 vs. 5071.7 pt-yrs) studies. Probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 (Month 3) favoured tofacitinib and were similar in older and younger patients, with overlapping CIs. IRs for SAEs and discontinuations due to AEs were generally numerically higher in older versus younger patients, irrespective of treatment.

Older patients receiving tofacitinib 5 or 10 mg BID had a similar probability of ACR20 or ACR50 response and, due to comorbidities, a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients.

To explore the impact of the COVID-19 pandemic on treat-to-target strategies (disease activity, remission rates) and access to physical consultations in patients with inflammatory rheumatic disease, as well as to explore characteristics of patients with/without physical consultations in the clinic and the impact of early vs established disease. Patients with RA, PsA or axial SpA (axSpA) prospectively followed in the nationwide DANBIO registry answered online questionnaires and reported patient-reported outcomes (PROs) in June and November 2020. Patient characteristics, disease activity and physical consultations in the clinic before and during the pandemic were identified in DANBIO [all patients and subgroups with early disease (disease duration ≤2 years)]. In individual patients, changes in PROs before and during the pandemic were calculated. Characteristics of patients with/without physical consultations were described (age, gender, education level, comorbidities, disease duration, treatment). We included 7836 patients (22% of eligible patients), 12% of which had early disease. PROs were stable before and during the pandemic, with median changes approximating zero, as well as in patients with early disease. Remission rates were stable. The relative decrease in the number of patients with physical consultations was 21-72%, which was highest in axSpA. Characteristics of patients with/without physical consultations were similar. Self-reported satisfaction with treatment options and access was >70%; the preferred contact form was physical consultation (66%).

In this nationwide study performed during the first 8 months of the pandemic, patient satisfaction was high and the PROs and remission rates remained stable despite the remarkable reduction in physical consultations, as well as in patients with early disease. Characteristics of patients with/without physical consultations appeared similar.

The purpose of the present study was to examine the effects of knee taping on perceived pain, difficulty and stability during functional activities (squat, step-down, and stair up and down) in older adults with knee osteoarthritis (OA). A total of 50 older participants with knee OA participated in this study. The experimental group received non-elastic taping (NET) and the control group received sham taping. Perceived knee pain on an 11-point scale (0 = no pain, 10 = worst pain), and difficulty (1 = no difficulty, 5 = extreme difficulty) and stability (1 = no unstable, 5 = extreme unstable) on a 5-point scale during functional tests (squat, step-down test, and stair up and down) were reported at baseline and post-taping application. At post-taping, pain intensity, difficulty and stability during squat, step-down test, and stair up and down were significantly improved in the NET group. In the control group, there was significant decreased pain intensity during squat and stair up and down; however, there were no significant change of other variables. Compared with the control group, the NET significantly improved perceived pain, difficulty and stability during all tasks after the taping application.

The present study showed that NET application can improve perceived pain intensity, difficulty and stability during functional tests in older adults with knee OA. NET can be recommended to improve pain, stability and difficulty during squat, step-down, and stair up and down in older adults with OA. Geriatr Gerontol Int 2018; 18: 1206-1210.

To examine prospective relations between a wide array of measures of social functioning and pain, while controlling for disease duration and activity and functional grade. As part of a larger study on health care utilization, longitudinal data were collected from 136 Dutch and 98 German outpatients on clinical status and pain. Social data included information on sexual handicap, spouse behavior, loneliness, daily emotional support, and the maintenance of pleasurable life domains. Pain severity was assessed at baseline and 12 months later with standard measures of pain and analyzed with hierarchical regressions. Social measures obtained at baseline were consistently associated with pain at followup. Depression was a moderate correlate of pain in the Dutch and German samples. The regressions revealed that patient reports of negative spouse behavior (such as avoidance and critical remarks) and baseline depression predicted worse pain outcome, and this association remained significant in analyses controlling for baseline pain. The level of formal education was a weak correlate of disability, emotional support, and pain. Daily emotional support and social life domains associated with positive affect had an indirect influence on outcome. The absence of strong rather than weak social ties was the component of the loneliness construct linked to pain. These associations between social prognostic factors and pain severity, however, were mediated by psychological functioning at baseline.

The social environment was found to operate on the core health outcome, pain severity, via several pathways. Social functioning may be affected by rheumatoid arthritis (RA) progression, but it also appears to form a determinant of future health outcome. Not only the status of being married but also the quality of the relationship in terms of long-term stress and emotional support may be useful prognostic factors in RA.

Rituximab has broad and increasing application in rheumatic diseases. It is known from lymphoma studies that natural killer (NK) cells can lyse rituximab-coated transformed B cells. However, the role of NK cells in mediating rituximab-induced depletion of non-malignant B cells is unknown. The purpose of this study was to provide fundamental data on rituximab-mediated effects on NK cells in PBMCs without tumor cells, in order to simulate effects that could be relevant in patients with rheumatic disease. Freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured overnight with therapeutic antibodies. NK cells were isolated using a commercial kit or depleted from PBMCs using anti-CD56 and anti-CD16 monoclonal antibodies and magnetic beads. Cells were analyzed by multicolor flow cytometry. Cytotoxicity assays were performed using (51)Cr-labeled K562 target cells. Addition of rituximab to PBMCs resulted in depletion of B cells, which was dependent on NK cells and serum factors. The extent of B cell depletion correlated with the percentage of NK cells. Following incubation with rituximab, NK cells within PBMCs were activated, degranulated and downregulated the low affinitiy Fc-γ-receptor CD16 (FcγRIIIA). The co-activating receptor CD137 (41BB) was upregulated on a fraction of NK cells. NK cell function was altered in some donors in whom we observed rituximab-dependent reduction in NK cell cytotoxicity towards K562 tumor cells.

NK cells mediate rituximab-induced B cell depletion. Rituximab induces altered NK cell phenotype and function.

To determine the frequency of radiographic abnormalities in hand/wrist radiographs of children with newly diagnosed polyarticular juvenile rheumatoid arthritis (polyJRA) because radiographs of small joints are an important tool in assessing outcomes in RA and there are clinical similarities between RA and polyJRA. A medical record review was performed to identify cases of polyJRA seen at Mayo Clinic from January 1, 1994, to December 31, 2001. Hand/wrist radiographs, obtained at the time of diagnosis, were reviewed by 3 radiologists with attention to periarticular osteopenia, joint space narrowing (JSN), or erosion. At least 2 radiologists had to independently identify abnormal findings on the same radiograph. The relative carpal length (RCL), judged by Poznanski's method, was also determined. From the review of 159 medical records, 60 cases of newly diagnosed polyJRA were identified. Twenty-five of these had hand/wrist radiographs at diagnosis; 18 sets were available for this study. Of those, 2/3 were female, 6% (1/18) had subcutaneous nodules, 7% (1/14) had elevated levels of serum rheumatoid factor, and 44% (7/16) had elevated serum levels of antinuclear antibodies. Median age at diagnosis was 10.2 years, median duration of hand/wrist symptoms at diagnosis was 10 months, and median number of joints with either swelling, pain on range of motion (ROM), or limited ROM was 14.5. Sixty-one percent of radiographs taken at the time of diagnosis of polyJRA were abnormal. While 44% had periarticular osteopenia, 28% had either erosions or JSN. Six (33%) had RCL > 2 SD below the mean for age. Five (83%) of those with RCL, > 2 SD below the mean for age, had periarticular osteopenia, JSN, or erosion.

We conclude the frequency of abnormal hand/wrist radiographs is very high very early in the course of polyJRA. More studies are needed to determine to what extent these radiographic abnormalities correlate with clinical outcomes.

Fibromyalgia is difficult to treat and requires the use of multiple approaches. This study is a randomized controlled trial of qigong compared with a wait-list control group in fibromyalgia. One hundred participants were randomly assigned to immediate or delayed practice groups, with the delayed group receiving training at the end of the control period. Qigong training (level 1 Chaoyi Fanhuan Qigong, CFQ), given over three half-days, was followed by weekly review/practice sessions for eight weeks; participants were also asked to practice at home for 45 to 60 minutes per day for this interval. Outcomes were pain, impact, sleep, physical function and mental function, and these were recorded at baseline, eight weeks, four months and six months. Immediate and delayed practice groups were analyzed individually compared to the control group, and as a combination group. In both the immediate and delayed treatment groups, CFQ demonstrated significant improvements in pain, impact, sleep, physical function and mental function when compared to the wait-list/usual care control group at eight weeks, with benefits extending beyond this time. Analysis of combined data indicated significant changes for all measures at all times for six months, with only one exception. Post-hoc analysis based on self-reported practice times indicated greater benefit with the per protocol group compared to minimal practice. clinicaltrials.gov NCT00938834.

This study demonstrates that CFQ, a particular form of qigong, provides long-term benefits in several core domains in fibromyalgia. CFQ may be a useful adjuvant self-care treatment for fibromyalgia.

To investigate associations between antecedent stressful life events and occurrence of juvenile arthritis (JA). The study population comprised patients with JA referred to a pediatric rheumatology clinic between 1981 and 2010. A questionnaire, which was developed as a screening tool by the clinic, was completed at the first clinic visit by patients' parents and, for comparison, by parents of unrelated age, sex, geographically, and temporally matched healthy controls. The entire questionnaire captured a broad array of clinical, demographic, psychosocial, and environmental data, including questions about stressful life events from 686 patients with JA and from 1042 controls. Patients were more likely to have experienced a serious upset (OR 4.81; p < 0.0001), a currently ill family member (OR 2.29; p < 0.0001), separated parents (OR 1.96; p < 0.0001), or difficulties with interpersonal relationships (OR 2.54; p < 0.0001) prior to first clinic presentation compared to controls. Children with oligoarticular JA were more likely than controls to have experienced a serious upset (OR 3.46; p = 0.008), an ill family member (OR 3.79; CI 2.02, 7.11; p < 0.0001), or problems with interpersonal interactions (OR 3.32; p < 0.0001). Children with polyarticular JA were more likely to have experienced a serious upset (OR 5.68; p < 0.0001), separated parents (OR 2.66; p = 0.001), a deceased parent (OR 6.75, p = 0.017), or problems with interpersonal relationships (OR 2.39; p = 0.009). No significant differences were observed when comparing systemic JA patients to controls.

Strong associations between stressful life events antedating the first clinic visit of patients with JA indicate that life event stresses should be identified and addressed when first encountering and managing children with JA.

To validate the measurement properties and the detection performance of the FLARE-RA questionnaire in a longitudinal prospective study. To validate the FLARE-RA self-administered questionnaire, we conducted a prospective trial in rheumatoid arthritis (RA) patients to document: 1) content and construct validity by factor analysis, convergent validity by Pearson's correlation with routine assessment of patient index data (Routine Assessment of Patient Index Data 3 [RAPID-3] questionnaire), RA Impact of Disease (RAID) score, Disease Activity Score in 28 joints (DAS28), and Health Assessment Questionnaire (HAQ), 2) reliability (intraclass correlation coefficient [ICC] and Bland-Altman plot), and 3) feasibility of use. Patients were examined and questionnaires were collected at baseline and 3 months, and every week in between for RAPID-3. We recruited 138 patients from 13 centers: 81.9% women, mean age 57.4 years, mean DAS28 2.9, mean C-reactive protein level 6.2 mg/liter, 84.4% rheumatoid factor positive, 78.0% anti-citrullinated protein antibody positive, and 78.8% with erosive disease. At baseline, the mean ± SD FLARE-RA score was 2.3 ± 2.3. The content and construct validity of FLARE-RA was good. A substantial floor effect, but no ceiling effect, was observed. Principal components analysis revealed 1 domain disentangled in 2 subdomains: physical and emotional. The FLARE-RA total score was correlated with the DAS28 (r = 0.63, P < 0.001), RAID (r = 0.80, P < 0.001), RAPID-3 (r = 0.77, P < 0.001), and HAQ (r = 0.53, P < 0.001). The ICC for reliability was 0.94 (95% confidence interval 0.92-0.96).

The FLARE-RA self-administered questionnaire represents a valid and valuable instrument to detect RA flare between visits to the physician.

The authors describe a 68-year-old woman in whom ischemic choroidopathy and optic neuropathy developed in association with primary Sjögren's syndrome with central nervous system involvement. Diagnosis of primary Sjögren's syndrome was made upon the association of keratoconjunctivitis sicca, minor salivary gland biopsy and serologic abnormalities. Fluorescein angiography showed signs highly suggestive of ischemic choroidopathy. The authors discuss differential diagnosis and pathophysiology of such choroidal manifestations. Treatment consisted in massive steroid therapy. Secondarily, an immunosuppressant agent (azathioprine) was successfully added because of neurological recurrences.

Primary Sjögren's syndrome should be considered in the differential diagnosis of ischemic choroidopathy.

Cross-sectional observational design. To compare physical activity levels in men and women with end-stage knee osteoarthritis to those of a comparison group and to examine the relationship between physical activity level and physical performance. Osteoarthritis of the knee is associated with significant losses in functional performance and high social costs. Although reductions in physical activity are reported, they have not been quantified or explored. Fifty-nine candidates awaiting total knee arthroplasty (TKAC group) and 79 individuals without osteoarthritis (comparison group) participated. Physical activity was assessed using the Voorrips Questionnaire. Performance measures included fast self-paced walk test, timed up-and-go test, and a timed stair performance measure. A subset of subjects completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and underwent muscular strength and endurance testing. The effects of gender and group were tested using GLM ANOVA. Pearson product moment correlations were used to examine relationships between the variables. All aspects of physical activity were lower (P<.001) in the TKAC group, with a moderate difference in household score (18%) and a large difference in leisure activities (63%). Unlike the comparison group, modest but significant correlations (r = 0.31-0.33, P<.03) were observed between overall physical activity and performance test scores for the TKAC group. Physical activity was not significantly related to pain reported on the WOMAC or during the performance tasks.

The belief that pain limits the physical activity of patients with severe osteoarthritis requires further investigation. The profound differences between a comparison group and patients with end-stage osteoarthritis in physical activity have critical implications for the well-being and effective treatment of this population.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). It is not known whether a specific inhibitor of COX-2 will provide efficacy in osteoarthritis (OA) comparable with NSAIDs. Therefore, we compared the efficacy and safety of the rofecoxib, which specifically inhibits COX-2, with those of the NSAID ibuprofen in patients with OA. To compare the clinical efficacy and tolerability of rofecoxib (12.5 and 25 mg once daily) with ibuprofen (800 mg 3 times daily). A randomized, double-blind trial of 809 adults with OA was conducted. Patients with OA in whom the knee or hip was the primary source of pain were randomized to 1 of 4 treatment groups on demonstration of disease activity: placebo; rofecoxib, 12.5 or 25 mg once daily; or ibuprofen, 800 mg 3 times daily. Clinical efficacy and safety were monitored during a 6-week treatment period. Both doses of rofecoxib demonstrated efficacy clinically comparable with ibuprofen as assessed by 3 primary end points (pain walking on a flat surface [Western Ontario and McMaster Universities Osteoarthritis Index], patient global assessment of response to therapy, and investigator global assessment of disease status) according to predefined comparability criteria. Both rofecoxib doses and the ibuprofen dose provided significantly (P<.001) greater efficacy than placebo on all primary end points. Results from secondary end points were consistent with those of the primary end points. All treatments were well tolerated; the overall incidence rates of clinical adverse experiences were not significantly different (P>.05) among the treatment groups.

Rofecoxib was well tolerated and provided clinical efficacy comparable with a high dose of the NSAID ibuprofen.

Several studies underline the relevance of the genetic background for the response to therapy. We evaluated the relationship between the polymorphism of the HS1,2A enhancer, located in the 3' regulatory region of the heavy immunoglobulin chain (IgH), and the response to B cell depletion therapy (BCDT) with Rituximab (RTX). Fifty rheumatoid arthritis (RA) patients (42 women; disease duration 13.9 ± 10.6 years) treated with RTX, not responsive to previous DMARDs and/or TNFα inhibitors therapies, and 220 healthy subjects were enrolled in the study. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described. Disease activity was assessed every three months according to the European League Against Rheumatism's (EULAR) criteria. All RA patients were seropositive for at least one of the tested autoantibodies: rheumatoid factor (FR IgA, FR IgM e FR IgG), anti-cyclic citrullinated peptides (anti-CCP IgA, anti-CCP IgM e anti-CCP IgG) and anti-vimentin antibodies. RA patients had an increased frequency of the allele*2 (60.0%) of the HS1,2A enhancer compared to healthy subjects (42.0%; OR(95%ICs): 2.07 (1.33-3.22)). Patients with a good EULAR response at 6 months follow-up visit had an increased frequency of genotype 2/2 (47.1%) compared to poor-responders RA patients (genotype 2/2: 18.2%, OR(95%ICs): 4.00 (1.09-14.68)). All the patients with a good EULAR response had the allele*2, thus showing a possible association with the allele in this population.

The presence of allele*2 seems to be related to a good response to BCDT with RTX in seropositive RA patients, thus highlighting the role of the HS1,2A enhancer in B cell maturation and class-switch recombination.

To evaluate drug survival, efficacy, side effects, and longterm toxicity of azathioprine treatment in patients with juvenile chronic arthritis (JCA). In an uncontrolled, prospective study we evaluated 129 consecutive patients with JCA refractory to therapy in whom azathioprine treatment was begun during 1980-1989. In the first 29 patients, a 2 year trial was planned, while for the remaining 100 patients the protocol was to continue until remission or dropout. The median treatment period was 13 months (range 3 days-8.5 yrs). Patients were assessed every 2 months for 2 years for efficacy, side effects, growth and need for glucocorticoids, and outcome evaluated in late 1996. Remission without drugs was attained in 19 patients (15%); in addition, temporary remission in patients continuing treatment was attained in 18 cases (14%). Treatment was discontinued due to side effects in 18 cases (14%); in two-thirds of these cases side effects occurred during the first 2 months. Of the total number of patients, 49 (38%) completed 2 years of treatment, with significant improvement in both clinical and laboratory indices of disease activity. Treatment had no noticeable effect on iridocyclitis. One patient died of cytomegalovirus infection during azathioprine treatment.

Azathioprine is a useful drug in severe JCA, with a sustained effect and acceptable side effects. Even in cases of incomplete remission, its glucocorticoid sparing effect was noteworthy.

Chondrocytes are highly sensitive to variations in extracellular glucose and oxygen levels in the extracellular matrix. As such, they must possess a number of mechanisms to detect and respond to alterations in the metabolic state of cartilage. In other organs such as the pancreas, heart and brain, such detection is partly mediated by a family of potassium channels known as K(ATP) (adenosine 5'-triphosphate-sensitive potassium) channels. Here we investigate whether chondrocytes too express functional K(ATP) channels, which might, potentially, serve to couple metabolic state with cell activity. Immunohistochemistry was used to explore K(ATP) channel expression in equine and human chondrocytes. Biophysical properties of equine chondrocyte K(ATP) channels were investigated with patch-clamp electrophysiology. Polyclonal antibodies directed against the K(ATP) Kir6.1 subunit revealed high levels of expression in human and equine chondrocytes mainly in superficial and middle zones of normal cartilage. Kir6.1 was also detected in superficial chondrocytes in osteoarthritic (OA) cartilage. In single-channel electrophysiological studies of equine chondrocytes, we found K(ATP) channels to have a maximum unitary conductance of 47 +/- 9 pS (n=5) and a density of expression comparable to that seen in excitable cells.

We have shown, for the first time, functional K(ATP) channels in chondrocytes. This suggests that K(ATP) channels are involved in coupling metabolic and electrical activities in chondrocytes through sensing of extracellular glucose and intracellular adenosine triphosphate (ATP) levels. Altered K(ATP) channel expression in OA chondrocytes may result in impaired intracellular ATP sensing and optimal metabolic regulation.

Osteoarthritis is currently one of the most common chronic diseases. As life expectancy increases, its prevalence and incidence are expected to rise. At present, more and more evidences prove the correlation between the complement system and osteoarthritis (OA). This study aims to investigate complement C5's influence on the effect of MK801 on osteoarthritis synovial fibroblasts (OA-SFs). We used IL-1b to induce OA-SFs derived from mice to obtain OA-SFs. And we performed RT-PCR and Western Blot assays to evaluate the expression levels of associated mRNA and protein. The alteration of MAC expression on OA-SFs cell membrane was evaluated by immunofluorescence assay. The expression of related inflammatory factors of OA-SFs was evaluated by ELISA experiment. MK801 could significantly inhibit the expression of osteoarthritis (OA) marker factors, such as: membrane attack complex (MAC), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-13 (MMP13). Meanwhile, MK801 can significantly inhibit the expression of complement C5 (C5) in OA-SFs. Immunofluorescence assay showed that MAC expression on OA-SFs cell membrane was significantly inhibited by MK801. The nucleo-plasmic separation experiment demonstrated that MK801 could significantly inhibit the activation of Nuclear factor-κB (NF-κB) signaling pathway in OA-SFs. Futhermore, koncking down the expression of C5 reversed the inhibition MK801 on the expression of OA-SFs inflammatory factors.

These results illustrated two points: first, MK801 inhibited the generation of MAC and the release of inflammation factors in OA-SFs through C5; second: MK801 inhibited the activation of NF-κB signaling pathway in OA-SFs.

The aim of this study was to compare the efficacy and safety of rituximab (RTX) as a function of patient age. We included all rheumatoid arthritis patients in the AutoImmunity and Rituximab registry with a 2-year followup. Of the 1,709 patients, 191 were age ≥75 years, 417 were ages 65–74 years, 907 were ages 50–64 years, and 194 were age <50 years. At baseline, the elderly and very elderly patients presented with longer disease duration, a higher incidence of erythrocyte sedimentation rate and C-reactive protein level, a lower incidence of previous tumor necrosis factor α (TNFα) therapy, and a smaller number of previously used TNFα agents. Disease activity, rheumatoid factor (RF), or anti–cyclic citrullinated peptide (anti-CCP) antibodies and corticosteroid therapy were not statistically different among the groups. At 24 months, no significant difference was shown among the groups for RTX discontinuation rates (36.1% if age <50 years, 32.6% if ages 50–64 years, 34.5% if ages 65–74 years, and 32.5% if age >75 years). The reasons for discontinuation (inefficacy, adverse events) were the same in all 4 groups. Infections were more common in the elderly. Patients ages 65–75 years were more likely to be good responders than nonresponders at 1 year of followup than patients age ≥75 years (odds ratio 3.81, 95% confidence interval 1.14–12.79) after adjustment on disease duration, RF/anti-CCP positivity, corticosteroids, anti-TNF use, and baseline Disease Activity Score in 28 joints (DAS28). After the sixth month, the decrease in DAS28 score was less marked in the population age >75 years than in the group age <50 years.

The efficacy and safety of RTX is affected by age.

To review the clinical performance of the anatomic medullary locking (AML) femoral stem in total hip arthroplasty. A clinical and radiographic review. A tertiary lower limb joint replacement centre. Two hundred and twenty-one patients with noninflammatory gonarthrosis. Two hundred and twenty-seven primary total hip arthroplasties with the noncemented AML component completed by two surgeons. Independent review by two experienced reviewers of the postoperative Harris hip score, radiographs of component fixation, size and degree of diaphyseal fill. Harris hip score was 84 (range from 43 to 98); component fixation showed bone ingrowth in 41%, stable fixation with fibrous ingrowth in 56% and unstable fixation in 3%; severe thigh pain in 4% of cases correlated with unstable fixation, and there was mild thigh pain in 20% of cases.

The AML femoral stem performs well in replacement arthroplasty compared with other noncemented stems.

Hemophagocytes (HPCs) are activated macrophages that have engulfed other hematopoietic cells. Although HPCs are rarely identified in normal spleen tissue and bone marrow, an excess of these macrophages characterizes many cytokine storm syndromes, particularly macrophage activation syndrome and hemophagocytic lymphohistiocytosis. This study was undertaken to assess the functions of HPCs and their significance in acute inflammatory conditions. HPCs were generated in wild-type mice using repeated stimulation with Toll-like receptor 9 (TLR-9) and interleukin-10 receptor blockade. RNA was extracted from HPCs that had been isolated by lasercaptured microdissection. Transcriptional profiles of the HPCs were then compared to those of resting splenic macrophages. In addition, bone marrow samples were obtained from a diverse cohort of patients in whom excess hemophagocytosis was identified by clinical bone marrow biopsy or aspiration. The bone marrow samples were analyzed by immunohistochemistry for markers of classic (CD64) or alternative (CD163 and CD206) macrophage activation. Differential gene expression and gene set enrichment analyses of murine HPCs identified upregulation of genes and gene sets associated with alternative activation of HPCs. Immunohistochemical analyses of HPCs in human bone marrow samples showed universal staining of HPCs for CD163, but rarely for CD206 or CD64.

Laser-captured murine TLR-9– induced HPCs had a transcriptional profile similar to that of alternatively activated macrophages. In addition, HPC expression of CD163 was confirmed in a uniquely diverse cohort of patients with hemophagocytic syndromes. Collectively, these data support the hypothesis that HPCs have both immunoregulatory and clean-up functions.

Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis (RA) patients receiving preventive treatment for osteoporosis. A small increase in lumbar bone mineral density (BMD) during the first year of treatment was recorded, regardless of use of glucocorticoids. This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis. Early RA patients were included in the CAMERA-II trial: a randomized, placebo-controlled, double-blind 2-year trial, in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied. All patients received calcium, vitamin D and bisphosphonates. Disease activity was assessed every 4 weeks. Radiographs of hands and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment. BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6% during the first year (p<0.001), but not at the hip; at none of the time points did BMD differ significantly between the prednisone and placebo group. Higher age and lower weight at baseline and higher disease activity scores during the trial, but not glucocorticoid therapy, were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses.

Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates. A small increase in lumbar BMD during the first year of treatment was found, regardless of use of glucocorticoids.

To compare 3 different hyaluronan (HA) preparations used as therapeutic agents for osteoarthritis pain in humans in order to establish the degree to which a single application affects the sensitivity of nociceptors in both the normal and the acutely inflamed rat joint. In anesthetized rats, single-unit recordings were performed from the medial articular nerve of the right knee joint under normal conditions and during an acute experimental arthritis. Fifty fine afferent units (conduction velocities 0.8-15.3 meters/second) responded to passive movements of the knee joint. They were exposed to a torque meter-controlled, standardized stimulus protocol consisting of innocuous and noxious inward and outward rotations of the joint. This stimulus protocol of 50 seconds' duration was repeated every 5 minutes for 2-3 hours. Three commercially available HA preparations and a buffer solution, the solvent of these preparations, were injected intraarticularly after discharges resulting from 6 stimulus protocols were averaged and used as controls. Both in normal and in inflamed joints, the injection of Hyalgan did not reduce nerve impulse frequency of the evoked discharges. The injections of Orthovisc had no effect in normal joints, but produced a transient frequency reduction of the evoked discharge in inflamed joints. Synvisc significantly reduced (by an average of 50%) the impulse discharge in both normal and inflamed joints 50 minutes after injection, and this level of impulse discharge continued until the end of the recording period (120-130 minutes after injection). The buffer, which had elastoviscous properties substantially different from those of Hyalgan, Orthovisc, and Synvisc, had no such effect.

We conclude that the elastoviscous properties of HA solutions are determining factors in reducing pain-eliciting nerve activity both in normal and in inflamed rat joints.

Progressive pseudorheumatoid dysplasia (PPRD), a noninflammatory condition, needs to be differentiated diagnostically from juvenile rheumatoid arthritis (JRA). Demonstration of an unusually large and often early-appearing os trigonum helps distinguish PPRD from JRA. Ankle images in four children with PPRD were reviewed. The os trigonum was abnormally enlarged in all PPRD subjects and was shown to have appeared or fused earlier than normal in two subjects.

A large and early os trigonum ossification helps differentiate PPRD from JRA.

To define the performance of Minor Salivary Gland Biopsy (MSGB) and Dry Eye Tests (DET) to detect occult Sjögren Syndrome (SS) among Interstitial Pneumonia with Autoimmune Features (IPAF) patients. Prospective study. Interstitial Lung Disease (ILD) patients without defined Connective Tissue Disease and one or more IPAF classification domains or xerophthalmia were included. MSGB, Schirmer's test (ST) and Ocular Staining Score (OSS) were performed in a blinded manner by experienced specialists. MSGB with ≥1 focus of lymphocytes and Dry Eye Test (DET) with OSS ≥ 5 and/or ST < 5 s were considered positive. SS was diagnosed according to the ACR 2016 criteria. 534 patients on the first consult were screened. 67 patients had at least one IPAF criteria, 53 (79.1%) female, mean age (SD) 64.2 years old (10.8). Positive ST in 36 (53.7%), positive OSS in 29 (43.3%) and positive MSGB in 36 (53.7%) were found. Finally, 27 (40.3%) met SS diagnostic criteria. 25 (37.3%) and 18 (26.8%) of them did not report dry eyes or dry mouth, respectively. 53 (79.1%) had negative anti SSA/Ro, 57 (85.1%) had negative anti LA/SSB, 30 (44.7%) had negative ANA, and 52 (77.6%) had negative RF, respectively. A significantly higher proportion of ANA (+), anti-SSA/Ro (+), anti-SSB/La (+), positive DET and positive MSGB were found in the SS population.

A significant proportion of patients with occult SS were found in our study. MSGB and DET may be considered in the evaluation of IPAF patients.

Patients with knee pain as a result of osteoarthritis or degenerative meniscal injury may seek treatment through arthroscopic surgery. How effective arthroscopic debridement with or without meniscectomy is for relieving pain and improving patients' functional outcomes is uncertain. To conduct an evidence update of an evidence-based analysis (EBA) conducted in 2005 to determine if arthroscopic debridement for osteoarthritis of the knee or for meniscal injury from degenerative causes improve patient outcomes. A literature search was performed using Ovid MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, Embase, and all EBM databases, for studies published from January 1, 2005, to February 4, 2014. A systematic review of the literature was conducted, limited to randomized controlled trials (RCTs) that examined the effectiveness of arthroscopic debridement with or without meniscectomy. Quality assessment of the body of literature was conducted using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 8 RCTs were identified, 2 from the original EBA plus 6 that were published since that time. The studies included patients with a range of indications for treatment and severity of osteoarthritis. Moderate-quality evidence showed no statistically significant difference in pain or functional status between patients who received arthroscopic treatment versus placebo (e.g., sham surgery). Low-quality evidence showed no statistically significant difference in pain or functional status between patients who received arthroscopic treatment versus usual care (e.g., physical therapy). Heterogeneity across the study populations, interventions, and reported measures limited the ability to calculate a summary effect estimate; however, all studies demonstrated consistency in their findings.

The evidence does not show the superiority of arthroscopic debridement with or without meniscectomy in patients with osteoarthritis of the knee or with meniscal injury from degenerative causes.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and is caused by a multitude of well-studied disorders. However, the association between JIA and/or its treatment and sinonasal inflammatory disease (SNID) has never been studied. We therefore investigated this relationship to gain more insight into burdening pathologies connected to JIA. Retrospective evaluation. A retrospective evaluation according to the Lund-Mackay score of cone-beam computed tomography scans (CBCT) performed in 70 children affected by JIA and compared to CBCT scans of 124 healthy controls was conducted. The prevalence of sinonasal opacification and adenoid hypertrophy in patients affected with JIA was compared with findings obtained in unaffected children. JIA was significantly associated with SNID (P = .030). Of patients with JIA, 18.6% had SNID, whereas in children without JIA, only 8.1% had SNID. The odds ratio values were 5.38 (95% confidence interval [CI]: 1.90-15.26) for treated and 0.92 (95% CI: 0.18-4.83) for untreated JIA. No clear difference was found depending on the duration of JIA. No association was found between adenoid hypertrophy and SNID (P = .816). 3b.

Our data suggest that JIA patients, especially when undergoing immunosuppressive therapy, should be subjected to an ear, nose, and throat evaluation. A prospective study including clinical evaluation would be of the utmost importance to provide evidence on which to base comprehensive healthcare for these patients.

To investigate changes in illness perceptions in patients with osteoarthritis (OA) and the association of those changes with disability, and to determine the predictive value of illness perceptions in disability. Illness perceptions and disability were measured at baseline and after 6 years in 241 patients with OA at multiple sites (mean age 59.0 years, 82.2% women) using the revised Illness Perception Questionnaire (IPQ-R) and the Health Assessment Questionnaire (HAQ), respectively. Mean changes for each IPQ-R dimension were reported and related to progression of disability, defined as the highest quartile of HAQ score change. The predictive value of baseline illness perceptions in disability at 6 years (with high disability defined as the highest quartile of HAQ score) was assessed using logistic regression. Illness perceptions changed over time, and these changes were related to the progression of disability. Patients with progression of disability had an increase in symptoms attributed to OA, perceived consequences, perceived disease chronicity, negative emotions associated with OA and beliefs about immunity as causal factor, and a decrease in perceived control and understanding of OA compared with patients without progression of disability. Moreover, a higher number of symptoms attributed to OA, less perceived control, and more perceived consequences of OA at baseline were predictive of high disability after 6 years.

Illness perceptions in patients with OA changed over time, and these changes were related to outcome. Moreover, illness perceptions were predictive of disability. This may imply that interventions aimed at changing illness perceptions can contribute to better functional outcome.

Fibromyalgia syndrome (FMS) is characterized by uncertainty in diagnosis, treatment, and outcome. This study assessed the role of uncertainty of illness in relationship satisfaction in patients with FMS and osteoarthritis (OA). A total of 51 patients with FMS responded to self-report instruments assessing their uncertainty about their illness, functional ability, average pain, and relationship satisfaction. Their partners independently reported on their sense of caregiver burden and their supportiveness toward the patients. Thirty-two patients with OA and their partners served as a control group. Patients' functional ability and pain were related to partner caregiver burden. Partner caregiver burden was related to lower levels of partner supportiveness for the FMS dyads, but not for the OA dyads. Relationship satisfaction of patients with FMS was related to their higher levels of uncertainty of illness in interaction with their functional disability and pain and their partners' supportiveness. Under high levels of uncertainty of illness, low levels of partner supportiveness were related to lower patient relationship satisfaction, whereas low levels of uncertainty of illness were significant interacting variables in the OA sample.

The results suggest that uncertainty of illness is a prominent feature affecting patients with FMS in their relationships with their partners. Suggestions for additional research to explore the role of uncertainty of illness in social relationships are presented, and the therapeutic implications for patient/partner relationships are explored.

The aim of this study was to determine outcomes of total hip replacement (THR) with the Lemania cemented femoral stem. A total of 78 THR patients were followed and compared to 17 "fit", healthy, elderly and 72 "frail" elderly subjects without THR, using clinical outcome measures and a portable, in-field gait analysis device at five and ten years follow-up. Forty-one patients (53%), mean age 83.4 years, available at ten years follow-up, reported very good to excellent satisfaction. Mean Harris Hip and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were 81.2 and 10.5 points, respectively, with excellent radiological preservation of proximal femur bone stock. Spatial and temporal gait parameters were close to the fit group and better than the frail group.

Lemania THR demonstrated very good, stable clinical and radiological results at ten years in an older patient group, comparable to other cemented systems for primary THR. Gait analysis confirmed good walking performance in a real-life environment.

The pharmacology, pharmacokinetics, clinical efficacy, and safety of febuxostat are reviewed. Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase for the management of hyperuricemia in patients with gout. The ability of febuxostat to decrease serum uric acid production through selective inhibition of enzyme xanthine oxidase has been established in short-term Phase II and III clinical trials and long-term open-label studies. Clinical studies have revealed that febuxostat lowers serum uric acid levels more potently than allopurinol while having minimal effects on other enzymes associated with purine and pyrimide metabolism. The most frequent adverse events reported in clinical trials with febuxostat were liver function abnormalities, nausea, arthralgias, and rash. More cardiovascular thromboembolic events occurred in randomized trials in patients treated with febuxostat. Although a causal relationship has not been established, patients should be monitored for signs and symptoms of myocardial infarction and stroke. Febuxostat is available as 40- and 80-mg tablets. The recommended starting dosage is 40 mg orally once daily. If serum uric acid concentrations are not less than 6 mg/dL after two weeks, the dosage can be increased to 80 mg orally once daily. Dosage adjustments are not needed in elderly patients or patients with mild or moderate renal or hepatic impairment.

Febuxostat is efficacious as a second-line therapy in lowering serum uric acid levels in patients with gout. Febuxostat may be an alternative for patients with gout who are unable to take allopurinol due to hypersensitivity, intolerance, or lack of efficacy.

The risk of periodontitis (PD) is increased in the patient group of rheumatoid arthritis (RA). RA and PD also shared some pathological mechanism. The aim of this study is to investigate the risk of RA associated with PD exposure. This study identified 3 mutually exclusive cohorts using the 1999-2010 Taiwanese National Health Insurance Research Database (NHIRD) to investigate the association between PD and the risk of incident RA. All patients with PD in 2000 were identified from the database of all enrollees as the PD cohort. From the representative database of 1,000,000 enrollees randomly selected in 2010 (LHID2010), individuals without any periodontal disease (PO) during 1999-2010 were selected as the non-PO cohort. Individuals who were not included in the non-PO cohort and received dental scaling (DS) no more than two times per year during 1999-2010 were selected as the DS cohort from LHID2010. Using cox proportional regression analysis, hazard ratios (HRs) with 95% confidence intervals (Cis) were calculated to quantify the association between PD exposure and RA development. In the three-group comparison using the non-PO cohort as reference, we found that the risk of RA was higher in the PD and DS cohorts (HRs, 1.89 and 1.43; 95% CIs, 1.56-2.29 and 1.09-1.87, respectively). For comparisons between two cohorts, the PD cohort had a higher risk of RA than the non-PO and DS cohorts (HRs, 1.91 and 1.35; 95% CIs, 1.57-2.30 and 1.09-1.67, respectively).

PD was associated with an increased risk of RA development.

We aimed to determine the agreement between rheumatologist-judged inflammatory back pain (IBP) and criteria defining IBP in patients with psoriatic arthritis (PsA) and predictive value of IBP in identifying axial involvement in PsA. Using prospectively collected data, we investigated the agreement between rheumatologist judgement of IBP and IBP criteria (Calin, Rudwaleit and Assessment of Spondyloarthritis International Society) using the kappa coefficient. We also determined the sensitivity, specificity and likelihood ratios of the presence of back pain, rheumatologist-judged IBP and the three IBP criteria for detecting axial PsA (AxPsA). Finally, we compared the clinical and genetic markers in patients with PsA with axial radiological changes with and without back pain. 171 patients (52% male, mean age 46.6 years) were identified. Ninety-six (56.13%) patients reported chronic back pain. Sixty-five (38.01%) had IBP. 54 (32%) patients had evidence of radiological change in the spine. The agreement between rheumatologist judgement of IBP and IBP criteria was highest for the Calin criteria (0.70). Positive likelihood ratio for the presence of radiological axial involvement was highest for Rudwaleit criteria (2.17). No differences between patients with AxPsA with or without back pain were found, except for higher Bath Ankylosing Spondylitis Disease Activity Index and lower prevalence of human leucocyte antigen-B*38 in those with back pain.

Rheumatologist-judged IBP or the criteria for IBP developed for ankylosing spondylitis may not perform well when ascertaining axial involvement in PsA.

Upper limit of methotrexate (MTX) for patients with rheumatoid arthritis (RA) was recently increased from 8 to 16 mg/week in Japan. We therefore examined the effect of concomitant MTX dose on the efficacy of adalimumab (ADA) in clinical practice. Sixty-one consecutive RA patients treated with ADA were followed for minimum 52 weeks and retrospectively compared by MTX dose; patients receiving concomitant MTX of 10 mg/week or more (MTX ≥10 mg group) and <10 mg/week (MTX <10 mg group). Disease activity and remission were evaluated by the disease activity score 28 (DAS28) criteria. The MTX ≥10 mg group consistently showed better improvement in DAS28 and resulted in more patients (52.8%) with DAS28-remission compared with the MTX <10 mg group (26.1%). Multivariate analysis showed that MTX ≥10 mg had a significant effect on DAS28 remission with odds ratio of 5.12. ADA retention rate was 72.2% in MTX ≥10 mg group compared with 52.0% in MTX <10 mg group. Discontinuation of ADA due to adverse events were comparable in the MTX ≥10 mg and MTX <10 mg groups (11.1% vs. 12.0%).

These findings support the critical role of concomitant MTX in the efficacy of ADA, and recommend use of MTX ≥10 mg in Japanese RA patients.

A standardized process using data from the Occupational Information Network (O*NET) is applied to estimate the association between long-term aggregated occupational exposure and the risk of contracting chronic diseases later in life. We demonstrate this process by analyzing relationships between O*NET physical work demand ratings and arthritis onset over a 32-year period. The National Longitudinal Survey of Youth provided job histories and chronic disease data. Five O*NET job descriptors were used as surrogate measures of physical work demands. Logistic regression measured the association between those demands and arthritis occurrence. The risk of arthritis was significantly associated with handling and moving objects, kneeling, crouching, and crawling, bending and twisting, working in a cramped or awkward posture, and performing general physical activities.

This study demonstrates the utility of using O*NET job descriptors to estimate the aggregated long-term risks for osteoarthritis and other chronic diseases when no actual exposure data is available.

Although mortality among patients with rheumatoid arthritis (RA) is higher than in the general population, the relative contribution of comorbid diseases to this mortality difference is not known. This study was undertaken to evaluate the contribution of congestive heart failure (CHF) and ischemic heart disease (IHD), including myocardial infarction, to the excess mortality in patients with RA, compared with that in individuals without RA. We assembled a population-based inception cohort of individuals living in Rochester, Minnesota, in whom RA (defined according to the criteria of the American College of Rheumatology [formerly, the American Rheumatism Association]) first developed between 1955 and 1995, and an age- and sex-matched non-RA cohort. All subjects were followed up until either death, migration from the county, or until 2001. Detailed information from the complete medical records was collected. Statistical analyses included the person-years method, cumulative incidence, and Cox regression modeling. Attributable risk analysis techniques were used to estimate the number of RA deaths that would be prevented if the incidence of CHF was the same in patients with RA and non-RA subjects. The study population included 603 patients with RA and 603 subjects without RA. During followup, there was an excess of 123 deaths among patients with RA (345 RA deaths occurred, although only 222 such deaths were expected). The mortality rates among patients with RA and non-RA subjects were 39.0 and 29.2 per 1,000 person-years, respectively. There was a significantly higher cumulative incidence of CHF (but not IHD) in patients with RA compared with non-RA subjects (37.1% versus 27.7% at 30 years of followup, respectively; P < 0.001). The risk of death associated with either CHF or IHD was not significantly different between patients with RA and non-RA subjects. If the risk of developing CHF was the same in patients with RA and individuals without RA, the overall mortality rate difference between RA and non-RA hypothetically would be reduced from 9.8 to 8.0 excess deaths per 1,000 person-years; that is, 16 (13%) of the 123 excess deaths could be prevented.

CHF, rather than IHD, appears to be an important contributor to the excess overall mortality among patients with RA. CHF contributes to this excess mortality primarily through the increased incidence of CHF in RA, rather than increased mortality associated with CHF in patients with RA compared with non-RA subjects. Eliminating the excess risk of CHF in patients with RA could significantly improve their survival.

To compare physical disability, mental health, fatigue and health-related quality of life (HRQoL) across juvenile idiopathic arthritis (JIA) categories in adulthood and between JIA and adult-onset rheumatic diseases. Cross-sectional analysis nested in a cohort of adult patients with JIA registered in the Rheumatic Diseases Portuguese Register (Reuma.pt). Physical disability (Health Assessment Questionnaire-Disability Index), mental health symptoms (Hospital Anxiety and Depression Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F)) and HRQoL (EuroQol-5D (EQ5D) and Short Form (SF-36)) were compared across JIA categories. Patients with polyarticular JIA and enthesis-related arthritis (ERA) JIA were compared respectively to patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA), matched for gender and age, adjusted for disease duration and activity. 585 adult patients with JIA were included. Comparison across JIA categories showed that persistent oligoarthritis and patients with ERA reported a higher score in EQ5D and SF-36 physical component when compared with other JIA categories.Polyarticular JIA reported less disability and fatigue than patients with RA (median Health Assessment Questionnaire of 0.25 vs 0.63; p<0.001 and median FACIT-F score 42 vs 40 ; p=0.041). Polyarticular JIA had also better scores on EQ5D and all domains of SF-36, than patients with RA. Patients with ERA reported less depression and anxiety symptoms (0% vs 14.8%; p=0.003% and 9% vs 21.3%; p=0.002) and less fatigue symptoms (45 vs 41; p=0.01) than patients with SpA.

Persistent oligoarticular JIA and ERA are the JIA categories in adulthood with better HRQoL. Overall, adult polyarticular and patients with ERA JIA have lower functional impairment and better quality-of-life than patients with RA and SpA.

To determine in a prospective population-based cohort study relationships between different measures of body mass and the incidence of severe knee and hip osteoarthritis defined as arthroplasty of knee or hip due to osteoarthritis. Body mass index (BMI), waist circumference, waist-hip ratio (WHR), weight and percentage of body fat (BF%) were measured at baseline in 11,026 men and 16,934 women from the general population. The incidence of osteoarthritis over 11 years was monitored by linkage with the Swedish hospital discharge register. 471 individuals had knee osteoarthritis and 551 had hip osteoarthritis. After adjustment for age, sex, smoking and physical activity, the relative risks (RR) of knee osteoarthritis (fourth vs first quartile) were 8.1 (95% CI 5.3 to 12.4) for BMI, 6.7 (4.5 to 9.9) for waist circumference, 6.5 (4.6 to 9.43) for weight, 3.6 (2.6 to 5.0) for BF% and 2.2 (1.7 to 3.0) for WHR. Corresponding RR for hip osteoarthritis were 2.6 (2.0 to 3.4) for BMI, 3.0 (2.3 to 4.0) for weight, 2.5 (1.9 to 3.3) for waist, 1.3 (0.99 to 1.6) for WHR and 1.5 (1.2 to 2.0) for BF%.

All measures of overweight were associated with the incidence of knee osteoarthritis, with the strongest relative risk gradient observed for BMI. The incidence of hip osteoarthritis showed smaller but significant differences between normal weight and obesity. Our results support a major link between overweight and biomechanics in increasing the risk of knee and hip osteoarthritis in men and women.

Chloroquine is a drug that is widely used in rheumatology and occasionally prescribed in dermatology. From a neurotoxicological point of view, chloroquine can have effects on the peripheral nerves, muscles, neuromuscular junctions and the central nervous system. In this study we analyse the clinical, neurophysiological and anatomopathological findings in two patients with chloroquine induced neuromyopathy, which took the form of a polyradiculoneuropathy. Case 1: a 75 year old female with rheumatoid arthritis treated with daily doses of 250 mg of chloroquine for four years. The patient visited because of several months history of predominantly proximal progressive tetraparesis with areflexia. Analytical tests and lumbar puncture were normal. Electromyogram (EMG): proximal myopathic and distal neuropathic patterns. Muscular biopsy: vacuolar myopathy with accumulations of phagolysosomes, lipids, lipofuscin, myelinic curvilinear bodies. Case 2: a 74 year old female with arthropathy treated with daily doses of 250 mg of chloroquine for nine months. The patient presented a progressive proximal paraparesis with generalised areflexia. Analytical tests and lumbar puncture were normal. EMG: mixed sensory motor polyneuropathy, myogenic pattern with high frequency discharges in the iliac psoas and a neurogenic pattern in the distal muscles. Muscular biopsy: vacuolar myopathy suggesting a myopathy due to chloroquine. After stopping treatment with this drug the patients progressed favourably.

Chloroquine can induce a clinical pattern that suggests a polyradiculoneuropathy. It is important to establish a history of having taken this drug. If this is indeed the case, then an electromyographic study of the most proximal muscles should be performed in order to detect a myogenic pattern and the same exploration should be applied to the distal muscles to reveal a neurogenic pattern. The final diagnosis will be established by muscular biopsy.

To investigate potential differences in phenotype and behaviour of immature (iDC) and mature dendritic cells (mDC) from patients with RA and healthy subjects. iDC and mDC were derived from blood monocytes of patients with RA and healthy controls following standardised protocols. FACS was used to analyse expression of FcgammaRI, II, and III and molecules to characterise DC. Discrimination between FcgammaRIIa and FcgammaRIIb was achieved by RT-PCR. Immunohistochemistry was performed on synovial biopsy specimens of three patients with RA and three healthy controls. TNFalpha production by iDC and mDC upon FcgammaR dependent stimulation was compared between patients with RA and controls by ELISA. iDC from patients with active RA but not from patients with inactive RA or healthy controls markedly up regulated FcgammaRII. mDC from patients with active RA also lacked the physiological down regulation of FcgammaRII that occurs upon maturation in both control groups. RT-PCR analysis confirmed the increased expression of FcgammaRII in RA-especially marked for FcgammaRIIb. FcgammaR dependent stimulation of DC using antigen-IgG immune complexes (IC) significantly increased TNFalpha production by DC from healthy subjects, but significantly decreased TNFalpha by DC from patients with RA. Overlapping expression patterns between FcgammaRII and DC-LAMP in the synovial tissue of patients with RA imply that in vivo, also, mature DC express increased levels of FcgammaRIIb.

The presence and altered characteristics of DC during active RA suggest that DC help to modulate autoimmunity in RA. Further studies should elucidate the role of local factors in altering the function of DC in RA and in increasing expression of FcgammaRII.

Mesenchymal stem cells (MSCs) have the ability to differentiate into different types of cells of the mesenchymal lineage, such as osteocytes, chondrocytes, and adipocytes. It is also known that under inflammatory stimuli or in the appropriate experimental conditions, they can also act as regulators of inflammation. Thus, in addition to their regenerating potential, their interest has been extended to their possible use in cell therapy strategies for treatment of immune disorders. To analyze, by RNA-seq analysis, the transcriptome profiling of allogenic MSCs under RA lymphocyte activation. We identified the differentially expressed genes in bone marrow mesenchymal stem cells after exposure to an inflammatory environment. The transcriptome profiling was evaluated by means of the precise measurement of transcripts provided by the RNA-Seq technology. Our results evidenced the existence of blocking of both regenerative (differentiation) and immunomodulatory phenotypes under inflammatory conditions characterized by an upregulation of genes involved in immune processes and a simultaneous downregulation of genes mainly involved in regenerative or cell differentiation functions.

We conclude that the two main functions of MSCs (immunomodulation and differentiation) are blocked, at least while the inflammation is being resolved. Inflammation, at least partially mediated by gamma-interferon, drives MSCs to a cellular distress adopting a defensive state. This knowledge could be of particular interest in cases where the damage to be repaired has an important immune-mediated component.

Histone H3 lysine 4 trimethylation(H3K4me3) is an important epigenetic modification and associated with active transcription in multiple organisms. In systemic lupus erythematosus (SLE), global and gene-specific DNA methylation changes have been demonstrated to occur. However, to date, our knowledge about the alterations in the histone lysine methylation in SLE is known little. This study aimed to investigate the variations in H3K4me3 in CpG island regions in the peripheral blood mononuclear cells (PBMCs) of SLE patients and the controls, including rheumatoid arthritis patients and healthy subjects. PBMCs were isolated by density gradient centrifugation from 10 active SLE patients, 7 inactive SLE patients, 8 rheumatoid arthritis patients and 8 healthy volunteers. H3K4me3 variations were analysed by using chromatin immunoprecipitation linked to the microarray (ChIP-chip) approach. ChIP-real time PCR was used to validate the microrray results. Expression analysis by qRT-PCR revealed correlations between mRNA and H3K4me3 levels. In addition, DNA methylation status was also further analysed by Methyl-DNA immunoprecipitation-quantitative PCR. Many key relevant candidate genes (such as PTPN22, LRP1B etc.) displaying differential changes in H3K4me3 in SLE versus controls (rheumatoid arthritis patients, healthy subjects) were identified. The results of ChIP-real time PCR were coincided well with those of microarray. Aberrant DNA methylation can also be found on selected randomly positive genes (WDR5, SLC24A3, PTPN22, LRP1B METT10D and CDH13).

Our results first indicate that there are significant alterations of H3K4me3 in PBMCs of SLE patients, and H3K4me3 alterations are associated with the pathogenesis of the SLE. Such novel findings show the significance of H3K4me3 as a potential biomarker or promising target for epigenetic-based lupus therapies.

Osteoarthritis (OA) is associated with destruction of type II collagen-rich hyaline articular cartilage. We hypothesized that classical interstitial collagenases cleave collagen type II, leading to the increased expression of the 3/4 native type II collagen fragment (COL2-3/4C) and the corresponding denatured type II collagen fragment (COL2-3/4M), which could correlate with different cartilage destruction grades. In addition, we assessed whether these fragments could be measured in joint fluid and serve as diagnostic markers. Cartilage specimens were obtained from the femoral heads of hip joints from total hip replacement operations. Articular gliding surfaces of the cartilage were categorized into normal (G0), fibrillated (G1), superficiallyfissured (G2) and deeplyfissured (fissures that reach to the subchondral bone) (G3). A histological scoring of the cartilage was also used. COL2-3/4C and COL2-3/4M were detected by immunohistochemical staining. Dot blotting was used to detect these fragments in joint fluid. COL2-3/4C and COL2-3/4M were found in the perichondrocyte matrix around lacunae. Such COL2-3/4C (p < 0.05) and COL2-3/4M (p < 0.05) immunoreactivity was significantly increased in G3 and G2 compared to GO and G1. A positive correlation (n = 35, Spearman rank correlation) was observed between the histological score and the percentage of COL2-3/4C positive lacunae (r = 0.43, p = 0.01) and COL2- 3/4M positive lacunae (r = 0.53, p = 0.001). All 7/7 joint fluid samples contained COL2-3/4C in dot blots whereas only 4/7 contained COL2-3/4M.

Collagenase-cleaved collagen--both native and denatured--increases as the severity of OA increases, assessed using a macroscopic clinical and microscopic histological grading system. Collagen degradation was always most apparent around chondrocytes. Furthermore, the native COL2-3/4C fragment has potential as a joint fluid marker for OA.

To evaluate systemic inflammatory biomarkers in symptomatic knee osteoarthritis (OA) and their association with radiographic and biochemical OA progression. Lipopolysaccharide (LPS) binding protein (LBP), soluble Toll-like receptor 4 (sTLR4) and interleukin 6 (IL-6) were measured in plasma of 431 knee OA patients from the doxycycline (DOXY) trial at baseline and 18 months. Plasma lipopolysaccharide and lipopolysaccharide binding protein (LBP) were also measured at 12 months. As a biochemical indicator of disease activity and OA progression, urinary (u) C-telopeptide of Type II collagen (uCTX-II) was measured in samples collected at baseline and 18 months. Change over 16 months in radiographic tibiofemoral joint space width (JSW in mm) and joint space narrowing (JSN≥0.5 mm) were used to indicate radiographic OA progression. Change over 18 months for uCTX-II was used as a secondary outcome. Both univariate and multivariable regression analyses were performed to test the association between Z-score transformed biomarkers and outcomes. Baseline LBP and time-integrated concentration (TIC) of LBP over 12 and 18 months were associated with worsening joint space width (JSW) (parameter estimates: -0.1 to -0.07) and JSN (OR: 1.32 to 1.42) adjusting for treatment group, age, body mass index (BMI) and corresponding baseline radiographic measures. Baseline sTLR4 and TIC over 18 months were associated with change in uCTX-II over 18 months (adjusted parameter estimates: 0.0017 to 0.0020). Results were not modified by treatment with doxycycline.

Plasma LBP and sTLR4 were associated with knee OA progression over 16-18 months. These results lend further support for a role of systemic low-grade inflammation in the pathogenesis of knee OA progression.

Coronal deformity correction with total knee arthroplasty (TKA) is an important feature in the treatment of osteoarthritis (OA). The hypothesis of this study was that bone morphology would be different in varus and valgus deformity, both before osteoarthritis development as well as during and after the disease process of OA. Retrospective study with measurements on preoperative and postoperative full leg standing radiographs of 96 patients who underwent TKA. The included patients were selected for this study because they had an OA knee on one side and a non-arthritic knee on the contralateral side presenting the same type of alignment as the to-be-operated knee (varus or valgus alignment on both sides). The control group of 46 subjects was a group of patients with neutral mechanical alignment who presented for ligamentous problems. A single observer measured mechanical alignment, anatomical alignment, anatomical-mechanical femoral angle and intra-articular bone morphology parameters with an accuracy of 1°. Varus OA group has less distal femoral valgus (mLDFA 89°) than control group (87°) and valgus OA group (mLDFA 85°). Varus OA group has same varus obliquity as control group (MPTA 87°) but more than valgus OA group (MPTA 90°). Joint Line Congruency Angle (JLCA) is 3°open on lateral side in varus and medially open in valgus OA group (2°). The non-arthritic valgus group presents a constitutional mechanical valgus of 184° Hip-Knee-Ankle (HKA) angle. Varus deformity in OA as measured with an HKA angle (HKA) <177° is a combination of distal femoral wear, tibial varus obliquity and lateral joint line opening. Valgus deformity in OA with an HKA > 183° is a combination of femoral distal joint line obliquity and wear combined with medial opening due to medial collateral ligament stretching. The clinical importance of bone morphotype analysis is that it shows the intra-articular potential of alignment correction when mechanical axis cuts are performed. Level IV study.

Bone morphology in varus and valgus deformity is different before and after osteoarthritis. Perpendicular cuts to mechanical axes do not necessarily lead to neutral mechanical axis. Constitutional mechanical valgus was observed as 184° HKA angle before the development of OA.

Hematuria is considered a marker of active renal disease in ANCA-associated glomerulonephritis (ANCA-GN) with induction immunosuppression often continued until hematuria has resolved. We aim to determine whether longer hematuria duration is associated with lower estimated glomerular filtration rate (eGFR) at 1 year. We conducted a retrospective study of 55 patients with biopsy-proven ANCA-GN. Linear regression models were constructed to determine predictors of eGFR at 1 year. The primary exposure was hematuria (>5 rbc/hpf) duration, defined as <90 days vs. ≥ 90 days following renal biopsy. Covariates included age, gender, ANCA type, baseline eGFR, and baseline proteinuria. Mean age at diagnosis was 58 years (53% male, 80% Caucasian, 38% PR3-ANCA, and 45% MPO-ANCA). At baseline, all patients had hematuria, 95% had proteinuria, and mean serum creatinine was 3.1 [standard deviation (SD) = 2.3]mg/dL. Overall, 93% were treated with steroids in combination with either cyclophosphamide or rituximab. Mean hematuria duration was 92 (SD = 77) days with 34 (62%) patients having hematuria resolution within 90 days. Older age and lower baseline eGFR were associated with lower eGFR at 1 year (p = 0.03 and p < 0.001, respectively). Hematuria resolution (<90 days vs. ≥ 90 days) was not predictive of eGFR at 1 year (p = 0.93).

In ANCA-GN, hematuria duration does not predict eGFR at 1 year. Our findings provide support that among individuals who are otherwise considered to be in clinical remission, the persistence of hematuria should not delay transition from induction to maintenance immunosuppression.

Surface replacement of the hip is aimed especially at active patients, and it seems to achieve optimal functional results in a short time if associated with a tailored rehabilitation protocol. To assess the functional outcome in a group of active patients after hip resurfacing. Clinical measurement and controlled laboratory study in a case series. Gait-analysis laboratory. 8 patients and a control group of 10 subjects. Patients treated with Birmingham hip-resurfacing system and a tailored rehabilitation protocol Clinical assessment (Harris Hip Score [HHS]) and instrumented gait analysis including muscular electromyographic assessment. Patients were assessed preoperatively and at 3 and 9 mo follow-up after surgery. HHS showed a significant increase from the baseline to 3- (P = .008) and 9-month (P = .014) follow-up; 5 patients returned to sport. Gait pattern in the presented case series of patients improved substantially 3 mo postoperatively, and minimal further changes were present 9 months postoperatively. Residual abnormalities of time-distance and hip-kinematics parameters were consistent with a slow gait. A complete restoration of the muscle-activation pattern during gait was achieved.

Hip resurfacing associated with a rehabilitation protocol based on the characteristics of the implant provides excellent clinical and functional outcome, especially for very active patients.

Osteoarthritis is the leading cause of disability worldwide; cartilage degeneration and defects are the central features. Significant progress in tissue engineering holds promise to regenerate damaged cartilage tissue. However, a formidable challenge is to develop a 3-dimensional (3D) tissue construct that can regulate local immune environment to facilitate the intrinsic osteochondral regeneration. To evaluate efficacy of a 3D-printed decellularized cartilage extracellular matrix (ECM) and polyethylene glycol diacrylate (PEGDA) integrated novel scaffold (PEGDA/ECM) together with the natural compound honokiol (Hon) for regenerating osteochondral defect. Controlled laboratory study. We used a stereolithography-based 3D printer for PEGDA/ECM bioprinting. A total of 36 Sprague-Dawley rats with cylindrical osteochondral defect in the trochlear groove of the femur were randomly assigned into 3 different treatments: no scaffold implantation (Defect group), 3D printed PEGDA/ECM scaffold alone (PEGDA/ECM group), or Hon suspended in a 3D-printed PEGDA/ECM scaffold (PEGDA/ECM/Hon group). 12 rats that underwent only medial parapatellar incision surgery were used as normal controls. The femur specimens were postoperatively harvested at 4 and 8 weeks for gross, micro-CT, and histological evaluations. The efficacy of PEGDA/ECM/Hon scaffold on the release of proinflammatory cytokines from the macrophages stimulated by lipopolysaccharide (LPS) was evaluated in-vitro. In vitro results determined that PEGDA/ECM/Hon scaffold could suppress the release of proinflammatory cytokines from macrophages that were stimulated by LPS. Macroscopic images showed that the PEGDA/ECM/Hon group had significantly higher ICRS scoring than that of defect and PEGDA/ECM groups. Micro-CT evaluation demonstrated that much more bony tissue was formed in the defect sites implanted with the PEGDA/ECM scaffold or PEGDA/ECM/Hon scaffold compared with the untreated defects. Histological analysis showed that the PEGDA/ECM/Hon group had a significant enhancement in osteochondral regeneration at 4 and 8 weeks after surgery in comparison with the ECM/PEGDA or defect group.

This study demonstrated that 3D printing of PEGDA/ECM hydrogel incorporating the anti-inflammatory phytomolecule honokiol could provide a promising scaffold for osteochondral defect repair.

To identify long noncoding RNAs (lncRNAs), including long intergenic noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes, associated with the inflammatory response in human primary osteoarthritis (OA) chondrocytes and to explore their expression and function in OA. OA cartilage was obtained from patients with hip or knee OA following joint replacement surgery. Non-OA cartilage was obtained from postmortem donors and patients with fracture of the neck of the femur. Primary OA chondrocytes were isolated by collagenase digestion. LncRNA expression analysis was performed by RNA sequencing (RNAseq) and quantitative reverse transcriptase-polymerase chain reaction. Modulation of lncRNA chondrocyte expression was achieved using LNA longRNA GapmeRs (Exiqon). Cytokine production was measured with Luminex. RNAseq identified 983 lncRNAs in primary human hip OA chondrocytes, 183 of which had not previously been identified. Following interleukin-1β (IL-1β) stimulation, we identified 125 lincRNAs that were differentially expressed. The lincRNA p50-associated cyclooxygenase 2-extragenic RNA (PACER) and 2 novel chondrocyte inflammation-associated lincRNAs (CILinc01 and CILinc02) were differentially expressed in both knee and hip OA cartilage compared to non-OA cartilage. In primary OA chondrocytes, these lincRNAs were rapidly and transiently induced in response to multiple proinflammatory cytokines. Knockdown of CILinc01 and CILinc02 expression in human chondrocytes significantly enhanced the IL-1-stimulated secretion of proinflammatory cytokines.

The inflammatory response in human OA chondrocytes is associated with widespread changes in the profile of lncRNAs, including PACER, CILinc01, and CILinc02. Differential expression of CILinc01 and CIinc02 in hip and knee OA cartilage, and their role in modulating cytokine production during the chondrocyte inflammatory response, suggest that they may play an important role in mediating inflammation-driven cartilage degeneration in OA.

To evaluate the efficacy and safety of leflunomide (LEF) as induction treatment in a series of Takayasu arteritis (TA) patients based on a Chinese cohort. Fifty-six patients from the East China TA cohort treated with LEF for at least 3 months were enrolled in this study, including the naïve LEF treatment patients (n = 41) and the cyclophosphamide (CYC)-resistant LEF treatment patients (n = 15). Data in clinical features, NIH score and angiography were collected. Response to treatment was assessed by rates of complete remission (CR) and partial remission (PR) and response rate (RR) after 6 and 12 months of treatment. The total CR rate and RR were 67.86% and 83.93% after 6 months, and 55.36% and 69.64% after 12 months, respectively. ESR and CRP levels and NIH scores decreased significantly after 12 months of LEF treatment (P < 0.05). Patients of CYC-resistant switched to LEF and reached the CR of 60.00% (9/15) and RR of 86.67% (13/15) after 6 months, and 73.33% (11/15) and 80.00% (12/15) after 12 months, respectively, with decrease in NIH scores (all P < 0.05). After following up for 14.44 ± 6.86 months, 48 patients (85.71%) continued LEF treatment with good tolerance. One patient died from progression of TA after 2 months, 2 patients relapsed, and 3 patients with side effects were switched to other immunosuppressive agents.

LEF led to a quick induction and sustained remission of TA, especially in refractory cases, and therefore, should be considered as an alternative treatment for TA.

To evaluate the efficacy and safety of two different targeted approaches-abatacept or tocilizumab-after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies of interleukin 6 (IL-6) and B cells in patients receiving rituximab therapy. Consecutive series of patients who had discontinued rituximab therapy owing to inefficacy or toxicity were treated with abatacept (n=16) or tocilizumab (n=35). Clinical response and reasons for discontinuation were evaluated. Serial blood and synovial samples were obtained from a group of 57 and 25 rituximab-treated patients, respectively, and were analysed for B cells and IL-6 using flow cytometry, immunohistochemistry and quantitative real-time PCR. In the abatacept group, mean (SEM) Disease Activity Score in 28 joints calculated using the erythrocyte sedimentation rate (DAS28-ESR) reduced from 5.69 (0.42) at baseline to 4.94 (0.44) at 6 months (p=0.12). In the tocilizumab group: mean (SEM) DAS28- ESR reduced from 5.75 (0.21) at baseline to 3.28 (0.26) at 6 months (p<0.001). This was paralleled by a significant swollen joint count reduction in the tocilizumab (5.47 (0.70) to 2.70 (0.61), p=0.033), but not abatacept (6.23 (1.3) to 4.15 (1.2), p=0.26), group. In the synovium, despite complete depletion of B cells in 19/22 patients, IL-6 mRNA expression was not significantly reduced after rituximab. Blood B cell numbers remained low 12 months after rituximab. Serum IL-6 was raised at baseline and significantly higher in rituximab clinical non-responders (p=0.035) than responders. A significant reduction in serum IL-6 was seen in rituximab clinical responders (p=0.005) but not in non-responders (p=0.237).

In patients with rheumatoid arthritis for whom rituximab therapy failed despite adequate B cell depletion, IL-6-directed therapy might be a more logical and effective treatment choice than T cell costimulation blockade. Further controlled studies investigating other possible mechanisms are needed to validate these initial findings.

Cardiac involvement, a common and often fatal complication of systemic sclerosis (SSc), is currently detected by standard echocardiography enhanced by tissue Doppler echocardiography (TDE). The performance of the biomarker of cardiovascular disease, N-terminal pro-brain natriuretic peptide (NT-proBNP), in the detection of cardiac involvement by SSc was examined. A total of 69 consecutive patients with SSc (mean (SD) age 56 (13) years, 56 women) were prospectively studied with standard echocardiography and TDE measurements of longitudinal mitral and tricuspid annular velocities. Plasma NT-proBNP was measured in all patients. Overall, 18 patients had manifestations of cardiac involvement, of whom 7 had depressed left ventricular and 8 depressed right ventricular myocardial contractility, and 8 had elevated systolic pulmonary arterial pressure. Patients with reduced contractility had increased mean (SD) NT-proBNP (704 (878) pg/ml versus 118 (112) pg/ml in patients with normal myocardial contractility, p<0.001). Similarly, NT-proBNP was higher in patients with (607 (758) pg/ml) than in patients without (96 (78) pg/ml) manifestations of overall cardiac involvement (p<0.001). Receiver operating characteristic analysis showed NT-proBNP reliably detected depressed myocardial contractility and overall cardiac involvement (area under the curve 0.905 (95% CI 0.814 to 0.996) and 0.935 (95% CI 0.871 to 0.996), respectively). Considering patients with SSc with normal echocardiography and TDE as controls, and using a 125 pg/ml cut-off concentration, sensitivity and specificity were 92% and 71% in the detection of depressed myocardial contractility, and 94% and 78% for overall cardiac involvement.

NT-proBNP reliably detected the presence of cardiac involvement and appears to be a very useful marker to risk stratify patients presenting with SSc.

To estimate the excess healthcare use and work disability attributable to knee osteoarthritis (OA) in the first 5 years following diagnosis. Among individual aged 40-80 years who resided in Skåne on 31 The estimated 5-year incremental effects of knee OA per-patient were 16.8 (95% CI: 15.8, 17.7) healthcare consultations, 0.7 (0.4, 1.1) inpatient days, 420 (372, 490) defined daily dose of prescribed medications, and 21.8 (15.2, 30.0) net disability days. Primary care consultations constituted about 73% of the excess healthcare consultations. Most of these incremental effects occurred in the first year after diagnosis. Better survival in the knee OA group accounted for 0.7 (95% CI: 0.5, 0.8) and 1.4 (0.7, 2.6) of the excess healthcare consultations and net disability days, respectively. Both estimated total and incremental resources use were generally greater for women than men with knee OA.

Knee OA was associated with considerable excess healthcare use and work disability independent of pre-diagnosis resources use, comorbidity, and sociodemographic characteristics.

To investigate the association between features of ultrasound-detected inflammation and development of erosive disease in patients with hand osteoarthritis (OA) over 2.3 years of followup. The study group comprised 56 consecutive patients with hand OA (mean age 61 years, 86% female) fulfilling the American College of Rheumatology criteria. Effusion, synovial thickening, and power Doppler signal in all interphalangeal (IP) joints were assessed with ultrasonography, using standardized methods, at baseline and followup. Radiographs were scored at both time points for osteophytes/joint space narrowing using the Osteoarthritis Research Society International method and for erosive disease (E phase [erosive] and R phase [remodeling]) using the method described by Verbruggen and Veys. Erosion development was defined as progression from N phase (normal) to E phase or R phase. Joints that were in E phase or R phase at baseline were excluded. Associations were analyzed using generalized estimating equations with adjustment for age, sex, body mass index, and baseline structural abnormalities. At baseline, 51 IP joints (in 18 patients) and at followup 89 IP joints (in 26 patients) had erosions; thus, erosions developed in 38 IP joints. Moderate/severe synovial thickening and a power Doppler signal at baseline were associated with erosion development (adjusted odds ratio [OR] 8.8, 95% confidence interval [95% CI] 2.4-32.3 and OR 7.1, 95% CI 1.9-26.9, respectively). Persistent inflammation was particularly associated with the development of erosions.

Ultrasound-detected features of inflammation are associated with the development of erosions in patients with hand OA, suggesting that inflammation plays a role in the pathogenesis of hand OA and could be a therapeutic target.

Fibromyalgia (FM) affects up to 6% of U.S. adults, resulting in a significant burden on the health care system and poor quality of life for patients. Duloxetine, pregabalin, and milnacipran are approved for management of FM; however, consensus is lacking regarding optimal therapy. Patients with FM taking approved medications often do not experience meaningful symptom relief, and many experience intolerable adverse events. To assess treatment patterns associated with available and commonly used medications for the management of FM using U.S. health insurance claims. This retrospective analysis used the MarketScan claims database to identify adults with a first diagnosis of FM (ICD-9-CM code 729.1) between 2009 and 2011 with continuous health plan enrollment for 12 months pre- and post-index. Medications of interest were pregabalin, gabapentin, duloxetine, milnacipran, cyclobenzaprine, and tramadol. These are 6 of the 8 medications recommended by the American College of Rheumatology (ACR) for treating FM; the other 2 (amitriptyline and venlafaxine) were only included in some initial assessments. The Charlson Comorbidity Index (CCI) was used to assess overall comorbidity burden. Endpoints included proportion of patients treated within 1 year after first diagnosis; initial treatment pattern; adherence over the first-year follow-up period for the medications of interest; and discontinuation, switching, and combination therapy patterns among pain medications of interest at different time points. Proportion of days covered (PDC; defined as number of days in the period when the patient had drug supply divided by the number of days in the period) was used to define adherence, which was categorized as low (PDC < 50%), medium (PDC 50% to < 80%), or high (PDC ≥ 80%). The time to discontinuation (defined as the first drug supply gap ≥ 90 days) was estimated using Kaplan-Meier analysis. Overall, 240,144 patients met the inclusion criteria. Patients were predominantly women (68%), had preferred provider organization insurance coverage (68%), and had a CCI score < 1 at baseline (69%). Only 31% (n = 74,738) initiated a treatment with a prescription medication listed in the ACR guidelines, and many patients received less than the recommended dose. Most (n = 70,919) patients initially received monotherapy with one of the 8 prescription medications. Of those who started with ≥ 2 medications (n = 3,819), cyclobenzaprine plus tramadol was the most frequent combination. Adherence was suboptimal for all 6 medications of interest. Duloxetine had the highest mean PDC (59%); for all other agents, mean PDC was < 50%. With the exception of duloxetine, discontinuation rates at 6 months were > 50% for all agents. Alterations in therapy were common. Among patients who discontinued their initial treatment of duloxetine, pregabalin, or milnacipran, approximately one-third had switched treatments within 90 days after their first prescription. For those who maintained their initial treatment agent, approximately 50% of patients added a second pain medication within 1 year of treatment initiation.

The evidence suggests that patients with FM often do not receive 1 of the prescription medications recommended by ACR guidelines, and those who do are commonly prescribed lower-than-recommended doses, potentially resulting in poor effectiveness and tolerability. Discontinuation, switching, and addition of new pain medications are common, which may indicate low levels of satisfaction with initial treatment. New therapies with improved effectiveness and better tolerability are urgently needed for patients with FM.

To measure interleukin 6 (IL-6) salivary and serum concentrations in primary Sjögren's syndrome (SS), to correlate these data with the clinical presentation in patients, and to determine if salivary IL-6 is reflective of local exocrine involvement or of the underlying autoimmune disorder. Thirty-one patients with primary SS, 15 with primary biliary cirrhosis (PBC), and 14 healthy controls were studied. Parotid secretion was stimulated with 2% citric acid and collected using a Carlson-Crittenden collector. Concentrations of salivary and serum IL-6 were determined using a high sensitivity ELISA. Serologic autoimmune disease markers and salivary functional and histopathologic disease markers in the patients with SS were correlated with salivary and serum IL-6 levels. Mean serum IL-6 concentrations were elevated in both patient groups (SS = 3.05 pg/ml, PBC = 3.07 pg/ml, healthy subjects = 0.843 pg/ml). Mean stimulated salivary IL-6 concentrations were elevated only in the patients with SS (16.21 pg/ml) compared to the PBC (1.07 pg/ml) and healthy subjects (0.769 pg/ml). No correlation was found between serum and salivary IL-6 concentrations for any group. Positive correlations were found between salivary IL-6 concentrations and serum IgG concentrations and between salivary IL-6 and erythrocyte sedimentation rate. Higher IL-6 concentrations were associated with increased disease activity.

Salivary IL-6 concentration is elevated in SS compared to healthy subjects and patients with another systemic autoimmune disease without salivary gland involvement. Elevated salivary IL-6 concentrations in SS are reflective of local exocrine involvement and may serve as a useful monitor of disease activity.

The dual-energy CT (DECT) algorithm for urate detection is feasible only if hyperdense deposits are present. Based on our experience, around half of the performed DECT examinations show no such deposits and thus were useless for this indication. Our diagnostic accuracy study investigates whether conventional radiographs can serve as gatekeeper test prior to DECT for reliable exclusion of such radiopaque deposits. In this retrospective study, 77 clinically indicated DECT examinations of the hand (n = 29), foot (n = 36) and ankle (n = 12) of 55 patients (13 female, mean age 62±15 years) with suspected gouty arthritis were included. Two blinded readers independently evaluated DECT, gray-scale CT images (reference standard) and corresponding standardized radiographs for the presence/location of dense soft tissue deposits. Interreader agreement for detection of soft tissue deposits with DECT and radiographs was excellent (DECT: both readers, κ = 1; radiographs: both readers, κ = 0.94). DECT showed soft tissue deposits in 54/77 DECT (70%) scans. 30/54 scans (56%) showed deposits on the corresponding radiographs, while in 24 scans (44%) no deposits were seen on radiographs. Test performance of radiographs for soft tissue deposit detection: sensitivity 56%, specificity 100%, PPV 100%, NPV 48.9%, and accuracy 69%. Low density of the deposits was the main reasons for false-negative radiographs (19 cases, 79%), followed by superimposition of deposits by osseous structures (5 cases, 21%).

Conventional radiographs of the hand, foot and ankle cannot serve as a gatekeeper test for reliable exclusion of radiopaque soft tissue deposits prior to DECT.

This review stated the possible application of the active components of licorice, glycyrrhizin (GL) and glycyrrhetinic acid (GA), in rheumatoid arthritis (RA) treatment based on the cyclooxygenase (COX)-2/thromboxane A2 (TxA2) pathway. The extensive literature from inception to July 2015 was searched in PubMed central, and relevant reports were identified according to the purpose of this study. The active components of licorice GL and GA exert the potential anti-inflammatory effects through, at least in part, suppressing COX-2 and its downstream product TxA2. Additionally, the COX-2/TxA2 pathway, an auto-regulatory feedback loop, has been recently found to be a crucial mechanism underlying the pathogenesis of RA. However, TxA2 is neither the pharmacological target of non-steroidal anti-inflammatory drugs (NSAIDs) nor the target of disease modifying anti-rheumatic drugs (DMARDs), and the limitations and side effects of those drugs may be, at least in part, attributable to lack of the effects on the COX-2/TxA2 pathway. Therefore, GL and GA capable of targeting this pathway hold the potential as a novel add-on therapy in therapeutic strategy, which is supported by several bench experiments.

The active components of licorice, GL and GA, could not only potentiate the therapeutic effects but also decrease the adverse effects of NSAIDs or DMARDs through suppressing the COX-2/TxA2 pathway during treatment course of RA.

During aging, advanced glycation end products (AGEs) accumulate in articular cartilage. In this study we determined whether AGEs induce endoplasmic reticulum (ER) stress and studied the ER stress-activated pathways that stimulate cyclooxygenase-2 (COX-2) expression in human chondrocytes. Chondrocytes were stimulated with AGE-BSA. Gene expression was determined by quantitative PCR and protein expression was studied by immunoblotting. Studies to elucidate involved pathways were executed using siRNAs and specific inhibitors of eukaryotic initiation factor-2α (eIF2α), MAPKs and NF-κB. AGE-BSA induced expression of GRP78 with concomitant increase in COX-2 expression was observed in human chondrocytes. In addition, expression of Bag-1, an ER stress marker was also increased by AGE-BSA. RAGE knockdown inhibited AGE-BSA-induced expression of GRP78 and COX-2. Treatment with eIF2α inhibitor or eIF2α knockdown inhibited AGE-BSA-induced expression of GRP78 and COX-2 with decreased PGE(2) production. Treatment with SB202190 inhibited AGE-BSA-induced expression of GRP78 and COX-2, while treatment with PD98051 inhibited AGE-BSA-induced GRP78 protein expression but had no effect on COX-2 protein expression. SP600125 had no effect on either GRP78 or COX-2 protein expression. Bay 11-7082 suppressed AGE-BSA-induced GRP78 and COX-2 expression. AGE-BSA-induced activation of NF-κB was inhibited by treatment with SB202190 and by eIF2α knockdown, but was not inhibited when chondrocytes were treated with SP600125 or PD98059.

This study demonstrates that AGEs induce ER stress and stimulate the expression of COX-2 through eIF2α, p38-MAPK and NF-κB pathways in human chondrocytes. Our results provide important insights into cartilage degradation in osteoarthritis associated with latent ER stress.

IL2RA/CD25, the gene for interleukin-2 receptor alpha, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T cells and the association of single-nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS). The aim of this study was to determine whether SNPs within the IL2RA/CD25 gene are associated with juvenile idiopathic arthritis (JIA). Three SNPs within the IL2RA/CD25 gene, that previously showed evidence of an association with either RA, MS, or type 1 DM, were selected for genotyping in UK JIA cases (n=654) and controls (n=3,849). Data for 1 SNP (rs2104286) were also available from North American JIA cases (n=747) and controls (n=1,161). Association analyses were performed using Plink software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. SNP rs2104286 within the IL2RA/CD25 gene was significantly associated with UK JIA cases (OR for the allele 0.76 [95% CI 0.66-0.88], P for trend=0.0002). A second SNP (rs41295061) also showed modest evidence for association with JIA (OR 0.80 [95% CI 0.63-1.0], P=0.05). Association with rs2104286 was convincingly replicated in the North American JIA cohort (OR 0.84 [95% CI 0.65-0.99], P for trend=0.05). Meta-analysis of the 2 cohorts yielded highly significant evidence of association with JIA (OR 0.76 [95% CI 0.62-0.88], P=4.9x10(-5)).

These results provide strong evidence that the IL2RA/CD25 gene represents a JIA susceptibility locus. Further investigation of the gene using both genetic and functional approaches is now required.

Mesenchymal stem cells (MSCs) are found in synovial fluid (SF) and can easily be harvested during arthrocentesis or arthroscopy. However, SF-MSC characterization and chondrogenicity in collagen sponges have been poorly documented as well as their hypothetical in vivo chondroprotective properties with intra-articular injections during experimental osteoarthritis (OA). SF-MSCs were isolated from human SF aspirates in patients suffering from advanced OA undergoing total knee joint replacements. SF-MSCs at passage 2 (P2) were characterized by flow cytometry for epitope profiling. SF-MSCs at P2 were subsequently cultured in vitro to assess their multilineage potentials. To assess their chondrogenicity, SF-MSCs at P4 were seeded in collagen sponges for 4 weeks under various oxygen tensions and growth factors combinations to estimate their gene profile and matrix production. Also, SF-MSCs were injected into the joints in a nude rat anterior cruciate ligament transection (ACLT) to macroscopically and histologically assess their possible chondroprotective properties,. We characterized the stemness (CD73+, CD90+, CD105+, CD34-, CD45-) and demonstrated the multilineage potency of SF-MSCs in vitro. Furthermore, the chondrogenic induction (TGF-ß1 ± BMP-2) of these SF-MSCs in collagen sponges demonstrated a good capacity of chondrogenic gene induction and extracellular matrix synthesis. Surprisingly, hypoxia did not enhance matrix synthesis, although it boosted chondrogenic gene expression (ACAN, SOX9, COL2A1). Besides, intra-articular injections of xenogenic SF-MSCs did exert neither chondroprotection nor inflammation in ACLT-induced OA in the rat knee.

Advanced OA SF-MSCs seem better candidates for cell-based constructs conceived for cartilage defects rather than intra-articular injections for diffuse OA.

A pragmatic, single-centre, double-blind randomized clinical trial was conducted in a NHS teaching hospital to evaluate whether there is a difference in functional knee scores, quality-of-life outcome assessments, and complications at one-year after intervention between total knee arthroplasty (TKA) and patellofemoral arthroplasty (PFA) in patients with severe isolated patellofemoral arthritis. This parallel, two-arm, superiority trial was powered at 80%, and involved 64 patients with severe isolated patellofemoral arthritis. The primary outcome measure was the functional section of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 12 months. Secondary outcomes were the full 24-item WOMAC, Oxford Knee Score (OKS), American Knee Society Score (AKSS), EuroQol five dimension (EQ-5D) quality-of-life score, the University of California, Los Angeles (UCLA) Physical Activity Rating Scale, and complication rates collected at three, six, and 12 months. For longer-term follow-up, OKS, EQ-5D, and self-reported satisfaction score were collected at 24 and 60 months. Among 64 patients who were randomized, five patients did not receive the allocated intervention, three withdrew, and one declined the intervention. There were no statistically significant differences in the patients' WOMAC function score at 12 months (adjusted mean difference, -1.2 (95% confidence interval -9.19 to 6.80); p = 0.765). There were no clinically significant differences in the secondary outcomes. Complication rates were comparable (superficial surgical site infections, four in the PFA group versus five in the TKA group). There were no statistically significant differences in the patients' OKS score at 24 and 60 months or self-reported satisfaction score or pain-free years.

Among patients with severe isolated patellofemoral arthritis, this study found similar functional outcome at 12 months and mid-term in the use of PFA compared with TKA. Cite this article:

To determine the prevalence of depressive and anxiety symptoms in patients with rheumatoid arthritis (a chronic inflammatory disease) in comparison to a control group with osteoarthritis (a chronic non-inflammatory degenerative disease) and to identify the sociodemographic and clinical variables associated with depressive symptoms in these patients. Sixty-two rheumatoid arthritis patients and 60 osteoarthritis patients participated in the study. Sociodemographic and clinical data were collected and the Hospital Anxiety and Depression Scale and the Disability Index of the Health Assessment Questionnaire were applied. The prevalence of depressive symptoms was of 53.2% in rheumatoid arthritis and 28.3% in osteoarthritis (p = 0.005). The prevalence of anxiety symptoms was of 48.4% in rheumatoid arthritis and 50.0% in osteoarthritis (p = 0.859). The mean (and standard deviation) scores in the Disability Index of the Health Assessment Questionnaire were 1.4 (0.8) in rheumatoid arthritis and 1.4 (0.6) in osteoarthritis (p = 0.864). Rheumatoid arthritis patients with depressive symptoms had lower education and higher disease activity and functional disability.

Although these two rheumatic diseases are similar in terms of the pain and functional disability that they cause, a significantly higher prevalence of depressive symptoms was found in rheumatoid arthritis patients. This difference might be explained by the hypothesis of a neuroimmunobiological mechanism related to cytokines in inflammatory diseases, which has been considered as a candidate to the development of depressive symptoms.

To evaluate the safety and efficacy of ocrelizumab (OCR) in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). RA patients with an inadequate response to MTX 6-8 mg/week received an infusion of 50, 200, or 500 mg OCR or placebo on Days 1 and 15 and were observed for 24 weeks. The double-blind period was prematurely terminated because of a possible risk for serious infection from OCR. A total of 152 patients were randomized into the study. The incidence of infection was 37.7% (43/114) in the OCR groups combined, compared to 18.9% (7/37) in the placebo group. Serious infections occurred in 7 patients in the OCR groups combined; there were no serious infections in the placebo group. Among the serious infections, Pneumocystis jirovecii pneumonia occurred in 2 patients in the OCR 200 mg group. The American College of Rheumatology 20% response rates at Week 24 (the primary endpoint) of the OCR 50, 200, and 500 mg groups were 54.1% (p = 0.0080), 55.6% (p = 0.0056), and 47.2% (p = 0.044), respectively, all significantly higher than that of the placebo group (25.0%).

These results suggest inappropriate benefit-risk balance of OCR in this patient population. Because rituximab is not approved for treatment of RA in Japan, it will be necessary to investigate safety and efficacy of other anti-B cell therapies in Japanese patients with RA. (ClinicalTrials.gov NCT00779220).

The present study was undertaken to assess the comparative responsiveness of outcome measures used for the assessment of pain and function in individuals with osteoarthritis (OA) of the first metatarsophalangeal (MTP) joint. Eighty-eight patients (mean ± SD age 57.2 ± 10.2 years) with OA of the first MTP joint who participated in a randomized trial completed the Foot Health Status Questionnaire (FHSQ), the Foot Function Index Revised Short Form (FFI-RS), and 100-mm visual analog scales (VAS) of pain and stiffness at baseline and 12 weeks. Responsiveness of the subscales for each outcome measure was determined using paired t-tests, Cohen's d coefficient, the standardized response mean (SRM), and the Guyatt index (GI). Sample size estimations were calculated based on minimal important differences (MIDs). All outcome measures were sensitive to change and demonstrated at least medium effect sizes. Three outcome measures exhibited large or very large effect sizes for Cohen's d coefficient, the SRM, and the GI: the FHSQ pain subscale (d = 1.03; SRM 1.10, GI score 1.30), the FFI-RS pain subscale (d = 1.09; SRM 1.05, GI score 1.73), and the 100-mm VAS of pain severity while walking (d = 1.22; SRM 1.07, GI score 1.78). Sample size calculations indicated that between 20 and 33 participants per group would be required to detect MIDs using these measures.

The FHSQ pain subscale, FFI-RS pain subscale, and the 100-mm VAS of pain severity while walking are the most responsive outcome measures for the assessment of pain and function in individuals with OA of the first MTP joint. These findings provide useful information to guide researchers in selecting appropriate outcome measures for use in future clinical trials.

Granulomatous autoinflammatory diseases are monogenic syndromes caused by mutations in the region encoding the nucleotide-binding domain of the nucleotide-binding oligomerization domain-containing 2 gene. Blau syndrome and early-onset sarcoidosis are familial and sporadic forms of the same disease and are very rare. Many organ systems may be involved; however, neurologic involvement is infrequent. We reported a case of encephalitis in a 12-year-old girl followed with a diagnosis of early-onset sarcoidosis. The patient was diagnosed with juvenile idiopathic arthritis at 3 years of age. We considered druginduced sarcoidosis at 6 years of age with granulomatous inflammation of liver and kidney. Small joint involvement and camptodactyly developed during follow-up. M315T mutation was detected in the NOD2 gene supporting the diagnosis of early-onset sarcoidosis. The patient suffered from encephalopathy when she was under methotrexate, infliximab, and systemic steroid treatment at 12 years of age. Cerebrospinal fluid limbic encephalitis antibody panel was negative.

Encephalopathy is not common in Blau syndrome and early-onset sarcoidosis. The cause of encephalopathy in our patient was interpreted as autoimmune encephalitis.

Transition from pediatric to adult care can be a challenging process which leaves young people vulnerable to interruptions of care and worsening disease status. Efforts to improve transition processes and outcomes have included development of individualized transition plans, creation of transition clinics, and utilization of transition coordinators. Few interventions have assessed transition outcomes quantitatively. We assessed transition outcome and satisfaction of a social worker-centered transition program in a pediatric rheumatology clinic. The social worker met with patients who were 16 years or older and their families, provided transition education materials, assisted patients in developing an individualized transition plan, assisted in making appointments with an adult rheumatologist at time of transfer of care, and followed up with patients to assess transition outcomes. Patients were contacted 6-8 months after initial appointment with the adult rheumatologist to assess whether they remained in the care of the adult provider. Participants then completed a questionnaire to rate their satisfaction with the transition program. 210 adolescents and young adults participated in the transition program. Twenty-six similarly aged patients were eligible for transition services but did not participate in the program and were used as controls. Of the patients who participated in the program, 42% were considered to have transitioned successfully to adult care compared to 23% of controls (p-value = 0.002) of all patients. In the survey of satisfaction, 81% of participants said that they were satisfied with the transition process.

This study shows that a social worker transition coordinator can significantly improve the rate of pediatric rheumatology patients who successfully transition to adult care. Furthermore, patients are largely satisfied with this process.

Methotrexate (MTX) is used frequently as a disease modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), and patients tend to continue taking this drug for longer periods than alternative single agents. The shape of the therapeutic response beyond one or 2 years, however, has not been fully studied. We examined the properties of the pure MTX "therapeutic segment," that period that begins with start of MTX and terminates when MTX is discontinued or another DMARD is added, by observational study. We studied new MTX starts for the period 1988 through 1996 for 437 patients from a parent cohort of 4253 patients. Patients were drawn from 8 Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) data centers: 2 community based populations; 2 private rheumatological practices; 2 university referral practices; and 2 university clinics for underserved minority urban populations. Health Assessment Questionnaire (HAQ) Disability Index scores (0-3) were obtained prospectively each 6 months. At MTX start, patients had relatively long average disease duration of 16.7 years, and had moderately severe disability, with an initial HAQ mean disability score of 1.48. Over the 10 year period examined in the parent cohort of 4253 patients (and thus irrespective of therapy), the prevalence of MTX use rose from 19% to 45%, while mean HAQ disability declined from 1.34 to 1.11. This correspondence is consistent with an accrual of benefits from more frequent use of MTX and other DMARD over this period. The MTX therapeutic segment revealed a distinct shape. HAQ-Disability Index values began at 1.48 at baseline and declined to a maximal improvement of 1.23 at 30 months. This long period to maximum benefit may have been partly driven by a slow titration upward to an optimal dosage. After 42 months, disability for this population began to re-progress and reached 1.39 at 84 months, still below the pretreatment baseline. Re-progression to baseline was about 8 or more years. Cumulative disability averted with MTX treatment for this population was roughly 1.30 disability-unit-years.

MTX treatment of RA in practice differs substantially from common perception and appears suboptimal by being too little, too late, and too long to treatment change. A modification of the "sawtooth strategy" in which the disease is "ratcheted down" by change of MTX therapy at 3 years or when re-progression has proceeded halfway to baseline, rather than waiting for return to baseline, is suggested by these data. Also suggested is the need for more rapid upward dosage titration and longer maintenance of an optimal or highest tolerated dosage. "Therapeutic segment" data provide insights into strategic approaches to management of RA since they allow estimation of population aggregate properties such as time to maximum benefit and the time to return to baseline.

Osteolysis and subsequent prosthesis loosening is the most common cause for revision following total knee arthroplasty (TKA) or total hip arthroplasty (THA). Hormone replacement therapy (HRT) could reduce osteolysis through its antiresorptive effects. We studied whether HRT use is associated with reduced revision rates in a community-based cohort of women undergoing TKA or THA for osteoarthritis. Female participants in the General Practice Research Database undergoing a primary TKA or THA from 1986 to 2006 were included. We excluded patients aged <40 years at the date of primary, and those with a history of previous hip fracture or rheumatoid arthritis. Women with at least 6 months of HRT were identified as HRT users. We further explored the associations among HRT use of ≥12 months, adherence (medication possession ratio) and cumulative use and revision risk. Cox models were fitted to model implant survival in years. Propensity score matching was used to control for confounding. We matched 2700 HRT users to 8100 non-users, observed for a median (IQR) of 3.3 (1.5-6.1) years after TKA/THA. HR for HRT ≥6 months was 0.62 (95% CI 0.41 to 0.94), whereas HR for ≥12 months was 0.48 (0.29 to 0.78). Higher adherence and therapy duration were associated with further reductions in revision rates. Preoperative HRT appeared unrelated to implant survival.

HRT use is associated with an almost 40% reduction in revision rates after a TKA/THA. These findings require replication in external cohorts and experimental studies.

Fibromyalgia is a common disease, but little is known on its real prevalence in France. This epidemiological study aimed to assess fibromyalgia (FM) prevalence in the French metropolitan population, based on a multi-step sampling analysis, combining national screening and clinical confirmation by trained specialists. a sampling method on the entire national territory was used: patients over 18 years of age accepting to take part in the study were contacted by telephone using the LFES Questionnaire, a screening test for FM. The, for patients detected by the LFESQ, a visit with a FM-trained rheumatologist was proposed to confirm FM, based on 1990 ACR criteria. Each detected patient completed the following self-questionnaires: SF36, HADS, stress VAS, Co-morbidities and Regional pain score. 3081 patients were contacted in 5 representative French regions, of which 232 patients were screened for FM. A fibromyalgia diagnosis was then confirmed by rheumatologist in 20 cases (17 female and 3 male, 56.9 ± 13.2 years). The final estimated FM prevalence was 1.6 (CI95: 1.2%; 2.0%). No significant difference was detected between the patients accepting (CS+) and refusing (CS-) rheumatologist visit for the SF36 score, regional pain score, stress VAS scale and co-morbidities. In patients detected for FM by the LFESQ, we found a statistically significant decrease in quality of life and a statistically significant increase in stress level in patients with a confirmed diagnosis (FM+) (6.3 ± 1.9) compared to patients with an invalidated diagnosis (FM-) (4.4 ± 2.8; p = 0.007). The study also demonstrated a significant association, independently of ACR criteria, between the diagnosis of FM and several factors such as regional pain score > 10, elevated stress level, low SF36 scale score and presence of gastro-intestinal disorder co-morbidities.

Fibromyalgia is a common condition; the 1.6% prevalence calculated in the French population in our study corroborates the figures published in the European literature. Our results also suggest that criteria such as regional pain score, stress level or SF36 quality of life, could represent useful tools in fibromyalgia diagnosis.

This study examines polyfunctional T-cells in psoriatic arthritis (PsA) synovial tissue and their associations with clinical disease and implications for therapy. PsA synovial tissue was enzymatically/mechanically digested to generate synovial tissue single cell suspensions. Frequencies of polyfunctional CD4, CD8, T-helper 1 (Th1), Th17 and exTh17 cells, using CD161 as a marker of Th17 plasticity, were determined by flow cytometry in matched PsA synovial tissue and peripheral blood. Synovial T-cell polyfunctionality was assessed in relation to Disease Activity in PSoriatic Arthritis (DAPSA) and in synovial cell suspensions cultured with a current mode of treatment, phosphodiesterase 4 (PDE4) inhibitor. PsA synovial tissue infiltrating CD4

These data demonstrate enrichment of polyfunctional T-cells in PsA synovial tissue which were strongly associated with DAPSA and ex vivo therapeutic response.

To assess how socioeconomic deprivation influences the presentation, treatment, and outcome of patients with rheumatoid arthritis (RA). Three year follow up of 869 consecutive patients with RA from nine hospital rheumatology clinics, with patients categorised by the Carstairs deprivation score of their enumeration district of residence. Outcomes included Health Assessment Questionnaire (HAQ), joint and pain scores, grip strength, functional grade, radiological evidence of bony erosions, and medical/surgical interventions. Patients from more deprived enumeration districts presented with more severe disease as judged by the HAQ score and joint scores. An increase from the 5th to the 95th centile of the Carstairs distribution was associated with an odds ratio of 1.87 (95% confidence interval (95% CI) 1.31 to 2.66) for an above-median HAQ score and 1.77 (95% CI 1.23 to 2.54) for an above-median joint score. Statistically non-significant deprivation trends were seen with erythrocyte sedimentation rate, pain score, and grip strength. By three years, despite no important differences in clinical management, socioeconomic differentials had worsened or remained unchanged such that clear deprivation trends were then seen in HAQ (p=0.002) and joint scores (p=0.001), in grip strength (p=0. 008), and in functional grade (p=0.003). The association between deprivation and HAQ at three years was present after adjustment for age, sex, treatment centre, and HAQ at presentation (adjusted odds ratio 1.74, 95% CI 1.1 to 2.74).

Socioeconomic deprivation was associated with a worse clinical course of rheumatoid disease, and this effect was already apparent at presentation, but not with systematic differentials in its treatment. This suggests that individual susceptibility and lifestyle factors contribute to socioeconomic differentials in outcome, an observation that has implications for clinical management.

To determine whether treatment with the chimeric anti-tumor necrosis factor alpha antibody infliximab could reduce cellularity by the induction of apoptosis in synovial tissue. Twenty-four rheumatoid arthritis patients with active disease were randomized to receive either infliximab (3 mg/kg) (n = 12) or placebo (n = 12) intravenously. All patients were subjected to arthroscopic synovial biopsy directly before initiation of treatment. A second arthroscopic synovial biopsy of the same index joint was performed 48 hours after the first arthroscopy. After the second arthroscopy, the patients who had initially received placebo were also treated with infliximab in an extension study. A third arthroscopy was performed in all patients on day 28. Immunohistologic analysis was performed to characterize the cell infiltrate. In situ detection of apoptotic cells was performed by TUNEL assay and electron microscopy. At 48 hours after initiation of infliximab treatment, there was a significant reduction in the number of intimal macrophages; this was not observed in the placebo group. The number of sublining macrophages, T cells, and plasma cells also tended to be decreased in infliximab-treated patients, but not in the placebo group. Of interest, we did not detect any increase in the number of apoptotic cells after infliximab treatment.

Infliximab therapy may reduce the number of inflammatory cells in rheumatoid synovial tissue as soon as 48 hours after initiation of treatment, but apparently not by induction of apoptosis. Conceivably, decreased cell infiltration primarily results from early inhibition of cell migration.

Rheumatic diseases are among the most common and debilitating health problems in the United States. These diseases are chronic, can result in severe decrements of physical and psychosocial functioning and affect patients' overall quality of life. A consensus regarding the best patient outcomes to be measured in randomized, controlled trials and prospective natural history studies is essential to provide best estimates of efficacy and safety of interventions across diverse patient populations. Face-to-face English- and Spanish-language cognitive interviews were conducted among urban Hispanic and African American patients with rheumatic disease to develop a questionnaire booklet. Six measures validating patient-reported outcomes were included: the Arthritis Self-Efficacy Scale, the Stanford Health Assessment Questionnaire Disability Index, the Wong-Baker Faces Pain Scale, the Short Acculturation Scale, the Center for Epidemiologic Studies Depression Scale and the Inventory of Complementary and Alternative Medicine Practices. A sample of patients (n = 15) attending the National Institute of Arthritis and Musculoskeletal and Skin Diseases Community Health Center participated in the initial interviews. Revised measures were further tested for reliability in a separate sample of patients (n = 109) upon enrollment at the health center. Cognitive interviews provided feedback for questionnaire modifications and methods to enhance content validity and data quality, including discarding redundant questions, providing visual aids and concrete examples when appropriate and increasing the use of racially and ethnically concordant interviewers. The cognitive interviews further elucidated that some contextual assumptions and language usage in the original questionnaires may not have taken each respondent's environmental and sociocultural context into consideration. Internal reliability for previously tested measures remained high (Cronbach's α = 0.87-0.94).

Cognitive interviewing techniques are useful in a diverse sample of racial and ethnic minority patients with rheumatic disease as a method to assess the content validity of the specific outcome measures selected. The data collection approaches and methods described here ultimately enhance data quality. Vigilance is required in the selection of outcome measures in studies or in practice, particularly with each new language translation and/or culturally unique or diverse sample.

To provide an overview of evidence on the experiences and needs of adults living with rheumatoid arthritis (RA). Many research have studied the impact of RA on one's quality of life, but no reviews have examined the overall experiences of patients living with RA. An integrative review was performed to synthesize the experiences and/or needs of adult patients with RA based on articles retrieved from databases of CINAHL, Scopus, PubMed, PsycINFO and Web of Science, and published between January 2003 and March 2014 in English. A total of 38 studies were reviewed. RA has adverse effects on patients' quality of life due to its negative impacts in their physical and psychosocial aspects of health. Patients with RA cope with these impacts using various methods and are frequent users of healthcare services. However, few studies have evaluated patients' further needs in coping or the effectiveness of their coping mechanisms, and patients' experiences with health care. Establishing a positive healthcare professional-patient relationship is crucial and healthcare professionals are in a position to provide greater informational and emotional support to patients. Policy makers and healthcare organizations need to look into ways to enhance the healthcare services to better suit RA patients' needs.

This review provides evidence for healthcare professionals to gain a better understanding of RA patients' experiences and needs. Future studies can explore interventions that will enhance the quality of current healthcare practices and ultimately improve patients' quality of life.

Levels of activated protein C (APC) are elevated in the synovial fluid of patients with osteoarthritis (OA), and increased APC levels are correlated with the levels of active matrix metalloproteinase 2 (MMP-2). This study sought to investigate whether APC is a relevant protein for activation of MMPs in the degradation of human OA cartilage, and to elucidate its mechanisms of action. Human articular cartilage was cultured with or without interleukin-1α (IL-1α), in the presence or absence of APC or protein C, and an MMP or serine proteinase inhibitor. Aggrecan and collagen release and chondrocyte gene expression levels were quantified. Aggrecanase and MMP cleavage of aggrecan was examined with neoepitope-specific antibodies, and MMP activity was measured using gelatin zymography and fluorogenic peptide assay. In human OA cartilage, APC induced aggrecan and collagen release, whereas in non-OA cartilage, costimulation with IL-1α was required. Inhibition of MMP activity reduced APC-induced cartilage proteolysis, and MMP-induced aggrecanolysis was confirmed by Western blotting. In cultures with APC alone, the activity of MMPs 2, 9, and 13 was significantly increased in OA cartilage, although APC could not directly activate MMPs 2 or 9. Expression of MMP1, MMP2, MMP9, MMP13, TIMP1, and TIMP3 was not altered by APC in OA cartilage. Human OA chondrocytes expressed messenger RNA for protein C, endothelial protein C receptor, thrombomodulin, and protease-activated receptor 1, but these were unaltered or down-regulated by APC. The induction of MMP activation and cartilage degradation by APC was dependent on its serine protease activity.

APC is a physiologically relevant activator of MMPs and cartilage breakdown in human OA. The effects of APC are dependent on its proteolytic activity and as-yet-undefined cell and/or cartilage matrix factors, and inhibition of this pathway may provide a novel therapeutic target to halt the progression of cartilage damage in OA.

Patients with Still's disease show a prominent acute phase reaction. Our hypothesis is that under these circumstances the iron uptake of ferritin will not keep pace with its synthesis, and is therefore not a valid reflection of the iron status in these patients. Previously we developed a method to measure the iron content of ferritin; we investigated the usefulness of this method to establish the iron status of patients with anemia of inflammation. In 9 patients with adult onset Still's disease (AOSD) we observed high ferritin concentrations and measured the iron saturation of ferritin. The mean value of saturation was 9.1%, while saturation in the healthy control group was 17.8%, a statistically significant difference (p < 0.005). Soluble transferrin receptor concentrations indicated a functional iron deficiency.

We conclude that the acute phase ferritin in patients with AOSD contains less iron in comparison to ferritin in healthy controls. We suggest that soluble transferrin receptor is the method of choice in estimating the iron status of patients with an acute phase reaction.

Clinical trials of the anti-interleukin-17A (anti-IL-17A) antibody secukinumab have demonstrated a crucial role of the cytokine IL-17A in the pathogenesis of spondyloarthritis (SpA); however, its cellular source in this condition remains a matter of controversy. Group 3 innate lymphoid cells (ILC3s) have been recently identified as potent producers of proinflammatory cytokines, including IL-17A and IL-22, in a number of different tissues. This study was undertaken to characterize the presence and composition of ILCs, and investigate whether these cells are an important source of IL-17A, in the synovial tissue (ST) of patients with SpA. Matched ST, synovial fluid, and peripheral blood (PB) samples were obtained from SpA patients with actively inflamed knee joints. ILC subsets were characterized by flow cytometry. Gene expression analysis at the single-cell level was performed directly ex vivo and after in vitro activation. An IL-17A enzyme-linked immunospot assay was used to detect IL-17A-secreting cells. ILCs, and particularly NKp44+ ILC3s, were expanded in inflamed arthritic joints. Single-cell expression analysis demonstrated that ST ILCs were clearly distinguishable from ST T cells and from their PB counterparts. Expression of the Th17 signature transcripts RORC, AHR, and IL23R was detected in a large proportion of ST ILC3s. These cells were capable of inducing expression of IL22 and CSF2, but not IL17A, in response to in vitro restimulation.

Our findings demonstrate that absolute and relative numbers of ILC3s are enriched in the synovial joints of patients with SpA. However, these cells are not a significant source of IL-17A in this disease.

In granulomatosis with polyangiitis (GPA), a complex autoimmune small-vessel vasculitis frequently associated with chronic necrotizing inflammation of the nasal mucosa, elevated nasal Staphylococcus (S.) aureus carrier rates are a risk factor for relapse. As cytokines are primarily involved in the regulation of defense against potentially pathogenic microorganisms, the aim of this study was to compare healthy individuals and GPA patients with respect to their baseline cytokine expression of nasal epithelial cells (NEC), which form the first barrier against such triggers. The ability of S. aureus to influence the nasal microenvironment's cytokine secretion was assessed by exemplary stimulation experiments. Baseline expression of 19 cytokines of primary NEC of GPA patients and normal controls (NC) was quantified by a multiplex cytokine assay. Stimulation experiments were performed with supernatants of S. aureus and expression of interleukin-8 was determined by ELISA. In GPA, an altered pattern of baseline cytokine expression with significantly up-regulated G-CSF and reduced interleukin (IL)-8 concentrations was observed. Both NEC of GPA patients and NC responded to stimulation with S. aureus, but GPA patients displayed a significantly lower IL-8 secretion and a diminished dynamic range of response towards the stimulus.

The data presented underline the hypothesis of a disturbed epithelial nasal barrier function in GPA. The dysregulated baseline expression of G-CSF and IL-8 and the reduced response to microbial stimulation may facilitate changes in the composition of the nasal flora and favour an imbalanced inflammatory response, which might be relevant for the disease course.

The early diagnosis of temporomandibular joint (TMJ) involvement in patients with juvenile idiopathic arthritis (JIA) before joint destruction and growth disturbances could allow for interceptive treatment. The purpose of this article is to report early TMJ arthroscopic findings in patients with JIA. This was a case series of 3 patients with JIA treated at the Emory University Division of Oral and Maxillofacial Surgery from July 2011 through December 2012. Patients were included if they had a confirmed diagnosis of JIA, did not respond to anti-rheumatologic medication, and had TMJ pain or limited mouth opening. All patients underwent TMJ arthroscopy with an injection of triamcinolone hexacetonide. Demographics, medical history, magnetic resonance imaging findings, arthroscopic findings, and postoperative course were reported. Three female patients (mean age, 12.5 yr; 5 joints) underwent arthroscopy. Arthroscopic findings consisted of mild to moderate synovitis and grade 2 to 4 chondromalacia with or without fibrosis. Postoperatively, all patients had improvement in pain and mouth opening.

There was a positive correlation between duration of JIA activity in the TMJ and severity of arthroscopic findings. Arthroscopic lysis and lavage combined with triamcinolone hexacetonide injection resulted in improvement in pain and range of motion.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology. It is known that RA patients have a reduced life expectancy when compared with the general population. Rheumatic diseases are numerous and occur with high variability; some of them develop very rapidly while others occur chronically provoking disability throughout life. Anesthetic risks in osteoarticular disorders involve not only the mechanical deformations caused by the disease, but also the cardiovascular, respiratory, renal, and digestive systems. The purpose of this review was to stress the importance of stages in disease process that may affect anesthesia control before, during, and after surgery, highlighting the authors' experience in a retrospective review of patients with juvenile rheumatoid arthritis (JRA) undergoing placement of orthopedic prosthesis with emphasis on intubation techniques.

Rheumatoid arthritis patients can present a number of complex problems for the anesthesiologist. This requires careful preoperative evaluation; anesthesia requires experience with the technique; and postoperative care should be judiciously chosen to meet the specific needs of the patient. The procedure requires effective communication among surgeon, rheumatologist and anesthesiologist so each member of the multidisciplinary team can contribute with his/her expertise in order to better benefit the patient.