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Dry mouth is associated with salivary gland hypofunction, which may result from several conditions such as Sjögren's syndrome (SS), head and neck cancers, and side effects of medications. The Saxon test is a useful diagnostic method for hyposalivation in clinical settings. However, previous reports indicate that the test has mostly been used for patients with SS. In the present study, we focused on patients with dry mouth who were not diagnosed with SS (patients without SS). For patients without SS (n = 302), we examined the factors affecting Saxon test scores using multiple regression analysis. Additionally, we performed a correlation analysis comparing the Saxon test with other diagnostic methods. In 57.6% patients, the Saxon test score was more than 2.00 g/2 min, which is considered negative for hyposalivation. Multiple regression analysis revealed that the age and sex of patients significantly influenced test scores. The mean Saxon test score was less than 2.00 g/2 min in older patients and women. Moreover, the test showed a significant correlation with other methods used to measure salivary flow.

The Saxon test is useful not only for patients with SS but also for patients without SS.

Resveratrol is a naturally occurring polyphenol, which possesses chemotherapeutic potential through its ability to trigger apoptosis. The objective of this study was to investigate the major determinant for the apoptotic cell death induction by resveratrol in fibroblast-like synoviocytes (FLS) derived from patients with RA. The effect of resveratrol on apoptotic cell death was quantified in a population of subG1 in RA FLS by flow cytometry. The underlying signalling mechanism for apoptotic death was examined by analysing mitochondrial membrane potential, activation of the caspase cascade and translocation of Bid. We show that activation of caspase-8 is essential for triggering resveratrol-induced apoptotic signalling via the involvement of the mitochondrial pathway in RA FLS. Our findings also suggest that this enhanced apoptosis caused by resveratrol occurred in RA FLS irrespective of p53 status. Exposure to resveratrol caused extensive apoptotic cell death, along with a caspase-dependent (activation of caspase-9 and -3, poly ADPribose polymerase (PARP) cleavage and mitochondrial cytochrome c release) or caspase-independent [translocation of apoptosis-inducing factor (AIF) to the nucleus] signalling pathway. Analysis of upstream signalling events affected by resveratrol revealed that the activated caspase-8 triggered mitochondrial apoptotic events by inducing Bid cleavage without any alteration in the levels of Bax, Bcl-xL or Bcl2. The caspase-8 inhibitor or over-expression of crmA abrogated cell death induced by resveratrol and prevented processing of the downstream cascade.

The results suggest that resveratrol causes activation of caspase-8, which in turn results in modulation of mitochondrial apoptotic machinery to promote apoptosis of RA FLS.

To test the usefulness of the Chapel Hill nomenclature, supplemented with surrogate parameters, as diagnostic criteria for primary vasculitides. To prospectively evaluate vasculitis patients according to a standardised clinical and para-clinical programme. In accordance with the Chapel Hill publication surrogate parameters were used: proteinuria, haematuria and red blood cell casts (glomerulonephritis), angiographic or ultrasonic demonstration of aneurysms or stenoses (arteritis), radiological lung infiltrates or cavitations of more than one month's duration (granuloma in the lungs), bloody nasal discharge or crusts, chronic sinusitis, otitis and/or mastoiditis, bone and/or cartilage destruction, and acute hearing loss (granuloma in upper airways). The following entities were diagnosed: giant cell arteritis (n=14), Takayasu arteritis (n=1), polyarteritis nodosa (n=2), Wegener's granulomatosis (n=27), Churg-Strauss syndrome (n=2), microscopic polyangiitis (n=12), Henoch-Schönlein purpura (n=2), cutaneous leucocytoclastic angiitis (n=37), and secondary vasculitis (n=21). Giant cell arteritis and cutaneous leucocytoclastic angiitis were in all cases diagnosed by biopsy. Using the Chapel Hill nomenclature supplemented with surrogate parameters, only 8 of 27 patients were diagnosed with Wegener's granulomatosis, and 3 of 12 cases with microscopic polyangiitis. The number of patients in the remaining diagnostic entities were considered to few to evaluate.

The Chapel Hill nomenclature, supplemented with surrogate parameters, failed to act as diagnostic criteria in Wegener's granulomatosis and microscopic polyangiitis. The following diagnostic criteria are proposed for Wegener's granulomatosis: (1) Biopsy or surrogate parameter for granulomatous inflammation in the respiratory system and (2) Biopsy verified necrotising vasculitis in small to medium sized vessels or biopsy/surrogate parameter for glomerulonephritis or positive PR3-ANCA test and (3) Lack of eosinophilia in blood and biopsy samples. The following diagnostic criteria are proposed for microscopic polyangiitis: (1) Biopsy verified necrotising vasculitis in small vessels and/or glomerulonephritis with few or no immune deposits and (2) Involvement of more than one organ system as indicated by biopsy verified vasculitis in small to medium sized vessels or surrogate parameter for glomerulonephritis and (3) Lack of biopsy and surrogate parameter for granulomatous inflammation in the respiratory system. Using these criteria all Wegener's patients and 9 of 12 patients with microscopic polyangiitis could be diagnosed.

Cyclo-oxygenase (COX)-2 inhibitors have been the target of severe criticism, more so following the withdrawal of Rofecoxib. Post-marketing surveillance of Celecoxib in Asian Indians, who are predisposed to premature athero-thrombotic events, has not been studied. To study the adverse effects of Celecoxib and compare them with those of other non-steroidal anti-inflammatory drugs (NSAIDs) in an Asian Indian cohort. This is a retrospective chart review with convenience sampling of patients on NSAIDs (at least five tablets a week, for at least 3 months prior to the study), attending the Rheumatology clinic of a tertiary care institution in south India between June 2004 and November 2004. Those with pre-existing heart disease, hypertension, thrombo-embolic disease, peptic ulcer and patients on corticosteroids were excluded. All the recorded adverse events were noted and compared between the Celecoxib and non-selective NSAID users. Univariate analysis using Chi-square test was performed. Of the 1387 patients included, 915 were on Celecoxib. In the NSAID group, 204 had used multiple NSAIDs in sequence. Of the Celecoxib users, 164 had switched over to an NSAID during the study period. New onset of hypertension was significantly higher in the Celecoxib users as compared to non-selective NSAID users (3.06% vs. 1.27%, P = 0.04). However, those who had switched over to NSAIDs did not show this trend. NSAID users, on the other hand, had significant gastrointestinal (GI) toxicity (2.54% vs. 0.327%, P = 0.001). A significant number of Celecoxib users who switched over to NSAIDs also developed GI toxicity (6.1% vs. 1.21%, P = 0.018) over a shorter time span, as compared to the continuous NSAID users. Multiple NSAID users had higher adverse events (6.37% vs. 2.23%, P = 0.023) as compared to single NSAID users.

Celecoxib significantly increased the incidence of new onset hypertension in this cohort of Indian patients with rheumatic diseases. No thromboembolic events were documented.

Fifteen to thirty percent of patients report no or little functional improvement 12 months after total knee replacement (TKR). Self-reported psychological distress prior to knee replacement is common and there is some evidence that it may be an important determinant of poor functional outcome in the short to medium term. The aim of this study was to review systematically the literature on the relationship between preoperative psychological distress and post-operative functional outcome after TKR. A literature search through the University of Melbourne Library Catalogue, Web of Science, SCOPUS-V.4, Medline, CINAHL PLUS, PsycINFO, Pubmed and the Cochrane Library was performed with the following key words and terms: joint replacement, arthroplasty, mental health, pre-operative distress, preoperative distress, psychological distress and knee. Additional screening of the reference lists was performed. All eligible publications were quality assessed by two independent reviewers according to the Newcastle-Ottawa Scale. The search found 10 cohort studies. The results of the studies were conflicting as six studies found a correlation between preoperative distress and functional outcome, whereas four did not.

The results from this review are conflicting. The use of different questionnaires to assess psychological distress and functional outcome makes it difficult to draw any conclusions. Future research should focus on using appropriate scales to measure exposure and outcome. We suggest using disease-specific questionnaires to assess preoperative psychological distress and a sensitive knee-specific outcome score to assess post-operative function.

To evaluate preoperative soft tissue balance for total knee arthroplasty (TKA), varus/valgus stress radiographs has been used in previous studies. While the joint line of femur and tibia is almost parallel in healthy and postoperative knees, osteoarthritis (OA) knees exhibit articular cartilage wear that causes the joint line tilting even in a non-stress condition. Therefore, the exact angle of the joint line might mislead to understand the joint laxity in OA knees. The purpose of this study was to evaluate soft tissue balance in varus OA knees using preoperative stress radiographs under three different constant loads, taking the articular cartilage wear into consideration. One hundred and eighteen varus-deformed OA knees in 102 patients were investigated before primary TKA. Preoperative knee radiographs were obtained in the anteroposterior view with no stress (defined as the neutral condition) and with varus and valgus stresses (5, 10, and 15 kg) in extension. Two different types of joint line angle (JLA), the absolute JLA (an exact angle of joint line) and the relative JLA (the absolute JLA minus the JLA in the neutral condition), were compared for the same load with the paired t test. The absolute JLA was 7.9 ± 1.2°/- 1.5 ± 2.2° under varus/valgus 15 kg stress, 6.7 ± 2.4°/- 0.3 ± 2.1° under varus/valgus 10 kg stress, and 4.7 ± 2.4°/1.1 ± 2.2° under varus/valgus 5 kg stress. Significant differences in the numerical values of the absolute JLA were observed between varus and valgus stresses for each load. The neutral JLA was 3.2 ± 2.0°. The relative JLA was 4.8 ± 2.1°/- 4.7 ± 1.8° under varus/valgus 15 kg stress, 3.5 ± 2.0°/- 3.5 ± 1.8° under varus/valgus 10 kg stress, and 1.5 ± 1.9°/- 2.1 ± 1.8° under varus/valgus 5 kg stress. No significant differences in the numerical values of the relative JLA were observed between varus and valgus stresses for each load. IV.

Consideration of cartilage wear allowed knee laxity to be evaluated more precisely in this study than in previous reports. It was shown that medial soft tissue contracture did not always exist, even in varus OA knees. Regarding clinical relevance, surgeons should be aware that underestimating medial soft tissue laxity due to reliance on the absolute JLA might lead to excessive medial tissue release and result in postoperative instability and lower patient satisfaction.

Several cases of rheumatoid arthritis (RA) with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated crescentic glomerulonephritis (CrGN) have been reported. However, its clinical characteristics are not clear. We summarized 3 patients of concurrent RA and MPO-ANCA-associated CrGN, diagnosed in our hospital from 1992 to 2006, and compared their clinicopathological data with those of 10 MPO-ANCA-associated CrGN patients without RA in the same period. All three RA patients were middle-aged or young adult women with 7-14 years of RA history. The initial clinical symptom was microhematuria, and mean duration from hematuria onset to histological confirmation of CrGN was 17 months. At renal biopsy, serum creatinine concentration (sCr) was modestly elevated, with the mean value of 3.4 mg/dl. Crescents were detected in 30% of glomeruli, whereas advanced glomerular sclerosis, tubular atrophy, and interstitial fibrosis were also observed. In comparison with patients without RA, patients with RA were significantly younger and showed a longer duration from the onset to histological confirmation of CrGN. Serum creatinine concentration at referral was significantly lower; however, estimated glomerular filtration rate (eGFR) was comparable. The Birmingham Vasculitis Activity Score and the Disease Extent Index were significantly lower, and pathological examination showed less crescent formation and a tendency to advanced glomerular sclerosis in patients with RA.

In patients with RA, MPO-ANCA-associated CrGN appeared to develop at younger ages and often showed a slowly progressive deterioration of the renal function with slight extrarenal manifestations. These smoldering clinical features may result in late referral from rheumatologists to nephrologists and therefore poor prognosis.

The purpose of this study was to evaluate sleep disturbance prospectively before and after short-stem hip arthroplasty. A prospective study on 25 patients undergoing a primary unilateral total short-stem hip replacement was conducted. Patients were observed for six months. To evaluate the sleep quality and daytime sleepiness, the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale were used. To assess the general physical health status, we used the Short Form 36 Health Survey (SF-36). Pain was recorded on a visual analog scale. The physical health status of the patients improved significantly (p < 0.05) during the six month follow-up period in seven out of nine categories. During the first post-operative week, the sleep quality stayed on an equal level to the pre-operative state, following a steady improvement over the next months (6 months p = 0.00). The daytime sleepiness showed a significant improvement during all the follow-ups (6 months p = 0.00). Pain decreased significantly from baseline to six months post-operatively (p = 0.00). There was no correlation between pain and sleep quality or pain and daytime sleepiness.

According to our results, patients undergoing short-stem total hip arthroplasty can expect a 50% improvement of sleep quality and physical function six months after surgery.

Syndesmophytes in ankylosing spondylitis (AS) can occur anywhere along the vertebral rim, but little is known about how and where they develop, and particularly if they first form in certain locations along the rim. This information might provide clues to their aetiology. We examined the spatial distribution of syndesmophytes in the thoracolumbar spine in patients with AS using CT. We performed lumbar spine CT scans in 50 patients and used a validated computer algorithm to measure syndesmophyte heights in six intervertebral disc spaces. We measured heights every five radial degrees around the rim of each superior and inferior vertebral endplate. Syndesmophytes were observed in 208 of 296 intervertebral disc spaces. Both ascending and descending syndesmophytes were non-randomly distributed along the vertebral rim (p<0.0001 for deviation from uniform distribution). Syndesmophytes occurred most often at the posterolateral vertebral rim, and least commonly at the posterior rim and anterior rim. In disc spaces with only small isolated syndesmophytes, these were also most likely to occur at the posterolateral rim. Syndesmophyte distribution varied with the vertebral level. Localisation at the posterolateral rim was most pronounced at T10-T11, T12-T12 and T12-L1, while L2-L3 and L3-L4 exhibited little localisation.

Syndesmophytes are not randomly distributed around the vertebral rim, as might be expected if they develop solely in response to inflammation. Rather, they preferentially occur, and likely develop first, at the posterolateral rim. Studying factors that can lead to this pattern may help elucidate how syndesmophytes develop.

To test if interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-4, or IL-10 gene polymorphisms could be used as markers of susceptibility or severity in rheumatoid arthritis (RA). The study included 108 patients with early RA followed up for 2 years and 128 healthy controls. From genomic DNA, 6 polymorphisms in genes for IL-1beta, IL-1Ra, IL-10, and IL-4 were typed. Allelic frequencies and carriage rates were compared between RA patients and controls, between patients with erosive and nonerosive RA, and between patients with or without sustained remission. The RP1 allele of the IL-4 gene was found with a significantly higher frequency in RA patients compared with controls. The combination of an RA-related HLA-DR allele expressing shared epitope and the presence of allele E2 in IL-1beta exon 5 was found to expose patients to an increased risk of erosive disease, with an odds ratio of 8.20 (95% confidence interval 2.59-25.84, P < 0.0001). No significant association was observed between polymorphisms and the occurrence of sustained remission.

This report, for the first time, indicates an association between RA and a polymorphic IL-4 gene sequence located in 5q31-33. In addition, the results show the prognostic value of a polymorphism in IL-1beta exon 5, which allowed prediction of erosive disease with a specificity of 91.8% in 42.1% of patients. Although these observations are very interesting, they have to be considered preliminary and will need to be confirmed.

To analyze whether erosions, sclerosis, and squaring assessed on radiographs precede the development of syndesmophytes in patients with ankylosing spondylitis (AS). Patients with AS from the Outcome in Ankylosing Spondylitis International Study (OASIS) cohort were followed up for 12 years, with radiographs obtained every 2 years. Two readers (reader 1 and reader 2) scored radiographs according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and recorded abnormalities per vertebral corner. Progression from erosions, sclerosis, or squaring to (bridging) syndesmophytes was investigated using multilevel longitudinal (autoregressive and time-lagged) regression analysis. Interactions with reader and spinal region were investigated. The analysis included 211 patients (71% male, 85% HLA-B27 positive) with a mean ± SD age of 43 ± 13 years and a symptom duration of 21 ± 12 years. A total of 921 radiographs were included, with 20,509 (reader 1) and 20,568 (reader 2) vertebral corners evaluable. Erosions were found in 1% and 2.5%, sclerosis in 0.3% and 1.7%, squaring in 6.5% and 5.1%, and syndesmophytes in 25% and 27%, by reader 1 and reader 2, respectively. The odds ratio for a new syndesmophyte to occur within 2 years at the same vertebral corner if erosions, sclerosis, or squaring were present was 2.0 (95% confidence interval [95% CI] 1.7-2.3) for the cervical and lumbar spine together, 3.1 (95% CI 2.5-3.9) for the cervical spine, and 1.3 (95% CI 1.0-1.6) for the lumbar spine. When vertebral corners with erosions, sclerosis, and squaring were analyzed separately, this effect was statistically significant for erosions and for sclerosis, but not for squaring.

Erosions and sclerosis occur infrequently in patients with AS, but when they do occur, they precede the development of a new syndesmophyte, and are therefore important to assess.

Longitudinal quantitative evaluation of cartilage disease requires reproducible measurements over time. We report 8 years of quality assurance (QA) metrics for quantitative magnetic resonance (MR) knee analyses from the Osteoarthritis Initiative (OAI) and show the impact of MR system, phantom, and acquisition protocol changes. Key 3T MR QA metrics, including signal-to-noise, signal uniformity, T2 relaxation times, and geometric distortion, were quantified monthly on two different phantoms using an automated program. Over 8 years, phantom measurements showed root-mean-square coefficient-of-variation reproducibility of <0.25% (190.0 mm diameter) and <0.20% (148.0 mm length), resulting in spherical volume reproducibility of <0.35%. T2 relaxation time reproducibility varied from 1.5% to 5.3%; seasonal fluctuations were observed at two sites. All other QA goals were met except: slice thicknesses were consistently larger than nominal on turbo spin echo images; knee coil signal uniformity and signal level varied significantly over time.

The longitudinal variations for a spherical volume should have minimal impact on the accuracy and reproducibility of cartilage volume and thickness measurements as they are an order of magnitude smaller than reported for either unpaired or paired (repositioning and reanalysis) precision errors. This stability should enable direct comparison of baseline and follow-up images. Cross-comparison of the geometric results from all four OAI sites reveal that the MR systems do not statistically differ and enable results to be pooled. MR QA results identified similar technical issues as previously published. Geometric accuracy stability should have the greatest impact on quantitative analysis of longitudinal change in cartilage volume and thickness precision.

The aim of this retrospective study was to identify the preoperative patient-related factors affecting the soft tissue balancing in cruciate-retaining total knee arthroplasty. This is an important clinical issue, as the acquisition of adequate soft tissue balancing is essential for successful outcomes. The study group included 59 knees treated for medial compartment osteoarthritis. The extension gap was measured using the newly electric tensor that enables continuous quantification of a distraction force ranging from 0 to 40 lbf. We performed regression analyses to identify the relationship between preoperative factors and the extension gap. Patient height, weight, and percent mechanical axis showed univariate correlation with the extension gap of either 30 lbf or 40 lbf. In the multivariate regression analysis without encountering multicollinearity, percent mechanical axis was inversely associated with the extension gap (t-value = -2.31, p = 0.02 for 30 lbf; and t-value = -2.39; p = 0.02 for 40lbf) as a significant independent factor.

We revealed the significant influence of several factors on the absolute value of the extension gap. Particularly, the severity of preoperative coronal alignment was a statistically independent explanatory variable, and the extension gap was overvalued in knees with severe varus deformity. This influence should be considered when comparing different individual cases longitudinally. Our feasible strategies could lead to a better understanding about the soft tissue balancing in total knee arthroplasty.

To evaluate the safety and efficacy of once-weekly subcutaneous rilonacept 160 mg for prevention of gout flares in patients initiating or continuing urate-lowering therapy (ULT). This phase III study was conducted in the United States, South Africa, Europe, and Asia. Adults (n = 1315, 18-80 yrs) with gout, who were initiating or continuing ULT, were randomized to treatment with weekly subcutaneous injections of rilonacept 160 mg or placebo for 16 weeks followed by a 4-week safety followup. The primary endpoint was safety, assessed by adverse events (AE) and laboratory values. Efficacy was a secondary endpoint. Demographic and clinical characteristics were similar between treatments; predominantly male (87.8%), mean age 52.7 ± 11.3 years. Patients with ≥ 1 AE were 66.6% with rilonacept versus 59.1% placebo, with slightly more AE-related withdrawals with rilonacept (4.7% vs 3.0%) because of the greater incidence of injection site reactions (15.2% rilonacept, 3.3% placebo). Serious AE were similar in both groups, as were serious infections (0.9% placebo, 0.5% rilonacept); no tuberculosis or opportunistic infections occurred. Most common AE were headache, arthralgia, injection site erythema, accidental overdose, and pain in extremity. Of the 6 deaths, only 1 in the placebo group was considered treatment-related. At Week 16, rilonacept resulted in 70.3% fewer gout flares per patient (p < 0.0001), fewer patients with ≥ 1 and ≥ 2 gout flares (p < 0.0001), and 64.9% fewer gout flare days (p < 0.0001) relative to placebo.

Weekly subcutaneous administration of rilonacept 160 mg showed no new safety signals. The safety profile was consistent with previous studies. Rilonacept also significantly reduced the risk of gout flares. Clinicaltrials.gov identifier NCT00856206; EudraCT No. 2008-007784-16.

Syphilis has been making a comeback over the last 10 years. Neurosyphilis can occur at any stage of the infection but is difficult to diagnose because of the existence of misleading forms, of which we describe an example below. A 56-year-old woman presented symptoms evoking polymyalgia rheumatica and giant-cell arteritis in a context of ibuprofen treatment for a few weeks. She also had myodesospsia, syphilids and syphilitic roseola, together with laboratory indicators of inflammation. A lumbar puncture revealed lymphocytic meningitis and a positive Treponema Pallidum Haemagglutination Assay (TPHA) for cerebrospinal fluid, thus confirming the diagnosis of neurosyphilis. Moreover, the ophthalmologic examination showed optic neuritis with papilla lesions of syphilitic origin. This was successfully treated with a 3-week course of penicillin G infusions.

Symptoms evocative of Horton's disease and polymyalgia rheumatica can reveal syphilis, a disease dubbed "the great simulator" on account of the variety of clinical forms it can take.

Although a number of recent studies have described the outcome of surgical treatment of patients with rheumatoid cervical myelopathy, few have reported outcome in those unable to have surgery. We sought to examine the outcome in this group of patients regardless of surgical intervention. Retrospective and descriptive. Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, UK. Retrospective review of case notes of 40 patients (31 females, 9 males) with rheumatoid cervical myelopathy diagnosed 1988-1997. The mean age was 64 years (range 36-80 years). The mean duration of rheumatoid arthritis (RA) before the development of myelopathy was 21 years (range 5-44 years). The common impairments were paraesthesia in the arms, neck pain and weakness. Twenty-five patients (60%) were deemed fit for surgery (group I). Twenty-two patients successfully had operative treatment and the others refused. Twelve of the 15 patients who reported pain preoperatively obtained pain relief. Six of the 11 patients who were nonambulant (Ranawat class IIIB) were able to walk postoperatively. There were two deaths within six months (9% mortality) after primary surgery due to pneumonia and sepsis. Seven of the 15 patients managed conservatively (group II) because of coexisting medical complications died within six months of presentation (47% mortality).

The study confirms the overall benefit of surgical intervention in those who are medically stable. Following surgery some functional improvement may occur even in patients with severe myelopathy.

To investigate whether peptidyl arginine deiminase type IV gene (PADI4) polymorphisms contribute to rheumatoid arthritis (RA) susceptibility in Egyptians, whether they influence disease severity and activity, and whether they affect anti-mutated citrullinated vimentin antibodies (anti-MCV) level. Three PADI4 single nucleotide polymorphisms (SNPs) (PADI4-92, PADI4-96, and PADI4-102) were screened in 275 RA patients and 275 unaffected controls by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method. Serum anti-MCV levels were measured by enzyme-linked immunosorbent assay (ELISA). There were significant associations between RA susceptibility with the minor alleles of PADI4-92 and PADI4-102 [odds ratio (OD) and 95% confidence interval (CI) for the minor alleles of PADI4-92 and PADI4-102: 1.48 (1.17-1.88) and 2.05 (1.61-2.61) respectively] but not with PADI4-96 [OD and 95% CI for the C allele: 1.09 (0.86-1.39)]. PADI4 haplotypes 2 (GCC) and 3 (GCT) were also associated with RA susceptibility while PADI4 haplotypes 1 (CTC) may be protective against developing of this disease. A significant association was detected between PADI4 haplotypes and RA severity.

The PADI4 SNPs and haplotypes were associated with RA susceptibility, although no relation was observed between the PADI4 haplotypes and anti-MCV levels.

Rheumatoid arthritis has manifestations in various organs including ophthalmic involvement. The present study evaluates prevalence of dry eye and secondary Sjogren's syndrome using salivary scintigraphy which has not been used in previous reports. To evaluate the prevalence of secondary Sjogren's syndrome in patients with rheumatoid arthritis, including clinical characteristics and dry eye, compared with non-Sjogren's syndrome. Descriptive cross sectional study Sixty-one patients with rheumatoid arthritis were recruited at Siriraj Hospital during March 2009-September 2010 and filled in the questionnaires about dry eye for Ocular Surface Disease Index (OSDI) with a history taking of associated diseases, medications, duration of symptoms of dry eyes and dry mouth. The Schirmer I test without anesthesia, tear break-up time, rose bengal staining score, severity of keratitis and salivary scintigraphy were measured and analyzed. Prevalence of secondary Sjogren's syndrome and dry eye were 22.2% (95% CI 15.4 to 30.9) and 46.7% (95% CI 38.0 to 55.6), respectively. Dry eye interpreted from OSDI, Schirmer 1 test, tear break-up time and rose bengal staining was 16.4%, 46.7%, 82% and 3.3% respectively. Fifty-two percent of patients had a history of dry eye and dry mouth with mean duration 27.4 and 29.8 months, respectively. Superficial punctate keratitis and abnormal salivary scintigraphy were found in 58.2% and 77.8%. Duration of rheumatoid arthritis, erythrocyte sedimentation rate were not correlated with secondary Sjogren's syndrome. Dry eye from OSDI with secondary Sjogren's syndrome (33.3%) compared with non-Sjogren's syndrome (9.5%) was significant difference (p = 0.008). Adjusted odds ratio for secondary Sjogren's syndrome in OSDIL score > 25 was 13.8 (95% CI 2.6 to 73.8, p = 0.002) compared to OSDI score < 25.

Awareness and detection of dry eye syndrome and secondary Sjogren's syndrome in rheumatoid arthritis was crucial for evaluation of their severity and proper management.

This study investigated the in-vitro effects of a crystalline glucosamine sulfate (GS) preparation on DNA synthesis and on proteoglycan (PG) and type II collagen (coll II) production by human articular chondrocytes isolated from human osteoarthritic articular cartilage in a 3-dimensional culture system for 4, 8, and 12 days. Human articular chondrocytes from osteoarthritic femoral heads were isolated from their matrix by collagenase digestion and then cultured in suspension. Under constant agitation, cells aggregated and formed a cluster within a few days. The effects of GS (1-100 micrograms/ml) on chondrocytes were determined by quantifying DNA synthesis (by measurement of [3H]-thymidine uptake) as well as PG and coll II production using radiommunoassays (RIAs) specific for coll II and to human human cartilage PG. Cross-reaction with GS in the RIAs was not detected. Moreover, PG size distribution was determined by exclusion chromatography under associative conditions to determine the association of PG monomers with hyaluronic acid (HA) to form large molecular weight PG aggregates. Under the above conditions, PG production in culture media and chondrocyte clusters was increased by GS (10-100 micrograms/ml). DNA synthesis and coll II production were not modified by GS. In addition, GS did not modify the physico-chemical form of PG produced by cells during culture.

Glucosamine sulfate did not affect DNA synthesis nor coll II production but caused a statistically significant stimulation of PG production by chondrocytes from human osteoarthritic cartilage cultured for up to 12 days in 3-dimensional cultures.

To determine whether demographic, inflammatory, and metabolic factors predict elevated asymmetric dimethylarginine (ADMA) levels in rheumatoid arthritis (RA). A total of 67 RA patients [mean age 56 ± 12 years, median disease duration 8 (3-15) years] were assessed. Routine biochemistry tests, lipid profile, glycaemic profile [glucose, insulin, homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI)], and inflammatory markers were measured in all patients. ADMA levels were measured by enzyme-linked immunosorbent assay (ELISA). Regression analyses were performed to identify predictors of ADMA in RA. Regression analysis revealed that HOMA (β = 0.149, p = 0.003) was an independent predictor of ADMA in RA. From the drug factors, anti-hypertensive medication use was associated with lower ADMA levels (β = -0.081, p = 0.004). ADMA was not associated with RA disease-related parameters or any of the other cardiovascular risk factors that were assessed.

HOMA, a strong indicator of insulin resistance, seems to be the main predictor of elevated ADMA levels in RA patients; ADMA may reflect an important pathway linking abnormal insulin metabolism with endothelial dysfunction in RA.

To compare the risk of serious infections between the use of tumor necrosis factor inhibitors (TNFi) plus methotrexate (MTX) versus triple therapy among rheumatoid arthritis (RA) patients in a real-world setting. Using claims data from Truven MarketScan (2003-2014), we conducted a cohort study to compare RA patients receiving MTX who added a TNFi (TNFi plus MTX group) versus MTX plus hydroxychloroquine and sulfasalazine (triple therapy group). The primary outcome was any serious infection (i.e., a composite end point of hospitalized bacterial and opportunistic infections or herpes zoster). Secondary outcomes were individual components of the composite end point. To adjust for baseline confounding, we used propensity score (PS)-based fine stratification and weighting. A weighted Cox proportional hazards model estimated the hazard ratio (HR) and 95% confidence interval (95% CI) of the outcomes. After PS stratification (PSS) and weighting, we included a total of 45,208 TNFi plus MTX initiators and 1,387 triple therapy initiators. Mean age was 53 years and 70% were female. The incidence rate of any serious infection per 100 person-years was 2.46 in the TNFi plus MTX group and 2.03 in the triple therapy group. The PSS-weighted HR for any serious infection comparing TNFi plus MTX versus triple therapy was 1.23 (95% CI 0.87-1.74). For the secondary outcomes, the PSS-weighted HR was 1.41 (95% CI 0.85-2.34) for bacterial infection and 0.80 (95% CI 0.55-1.18) for herpes zoster.

In this real-world cohort of RA patients, we noted no substantially different risk of any serious infection, bacterial infection, or herpes zoster after initiating TNFi plus MTX versus triple therapy, although CIs were wide.

Primary Sjögren's syndrome (pSS) is associated with immunological dysfunctions--a well-known risk factor of shingles. This study aimed to examine the incidence and risk of shingles in adults with pSS and pharmacological treatments. This retrospective population-based cohort study was conducted using National Health Insurance claims data. Using propensity scores, 4,287 pSS adult patients and 25,722-matched cohorts by age, gender, selected comorbidities and Charlson comorbidity index scores were identified. Kaplan-Meier analysis and Cox regression were conducted to compare the differences in developing shingles. In pSS, oral and eye dryness are treated with substitute agents. Extraglandular features are often treated with pharmacological drugs including steroids and immunosuppressants. pSS patients were grouped as follows: no pharmacological drugs, steroids alone; immunosuppressants alone; combined therapies. During the follow-up, 463 adults with pSS (10.80%) and 1,345 control cohorts (5.23%) developed shingles. The cumulative incidence of shingles in pSS patients (18.74/1,000 patient-years) was significantly higher than controls (8.55/1,000 patient-years). The adjusted hazard ratio (HR) of shingles was 1.69 (95% confidence interval (CI) 1.50-1.90). In age-subgroup analyses, incidences of shingles in pSS increased with age and peaked in pSS patients aged ≧60; however, adjusted HRs decreased with age. Compared to control cohorts with no drugs, adjusted HRs for shingles in pSS patients were ranked from high to low as: combined therapies (4.14; 95% CI 3.14-5.45) > immunosuppressants alone (3.24; 95% CI 2.36-4.45) > steroids alone (2.54; 95% CI 2.16-2.97) > no pharmacological drugs (2.06; 95% CI 1.76-2.41). Rates of shingles-associated hospitalization and postherpetic neuralgia were 5.62% and 24.41%, both of which were significantly higher than those (2.60%; 13.01%) in the control cohorts.

Adults with pSS were at greater risk for shingles than control cohorts. Drug exposures significantly increased the risk of shingles in pSS.

To assess possible associations between inflammatory rheumatic disease and pregnancy complications/delivery practice. In a population based study proportions were compared of obstetrical complications and interventions at delivery notified to the Medical Birth Registry of Norway during the years 1967-95 in women with (3,403) and without (671,221) rheumatic disease. Women with rheumatic disease had significantly higher rates of preeclampsia and cesarean section. The relative risk of preeclampsia was particularly high in women with connective tissue disease in the years 1977-86. In women with inflammatory arthritides, the relative risk of preeclampsia was particularly high during 1987-95. The relative risk of cesarean section was high in all patient groups throughout the observation period and particularly in women with connective tissue disease.

High rates of preeclampsia and cesarean section in connective tissue disease pregnancies documented in a population based study emphasize the importance of monitoring and obstetrical interventions.

Metal-on-metal resurfacing arthroplasty is an attractive alternative to conventional total hip arthroplasty in patients with osteoarthritis secondary to developmental dysplasia of the hip (DDH). The purpose of this study was to assess the mid-term clinical outcome and mid-term survivorship of Metal-on-metal resurfacing arthroplasty in patients suffering from osteoarthritis secondary to DDH. Between May 2003 and Dec. 2005, 15 operations using ASR™ and 19 using Corin were performed in 29 patients to treat advanced osteoarthritis secondary to DDHs. There were 6 males (20.7%) and 23 females (79.3%), with an average age of 47.2 years (range, 36-64 years). Clinical and radiographic results were observed. All patients were followed up at the 1st, 2nd, 3rd, 6th, and 12th months after surgery and annually thereafter. The overall survival was 88.2% at a minimum follow-up of 8 years, but the survival was 91.2% after excluding the infections as the cause of component loosening and failure. The mean Harris hip score improved from 48.27±3.13 (range, 14-71) to 89.63±3.42 (range, 65-100) at latest follow-up. The flexion was from 75.14±8.05° to 107.21±9.34. Only 4 failed because of deep infection, femoral neck fracture, and aseptic loosening.

Metal-on-metal resurfacing arthroplasty showed perfect results at a minimum of 8-years of follow-up in our study, and may be a reasonable option for osteoarthritis secondary to developmental dysplasia of the hip (DDH).

To investigate whether the abnormal expression of inducible nitric oxide synthase (iNOS) by osteoarthritic (OA) human chondrocytes is associated with changes in the DNA methylation status in the promoter and/or enhancer elements of iNOS. Expression of iNOS was quantified by quantitative reverse transcriptase-polymerase chain reaction. The DNA methylation status of the iNOS promoter and enhancer regions was determined by bisulfite sequencing or pyrosequencing. The effect of CpG methylation on iNOS promoter and enhancer activities was determined using a CpG-free luciferase vector and a CpG methyltransferase. Cotransfections with expression vectors encoding NF-κB subunits were carried out to analyze iNOS promoter and enhancer activities in response to changes in methylation status. The 1,000-bp iNOS promoter has only 7 CpG sites, 6 of which were highly methylated in both control and OA samples. The CpG site at -289 and the sites in the starting coding region were largely unmethylated in both groups. The NF-κB enhancer region at -5.8 kb was significantly demethylated in OA samples compared with control samples. This enhancer element was transactivated by cotransfection with the NF-κB subunit p65, alone or together with p50. Critically, methylation treatment of the iNOS enhancer element significantly decreased its activity in a reporter assay.

These findings demonstrate the association between demethylation of specific NF-κB-responsive enhancer elements and the activation of iNOS transactivation in human OA chondrocytes, consistent with the differences in methylation status observed in vivo in normal and human OA cartilage and, importantly, show association with the OA process.

Knee extensor weakness has not been associated consistently with the risk for incident knee pain. Additionally, the balance of hamstring-to-quadriceps strength (H:Q ratio) may affect risk and has not been studied. The authors determined whether knee extensor weakness or muscle imbalance is a risk factor for development of frequent knee pain or stiffness and whether the effect is modified by lower limb alignment. Observational study. Community. Community-dwelling adults ages 50-79 years with or at risk of knee osteoarthritis based on obesity, knee injury, or surgery. A total of 1269 knees from women and 1006 knees from men without frequent knee symptoms at baseline and with 15- or 30- month follow-up outcome data were included. Isokinetic knee extensor and flexor strength as well as radiographic hip-knee-ankle alignment were measured at baseline. H:Q ratio was dichotomized, with normal being considered to be >/=0.6. Frequent knee symptoms at 15- or 30-month follow-up (frequent knee pain, aching, or stiffness on most days of the past month reported at both telephone contact just before and at visit). Mean +/- SD age was 62.2 +/- 8.0 years and mean body mass index (BMI) was 30.1 +/- 5.4 kg/m(2). Mean peak knee extensor strength (KES) was 132.6 +/- 42.4 and 76.9 +/- 25.3 N.m in men and women, respectively. Approximately 50% of knees in men and 59% of knees in women had an H:Q ratio <0.6. A total of 307 of 2275 eligible knees developed frequent knee symptoms at follow-up. Logistic regression controlling for age, BMI, femoral neck bone mineral density, activity score, and baseline Kellgren Lawrence grade revealed that neither KES nor H:Q ratio predicted the development of knee symptoms in gender-stratified or combined analyses. These results were unaffected by adjusting for lower limb alignment.

Neither concentric quadriceps strength nor H:Q ratios predicted the development of frequent knee symptoms at 15- or 30-month follow-up in this cohort.

Bone is thought to play an important role in osteoarthritis (OA) pathophysiology. Our aim was to look at specific features of OA and their relation to the ratio of medial:lateral tibial plateau bone mineral density (M:L BMD Ratio). We examined our research question in the Framingham OA Study Cohort. All participants had BMDs and weight-bearing plain radiographs of the knees (2002-2005). M:L BMD Ratios were calculated using BMD from medial and lateral regions in the tibial plateau. Knee x-rays were read for osteophytes (OSTs), joint space narrowing (JSN), and sclerosis (Osteoarthritis Research Society International (OARSI) scoring system). Knees were classified as having medial and/or lateral JSN if they had JSN >or=1 in the medial and/or lateral tibiofemoral compartments, respectively. Medial and/or lateral OSTs were defined as medial and/or lateral tibial and/or femoral OSTs >or=2, respectively. Medial sclerosis and lateral sclerosis were defined as medial and lateral tibial sclerosis >or=1, respectively. We performed a logistic regression with medial JSN as the outcome and with M:L BMD Ratio groups as predictor variables, using the median group as the referent. Analyses were adjusted for age, sex, and body mass index (BMI). Generalized estimating equations were used to adjust for correlation between knees. Identical analyses were performed with medial OSTs, medial sclerosis, lateral JSN, lateral OSTs, and lateral sclerosis as the outcomes. Mean age of 1612 subjects (3048 knees) was 63.9 (Standard Deviation (SD)+/-8.9), 56% were women, and mean BMI was 28.5 (SD+/-5.5). M:L BMD Ratio was positively associated with medial JSN (P for linear trend <0.0001) and negatively associated with lateral JSN (P for linear trend <0.0001). The relations of the ratio with medial and lateral OSTs were j-shaped with P for quadratic trends <0.0001. There were also strong associations between M:L BMD Ratio and compartment-specific sclerosis (P for linear trends <0.0001) with most knees with medial and lateral sclerosis being in the highest and lowest M:L BMD Ratio groups, respectively.

In summary, the extremes of the M:L BMD Ratio are strongly associated with individual radiographic features of OA. These findings add to existing evidence supporting the importance of understanding bone in OA pathophysiology.

To investigate the clinical effect of thunder-fire moxibustion combined with electroacupuncture in the treatment of cold-dampness knee osteoarthritis. A total of 72 patients with cold-dampness knee osteoarthritis were randomly divided into observation group and control group according to the random numbers generated by computer software, with 36 patients in each group. For the observation group, electroacupuncture was performed at the main acupoints of Dubi (ST35), Neixiyan (EX-LE4), Zusanli (ST36), Yanglingquan (GB34), Yinlingquan (SP9), Xuehai (SP10), Liangqiu (ST34), and Heding (EX-LE2) once a day, with a needle retaining time of 30 min, and thunder-fire moxibustion was performed at Shenque (CV8) and Guanyuan (CV4) in the form of suspended moxibustion once a day, with 30 min each time. The patients in the control group were given oral administration of diclofenac sodium double-release enteric-coated capsules, 75 mg each time, once a day, and Fugui Gutong capsules, 6 capsules a time and 3 times a day. Each course of treatment was 14 days, and both groups were treated for 2 courses, with an interval of 2 days between the two courses. Visual Analogue Scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Lequesne index were observed before the treatment, immediately after the treatment, and at 4 months after the treatment, and the outcome of traditional Chinese medicine (TCM) syndrome was compared between the two groups after treatment. Both groups had significant reductions in VAS score, WOMAC score, and Lequesne index immediately and at 4 months after the treatment (

Thunder-fire moxibustion combined with electroacupuncture has a better, more durable clinical effect and fewer adverse reactions than the drugs in the treatment of cold-dampness knee osteoarthritis.

To investigate whether there are any variations in chondrocyte susceptibility to an apoptotic stimulus between cells of articular cartilage (AC) from equine joints that differ in prevalence of osteoarthritis (OA). Cartilage from macroscopically normal equine metacarpophalangeal (MCP), proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints was used. Prior to culture, chondrocyte viability was assessed using the fluorescein diacetate (FDA) and propidium iodide paravital staining method. AC explants were subsequently treated with tumour necrosis factor-α (TNF-α) in combination with Actinomycin D to induce apoptosis. Apoptosis of chondrocytes in cartilage sections was assessed by expression of active caspase-3 using indirect immunohistochemistry and sections also histologically graded using a 'modified' Mankin scoring system. Prior to culture (mean ± standard deviation) chondrocyte viability was 80.7% (3.5). The extent of chondrocyte apoptosis induced by TNF-α/Actinomycin D varied markedly according to the joint type that the cartilage was sampled from. For MCP joints, the extent of overall chondrocyte apoptosis was significantly higher (P < 0.001) in stimulated explants (26.7%, 10.3) than that observed in unstimulated control samples (9.6%, 7.5). Conversely, chondrocytes from PIP and DIP joint cartilage did not respond significantly to apoptotic stimulation (P > 0.05). Significant variations in cellularity and thickness were also evident between cartilages of different joint types.

Data in this study demonstrate that chondrocytes from three equine joint types with varying prevalences of OA differ significantly in terms of susceptibility to apoptosis induction. This may provide a possible explanation for the joint-specific nature of the disease.

A cross-sectional study. The main goal of the study was to analyze posture of Fibromyalgia syndrome (FMS) in women compared with healthy subjects to establish if posture assessment could be useful to characterize the syndrome. Secondarily, we explored the impact of sedentary behavior on trunk posture. Pain has been associated with poor static postures, however there is little information on the effect of FMS, which is characterized by widespread pain, on trunk posture. One hundred eighteen women with FMS and 110 healthy counterparts participated in this study, in which trunk posture was assessed. The thoracic kyphosis, forward head position, and shoulder position (basal and maximum protraction) were measured. Further, maximum shoulder protraction and the ability to maintain the cervical and thoracic angle were assessed. To compare the differences in posture depending on the grouping, an independent Student t test was conducted. To analyze the differences between groups in the ability to maintain the position over a period of time and the differences in posture depending on more or less active lifestyles, two multivariate analysis of variance were performed. The results showed a significantly larger thoracic kyphosis, baseline shoulder protraction and lower craniovertebral angle and maximum protraction in FMG compared with CG (P < 0.05). FMG subjects exhibited an impaired ability to maintain the cervical and thoracic angles, as this varied throughout the test, unlike those of their counterparts. A sedentary lifestyle did not affect trunk posture in the FMS participants. 2.

FMS female population present an altered trunk posture and an inability to maintain trunk position. Since this does not appear to be influenced by a more or less active lifestyle, specific treatment programs are needed to manage this clinical condition.

To study the state of gut microsymbiocenosis in children with reactive arthritis (RA), with the assessment of biofilm formation (BFF) of microsymbionts and the ability to change cytokine levels (their anticyokine activity) in vitro. The investigation of gut microsymbiocenosis by means of bacteriological method was conducted in 34 children with RA and 25 relatively healthy 3 - 16 year- old children. Microorganisms were identified with the help of MALDI-TOF mass-spectrometry, anticytokine activity (ACA) of microsymbionts - according to Bukharin O.V et al. (2011), biofilm formation - according to O'Toole G.A., Kolter R. (1998). On the ground of species composition differences of gut microbiota discrimination model was created which allowed to separate the group of children with RA from healthy individuals. Microsymbiocenosis of patients with RA was characterized by increasing number of opportunistic microorganisms (OM) (enterobacteria, clostridia, bacteroides, and Candida), BFF and ACA level.

The obtained data greatly contribute.to the deciphering of spondylo- arthritis and disclose the role of microbial factor under given pathology. Hypercolonisation of human gut with OM, having pronounced ability to BFF and regulating cytokine level, promotes strengthening of arthritogenic potential and serves as additional marker of arthritis development risk in children.

Cell signaling via Toll-like receptors (TLRs) leads to synovial inflammation in rheumatoid arthritis (RA). We aimed to assess effects of TLR2 and TLR4 stimulation on proinflammatory cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with recent-onset RA, osteoarthrosis (OA), and healthy control (HC). PBMCs were stimulated with LPS, biglycan and cytokine mix. Cytokines were analyzed in supernatants with ELISA. Expression of toll-like receptors mRNA in leukocytes was analyzed using real-time qPCR. PBMCs from RA patients spontaneously produced less IL-6 and TNFalpha than cells from OA and HC subjects. LPS increased cytokines' production in all groups. In RA patients increase was dramatic (30 to 48-fold and 17 to 31-fold, for respective cytokines) compared to moderate (2 to 8-fold) in other groups. LPS induced 15-HETE generation in PBMCs from RA (mean 251%) and OA patients (mean 43%), although only in OA group, the increase was significant. TLR2 and TLR4 gene expressions decreased in response to cytokine mix, while LPS enhanced TLR2 expression in HC and depressed TLR4 expression in OA patients.

PBMCs from recent-onset RA patients are overresponsive to stimulation with bacterial lipopolysaccharide. TLR expression is differentially regulated in healthy and arthritic subjects.

Osteochondral allograft (OCA) transplantation is an effective treatment option for chondral and osteochondral defects of the knee. Patients treated with OCAs for reciprocal bipolar lesions of the knee would demonstrate significant clinical improvement. Case series; Level of evidence, 4. Between 1983 and 2010, OCAs were implanted for bipolar chondral lesions in 46 patients (48 knees). The 21 male and 25 female patients averaged 40 years of age (range, 15-66 years). Thirty-four lesions were tibiofemoral, and 14 were patellofemoral. Forty-two knees (88%) had undergone a mean of 3.4 previous surgeries (range, 1-8). The mean allograft area was 19.2 cm(2). Clinical evaluation included the modified Merle d'Aubigné-Postel (18-point), International Knee Documentation Committee (IKDC) pain and function, and Knee Society function (KS-F) scores. Further surgeries on the operative joint were documented. Survivorship of the bipolar OCA was 64.1% at 5 years. Thirty knees underwent further surgery; 22 knees (46%) were considered failures (3 OCA revisions, 14 total knee arthroplasties, 2 unicondylar arthroplasties, 2 arthrodeses, and 1 patellectomy). Among patients whose OCA was still in situ at follow-up, the mean follow-up was 7 years (range, 2.0-19.7 years). The mean 18-point score improved from 12.1 to 16.1; 88% (23/26 knees) of surviving allografts scored ≥15. The mean IKDC pain score improved from 7.5 to 4.7, and the mean IKDC function score improved from 3.4 to 7.0. The mean KS-F score improved from 70.5 to 84.1.

Osteochondral allograft transplantation is a useful salvage treatment option for reciprocal bipolar cartilage lesions of the knee. High reoperation and failure rates were observed, but patients with surviving allografts showed significant clinical improvement.

The aim of this study was to assess whether baseline characteristics in patients with undifferentiated arthritis or early RA affect the possibility of achieving drug-free remission after 1 year (DFR1 year) of early remission induction therapy. We included 375 patients participating in the IMPROVED study who achieved remission (DAS < 1.6) after 4 months (early remission) and were by protocol able to achieve DFR1 year. Having started with MTX plus prednisone, patients tapered prednisone to zero; after 8 months, those still in remission tapered MTX to zero, while those not in remission restarted prednisone. Characteristics of patients achieving and not achieving DFR1 year were compared. Logistic regression was performed to identify predictors of DFR1 year. After 1 year, 119 patients (32%) were in DFR. Presence of RF, fulfilling the 2010 criteria for RA, and a low tender joint count were associated with achieving DFR1 year, whereas presence of ACPA was not. None of the baseline characteristics was independently associated with DFR1 year. DFR1 year was sustained for 4 months in 65% of the patients. ACPA-positive patients less often had sustained DFR than ACPA-negative patients (58% vs 80%, P = 0.013).

After 1 year of remission-steered treatment, 32% of the patients who had achieved early remission after 4 months were able to taper medication and achieved DFR. Neither the presence of ACPA nor any other baseline characteristics were independently associated with achieving DFR1 year, but in ACPA-positive patients DFR was less often sustained.

The transforming growth factor-β (TGF-β) signaling pathway plays an essential role in maintaining homeostasis in joints affected by osteoarthritis (OA). However, the specific mechanism of non-SMAD and classical SMAD signaling interactions is still unclear, which needs to be further explored. In ATDC5 cells, USP15 overexpression and knockout were performed using the transfected lentivirus USP15 and Crispr/Cas9. Western blotting and immunofluorescence staining were used to test p-SMAD2 and cartilage phenotype-related molecular markers. In rat OA models, immunohistochemistry, hematoxylin and eosin (HE)/Safranin-O fast green staining, and histology were used to examine the regulatory activity of USP15 in TGF-β/SMAD2 signaling and the cartilage phenotype. Then, ERK2 overexpression and knockout were performed. The expressions of USP15, p-SMAD2, and the cartilage phenotype were evaluated in vitro and in vivo. To address whether USP15 is required for ERK2 and TGF-β/SMAD2 signaling, we performed rescue experiments in vitro and in vivo. Immunoprecipitation and deubiquitination assays were used to examine whether USP15 could bind to ERK2 and affect the deubiquitination of ERK2. Finally, whether USP15 regulates the level of p-ERK1/2 was evaluated by western blotting, immunofluorescence staining, and immunohistochemistry in vitro and in vivo. Our results indicated that USP15 stimulated TGF-β/SMAD2 signaling and the cartilage phenotype. Moreover, ERK2 required USP15 to influence TGF-β/SMAD2 signaling for regulating the cartilage phenotype in vivo and in vitro. And USP15 can form a complex with ERK2 to regulate ubiquitination of ERK2. Interestingly, USP15 did not regulate the stability of ERK2 but increased the level of p-ERK1/2 to further enhance the TGF-β/SMAD2 signaling pathway.

Taken together, our study revealed positive feedback regulation between USP15 and ERK2, which played a critical role in TGF-β/SMAD2 signaling to inhibit OA progression. Therefore, this specific mechanism can guide the clinical treatment of OA.

The present article aims to provide a systematic review of the influence of antitumor necrosis factor (TNF) on infection rates in patients with rheumatoid arthritis (RA). Medline was searched to obtain quality control information on infection rates in RA patients treated with anti-TNF. A high proportion of RA patients are now established users of anti-TNF agents. Data from national registries in European countries of patients with RA treated with anti-TNF suggest that biological therapies are closely linked to sepsis. Although previous studies reported a higher risk of infections, there are now emerging data with longer duration of follow-up that suggested an adjusted hazard risk of 1.2. Elderly patients and those with longstanding disease may have a higher rate of serious infections compared to their counterparts who were younger with early disease. There are now emerging data to suggest that anti-TNF therapy is associated with the development of neutropenia shortly after the commencement of treatment. The biologic registries found that RA patients treated with monoclonal antibodies are at increased risk of tuberculosis (TB) compared to those on TNF receptor blockers. This risk of infection needs to be weighed against the established benefits of TNF blockers.

Current evidence suggests that anti-TNF treatment in RA is closely linked to infection. Patients need to be aware of the risk of infection together with the established benefits of TNF blockers in order to give informed consent for treatment.

To evaluate height, sexual maturation, and the difference between final and expected height in girls with juvenile idiopathic arthritis and no glucocorticoid treatment for at least six months, as compared to a group of healthy girls. This cross-sectional study involved 44 girls with juvenile idiopathic arthritis, diagnosed according to the International League of Associations for Rheumatology criteria, and 59 healthy controls aged between 8 and 18 (incomplete) years with no comorbid chronic diseases. Demographic data were collected from all participants, and disease and treatment variables were compiled for the patient group. Anthropometric measurements were converted into Z-scores based on World Health Organization standards. Sexual maturation was classified according to Tanner stages. Body mass index and height Z-scores were lower in girls with juvenile idiopathic arthritis as compared to control participants. These values differed significantly in Tanner stage II. Three (6.8%) girls with juvenile idiopathic arthritis had height-for-age Z-scores <-2 (short stature). Girls with polyarticular juvenile idiopathic arthritis and higher cumulative glucocorticoid doses were significantly more likely to present with short stature. The percentage of prepubertal girls in the juvenile idiopathic arthritis group was significantly higher than that observed in the control group, (p=0.012). Age of menarche, adult height, and the difference between actual and expected height did not differ between groups.

These findings suggest that even six months after the suspension of glucocorticoid treatment, children with polyarticular/systemic juvenile idiopathic arthritis subtypes are still susceptible to low height and delayed puberty.

T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) is a novel transmembrane protein that is involved in the regulation of T-helper 1 (Th1)-cell-mediated immunity. This study was undertaken to investigate the expressions of TIM-3 and its ligand galectin 9 (Gal-9) with respect to disease activity in rheumatoid arthritis (RA). Blood was collected from 39 RA patients and 31 healthy controls. Blood leucocyte TIM-3 and Gal-9 mRNA levels and RA disease activity were determined. Synovial tissue (ST) from five RA patients and five osteoarthritis (OA) patients were examined for TIM-3 mRNA expression and were also analysed for TIM-3 by immunohistology. TIM-3 mRNA expression was significantly higher in the ST of RA patients than in the ST of OA patients. TIM-3 was expressed in the synovial sublining area in ST of RA patients but not in OA ST. TIM-3 mRNA expression from peripheral blood mononuclear cells (PBMCs) of RA patients was negatively correlated with the 28-joint Disease Activity Score (DAS28). Gal-9 mRNA level in PBMCs of RA patients was higher than in healthy controls, and was significantly higher in patients with low disease activity compared to those with moderate to high disease activity. Gal-9 mRNA expression in PBMCs of RA patients was positively correlated with forkhead box P3 (FoxP3) mRNA expression.

TIM-3 and its interaction with Gal-9 are closely associated with RA disease activity and may play an important role in the pathogenesis of RA. In addition to the negative regulatory effect of Gal-9 mediated through the TIM-3-Gal-9 pathway, Gal-9 may exert its suppressive effect on RA disease activity by modulation of regulatory T (Treg) cells.

The aim of this study was to differentiate septic from non-septic arthritis by measuring lactate concentration with (1)H magnetic resonance spectroscopy (HMRS) and by estimating total protein content with the assessment of T (2) values. In 30 patients with acute arthritis, synovial fluid was aspirated. Lactate concentrations were analyzed with single voxel HMRS at 1.5 T. T (2) relaxation times were mapped with a multi-spin echo sequence. All samples underwent microbiological testing and routine laboratory analysis to quantify lactate concentration and total protein content. Values obtained in septic and non-septic arthritis were compared with a Mann-Whitney U test. Synovial fluid from patients with septic arthritis (n = 10) had higher concentrations of lactate (11.4 +/- 4.0 mmol/L) and higher total protein content (51.8 +/- 10.7 g/L) than fluid obtained in non-septic arthritis (n = 20; 5.2 +/- 1.1 mmol/L and 40.4 +/- 6.9 g/L, respectively, p < 0.001 and <0.01, respectively). Measured lactate concentrations and T (2) relaxation times (as an indicator of total protein content) were moderately correlated to laboratory-confirmed lactate concentration (r (2) = 0.71) and total protein content (r (2) = 0.73). Markedly increased lactate concentrations (>6 mmol/L) in combination with low T (2) values (<550 ms) identify septic arthritis with a sensitivity of 70% and a specificity of 89%.

Spectroscopic measurements of lactate concentration in combination with the estimation of protein content using T (2) may be of value in the differentiation of septic from non-septic arthritis.

This study, FKB327-003, is a phase 3, open-label extension (OLE) study comparing the long-term immunogenicity of an adalimumab biosimilar, FKB327 (F), with the reference product (RP). In the OLE, patients completing 24 weeks of an initial randomized, double-blind (DB) study (Period 1) with clinical response and no safety concerns were rerandomized to F or RP, so that two-thirds of patients remained on the same treatment and one-third switched to the alternate treatment for weeks 24 through 54 (OLE weeks 0-30; Period 2), then all received F through week 100 (OLE week 76; Period 3). Treatment sequences were F-F-F (no switch), RP-F-F and RP-RP-F (single switch), and F-RP-F (double switch). Patients who entered the OLE study were evaluated for immunogenicity across switching sequences. The proportion of patients with positive antidrug antibody (ADA) status at the end of Period 1 was 61.7% and 60.0% for F and RP, respectively. The proportion of patients with positive ADA status did not increase throughout Period 1, and was similar for F and RP at all time points. At the end of Period 3, the proportion of patients with positive ADA status was lower in all treatment sequences, at 51.1%, 54.4%, 48.1%, and 42.5% for F-F-F, F-RP-F, RP-F-F, and RP-RP-F, respectively.

The RP and F showed comparable immunogenicity characteristics after long-term administration. Development of ADAs with the RP and F was similar, and was not impacted by switching and double switching between F and RP treatment.

To provide fundamental information for its exploiting. Aralia echinocaulis by the resource and identification study on. Resource survey and various identification were carried out. The county level distribution and ecological environment of A. echinocaulis were initially observed. It mainly distributed in the mountainous areas of the Yangtze River basin and the south, and was usually used as folk drug. This study also displayed its morphological, microscopic and chemophysical identification features.

The morphological features of original plant and crude drug, and the anatomical and chemophysical characteristics of A. echinocaulis are of identification value, and the species are also of greater development and utilization potentiality, but the resource does not support the sustainable utilization. Therefore, artificial propagation is apparently crucial to its exploitation.

Antibodies directed to proteins containing the non-standard amino acid citrulline, are extremely specific for rheumatoid arthritis (RA). Peptidylcitrulline can be generated by post-translational conversion of arginine residues. This process, citrullination, is catalysed by a group of calcium dependent peptidylarginine deiminase (PAD) enzymes. To investigate the expression and activity of four isotypes of PAD in peripheral blood and synovial fluid cells of patients with RA. The data presented here show that citrullination of proteins by PAD enzymes is a process regulated at three levels: transcription-in peripheral blood PAD2 and PAD4 mRNAs are expressed predominantly in monocytes; PAD4 mRNA is not detectable in macrophages, translation-translation of PAD2 mRNA is subject to differentiation stage-specific regulation by its 3' UTR, and activation-the PAD proteins are only activated when sufficient Ca(2+) is available. Such high Ca(2+) concentrations are normally not present in living cells. In macrophages, which are abundant in the inflamed RA synovium, vimentin is specifically citrullinated after Ca(2+) influx.

PAD2 and PAD4 are the most likely candidate PAD isotypes for the citrullination of synovial proteins in RA. Our results indicate that citrullinated vimentin is a candidate autoantigen in RA.

Growing evidence suggests increasing frequencies of autoimmunity and certain autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. This study was undertaken to investigate whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25-year span in the US. Serum ANA were measured by standard indirect immunofluorescence assays on HEp-2 cells in 14,211 participants age ≥12 years from the National Health and Nutrition Examination Survey, with approximately one-third from each of 3 time periods: 1988-1991, 1999-2004, and 2011-2012. We used logistic regression adjusted for sex, age, race/ethnicity, and survey design variables to estimate changes in ANA prevalence across the time periods. The prevalence of ANA was 11.0% (95% confidence interval [95% CI] 9.7-12.6%) in 1988-1991, 11.5% (95% CI 10.3-12.8%) in 1999-2004, and 15.9% (95% CI 14.3-17.6%) in 2011-2012 (P for trend < 0.0001), which corresponds to ~22 million, ~27 million, and ~41 million affected individuals, respectively. Among adolescents age 12-19 years, ANA prevalence increased substantially, with odds ratios (ORs) of 2.02 (95% CI 1.16-3.53) and 2.88 (95% CI 1.64-5.04) in the second and third time periods relative to the first (P for trend < 0.0001). ANA prevalence increased in both sexes (especially in men), older adults (age ≥50 years), and non-Hispanic whites. These increases in ANA prevalence were not explained by concurrent trends in weight (obesity/overweight), smoking exposure, or alcohol consumption.

The prevalence of ANA in the US has increased considerably in recent years. Additional studies to determine factors underlying these increases in ANA prevalence could elucidate causes of autoimmunity and enable the development of preventative measures.

To compare unicompartmental knee arthroplasty (UKA) and open-wedge high tibial osteotomy (OWHTO) in a long-term follow-up propensity score matching analysis. Patients who underwent UKA or OWHTO for unilateral medial unicompartmental osteoarthritis (OA) between 2004 and 2010 were included. The ROM, HSS score, KS score, WOMAC score, forgotten joint score, OA progression in patellofemoral and lateral compartments, and survivorship were compared within ten years of follow-up between 67 UKA and 67 OWHTO patients after propensity score matching for age, gender, body mass index, range of motion, and osteoarthritis (OA) grade. At the last follow-up, there were no significant differences between the two groups in clinical outcomes, but the WOMAC score showed better results after UKA (13.1 in UKA vs 18.9 in OWHTO, P = .011). The OA progression also showed no significant difference between the two groups. After a 10-year follow-up, the survival rate was higher in UKA patients (96.2%) than in OWHTO patients (87.7%), with no statistical difference (P = .06).

UKA showed better clinical outcomes and OA progressions than OWHTO. The survival rate presented a superiority of 8.5% for the UKA group in the 10-year follow-up, without significant difference.

We investigated the synovial and plasma glucosamine concentrations in osteoarthritic patients following oral administration of crystalline glucosamine sulphate at the therapeutic dose of 1500mg once-a-day for 14 days. Twelve osteoarthritic patients (six males and six females) received 14 consecutive once-daily oral administrations of crystalline glucosamine sulphate soluble powder (1500mg), in an open fashion. Plasma and synovial fluid were collected simultaneously from the same patient, at baseline and, at steady state (3h after the last dose). Glucosamine was determined in plasma and synovial fluid by liquid chromatography-tandem mass spectrometry. Median endogenous glucosamine concentrations in plasma and synovial fluid were 52.0ng/ml (0.29microM) and 36.5ng/ml (0.21microM), respectively (P=0.001), and varied substantially among patients (41-121ng/ml and <10-67ng/ml, respectively). Three hours after the last dose, glucosamine concentrations resulted increased from baseline in all patients with median increases of 20.5 and 21.5 folds in plasma and synovial fluid, respectively, the difference being not statistically significant (P=0.11). In plasma, the median post-treatment value was 1282ng/ml (7.17microM) and ranged from 600 to 4061ng/ml (3.35-22.7microM). The median post-treatment synovial glucosamine concentration was 777ng/ml (4.34microM), i.e., significantly lower than in plasma (P=0.001), and ranged from 577 to 3248ng/ml (3.22-18.1microM). Plasma and synovial glucosamine concentrations were highly correlated and were in the 10microM range.

Glucosamine is bioavailable both systemically and at the site of action (the joint) after oral administration of crystalline glucosamine sulphate in ostaeoarthritis patients. Steady state glucosamine concentrations in plasma and synovial fluid were correlated and in line with those effective in selected in vitro studies.

Detailed analysis of hematological manifestations (HM) in systemic lupus erythematosus (SLE) are limited and their clinical impact on disease remain obscure. Here, we aimed to decipher factors associated with different hematological abnormalities in SLE patients and to assess their impact on disease related outcomes. A dataset (GIPT) originating from SLE patients of six European tertiary centers was assessed. Six-monthly visits of each patient for at least 2 years were registered. The association between hematologic manifestations (HM; per ACR-1997criteria) and clinical/serologic variables, as well as the impact of HM on disease related outcomes (damage, infection and hemorrhage) were explored. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI2K), the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and events for any infection and hemorrhage were recorded. Results were compared with a cross-sectional, well-characterized SLE dataset from Sweden. Descriptive statistics, the generalized estimating equations (GEE), general linear models (GLM), Cox regression models were applied. We monitored 1425 longitudinal visits in 286 SLE patients with HM (GIPT dataset: 88% female, 95% Caucasian, 68% dsDNA positive). Thrombocytopenia (regression coefficient [95% confidence interval] 1.86[1.1-3.13]) and neurologic involvement (ACR-8) (2.1[1.10-3.89]) were associated with lymphopenia (<1000/mm

Lymphopenia in SLE is independently associated with neurologic involvement and organ damage accrual, and thus, may be considered as a marker of severe/progressive disease.

Patients with rheumatoid arthritis frequently consult for pain resulting from involvement of the tendons of the foot. This pain negatively affects foot biomechanics and quality of life. The most widely used treatment option for this condition is ultrasound-guided steroid injection, while other treatments were recommended such as heel pad, splints, and footwear. To evaluate a joint intervention (rheumatology and podiatry) comprising an orthotic-podiatric treatment and infiltrations. We evaluated the response using ultrasound monitoring, a pain scale, functional tests, and assessment of patient satisfaction. We performed a non-controlled blinded prospective interventional study of 96 patients with foot pain and selected those with ultrasound-confirmed tendon involvement. Patients enrolled started intervention treatment and were followed for 6 months. The outcome of the intervention was compared with the patient's baseline status. The pre-post differences in the secondary variables (pain, disability) were analyzed using the t test and contingency tables or the Mann-Whitney test. Using our protocol, we recorded a rapid and significant reduction in the intensity of pain, in the foot function index, and in the ultrasound parameters (grayscale and Doppler). Structural damage to the tendon improved more slowly, with significant outcomes only at the last visit with respect to baseline. Abnormal foot support was detected in 50% of patients, and 79.5% were using inappropriate footwear.

Our multidisciplinary therapeutic protocol enabled a very significant improvement in tendon involvement. It was well-tolerated, with a high degree of satisfaction, and was easily evaluated using ultrasound. No changes in background medication were necessary. Key Points • Multidisciplinary evaluation of patients with RA is advisable because it improves the treatment management in cases of inflammatory activity and structural abnormalities of the foot. • Comprising orthopedic-podiatric treatment (heel, splints, and suitable footwear) and infiltrations, in terms of clinical, ultrasound, and functional recovery of the foot tendons. • The therapy protocol we propose led to a significant improvement in pain relief and functional recovery.

The aim of this study was to examine the associations of tea consumption with the serum uric acid (SUA) level, hyperuricemia (HU) and the risk of gout. A comprehensive literature search up to June 2016, using PUBMED and EMBASE databases, was conducted to identify the relevant observational studies that examined the associations of tea consumption with the SUA level, HU and the risk of gout. A total of fifteen observational studies were included in this study, and nine studies were extracted for meta-analysis. For the SUA level, seven studies were included. According to the combined weighted mean difference (WMD), there was no significant difference between the highest and the lowest tea intake category in terms of the SUA level (WMD = 7.41 μmol/L, 95%CI: -2.34 to 17.15; P = 0.136). In subgroup analysis including three studies, green tea consumption was positively associated with the SUA level (WMD = 17.20 μmol/L, 95%CI: 7.00 to 27.40; P = 0.01). For the prevalence of HU, five studies were included. The overall multi-variable adjusted odds ratio (OR) for the highest versus the lowest category of tea consumption was 0.98 (95%CI: 0.77 to 1.24; P = 0.839). For the risk of gout, two prospective cohort studies showed that there was no relationship between tea consumption and the risk of gout in males and females, respectively.

The current evidences suggest that tea consumption does not seem to be associated with the SUA level, HU and the risk of gout. However, due to the limited number of studies, green tea consumption might be positively associated with the SUA level. More well-designed prospective cohort studies are needed to elaborate these issues further.

Removal of dead cells is essential in the maintenance of tissue homeostasis, and efficient removal prevents exposure of intracellular content to the immune system, which could lead to autoimmunity. The plasma protease factor VII-activating protease (FSAP) can release nucleosomes from late apoptotic cells. FSAP circulates as an inactive single-chain protein, which is activated upon contact with either apoptotic cells or necrotic cells. The purpose of this study was to investigate the role of FSAP in the release of nucleosomes from necrotic cells. Necrotic Jurkat cells were incubated with serum, purified 2-chain FSAP, and/or DNase I. Nucleosome release was analyzed by flow cytometry, and agarose gel electrophoresis was performed to detect DNA breakdown. Incubation with serum released nucleosomes from necrotic cells. Incubation with FSAP-deficient serum or serum in which FSAP was inhibited by a blocking antibody was unable to release nucleosomes from necrotic cells, confirming that FSAP is indeed the essential serum factor in this process. Together with serum DNase I, FSAP induced the release of DNA from the cells, the appearance of nucleosomes in the supernatant, and the fragmentation of chromatin into eventually mononucleosomes.

FSAP and DNase I are the essential serum factors that cooperate in necrotic cell DNA degradation and nucleosome release. We propose that this mechanism may be important in the removal of potential autoantigens.

The definition of remission in Rheumatoid Arthritis (RA) is still difficult to determine. An ultrasound of the hands may be important in helping confirm clinical remission. This study's aim was to evaluate the interest in using an ultrasound of the hands to confirm clinical remission, as well as comparing the various remission scores (DAS 28 VS, DAS 28 CRP, and SDAI) and the ultrasound data, in order to deduce the most accurate score to confirm this remission. In this prospective monocentric study, we studied patients with rheumatoid arthritis in clinical remission, according to DAS 28 VS, for at least 3 months without corticosteroid therapy. An ultrasound mode B / Doppler of the hands was taken by an experienced rheumatologist, involving 22 joints: wrists, Metacarpophalangeal (MCP) joints and proximal interphalangeal joints (PPI) bilaterally. Fifty-one patients were included. They were classified in remission according to DAS 28 VS as well as DAS 28 CRP, whereas the remission according to SDAI was achieved in 66.7% of our patients. Synovial hypertrophy and power Doppler were present in respectively 65% and 25% of the patients. SDAI was the most accurate score to confirm RA remission (p < 0.003).

SDAI appears to be the most appropriate score for the definition of remission in rheumatoid arthritis, but despite the use of the latter, ultrasound synovitis may still be present. Further work deserves to be done to clarify the value of ultrasound evaluation in the definition of RA remission.

The purpose of this study was to determine the prevalence of anti-CCP antibodies (anti-CCP Abs) and to assess associations between the presence of anti-CCP Ab and arthritis or arthralgia in SSc patients. Serum samples were obtained from 146 SSc patients. Anti-CCP Ab, anti-agalactosyl (AG) IgG Ab, IgM-RF, IgG-RF and MMP-3 were determined, respectively. The presence of anti-CCP Ab was found in 18/146 (12%) patients with SSc. Elevated levels of anti-AG IgG Abs, IgM- and IgG-RFs were observed in 50/146 (34%), 17/146 (12%) and 4/146 (3%), respectively. Serum anti-CCP Ab levels were significantly elevated in SSc-RA overlap patients compared with SSc patients with or without arthralgia (P < 0.05 or P < 0.001, respectively). Serum MMP-3 levels did not correlate with the presence of arthritis or arthralgia but were significantly associated with modified Rodnan total skin thickness score. In SSc-RA overlap patients, 10/11 (91%) patients were positive for two or more RA-related Abs.

The serum titre of anti-CCP Ab is higher in SSc-RA overlap patients than in SSc patients with or without arthralgia. The finding of high titres of anti-CCP Abs and the elevated levels combinatory with other RA-related Abs may help to define the diagnosis of SSc-RA overlap. MMP-3 might be a better marker to assess skin involvement rather than joint involvement in SSc patients.

Depression is a common mental disorder in rheumatoid arthritis (RA) patients and may provoke the onset of poor clinical prognoses. In view of this, whether or not the use of Chinese herbal medicines (CHMs) can alleviate the risk of depression still remains unclear. We conducted a longitudinal cohort study to evaluate the association between CHMs us and depression risk among RA patients. Using claims data from the National Health Insurance of Taiwan, we identified 6609 newly diagnosed RA patients aged 20 years or older between 1998 and 2010. From this sample, we recruited 3386 CHM users and randomly selected 3223 controls using propensity scores matching from the remaining cases as the non-CHMs users. They were followed until the end of 2012 to record depression incidence. A Cox proportional hazards regression model was used to compute the hazard ratio (HR) of depression with regard to the use of CHMs. During the 15-year follow-up, 249 CHM users and 314 non-CHM users developed depression, representing an incidence rate of 9.33 and 14.98, respectively, per 1000 person-years. We found that use of CHMs was associated with lower risk of depression by 38% (95% confidence interval 0.54-0.76). The most predominant effect was observed in those receiving CHMs for over 2 years (adjusted HR 0.34). Seven commonly prescribed CHMs could lessen the risk of depression: Chuan-niu-xi, Jie-geng, San-qi, Jia-wei-xia-yao-san, Dang-gui-nian-tong-tang, Zhi-gan-cao-tang, and Suan-zao-ren-tang.

This study supports that adding CHMs into conventional therapy may prevent subsequent depression risk for RA patients.

To observe the efficacy of platelet rich plasma on pain improvement in knee osteoarthritis patients and to explore the impact of various facotrs on pain reduction with such a treatment. The quasi-experimental study was conducted at the Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan, from October 2017 to April 2018 and comprised patients with primary knee osteoarthritis. The sample was sub-grouped into "normal", "overweight" and "obese" on the basis of body mass index. Two age-based sub-groups were also formed at ≤ 60 years and >60 years. Three injections of calcium gluconate activated 2.5ml platelet rich plasma were given in the knees at an interval of two weeks each. The pain score was calculated using the numerical rating scale at the 6th week. Data was analysed using SPSS 20. Of the 50 patients, 26(52%) were females and 24(48%) were males. The overall mean age was 59.6±9.6 years (range: 42-75 years), with 22(44%) aged ≤ 60 years. There were 21(42%) patients who were overweight, 7(14%) had normal weight and 22(44%) were obese. There was significant pain reduction post-treatment compared to the baseline (p<0.001). The reduction in pain was not significantly related to gender, age, knee osteoarthritis grade, or body mass index (p>0.05).

Platelet rich plasma significantly improved pain in knee osteoarthritis patients regradless of all age, gender, grade and body mass index.

We applied regression techniques to a large cohort of patients to understand why certain patients are prescribed medications to prevent glucocorticoid-induced osteoporosis (GIO). Rates of prescriptions to prevent osteoporosis were low. The presence of drugs and disorders associated with osteoporosis and gastrointestinal conditions actually are associated with a decreased likelihood of receiving osteoporosis-preventing medications. To understand why some patients are prescribed medications to prevent GIO while other patients are not, we examined whether there is an association among osteoporosis-inducing medical conditions or medications and prescriptions for osteoporosis prophylaxis in a large cohort of rheumatoid arthritis patients on chronic glucocorticoids. Department of Veterans' Affairs national administrative databases were used to construct a cohort (n = 9,605) and provide the data for this study. Multivariate logistic regression was performed to determine medical conditions and medications associated with dispensing of GIO-preventive medications, controlling for sociodemographic variables, comorbidities, glucocorticoid dosage, prior fractures, and rheumatoid arthritis severity. A subanalysis examined predictors of early GIO prevention. Subjects were more likely to receive GIO prophylaxis if they were older, African American, treated with multiple antirheumatic disease-modifying drugs, or received greater glucocorticoid exposure. The prescription of certain drug classes (loop diuretics and anticonvulsants) and conditions (malignancy, renal insufficiency, alcohol abuse, and hepatic disease) were associated with lower likelihood of GIO prophylaxis, despite putative links between these agents/conditions and osteoporosis. The presence of gastrointestinal disorders dramatically decreased likelihood of GIO prophylaxis. Few characteristics predicted the dispensing of GIO-preventing medications within 7 days of the initial glucocorticoid start date.

Rates of prescriptions to prevent osteoporosis in a cohort of older men with rheumatoid arthritis on chronic glucocorticoids were low. Gastrointestinal disorders and drugs and disorders potentially linked to osteoporosis are associated with diminished odds of being prescribed GIO-preventing medications.

Osteoarthritis (OA) is a degenerative joint disease inducing the degradation of the articular cartilage. Syndecan-4 (Sdc4) is a heparan sulfate proteoglycan, expressed under inflammatory conditions and by chondrocytes during OA. Little is known about Sdc4 shedding and its regulation in OA. Therefore, we investigated the regulation of Sdc4 shedding and underlying shedding mechanisms under OA conditions. Articular cartilage, serum, synovial fluid and synovial membrane from OA patients with different radiological severity were analyzed. ELISA, RT-qPCR and IHC for Sdc4, MMP-2 and -9 were performed. MMP inhibitors and siRNA were evaluated for their effect on Sdc4 shedding by ELISA and on IL-1 signaling by western blot (pERK/ERK). Shed Sdc4 was increased in synovial fluid of OA patients, but not in the serum and is a good predictor (AUC = 0.72) for OA severity with a sensitivity of 67.5% and specificity 65.2%. MMP-9, but not MMP-2, was increased in cartilage and synovial membrane at mRNA levels and in the synovial fluid at protein levels. Shed Sdc4 correlated with the amount of MMP-9 in synovial fluid. Further, the inhibition and knock-down of MMP-9 decreased the amount of shed Sdc4 in vitro. Increased Sdc4 shedding resulted in less phosphorylation of ERK upon IL-1β stimulation.

Shed Sdc4 might be a good prognostic biomarker for OA mediated cartilage degradation. MMP-9 seems to be the relevant sheddase for Sdc4 under OA conditions, desensitizing chondrocytes towards IL-1 signaling.

T helper (Th)-17 cells are increased in systemic sclerosis (SSc). We therefore assessed whether Th17 cells could modulate the inflammatory and fibrotic responses in dermal fibroblasts from healthy donors (HD) and SSc individuals. Fibroblasts were obtained from 14 SSc and 8 HD skin biopsies. Th17 clones were generated from healthy peripheral blood upon enrichment of CC chemokine receptor (CCR)-4/CCR6/CD161 expressing cells. Their cytokine production was assessed by flow cytometry and multiplex beads immunoassay. Fibroblast production of monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8, matrix metalloproteinase (MMP)-1, tissue inhibitor of metalloproteinase (TIMP)-1, MMP-2 and type-I collagen was quantified by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), and changes in their transcription levels assessed by real-time PCR. Intracellular signals were dissected by western blot and the use of pharmacological inhibitors. IL-17A, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) blocking reagents were used to assess the specificity of the observed effects. IL-17A increased MCP-1, IL-8 and MMP-1 production in a dose-dependent manner while having no effect on type I collagen in HD and SSc fibroblasts both at protein and mRNA levels. Nuclear factor-kappa B (NF-κB) and p38 were preferentially involved in the induction of MCP-1 and IL-8, while MMP-1 was most dependent on c-Jun N-terminal kinase (JNK). Supernatants of activated Th17 clones largely enhanced MCP-1, IL-8 and MMP-1 while strongly inhibiting collagen production. Of note, the production of MCP-1 and IL-8 was higher, while collagen inhibition was lower in SSc compared to HD fibroblasts. The Th17 clone supernatant effects were mostly dependent on additive/synergistic activities between IL-17A, TNF and in part IFN-γ. Importantly, the inhibition of type I collagen production induced by the Th17 clone supernatants was completely abrogated by blockade of IL-17A, TNF and IFN-γ mostly in SSc fibroblasts, revealing an intrinsic resistance to inhibitory signals in SSc.

Our findings demonstrate that in vitro Th17 cells elicit pro-inflammatory responses while restraining collagen production. Thus, the increased Th17 cell number observed in SSc may impact on the inflammatory component of the disease simultaneously potentially providing a protective role against fibrosis.

To determine the effect of rheumatoid arthritis (RA) on mortality rates. Longitudinal analyses of data from a cohort of Pima Indians from the Gila River Indian Community in Arizona, who were followed up during the period February 1965 through December 1989. Among 2,979 study subjects aged > or = 25 years, there were 858 deaths, 79 of which occurred in subjects with RA (36 men, 43 women). Age- and sex-adjusted mortality rates were slightly higher in subjects with RA than in those without (mortality rate ratio 1.28, 95% confidence interval [95% CI] 1.01-1.62). Among those with RA, mortality rates were higher in older subjects (mortality rate ratio 1.51 per 10-year increase in age, 95% CI 1.22-1.88), in male subjects (mortality rate ratio 2.23, 95% CI 1.44-3.45, adjusted for age), and in subjects with proteinuria (mortality rate ratio 1.88, 95% CI 1.02-3.46, adjusted for age and sex). Mortality rate ratios for these risk factors were similar in subjects without RA. In addition, among subjects with RA, rheumatoid factor (RF) positivity was predictive of death (mortality rate ratio 1.94, 95% CI 1.10-3.43), and the excess mortality was found primarily among subjects who were seropositive. The death rate from cardiovascular disease (mortality rate ratio 1.77, 95% CI 1.10-2.84) and from liver cirrhosis or other alcohol-related disease (mortality rate ratio 2.52, 95% CI 1.06-6.01) was increased in persons with RA.

The results of this population-based study suggest that although the risk of mortality in subjects with RA is significantly higher than in those without RA, the risk ratio is in the lower range of that described previously in studies of clinic-based cohorts. RF positivity as a predictor of early death among subjects with RA indicates that the immunologic processes in seropositive RA may contribute to the events that eventually lead to early death.

Evolving inflammatory bowel disease (IBD) is a matter of interest in patients with juvenile idiopathic arthritis (JIA) and might be associated with JIA therapy. Data from the German biologics registry (Biologika in der Kinderrheumatologie; BiKeR) from 2001 to 2013 were analyzed. There were 3071 patients with 8389 patient-years (PY) of observation followed. IBD was diagnosed in 11 patients, 8 with Crohn disease and 3 with ulcerative colitis. IBD incidence in patients with JIA was 1.31/1000 PY and higher than published IBD incidences in pediatric populations. Compared with the total BiKeR cohort, patients with IBD more commonly had enthesitis-related arthritis, extended oligoarthritis, psoriatic arthritis, and also rheumatoid factor (RF)-negative polyarthritis. No IBD occurred in patients with systemic JIA or RF-positive polyarthritis. In patients treated with methotrexate (MTX), the IBD incidence was significantly lower compared with patients not treated with MTX. Etanercept (ETN) monotherapy, but not the combination of ETN and MTX, was associated with an increased incidence of IBD.

Incidence of IBD in patients with JIA is higher than in the population. MTX turned out to be protective, even in combination with ETN.

To determine whether tumor necrosis factor microsatellite a (TNFa) polymorphism is associated with severity of rheumatoid arthritis (RA), and to examine the evidence for interaction between TNFa and the HLA-DRB1 shared epitope (SE). One hundred seventy-one community-based white female RA patients were genotyped for both TNFa and HLA-DRB1 alleles. We performed pairwise association analyses, stratified analyses, and multivariate logistic regressions to determine whether TNFa was associated with 4 measures of RA severity, and whether there was significant interaction between TNFa and the HLA-DRB1 SE. Simple pairwise analyses did not reveal significant association between TNFa polymorphism and RA severity. However, when the data were stratified by the presence versus absence of the SE, striking associations were observed between TNFa allele 11 (TNFa11) and RA severity. These analyses also demonstrated significant interaction between TNFa11 and the SE (P = 0.07-0.005), and this was confirmed in our multivariate regressions. Specifically, the most severe outcomes were observed among individuals who had inherited both TNFa11 and the SE (61-71% had severe RA based on 1 of the 4 outcomes). In contrast, individuals who had inherited TNFa11 in the absence of the SE had the best outcomes (8-21% with severe RA). The odds ratios comparing these 2 groups ranged from 8.8 to 22.7 for the 4 severity measures. The differential effect of TNFa11 according to the presence versus absence of the SE (and vice versa) illustrated their interaction with respect to RA severity.

The data suggest that TNFa is associated with RA severity through an interaction with the HLA-DRB1 SE.

To assess agreement between ultrasonography (transcutaneous and transrectal) and standing radiography in horses with fractures in the pelvic region and disorders of the coxofemoral joint. Case series. Warmblood horses (n=23) and 2 ponies. Medical records (1999-2008) of equids with pelvic or coxofemoral disorders that had pelvic radiography and ultrasonography were retrieved and results of both techniques compared. Radiography and ultrasonography each identified equal numbers of fractures of the tuber coxa (n=4), ilial shaft (2), ischium (3), femoral neck (2), and osteoarthritis/osis of the coxofemoral joint (6). Fractures of the ilial wing (4) were only identified by ultrasonography not by standing radiography. Of 9 acetabular fractures, 3 were identified on radiographs only, 5 were identified with both modalities. One pubic fracture was identified using ultrasonography and radiography. One acetabular and 1 pubic fracture were only diagnosed on necropsy. Ultrasonography is a rapid, safe imaging technique for detecting disorders of the pelvic region with a high diagnostic yield and is a preferred initial approach in horses with severe hindlimb lameness.

We found reasonable agreement (73%; 24/33) between ultrasonography and standing radiography for diagnosis of pelvic-femoral disorders. Ultrasonography was more useful for ilial wing fractures and radiography for acetabular fractures.

Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA. A case-control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped. In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55-0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61-1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62-0.93, P = 7.08 x 10(-3)). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor-negative polyarthritis [P = 0.038]).

Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.

This study aimed to report the clinical outcome of children with uveitis treated with anti-tumor necrosis factor alpha (TNF-α) agents. This included a retrospective cohort study. Children with uveitis treated with infliximab or adalimumab in 2008-2014 at five dedicated uveitis clinics were identified by database search. Their medical records were reviewed for demographic data, clinical presentation, ocular complications, and visual outcome. Systemic side effects and the steroid-sparing effect of treatment were documented. The cohort included 24 patients (43 eyes) of whom 14 received infliximab and 10 received adalimumab after failing conventional immunosuppression therapy. Mean age was 9.3 ± 4.0 years. The most common diagnosis was juvenile idiopathic arthritis-related uveitis (n = 10), followed by Behçet's disease (n = 4), sarcoidosis (n = 1), and ankylosing spondylitis (n = 1); eight had idiopathic uveitis. Ocular manifestations included panuveitis in 20 eyes (46.5%), chronic anterior uveitis in 19 (44.2%), and intermediate uveitis in 4 (9.3%). The duration of biologic treatment ranged from 6 to 72 months. During the 12 months prior to biologic treatment, while on conventional immunosuppressive therapy, mean visual acuity deteriorated from 0.22 to 0.45 logMAR, with a trend of recovery to 0.25 at 3 months after initiation of biologic treatment, remaining stable thereafter. A full corticosteroid-sparing effect was demonstrated in 16 of the 19 patients (84.2%) for whom data were available. Treatment was well tolerated.

Treatment of pediatric uveitis with anti-TNF-α agents may improve outcome while providing steroid-sparing effect, when conventional immunosuppression fails. The role of anti-TNF-α agents as first-line treatment should be further investigated in controlled prospective clinical trials.

To determine the degree of radiographic abnormalities based on Kellgren-Lawrence criteria, to determine posturography features in patients with knee OA. Ninety nine subjects were recruited by consecutive sampling at the outpatient clinic of Internal Medicine in Cipto Mangunkusumo Hospital. History taking and physical examination including rheumatology examination were conducted, followed by knee radiographic examination in weight bearing and 30 degree skyline position. A cross sectional design was performed to evaluate the variable results for degree of radiolographic abnormalites and posturography results. The subjects were 79.8% women and 20.2% men, mostly > or = 60 year-old (78.8%), with low education 76.8%, BMI > or = 23 74.7%, mean value of active VAS was 5.4, mean value of passive VAS 2.8. Mild radiographic abnormality was found in 77.8% subjects, and the others were severe, i.e. 22.2%. There were increase in length of postural sway, increase of postural sway velocity, and increase in area of postural sway in patients with knee OA compared with normal subjects with 40-60 years old.

There is an increase in nearly all variables of posturography in patients with knee OA.

Microparticles are small vesicles that are released from activated or dying cells and that occur abundantly in the synovial fluid of patients with rheumatoid arthritis (RA). The goal of these studies was to elucidate the mechanisms by which microparticles activate synovial fibroblasts to express a proinflammatory phenotype. Microparticles from monocytes and T cells were isolated by differential centrifugation. Synovial fibroblasts were cocultured with increasing numbers of microparticles. Gene expression was analyzed by real-time polymerase chain reaction and confirmed by Western blotting and enzyme immunoassay. Arachidonic acid labeled with tritium was used to study the transport of biologically active lipids by microparticles. The roles of NF-kappaB and activator protein 1 (AP-1) signaling were analyzed with electrophoretic mobility shift assay and transfection with small interfering RNA and IkappaB expression vectors. Microparticles strongly induced the synthesis of cyclooxygenase 2 (COX-2), microsomal prostaglandin E synthase 1 (mPGES-1), and prostaglandin E(2) (PGE(2)). In contrast, no up-regulation of COX-1, mPGES-2, cytosolic PGES, or phospholipase A(2) was observed. The induction of PGE(2) was blocked by selective inhibition of COX-2. Microparticles activated NF-kappaB, AP-1, p38, and JNK signaling in synovial fibroblasts. Inhibition of NF-kappaB, AP-1, and JNK signaling reduced the stimulatory effects. Arachidonic acid was transported from leukocytes to fibroblasts by microparticles. Arachidonic acid derived from microparticles was converted to PGE(2) by synovial fibroblasts.

These results demonstrate that microparticles up-regulate the production of PGE(2) in synovial fibroblasts by inducing COX-2 and mPGES-1. These data provide evidence for a novel mechanism by which microparticles may contribute to inflammation and pain in RA.

To validate the western Tennessee River limits of the originally described rheumatoid arthritis (RA) catchment area and to assess the possibility that absence of tuberculosis allowed the original development of RA. The hypothesis that RA was related to tuberculosis was once a driving force in treatment approach. RA initially was very limited in geographic distribution, in contrast to tuberculosis. Classical tubercular lesions were not observed in the rheumatoid catchment area in ancient times. Similarities between clinical and radiologic manifestations of spondyloarthropathy (SpA) and adjuvant arthritis raised the possibility of a potential conditioning role for occurrence of nonrheumatoid erosive arthritis. Skeletal samples from ancient RA catchment and non-catchment areas were compared for frequency of tubercular-relatable pathologies. Tubercular-relatable osseous pathologies were found only outside the rheumatoid catchment area (p < 0.0001). The original RA catchment area was confirmed not to extend beyond the western portion of the Tennessee River.

There is an inverse relationship between occurrence of tuberculosis and RA in the Archaic and Early Woodland periods of North America. The virtually universal presence of tuberculosis in contiguous Amerindian populations contrasts dramatically with its absence in the ancient catchment area for RA. Conversely, SpA and tuberculosis do occur in the same populations. Tuberculosis may represent a conditioning agent for development of SpA, but at least potentially provides protection against development of RA.

To evaluate the clinical effectiveness of manual physiotherapy and/or exercise physiotherapy in addition to usual care for patients with osteoarthritis (OA) of the hip or knee. In this 2 × 2 factorial randomized controlled trial, 206 adults (mean age 66 years) who met the American College of Rheumatology criteria for hip or knee OA were randomly allocated to receive manual physiotherapy (n = 54), multi-modal exercise physiotherapy (n = 51), combined exercise and manual physiotherapy (n = 50), or no trial physiotherapy (n = 51). The primary outcome was change in the Western Ontario and McMaster osteoarthritis index (WOMAC) after 1 year. Secondary outcomes included physical performance tests. Outcome assessors were blinded to group allocation. Of 206 participants recruited, 193 (93.2%) were retained at follow-up. Mean (SD) baseline WOMAC score was 100.8 (53.8) on a scale of 0-240. Intention to treat analysis showed adjusted reductions in WOMAC scores at 1 year compared with the usual care group of 28.5 (95% confidence interval (CI) 9.2-47.8) for usual care plus manual therapy, 16.4 (-3.2 to 35.9) for usual care plus exercise therapy, and 14.5 (-5.2 to 34.1) for usual care plus combined exercise therapy and manual therapy. There was an antagonistic interaction between exercise therapy and manual therapy (P = 0.027). Physical performance test outcomes favoured the exercise therapy group. Australian New Zealand Clinical Trials Registry ACTRN12608000130369.

Manual physiotherapy provided benefits over usual care, that were sustained to 1 year. Exercise physiotherapy also provided physical performance benefits over usual care. There was no added benefit from a combination of the two therapies.

Fibromyalgia is a condition characterized by chronic widespread muscle pain and fatigue. The primary objective of this study was to determine if pain, perceived cognitive fatigue, and perceived physical fatigue were enhanced in participants with fibromyalgia compared to healthy controls during a cognitive fatigue task, a physical fatigue task, and a dual fatigue task. In total, 24 people with fibromyalgia and 33 healthy controls completed pain, fatigue, and function measures. A cognitive fatigue task (Controlled Oral Word Association Test) and physical fatigue task (Valpar peg test) were done individually and combined for a dual fatigue task. Resting pain, perceived cognitive fatigue, and perceived physical fatigue were assessed during each task using visual analog scales. Function was assessed with shoulder range of motion and grip. People with fibromyalgia had significantly higher increases in pain, cognitive fatigue, and physical fatigue when compared to healthy controls after completion of a cognitive fatigue task, a physical fatigue task, or a dual fatigue task (P < 0.01) with the exception of perceived cognitive fatigue during the cognitive fatigue task. People with fibromyalgia performed equivalently on measures of physical performance and cognitive performance on the physical and cognitive fatigue tasks, respectively.

These data show that people with fibromyalgia show larger increases in pain, perceived cognitive fatigue, and perceived physical fatigue to both cognitive and physical fatigue tasks compared to healthy controls. The increases in pain and fatigue during cognitive and physical fatigue tasks could influence subject participation in daily activities and rehabilitation.

To assess the change in the Intermittent and Constant Osteoarthritis Pain (ICOAP)-scale scores in patients taking duloxetine or placebo and to characterize the responsiveness of the ICOAP by comparing the effect size associated with its scales to effect sizes seen with other pain scales used in this study. This was a secondary analysis of data from a 10-week, double-blind, randomized, flexible-dose, placebo-controlled trial that enrolled patients who had persistent moderate pain due to osteoarthritis (OA) of the knee, despite having received nonsteroidal anti-inflammatory drug (NSAID) therapy. The pain measures used in this study (focusing on the drug-placebo difference at week 8) were patient-rated pain severity, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Brief Pain Inventory (BPI), and the ICOAP. The mean difference between duloxetine and placebo at week 8 for patient-rated pain severity, the BPI average pain, WOMAC pain, and each ICOAP scale was statistically significant (P < 0.001 for each). The ICOAP total showed a moderate effect size of 0.53, whereas the constant and intermittent scores showed effect sizes of 0.47 and 0.49, respectively. The patient-rated pain severity and the BPI average pain showed similar moderate effect sizes of 0.59 and 0.53, respectively. ClinicalTrial.gov Identifier: NCT01018680.

The study demonstrated efficacy of duloxetine compared with placebo when using the ICOAP scale in a placebo-controlled trial. The observed treatment effect size for the ICOAP scores was similar to that for other reliable, valid and responsive pain assessments.

To evaluate prevalence of dose escalation among RA patients in normal clinical practice treated with etanercept, adalimumab or infliximab and to estimate its economic impact. A retrospective observational study of 739 patients with RA receiving continuous treatment with etanercept (n=319), adalimumab (n=313) or infliximab (n=107) for 18 months. Dose escalation, intensification of concomitant DMARDs and risk of dose escalation were evaluated, as well as costs. Significantly more patients prescribed adalimumab (10%, p<0.001) or infliximab (35%, p<0.001) experienced dose escalation compared with patients treated with etanercept (3%). DMARD or steroid dose adjustment, when added as criteria of escalation, occurred more often among patients treated with adalimumab (28%; p=0.022) or infliximab (47%; p<0.001) than those prescribed etanercept (19%). Independent of confounding covariates, hazard of dose escalation was significantly higher for either infliximab (28.1-fold) or adalimumab (4.9-fold) relative to etanercept. Escalation among subjects treated with either infliximab or adalimumab incurred statistically significant increases in total cost of care compared with non-escalators whereas such differences observed for subjects treated with etanercept were not significant.

Patients receiving monoclonal antibody therapies, adalimumab or infliximab, had significantly higher rates of dose escalation than patients receiving the soluble TNF receptor, etanercept, and related costs were higher.

Current management of rheumatoid arthritis (RA) focuses on inducing remission as early as possible to avoid lasting joint damage, and maintenance of remission has become important. A 12-month clinical trial in 834 patients with moderate RA investigated whether etanercept 50 mg/wk could be reduced to half dose or discontinued in patients who achieved low disease activity after 36 weeks. The objective of this study was to estimate the cost-effectiveness of the three maintenance strategies. A Markov model integrated the three strategies from the clinical trial and extrapolated to 10 years using data from the Swedish RA registry. Assumed treatment strategies after the trial were similar in all three arms, with patients failing to maintain remission on half-dose etanercept or methotrexate alone switching to the full dose of etanercept and patients maintaining remission on full-dose etanercept allowed switching to half dose. Resource use and utilities were taken from an observational study. Results are presented as cost/quality-adjusted life-year (QALY) (both discounted 3%) in the societal perspective. The cost/QALY gained with half-dose etanercept versus methotrexate ranged from €14,000 to €29,000: Longer simulations result in a higher cost/QALY, as the acquisition cost of etanercept increases. Half-dose etanercept technically dominates the full dose (lower costs [€-3000 to 6300] and similar effectiveness [0.007-0.011]).

Although ultimately all three strategies explored achieve a similar outcome as all three continuously manage patients to maintain remission, it appears that a dose reduction is the most advantageous strategy in patients with moderate disease activity.

To assess the responsiveness and reader time of a novel semiautomated tool to detect knee cartilage loss over 2 years in subjects with knee osteoarthritis. A total of 122 subjects from the Osteoarthritis Initiative progression cohort were selected. A reader used the software method to segment cartilage on double-echo steady-state sequence scans in the medial compartment of the femur from the baseline and 24-month visits. Change in cartilage volume (ΔV) was measured at a fixed weight-bearing (WB) location with respect to the 3-dimensional coordinate system based on cylindrical coordinates. Change was measured for 5 regions of varying WB surface area centered on the fixed point. The average change (ΔV), the SD of ΔV, and the standardized response mean (SRM) are reported. The SRM was −0.52 for the largest region and decreased in magnitude as smaller regions of cartilage were probed. The average evaluation time was <20 minutes per knee compartment, split approximately evenly between a technician and a trained reader.

The results establish that measurement of cartilage loss in a local region can be done efficiently and that the resultant measures are responsive to loss of cartilage over time. The coordinate system can potentially be used to objectively examine and establish a consistent location for all knees that is most responsive to change in cartilage volume. This technique can provide rapidly an objective quantitative measure of cartilage loss and could substantially reduce study costs for large trials and data sets.

C-telopeptide fragments of type II collagen (CTX-II) are created during articular cartilage breakdown and CTX-II is considered useful as a biomarker of osteoarthritis. The primary objective of the present study was to explore the relationship between urinary CTX-II concentration and patient characteristics, patient-reported outcome, muscle strength, and rehabilitation in patients with isolated focal knee cartilage lesions. Furthermore, the secondary objective was to examine differences in urinary CTX-II concentration between patients with focal cartilage lesions and healthy controls. 48 patients (mean age 33.4 years, standard deviation 9.0) with a focal full-thickness (International Cartilage Repair Society grade 3 or 4) cartilage lesion on the medial or lateral femoral condyle were included. After baseline assessments, the patients completed a 3-month rehabilitation program and 44 patients attended the 3 month follow-up. Baseline and follow-up assessments consisted of urinary CTX-II, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and isokinetic quadriceps and hamstring muscle strength measurements. CTX-II was also analysed in urine samples from 6 healthy individuals, serving as normal controls. Correlations were classified as very weak (correlation coefficient [r] < 0.20), weak (r = 0.20 - 0.39), moderate (r = 0.40 - 0.59), strong (r = 0.60 - 0.79), and very strong (r > 0.80). Except for age and quadriceps strength, no significant correlations were found between CTX-II concentrations and baseline characteristics, KOOS, or muscle strength. Except for age, all correlations were considered as weak or very weak. The patients with a focal cartilage lesion had significantly higher mean CTX-II concentration than the healthy control individuals both at baseline (p = 0.001) and at follow-up (p = 0.001). The mean CTX-II concentration tended to decrease during rehabilitation, but the reduction was not significant (p = 0.076). ClinicalTrials.gov NCT00885729.

The current exploratory study demonstrated that patients with a focal cartilage lesion of the knee had higher concentrations of urinary CTX-II than healthy individuals. In addition, CTX-II concentration tended to decrease during rehabilitation.

Aim of the study was to evaluate the choroidal thickness (CT) in patients with RA and detect the relation with disease activity and joint damage in patients with rheumatoid arthritisBACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with various extra-articular organ manifestations including ocular manifestationsMATERIALS AND METHODS: We included 59 eyes of 59 patients with RA and 59 eyes of 59 controls without RA in the study. Subfoveal and perifoveal CT were measured using enhanced depth imaging optic coherence tomography. Disease activity score 28 (DAS 28) and Larsen score were calculated for each patient with RA and compared with measurements of CT. CT was statistically thinner in patients with RA than controls, at subfoveal CT (p = 0.008), at 500 μm temporal to the fovea (p = 0.004), at 1000 μm temporal to the fovea (p = 0.010), at 1500 μm temporal to the fovea (p = 0.005), at 500 μm nasal to the fovea (p = 0.035). Additionally there was no correlation measurements of CT with disease activity and joint damage.

Subfoveal and perifoveal CT was significantly thinner in patients with RA than in healthy controls but there was no correlation detected between CT measurements and DAS 28 or Larsen scores (Tab. 5, Ref. 33).

To determine whether baseline or serial plasma concentrations of stromelysin (matrix metalloproteinase 3 [MMP-3]) protein might distinguish subjects with progressive radiographic knee osteoarthritis (OA) from those with stable disease. Subjects were 120 women with unilateral knee OA who participated in a 30-month randomized, placebo-controlled trial of structure modification with doxycycline. Anteroposterior views of both knees in a semiflexed position were obtained at baseline, 16 months, and 30 months. Subjects were selected to obtain comparisons of plasma MMP-3 levels between 60 progressors (21 taking doxycycline, 39 taking placebo) and 60 nonprogressors (30 taking doxycycline, 30 taking placebo) with respect to medial joint space narrowing (JSN) in the index knee. Each group consisted of 30 subjects who exhibited significant increases in knee pain. Blood samples were obtained semiannually for MMP-3 assay. Subjects in the placebo group whose MMP-3 concentration was in the upper tertile of the baseline distribution showed a 4-fold increase in the odds of progression of JSN as compared with the lower tertile (odds ratio 4.12, P = 0.037). Baseline MMP-3 levels were unrelated to knee pain. The within-subject mean of serial MMP-3 concentrations was associated with concurrent JSN in the placebo group over the 0-16-month interval (b = 0.18 mm/SD increase in the mean MMP-3, P < 0.01) and over the 16-30-month interval (b = 0.15, P < 0.05). Similar evidence of concurrent validity was found in the placebo group for the maximum of intercurrent MMP-3 values.

The baseline MMP-3 level was a significant predictor of JSN in this pilot study. Moreover, serial plasma MMP-3 levels reflected concurrent JSN in the placebo group over the 30-month period of observation.

Yearly vaccination against influenza is currently recommended to patients with rheumatoid Arthritis (RA). Antibody and cell-mediated responses are both involved in the defense against influenza. Humoral responses to influenza vaccine are impaired in RA patients treated with rituximab (RTX). The objectives of this study were to comparatively assess cell mediated and humoral responses to influenza vaccination in RA patients with or without RTX-induced CD20 B-cell depletion. Trivalent influenza subunit vaccine was administered to 46 RA patients and to 16 healthy controls. The RA group included 29 patients treated by RTX and 17 on conventional disease-modifying anti-rheumatic drugs (DMARDs), mostly methotrexate. Peripheral blood mononuclear cells and sera were obtained immediately before and 4-6 weeks after vaccination. Cell-mediated response to influenza antigens was evaluated by flow cytometry for activated CD4 T-cells. Humoral response was evaluated by haemagglutination inhibition assay. Cellular response: Cell-mediated responses were comparable in RTX-treated vs. DMARDs-treated patients. The recall postvaccination CD4+ cellular response was similar in RA patients and healthy controls. A positive correlation was found between CD19+ cell count on the day of vaccination and cellular response in RTX-treated RA patients. Humoral response: The antibody response rate was significantly impaired in the RTX group: being 26.4%, 68.4% and 47.1% in RTX-treated, DMARDs-treated and controls, respectively.

Cellular immunity to influenza vaccination in RTX-treated patients was similar to DMARDs-treated patients and healthy controls, while humoral immunity was severely impaired. The preservation of cellular immunity may explain the relatively low rate of infection among B-cell depleted patients.

Septic and gouty arthritis show the same clinical symptoms, but septic arthritis is an orthopedic emergency and needs immediate surgical intervention, whereas a systemic drug therapy is needed in acute gouty arthritis. The aim of this study was to investigate which inflammatory markers allow an accurate differentiation of septic and gouty arthritis. This was a retrospective examination of serum markers (peripheral white blood cells, C-reactive Protein and uric acid) and inflammatory markers in the synovial fluid (lactate, glucose, uric acid, lactate dehydrogenase, synovial fluid white blood cell count, total protein, and interleukin-6) in 53 patients with culture-verified septic arthritis and 29 with gouty arthritis. Receiver-Operating-Characteristic-curves with corresponding Area under the curve (AUC), sensitivity, specificity, likelihood-ratio and interval likelihood-ratios were calculated to define the diagnostic potential of the inflammatory markers. Synovial lactate showed the greatest diagnostic potential (AUC = 0.901, sensitivity = 89.5%, specificity = 77.3%, negative likelihood-ratio = 0.14) followed by synovial glucose (AUC=0.853) and synovial uric acid (AUC = 0.841).

Lactate in the synovial fluid has excellent diagnostic potential to differ septic arthritis from gouty arthritis. Synovial lactate levels above 10 mmol/L almost proofed septic arthritis, lactate levels lower than 4.3 mmol/L make it very unlikely.

To assess the responsiveness of the Fibromyalgia Impact Questionnaire (FIQ), patient ratings of pain intensity, number of tender points, and total tender point pain intensity score to perceived changes in clinical status in patients with fibromyalgia (FM). Using data from a randomized placebo controlled study evaluating efficacy of magnetic therapy in patients with FM, the ability of primary outcomes to detect clinically meaningful changes over a 6 month period was assessed by: (1) degree of association between outcome change scores and patient global ratings of symptom change (Spearman rank-order correlations); (2) ability of these scores to discriminate among groups of patients whose perceived health status had changed to varying degrees (ANOVA); (3) ability of these scores, individually and jointly, to discriminate between patients who had reported improvement and those who did not (logistic regression); (4) effect size, standardized response mean, and Guyatt's statistic were calculated to quantify responsiveness. Correlations showed the outcome measures were moderately responsive to perceived symptomatic change. For FIQ, pain intensity ratings and number of tender points, differences in change scores between globally improved and unchanged groups and between globally improved and worsened groups were significant; for total tender point pain intensity, the globally improved differed from worsened group. FIQ outperformed the other measures in discriminating between patients who reported improvement from those who did not. Summary statistics were consistent with discriminatory analyses, indicating the measures were sensitive to improvement, but relatively unresponsive to decline.

The FIQ was the most responsive measure to perceived clinical improvement and we recommend its inclusion as a primary endpoint in FM clinical trials.

Total knee arthroplasty (TKA) is associated with a risk of thromboembolism requiring routine thromboprophylaxis, but there is debate about the risk with unicondylar knee arthroplasty (UKA) as it is a more minor procedure. We sought to investigate the relative risk of thromboembolism with UKA compared to TKA and one-staged bilateral TKA (BTKA) by measuring the increase in circulating biochemical markers of thrombin generation during the procedures. Degree of surgical trauma was also assessed by measuring interleukin-6, a marker of metabolic injury. We prospectively studied a total of 75 patients: 25 patients undergoing UKA, unilateral TKA, and BTKA, respectively. All patients had surgery performed with tourniquet and received no tranexamic acid. Blood samples were taken during surgery and assayed for circulating markers of thrombin generation: prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes plus interleukin-6. Thrombin-antithrombin complexes, increased during all time points (P < .001) but was not significantly different between surgical treatment groups. F1+2 also rose significantly during surgery, with no significant difference between UKA and TKA. There was, however, a significant difference in F1+2 between BTKA and UKA or TKA (P < .02). Interleukin-6 rose minimally with UKA but rose significantly with TKA and BTKA (P < .001).

Based on these data of circulating biochemical markers, patients undergoing UKA are at similar risk of thromboembolism with respect to TKA despite a lower index of metabolic injury. We believe that UKA patients should receive thromboprophylaxis comparable to TKA patients.

The published long-term follow-up of modern total ankle arthroplasty is limited. We report results after a minimum of 10-year follow-up in a cohort of patients who underwent the Scandinavian Total Ankle Replacement (STAR™) in the United States. Between 1998 and 2003, 18 patients underwent total ankle arthroplasty for end-stage ankle degeneration and were available for follow-up at a minimum of 10 years postoperatively out of a consecutive series of 41 patients. All surgeries were performed by a single surgeon at a single institution. Clinical, radiographic, and functional examinations were performed. Revision was defined as failure of either the tibial or the talar metallic component. The mean length of follow-up was 12.6 years (range, 10.2 to 14.6). Overall implant survival was 94.4% (17/18). A total of 39% (7/18) required additional surgical procedures, most of which were performed greater than 9 years postoperatively, and 1 required a revision of the prosthesis. Preoperative VAS pain scale scores improved from 8.1 to 2.1 out of 10 at latest follow-up. Mean Buechel-Pappas Scale scores improved from 32.8 to 82.1 and mean AOFAS Ankle-Hindfoot Scale scores improved from 32.8 to 78.1 at latest follow-up. All patients reported their outcome as good or excellent. Level IV, cohort study.

In the current cohort of STAR ankle patients, implant survival, patient satisfaction, pain relief, and function were high. However, the rate of additional procedures was also high, which highlights the need for patient follow-up and additional long-term outcome studies on total ankle arthroplasty.

Data is lacking on comorbid personality disorders (PD) and fibromyalgia syndrome (FMS) in terms of prevalence, and associated healthcare and societal costs. The main aim of this study was to assess the prevalence of PD in FMS patients and to analyse whether the presence of comorbid PD is related to worse functional impairment and greater healthcare (medical visits, drug consumption, and medical tests) and societal costs. A cross-sectional study was performed using the baseline data of 216 FMS patients participating in a randomized, controlled trial carried out in three primary health care centres situated in the region of Barcelona, Spain. Measurement instruments included the International Personality Disorder Examination - Screening Questionnaire (IPDE-SQ), the Fibromyalgia Impact Questionnaire (FIQ), the Client Service Receipt Inventory (CSRI), and a socio-demographic questionnaire. Most patients (65 %) had a potential PD according to the IPDE-SQ. The most prevalent PD were the avoidant (41.4 %), obsessive-compulsive (33.1 %), and borderline (27 %). We found statistically significant differences in functional impairment (FIQ scores) between FMS patients with potential PD vs non-PD (59.2 vs 51.1; p < 0.001). Multivariate regression analyses revealed that higher FIQ total scores and the presence of potential PD were related to more healthcare costs (primary and specialised care visits).

As expected, PD are frequent comorbid conditions in patients with FMS. Our results suggest that the screening of comorbid PD in patients with FMS might be recommendable in order to detect potential frequent attenders to primary and specialised care.

Few studies have looked at longer term functional outcomes of rapid rehabilitation (physical therapy in the postanesthesia care unit on the day of surgery) for patients undergoing total knee arthroplasty. The purpose of this interdisciplinary study (physical therapy and nursing) was to assess the effect of a rapid rehabilitation program on inpatient length of stay (LOS) and functional recovery. Functional outcomes were measured by the Knee Injury Osteoarthritis Outcome Score presurgically and at 4 and 12 weeks postoperatively and by progression along a physical therapy rehabilitation pathway. Experimental group LOS was significantly shorter than the control group (p = .0261). Multilevel regression modeling showed that KOOS and physical therapy clinical pathway score trajectories did not differ significantly between groups. Patients receiving rapid rehabilitation were 2.5 (95% CI [0.958, 6.53]) times more likely to have a positive physical therapy rehabilitation trajectory than patients in the control group.

Findings validated earlier study results in terms of LOS; however, further research is needed to assess the effect of rapid rehabilitation on longer term functional outcomes.

The prevalence of hip osteoarthritis (OA) increases significantly with age. Although it is not clear whether joint space loss at the hip is a feature of normal aging or a reflection of the OA process, epidemiologic criteria for OA are based on narrowing alone. The aim of this study was to determine whether changes in joint space width occur with age, and whether there are sex differences, in asymptomatic subjects without hip OA. We identified a total of 1,806 subjects who had undergone intravenous urography between 1994 and 1996 and sent a questionnaire to the 1,527 of these subjects who were alive in 1998; 1,031 replies (68%) were received. All radiographs were read by an observer blinded to age, sex, and pain status. Individual radiographic features of OA (narrowing, osteophyte, sclerosis, and cysts) were graded, and an overall qualitative grade was allocated, according to a standard atlas. Minimum joint space width (JSW) was measured by metered caliper to within 0.1 mm. A total of 276 women (mean age 63 years) and 257 men (mean age 64 years) were identified who had never had hip pain (defined as having ever had pain on most days for at least 1 month) and who had no evidence of either joint space narrowing or osteophyte (grade 0, no structural changes). The minimum JSW in either hip was tabulated according to age. JSW measurement was reproducible (95% confidence limits of agreement) to within +/-0.5 mm. At all ages, men had larger JSW than women (3.85 mm in women, 4.19 mm in men, mean difference 0.34 mm; 95% confidence interval [95% CI] 0.24, 0.44). A significant decline in JSW with age was seen in women, with a mean difference between ages 45-54 and 75-84 years of 0.36 mm (95% CI 0.15, 0.58; P = 0.001). No significant change in JSW with age was seen in men (mean difference 0.16 mm; 95% CI -0.11, 0.43). Analysis of an additional 64 women and 61 men who were without hip pain and had overall qualitative grade 1-2 changes gave similar results. Implementing these results to alter the threshold for definition of hip OA in women from < or =2.5 mm to < or =2.2 mm reduced the prevalence of hip OA from 10.6% to 5.6%.

These sex differences in joint space have significant implications in terms of the major emphasis on joint space narrowing in definitions of hip OA. Women also have a significant progressive decline in joint space with age that is not seen in men. This suggests that in women, loss of cartilage may be an age-related phenomenon that is independent of other aspects of structural change. Consideration should be given to the development of sex-specific definitions of hip "OA."

To assess the influence of corticosteroids in the mineral content of patients with giant cell arteritis (GCA), 56 patients, 28 with polymyalgia rheumatica (PMR) and 28 with temporal arteritis (TA) were studied. The bone mineral density (BMD) in the lumbar spine and the femoral neck was measured by dual photon X-ray absorptiometry. A control group (48 people) comparable in age and sex was also evaluated. Compared with the controls, the patients with GCA had lower values of BMD in the femoral neck (men: p < 0.03; women: p < 0.001). In the lumbar spine differences were significant in women (p < 0.05) but not in men (p < 0.1). Multiple regression analysis showed that the BMD at L2-L4 in men correlated with height and weight and was inversely related to the cumulative dose of corticosteroids and the duration of treatment. The BMD at L2-L4 in women correlated with height and weight, but not with corticosteroids. Multiple regression analysis in men showed that age and the total dose of corticosteroids were significant independent predictors of femoral BMD. In women BMD in the femoral neck was correlated with age and weight, but not with corticosteroid treatment.

The total dose and duration of corticosteroid treatment have been shown to be determinant factors of bone mass in patients with GCA who received corticosteroids.

Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. This study was undertaken to investigate if using TENS during activity would improve movement-evoked pain and other patient-reported outcomes in women with FM. Participants were randomly assigned to receive active TENS (n = 103), placebo TENS (n = 99), or no TENS (n = 99) and instructed to use it at home during activity 2 hours each day for 4 weeks. TENS was applied to the lumbar and cervicothoracic regions using a modulated frequency (2-125 Hz) at the highest tolerable intensity. Participants rated movement-evoked pain (primary outcome measure) and fatigue on an 11-point scale before and during application of TENS. The primary outcome measure and secondary patient-reported outcomes were assessed at baseline (time of randomization) and at 4 weeks. After 4 weeks, a greater reduction in movement-evoked pain was reported in the active TENS group versus the placebo TENS group (group mean difference -1.0 [95% confidence interval -1.8, -0.2]; P = 0.008) and versus the no TENS group (group mean difference -1.8 [95% confidence interval -2.6, -1.0]; P < 0.0001). A reduction in movement-evoked fatigue was also reported in the active TENS group versus the placebo TENS group (group mean difference -1.4 [95% confidence interval -2.4, -0.4]; P = 0.001) and versus the no TENS group (group mean difference -1.9 [95% confidence interval -2.9, -0.9]; P = <0.0001). A greater percentage of the patients in the active TENS group reported improvement on the global impression of change compared to the placebo TENS group (70% versus 31%; P < 0.0001) and the no TENS group (9%; P < 0.0001). There were no TENS-related serious adverse events, and <5% of participants experienced minor adverse events from TENS.

Among women who had FM and were on a stable medication regimen, 4 weeks of active TENS use compared to placebo TENS or no TENS resulted in a significant improvement in movement-evoked pain and other clinical outcomes. Further research is needed to examine effectiveness in a real-world setting to establish the clinical importance of these findings.

To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case-control association study. 1300 SSc cases (961 white, 178 black and 161 Hispanic subjects) characterised for clinical skin forms (limited vs diffuse), SSc-specific autoantibodies (anticentromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 ribonucleoprotein (fibrillarin)) and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modelling for dominant, additive and recessive effects from HLA. The strongest positive class II associations with SSc in white and Hispanic subjects were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate between limited and diffuse SSc. SSc in black subjects was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR = 14). Moreover, it showed no linkage disequilibrium or gene interaction with DR/DQ. ACA was best explained by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in white and Hispanic subjects but DRB1*08 in black subjects.

These data indicate unique and multiple HLA-class II effects in SSc, especially on autoantibody markers of different subphenotypes.

Research has established a link between health status and symptoms of depression in persons with rheumatoid arthritis (RA), but the effects of "cognitive coping" variables have not been extensively studied. We examined the mediator effect of a cognitive coping variable (Pain Control and Rational Thinking factor score from the Coping Strategies Questionnaire) over the course of a pharmacological intervention. Data were analyzed from 54 persons with RA, all of whom met diagnostic criteria for major depression. Measures of depression, health status, and cognitive coping were collected at 4 different stages of a pharmacological (antidepressant) study as follows: (1) at baseline, (2) postintervention, (3) 6 month followup, and (4) 15 month followup. Results indicated that a direct relationship existed between health status and depression at all 4 time periods. However, this relationship was mediated by cognitive coping only at the postintervention and the 6 month followup.

A cognitive coping variable was found to mediate the relationship between health status and depression, but only at moderate levels of depression.

Rheumatoid arthritis (RA) is burdened by a significant increase in cardiovascular disease (CVD) risk. Amongst CVD risk factors, endothelial dysfunction and arterial stiffness represent powerful predictors of atherosclerosis and cardiovascular events in the general population and in RA patients. A systematic review of the literature was performed to identify the available data on the effect of non-TNF-targeted biologics licensed for the treatment of RA on endothelial function, arterial stiffness or subclinical atherosclerosis. MedLine (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science (WOS) databases were searched using a predefined strategy to identify relevant articles. The search strategy initially retrieved 389 records. After screening titles and abstracts, a total of 362 studies were excluded. Amongst the remaining 27 studies selected for final examination, 16 articles were included in the systematic literature review. Included studies demonstrated a significant effect of abatacept, anakinra, rituximab and tocilizumab in improving endothelial dysfunction associated with RA; the effect on arterial stiffness was less consistent and deserves further investigation. No significant effect of non-TNF-targeted biologics was observed for measures of subclinical atherosclerosis.

Non-TNF-targeted biologics have been associated with favorable effects on endothelial dysfunction as already demonstrated for TNF inhibitors. Future studies are needed to ascertain the impact of this mediations on arterial stiffness in RA patients.

Management of systemic lupus erythematosus (SLE) is complex and variability in practices exists. Guidelines have been developed to help improve the management of SLE patients, but there has been no formal evaluation of these guidelines. This study aims to compare the scope, quality, and consistency of clinical practice guidelines on the diagnosis, monitoring, and treatment of patients with SLE. Electronic databases were searched up to April 2014. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument and textual synthesis was used to appraise and compare recommendations. Nine clinical practice guidelines and 5 consensus statements were identified, which covered 7 topics: diagnosis, monitoring, treatment, neuropsychiatric SLE, lupus nephritis, antiphospholipid syndrome, and other manifestations of lupus. The methodological quality of the guidelines was variable, with the overall mean AGREE II scores ranging from 31% to 75%, out of a maximum 100%. Scores were consistently low for applicability, with only 1 guideline scoring above 50%. There was substantial variability in the treatments recommended for class II and V lupus nephritis, the recommended duration of maintenance therapy for class III/IV lupus nephritis (from 1 to 4 years), and timing of ophthalmologic examination for patients taking corticosteroids.

Published guidelines on SLE cover a complex area of clinical care, but the methodological quality, scope, and recommendations varied substantially. Collaborative and multidisciplinary efforts to develop comprehensive, high-quality evidence-based guidelines are needed to promote best treatment and health outcomes for patients with SLE.

Fibromyalgia may have negative effects on sexual function in women. To evaluate the sexuality of women with fibromyalgia and healthy control subjects, and to investigate the relation between sexuality and clinical parameters of fibromyalgia. Female Sexual Function Index (FSFI), Tender Points Count (TPC), Beck Depression Inventory (BDI), Fibromyalgia Impact Questionnaire (FIQ), and Visual Analog Scale (VAS). Clinical evaluation and surveys were done with 126 women with fibromyalgia and 132 healthy women. Patients with fibromyalgia had higher BDI scores and lower frequency of sexual intercourse than control subjects. The mean FSFI scores (total and all domains) were significantly lower in patients with fibromyalgia than control subjects. Mean FSFI scores (total and most domains) were significantly lower in patients with fibromyalgia who had BDI score≥17 than those who had BDI score<17. In women with fibromyalgia, a significant negative correlation was noted between total FSFI score, and both FIQ and BDI scores.

Fibromyalgia has negative effects on female sexual function that are aggravated by depression.

We report the case of a leg ulcer in a rheumatoid arthritis (RA) patient under treatment with leflunomide, discuss the influence of the drug on the aetiopathogenesis of the ulcer and describe its successful treatment. A 68-year-old woman with a 12-year history of RA developed a leg ulcer after 4 months of leflunomide treatment. Other ulcerogenic factors were ruled out. There were some clinical hints for rheumatoid vasculitis. The ulcer was resistant to ambulant conservative phase adapted wound bed preparation and a split skin transplantation failed. After omission of leflunomide and washout procedure with cholestyramine a second split skin transplantation resulted in complete healing. Leflunomide inhibits the division of activated T cells and thus inhibits among others the production of proinflammatory cytokines and the adhesion of cells to the endothelium. These mechanisms may partly explain the possible influence of leflunomide on the perpetuation of the ulcer. Until now, occurrence of vasculitis and leg ulcers has been described in one case each for the novel immunomodulator leflunomide. No successful treatment of a leg ulcer under leflunomide has been described yet. Omission of leflunomide and a washout treatment in our case led to a complete healing. This may indicate a critical role of leflunomide in the maintenance of this slow healing ulcer.

An association between leflunomide intake, occurrence of leg ulcers in RA patients and delayed wound healing should be considered.

To explore the efficacy of re-treatment with rituximab in patients with rheumatoid arthritis (RA) who were initial nonresponders to treatment, and to evaluate the effects of rituximab in RA when re-treatment is given in a standardized way based on the Disease Activity Score in 28 joints (DAS28), according to the international consensus statement. Patients with RA who had a DAS28 of > or =3.2 received up to 3 courses of rituximab at intervals of at least 6 months, regardless of whether the patient had responded to the first course of treatment with rituximab. Of the 30 patients with RA who were included in the study, 26 could be evaluated for the efficacy of treatment after 6 months. Eighteen patients qualified for re-treatment at 6 months, 6 patients were re-treated at a later time point because of a disease relapse, and 2 other patients were not re-treated because they had low disease activity. Seven of the 24 patients who qualified for re-treatment had not exhibited clinical improvement after the first treatment course. These patients typically did not respond to subsequent courses of rituximab. Of interest, in the 17 patients who had exhibited a clinical response to the first course of rituximab, the second and third treatment courses resulted in European League Against Rheumatism responses similar to those observed after the first course, and no major relapses occurred before re-treatment.

Rituximab re-treatment is not effective in patients who do not exhibit clinical improvement after the first treatment course, which is consistent with the notion that such patients represent a different pathogenetic subset of RA. Patients who initially responded to rituximab treatment experienced sustained benefit from DAS28-based systematic re-treatment according to the international consensus statement.

To investigate the prevalence of HBV infection and the risk of hepatitis B virus (HBV) reactivation in patients with inflammatory arthritis receiving tumour hecrosis factor alpha (TNFα) inhibitors. The liver function, serology of HBV and viral loads (HBV DNA) were tested before using TNFα inhibitors, at 3 months and 6 months. Patients with chronic hepatitis B (CHB) infection (HBV DNA > 1×10(3) copies/ml) were eliminated. A total of 162 patients were investigated including 156 patients who finished the study. Eleven (7.05%) patients were HBsAg-positive. Two patients with HBV DNA > 1×10(3) copies/ml were eliminated before starting anti-TNFα therapy. Among HBsAg-positive patients, HBV reactivation was documented in only one of the 11 patients. This patient with rheumatoid arthritis developed elevation of glutamic-pyruvic transaminase (ALT) and HBV DNA copies three months after infliximab therapy. Therefore lamivudine was given for three months, which translated into the fall of ALT and HBV DNA copies back to normal level. After follow-up for six months, the virology and serology remained stable. In contrast, none of the other 155 patients had demonstrated evidence of HBV infection or HBV reactivation.

The kinetics of HBV viral loads should be carefully monitored in patients with inflammatory arthritis and HBsAg-positive during anti-TNFα therapy. HBV reactivation should be treated with antiviral medicine through out the period of anti-TNFα therapy.

Currently, two pathogenic pathways describe the role of obesity in osteoarthritis (OA); one through biomechanical stress, and the other by the contribution of systemic inflammation. The aim of this study was to evaluate the effect of free fatty acids (FFA) in human chondrocytes (HC) expression of proinflammatory factors and reactive oxygen species (ROS). HC were exposed to two different concentrations of FFA in order to evaluate the secretion of adipokines through cytokines immunoassays panel, quantify the protein secretion of FFA-treated chondrocytes, and fluorescent cytometry assays were performed to evaluate the reactive oxygen species (ROS) production. HC injury was observed at 48 h of treatment with FFA. In the FFA-treated HC the production of reactive oxygen species such as superoxide radical, hydrogen peroxide

In our in vitro model of HC, a hyperlipidemia microenvironment induces an oxidative stress state that enhances the inflammatory process mediated by adipokines secretion in HC.

Intra-articular (IA) injections represent a commonly used modality in the treatment of hip osteoarthritis (OA). Commonly used injections include corticosteroids (CCS), hyaluronic acid (HA) and platelet-rich plasma (PRP). A network meta-analysis allows for comparison among more than two treatment arms and uses both direct and indirect comparisons between interventions. The objective of this network meta-analysis is to compare the efficacy of the various IA injectable treatments in treating hip OA at up to 6 months of follow-up. This is a systematic review and network meta-analysis. Bayesian random-effects model was performed to assess the direct and indirect comparisons of all treatment options. PubMed, Embase, Cochrane Central Register of Controlled Trials, Scopus and Web of Science, from inception to October 2019. Randomised controlled trials assessing the efficacy of CCS, HA, PRP and placebo in the form of IA saline injection for patients with hip OA. Eleven randomised controlled trials comprising 1353 patients were included. For pain outcomes at both 2-4 and 6 months, no intervention significantly outperformed placebo IA injection. For functional outcomes at both 2-4 and 6 months, no intervention significantly outperformed placebo IA injection. Regarding change from baseline at 2-4 months and 6 months, pooled data demonstrated that all interventions (including placebo), with the exception of HA+PRP, led to a clinically important improvement in both pain, exceeding the minimal clinically important difference.

Evidence suggests that IA hip saline injections performed as well as all other injectable options in the management of hip pain and functional outcomes.

Several studies from Western countries have analyzed the profile of pediatric rheumatology practices. Due to differences in demography and health care systems the profile in Israel may differ from those countries. To describe the profile of a pediatric rheumatology practice in Israel. All new patients seen during the course of 2000 as part of my pediatric rheumatology practice in Northern Israel were registered at their initial encounter. Recorded were demographic data, referral patterns, diagnoses, and disease-related data. Diagnoses were grouped together by types of condition. 242 new patients were seen. 39% of the patients had a rheumatic condition, 39% had non-inflammatory conditions, 12% had periodic fever syndromes and for 10% no definitive diagnosis was determined. 14% had chronic rheumatic diseases. The time until diagnosis was significantly greater and more physicians were involved in the evaluation of periodic fever syndromes than in other disease groups. Seventeen (7%) patients had juvenile rheumatoid arthritis (JRA). The minimum estimated incidence of JRA was 8.8 per 100,000 children.

Most patients seen did not have classic inflammatory rheumatic diseases, similar to data from other Western countries. Distinctive to Israel and the Middle East, periodic fever syndromes comprise a large proportion of the pediatric rheumatology practice. These syndromes are relatively difficult for community physicians to diagnose.

Preparation, in vitro and in vivo evaluation of indomethacin-loaded polymeric micelles based on amphiphilic polyphosphazene. Amphiphilic polyphosphazenes (PNIPAAm/EAB-PPPs) with poly (N-isopropylacrylamide) (PNIPAAm) and ethyl 4-aminobenzoate (EAB) as side groups were synthesized through thermal ring-opening polymerization and subsequent substitution reactions. Indomethacin (IND) loaded polymeric micelles based on PNIPAAm/EAB-PPPs were prepared by dialysis procedure. In vitro IND release kinetics was investigated in 0.1 M PBS (pH 7.4), while in vivo pharmacokinetics was performed in Sprague-Dawley rats. In vivo pharmacodynamic study was carried out based on two animal models, i.e. carrageenan-induced acute paw edema and complete Freund's adjuvant (CFA) induced ankle arthritis model. Drug loading capacity of micelles based on this type of amphiphilic copolymers was mainly determined by copolymer composition and the chemical structure of drug. In addition to the compatibility between drug and micellar core, hydrogen bonding interaction between drug and hydrophilic corona may significantly influence drug loading as well. In vitro drug release in PBS suggested that there was no significant difference in release rate between micelles based on copolymers with various EAB content. Compared with the rats administered with free IND aqueous solution, IND concentration in rats' plasma showed a prolonged maintenance in experimental group treated with IND-loaded polymeric micelles. In vivo pharmacodynamic study indicated that sustained therapeutic efficacy could be achieved through topical injection of the aqueous solution of IND-loaded micelles. Local delivery of IND can avoid the severe gastrointestinal stimulation, which was frequently associated with oral administration as evidenced by ulceration evaluation.

The promising results of current preliminary study suggest that this type of amphiphilic copolymers could be used as injectable drug carriers for hydrophobic drugs.

Chondromodulin-II (ChM-II) is a cartilage-derived protein involved in cartilage and bone repair. A study of Japanese patients with rheumatoid arthritis (RA) implicated an association between a 172G --> A (Val58Ile) polymorphism and radiographic damage. We analyzed ChM-II for polymorphisms and investigated the association with radiographically assessed joint destruction in German patients with RA. Possible interactions with the shared epitope (SE) were examined. DNA samples from 204 patients with RA, 81 patients with osteoarthritis, and 116 patients with gout, serving as controls, were sequenced. Radiographic damage was assessed by modified Larsen score. Allele and genotype frequencies between groups were compared by Cochrane-Armitage trend tests. Five missense mutations, one silent mutation, and 5 intronic polymorphisms were found. Allele and genotype frequencies were similar in both disease groups. Larsen scores were significantly higher in RA patients carrying the 172AA (Ile/Ile) genotype (Larsen 96.8), than in RA patients with the 172GA (Val/Ile; Larsen 69.5) or 172GG (Val/Val; Larsen 54.8; p = 0.001) genotypes. Odds ratios to develop more severe radiographic joint damage (Larsen score > 90; above 75th percentile) were 4 and 15.5 for the 172GA and 172AA genotypes, respectively. Presence of a 172A allele increased the risk for enhanced radiographic damage 3-fold. SE and ChM-II 172A alleles emerged as 2 independent risk factors. A potentiated interaction of these risk alleles could not be verified.

Our data indicate that ChM-II Val58Ile polymorphism is associated with radiographic progression of joint destruction, particularly in German patients with RA negative for SE.

The clinical approach of fibromyalgia is a cause of frustration for some professionals due to the controversy on its diagnosis, etiopathology and clinical management. The aim of this study was to explore the beliefs and knowledge on fibromyalgia among health professionals from different specialties of the public health service from Almería province. A descriptive and cross-sectional study was carried out. A questionnaire prepared ex profeso was applied to a sample of 103 clinicians from Primary Care Physicians, Mental Health, Internal Medicine and Rheumatology. The chi-square test was performed to explore the relationships among variables. 59.7% of Primary Care providers and 66.7% of Internal Medicine conceptualized fibromyalgia as a somatization. Likewise, 58.9% of Primary Care indicated that fibromyalgia should be considered in no case as a disabling illness, compared to 16.7% from Rheumatology, as well as for 42.5% of them the fibromyalgia diagnosis is not essential, compared to the amount of other specialties. Mood disorders were mentioned by 53.4% of Primary Care as entities from which fibromyalgia is difficult to discriminate. Sleep or gastrointestinal problems were mentioned by 83.3% and 50% of Rheumatology professionals, respectively. El abordaje clínico de la fibromialgia es causa de frustración para algunos profesionales por la controversia en su diagnóstico, etiopatología y manejo clínico. El objetivo del presente estudio fue explorar cuáles son las creencias y conocimientos hacia la fibromialgia por parte de profesionales de distintas especialidades del ámbito público de salud de la provincia de Almería. Se trató de un estudio descriptivo y transversal. Se aplicó un cuestionario elaborado ex profeso a una muestra de 103 clínicos de Atención Primaria, Salud Mental, Medicina Interna y Reumatología. Se exploró la relación de las variables mediante la prueba chi-cuadrado. El 59,7% de los profesionales de Atención Primaria y el 66,7% de los de Medicina Interna conceptuaron la fibromialgia como una somatización. Asimismo, el 58,9% de los profesionales de Atención Primaria indicó que en ningún caso había de considerarse como una enfermedad discapacitante, en comparación con el 16,7% de los de Reumatología, así como que para el 42,5% no era fundamental su diagnóstico, en comparación a la totalidad en otras especialidades. Los trastornos del ánimo, como entidades de las que resulta difícil de discriminar la fibromialgia, fueron mencionados por el 53,4% de los de Atención Primaria. Los problemas de sueño o problemas gastrointestinales se mencionaron en mayor medida como manifestaciones clínicas entre los de Reumatología (83,3% y 50%, respectivamente).

A high percentage of professionals considered fibromyalgia as a psychogenic entity, especially among Internal Medicine and Primary Care, highlighting in the last one a position against the consideration of disability and its difficult differentiation from mood disorders. These latest findings could be explained by beliefs or attitudes on the amplification of pain behaviors and secondary gains. A deeper knowledge on fibromyalgia symptoms from Rheumatology is highlighted. Methodological limitations and recommendations are discussed. Un alto porcentaje de profesionales conceptúan la fibromialgia como una entidad psicógena, en especial, profesionales de Medicina Interna y Atención Primaria, destacando en esta última una posición en contra de la consideración de discapacidad y su difícil diferenciación de los trastornos del ánimo. Estos últimos hallazgos podrían explicarse por creencias o actitudes respecto a la amplificación de las conductas del dolor y la obtención de ganancias secundarias. Destacan los conocimientos más profundos de la sintomatología en Reumatología. Se discuten las limitaciones metodológicas y recomendaciones.

HLA is the most strongly associated locus in rheumatoid arthritis (RA), accounting for up to one-third of the genetic contribution. Conditioning on the effect of true disease loci such as HLA can lead to increased power to detect effects at other loci and, in addition, allows investigation of the underlying disease models, including interactions. The aim of this study was to detect susceptibility loci for RA by conditioning on HLA in a large sample of affected sibling pairs (ASPs) and to test for evidence of interaction between novel loci and HLA. Genotype data from 3 whole-genome linkage scans for RA in a US population and a UK population were pooled, resulting in a combined data set of 886 ASPs. This pooling of data increased the power to detect loci showing low levels of heterogeneity. Nonparametric linkage analysis was performed to identify regions of interest. Joint 2-locus analysis was then performed for HLA and each of the loci that demonstrated evidence of linkage in the 886 ASPs. Evidence for linkage was most significant at HLA (P = 4 x 10(-16)), with 7 non-HLA loci showing some evidence for linkage (P = 0.05-0.003). Joint modeling of these loci with HLA provided evidence for linkage at a genome-wide significance level for loci on 6q (P = 2.7 x 10(-6)) and 16p (P = 2 x 10(-4)).

These data provide the most convincing evidence to date that 6q and 16p harbor susceptibility genes. In addition, these loci may interact with HLA, facilitating the search for candidate genes within this region.

To examine the prevalence and timing of nonbladder conditions in a community cohort of women with symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). As part of the Rand Interstitial Cystitis Epidemiology (RICE) study, we identified 3397 community women who met a validated case definition for IC/BPS symptoms. Each completed a survey asking if they had a physician diagnose them as having irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, migraines, panic attacks, or depression. If a positive response was received, subjects were asked to provide the age of symptom onset. All subjects were also asked to provide the date of IC/BPS symptom onset. A total of 2185 women reported a diagnosis of at least one of the nonbladder conditions. Onset of bladder symptoms was not consistently earlier or later than the onset of nonbladder symptoms. Depression tended to occur earlier (P < .05), whereas fibromyalgia generally occurred later (P < .05). Mean age of onset was lowest for migraine symptoms, depression symptoms, and panic attacks symptoms, and greatest for fibromyalgia and chronic fatigue syndrome symptoms. Mean age of irritable bowel syndrome and IC/BPS symptom onset was between these other conditions.

These findings confirm the common co-occurrence of IC/BPS with chronic nonbladder conditions. In women with IC/BPS symptoms and coexistent nonbladder conditions, bladder symptoms do not uniformly predate the nonbladder symptoms. These observations suggest that phenotypic progression from isolated bladder symptoms to regional/systemic symptoms is not a predominant pattern in IC/BPS, although such a pattern may occur in a subset of individuals.