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ID PMID Title PublicationDate abstract
23921318 Bacteremia in patients receiving TNF-alpha antagonists--a prospective multicenter study. 2013 Dec OBJECTIVE: TNF-alpha antagonists have changed the outcome of various chronic inflammatory diseases. Their use has spread widely and many patients receive those treatments for years. Previous reports found that the use of TNF-alpha antagonists may be associated with an increased risk of serious bacterial infections. We report 47 prospective bacteremia cases from the RATIO registry. METHODS: A national prospective study was conducted in France between 2004 and 2007 to collect severe bacterial infections in patients receiving TNF-alpha antagonists. All reported cases of bacteremia were validated by an expert committee. RESULTS: Forty-seven bacteremic episodes were reported. Staphylococcus aureus represented the most frequent causative pathogen (40%) and was mostly associated with bones and/or joints infections (68%) and with a worse outcome compared to that observed with other bacterial pathogens. CONCLUSIONS: Patients receiving TNF-alpha antagonists may develop bacteremia and S. aureus has to be included in the spectrum of the initial empiric antimicrobial therapy.
25437024 How well do patients understand written instructions?: health literacy assessment in rural 2014 Nov The aim of this study was to assess health literacy (word recognition and comprehension) in patients at a rural rheumatology practice and to compare this to health literacy levels in patients from an urban rheumatology practice.Inclusion criteria for this cross-sectional study were as follows: ≥18-year-old patients at a rural rheumatology practice (Mid-North Coast Arthritis Clinic, Coffs Harbour, Australia) and an urban Sydney rheumatology practice (Combined Rheumatology Practice, Kogarah, Australia). Exclusion criteria were as follows: ill-health precluding participation; poor vision/hearing, non-English primary language. Word recognition was assessed using the Rapid Estimate of Adult Literacy in Medicine (REALM). Comprehension was assessed using the Test of Functional Health Literacy in Adults (TOFHLA). Practical comprehension and numeracy were assessed by asking patients to follow prescribing instructions for 5 common rheumatology medications.At the rural practice (Mid-North Coast Arthritis Clinic), 124/160 patients agreed to participate (F:M 83:41, mean age 60.3 ± 12.2) whereas the corresponding number at the urban practice (Combined Rheumatology Practice) was 99/119 (F:M 69:30, mean age 60.7 ± 17.5). Urban patients were more likely to be born overseas, speak another language at home, and be employed. There was no difference in REALM or TOFHLA scores between the 2 sites, and so data were pooled. REALM scores indicated 15% (33/223) of patients had a reading level ≤Grade 8 whereas 8% (18/223) had marginal or inadequate functional health literacy as assessed by the TOFHLA. Dosing instructions for ibuprofen and methotrexate were incorrectly understood by 32% (72/223) and 21% (46/223) of patients, respectively.Up to 15% of rural and urban patients had low health literacy and <1/3 of patients incorrectly followed dosing instructions for common rheumatology drugs.There was no significant difference in word recognition, functional health literacy, and numeracy between rural and urban rheumatology patients.
24434273 A T cell gene expression panel for the diagnosis and monitoring of disease activity in pat 2014 Feb Systemic Lupus Erythematosus (SLE) remains a challenging disease to diagnose and follow, as no reliable biomarkers are known to date. We designed a gene expression panel with 40 genes known to play a role in SLE pathogenesis. We found that the combined expression of these genes in SLE T cells can accurately differentiate SLE from healthy individuals and patients with other autoimmune diseases. The accuracy of the test increased further (83%) when only three out of the initial genes (OAS2, CD70 and IL10) were used. A T cell score, calculated from the combined expression levels of these genes, correlated positively with various SLE activity markers in a cross-sectional cohort and in a few patients that were followed prospectively. These data showcase the usefulness of measuring mRNA levels of key molecules in diagnosing and following patients with SLE.
22786533 Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene trans 2013 Apr Antibodies against adeno-associated viral (AAV) vectors are highly prevalent in humans. Both preclinical and clinical studies showed that antibodies against AAV block transduction even at low titers, particularly when the vector is introduced into the bloodstream. Here we measured the neutralizing antibody (NAb) titer against AAV serotypes 2, 5, 6 and 8 in the serum and matched synovial fluid (SF) from rheumatoid arthritis patients. The titer in the SF was lower than that in the matched plasma samples, indicating a difference in distribution of NAb to AAV depending on the body fluid compartment. This difference was more evident for AAV2, against which higher titers were measured. Of all serotypes, anti-AAV5 antibodies were the least prevalent in both the serum and SF. We next evaluated the impact of B-cell depletion on anti-AAV antibodies in rheumatoid arthritis patients who received one or two courses of the anti-CD20 antibody rituximab as part of their disease management. A drop of NAb titer was observed in a subset of those subjects carrying NAb titers ≤1:1000; however, only in a minority of subjects titers dropped below 1:5. This work provides insights into strategies to overcome the limitation of pre-existing humoral immunity to AAV vectors.
24503398 [The short-term efficacy and safety of methotrexate plus low dose prednisone in patients w 2013 Dec OBJECTIVE: To evaluate the clinical efficacy and safety of methotrexate (MTX) plus low dose glucocorticoid in the treatment of rheumatoid arthritis (RA) from the "target control" point of view. METHODS: Patients diagnosed as RA according to American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2010 classification criteria were enrolled. All of the patients were prescribed with 15 mg/week MTX, 5 mg/week folic acid and prednisone (not exceeding 10 mg/day) orally. At week 0, 4, 12, disease activity and clinical efficacy were recorded. Co-primary assessment criterion was disease activity score (DAS28)-based on C-reactive protein (CRP). Secondary assessment criteria included EULAR response criteria, ACR response criteria, simplified disease activity index (SDAI) , clinical disease activity index (CDAI) . The tolerability and toxicity of MTX was recorded at week 4, 12. All patients were evaluated for the occurrence of adverse drug reactions associated with prednisone at week 12. RESULTS: A total of 76 patients were enrolled in the study. At week 4 and 12, 68 and 65 patients completed regular follow-up respectively. At week 12, there were 30 (46.2%), 9 (13.8%), 26 (40.0%) patients who met DAS28-CRP remission, low disease activity, middle and high disease activity criterion respectively. Three of nine patients who grouped in low disease activity after therapy were early or intermediate patients and didn't reach the target. Thus 36(55.4%) patients met the standard of target control. The percentage of patients who met the criteria of EULAR good response, the ACR criteria for 20% improvement (ACR20) , the ACR criteria for 50% improvement (ACR50), the ACR criteria for 70% improvement (ACR70) were 29.2%, 75.4%, 69.2%, 64.6%, respectively. The proportion of patients meeting the standard of treat to target using SDAI and CDAI were 76.9%, 58.5% respectively. The rate of liver injury, abdominal pain, abdominal distention and acid reflux, nausea were 11.8%, 4.4%, 4.4%, 2.9% respectively at week 4. At week 12, 4.6% of patients reported abdominal distention. There was only one patient (1.5%) each who complained of abdominal pain, nausea, loss of hair, varicella zoster virus infection and pulmonary infection at week 12. No serious adverse event was observed during the study. CONCLUSIONS: Based on the view of "target control", drug efficacy and safety, MTX plus low dose prednisone is still a useful therapeutic regimen for RA at present.
22739990 Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate 2013 Jun OBJECTIVE: To investigate the long-term effects of induction therapy with adalimumab (ADA) plus methotrexate (MTX) in comparison with placebo (PBO) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis (RA). METHODS: Patients with active early RA (disease duration of ≤12 months) were randomly assigned to receive 40 mg ADA subcutaneously every other week (eow) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks. Thereafter, all patients received MTX monotherapy up to week 48. The primary outcome was the Disease Activity Score 28 (DAS28) at week 48. Secondary outcomes included proportions of patients in remission (DAS28<2.6), ACR responses, Health Assessment Questionnaire (HAQ) score and radiographic progression. RESULTS: 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX. At baseline, DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups. At week 24, treatment with ADA/MTX compared with PBO/MTX resulted in a greater reduction in DAS28 (3.0±1.2 vs 3.6±1.4; p=0.009) and other secondary outcomes such as DAS28 remission rate (47.9% vs 29.5%; p=0.021) and HAQ (0.49±0.6 vs 0.72±0.6; p=0.0014). At week 48, the difference in clinical outcomes between groups was not statistically significant (DAS28: 3.2±1.4 vs 3.4±1.6; p=0.41). Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX (Sharp/van der Heijde score: ADA/MTX 2.6 vs PBO/MTX 6.4; p=0.03, Ratingen score: 1.7 vs 4.2; p=0.01). CONCLUSIONS: A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48, even after discontinuation of ADA treatment at week 24. This sustained effect was not found at the primary endpoint (DAS28 reduction).
25144752 Genetic polymorphisms affect efficacy and adverse drug reactions of DMARDs in rheumatoid a 2014 Nov Disease-modifying antirheumatic drugs (DMARDs) and biological agents are critical in preventing the severe complications of rheumatoid arthritis (RA). However, the outcome of treatment with these drugs in RA patients is quite variable and unpredictable. Drug-metabolizing enzymes (dihydrofolate reductase, cytochrome P450 enzymes, N-acetyltransferases, etc.), drug transporters (ATP-binding cassette transporters), and drug targets (tumor necrosis factor-α receptors) are coded for by variant alleles. These gene polymorphisms may influence the pharmacokinetics, pharmacodynamics, and side effects of medicines. The cause for differences in efficacy and adverse drug reactions may be genetic variation in drug metabolism among individuals. Polymorphisms in drug transporter genes may change the distribution and excretion of medicines, and the sensitivity of the targets to drugs is strongly influenced by genetic variations. In this article, we review the genetic polymorphisms that affect the efficacy of DMARDs or the occurrence of adverse drug reactions associated with DMARDs in RA.
23223421 Toll-like receptor-mediated, enhanced production of profibrotic TIMP-1 in monocytes from p 2013 Aug OBJECTIVES: To investigate whether monocytes contribute to matrix deposition in systemic sclerosis (SSc) by production of tissue-inhibitor of metalloproteinase-1 (TIMP-1). METHODS: Matrix metalloproteinase-1 (MMP-1) and TIMP-1 expression and secretion were measured by qRT-PCR and ELISA in circulating monocytes from patients with SSc, patients with rheumatoid arthritis (RA) and healthy controls (HC) and in healthy monocytes cultured in the presence of SSc or HC serum samples. Production of TIMP-1 was determined in response to a panel of Toll-like receptor (TLR) agonists and MyD88 inhibitory peptide. The functional effect of conditioned media from SSc and HC serum samples or TLR8-stimulated monocytes was studied in an MMP-1 activity assay. RESULTS: TIMP-1 production by monocytes was upregulated in patients with SSc compared with patients with RA and HC. Incubation of HC monocytes with SSc serum samples resulted in functionally active TIMP-1 production. However, pretreatment with MyD88 inhibitor, but not control peptide, decreased TIMP-1 secretion. TIMP-1 production was significantly stronger when SSc and HC monocytes were stimulated with TLR8 (ssRNA) agonist, but the response was more pronounced in SSc monocytes. TIMP-1 production after TLR stimulation was also strongly reduced in the presence of MyD88 inhibitory peptide or in the monocytes isolated from a patient with a genetic TLR signalling defect. MMP-1 activity was significantly inhibited in media from serum samples or TLR8-stimulated monocytes indicative of functional TIMP activity. CONCLUSIONS: This study demonstrates profibrotic properties of circulating monocytes from patients with SSc and a key role for TLR signalling, particularly TLR8, in TIMP-1 secretion and matrix remodelling.
23864142 Levels of dipeptidyl peptidase IV/CD26 substrates neuropeptide Y and vasoactive intestinal 2013 Nov Neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) have their biological half-lives controlled by dipeptidyl peptidase IV (DPP IV/CD26). Several lines of evidence suggest the involvement of NPY in the regulation of rheumatoid arthritis (RA), and VIP has already been identified as a potent anti-inflammatory factor that reduces joint inflammation. The role of DPP IV/CD26 in the pathogenesis of RA has been indicated, but its mediator actions involving NPY and VIP have not been well investigated, so the aim of this study was to find an association between NPY, VIP, and DPP IV/CD26 in RA patients. Assessment of NPY, VIP, DPP IV/CD26 as well as some other inflammatory markers was carried out in 20 RA patients being treated with different types of drugs. Control group consisted of 18 osteoarthritis patients. Synovial fluid and serum content of investigated molecules was determined by ELISA and DPP IV/CD26 activity was measured spectrophotometrically. Immunodetection showed elevated levels of NPY and VIP in RA patients, with a significant increase in synovial fluid, while concentration and activity of DPP IV/CD26 were significantly decreased in both synovial fluid and serum. Positive correlations between serum DPP IV/CD26 concentration and activity (R = 0.6961), as well as between serum and synovial fluid concentration of VIP (R = 0.7029) were found. In RA group, NPY, VIP, and DPP IV/CD26 concentrations were not affected by the administration of drugs. The results of this study indicate a connection between elevated concentration of NPY and VIP and decreased DPP IV/CD26 activity and concentration, suggesting a potential role of these molecules in the immunomodulation of RA.
24056140 Experience of structural onlay allografts for the treatment of bone deficiency in revision 2013 BACKGROUND AND AIMS: Loss of femoral bone stock in elective revision total hip arthroplasty poses unique and substantial challenges. Structural onlay allografts may provide mechanical stability for the cementless revision prosthesis and increase bone stock. MATERIAL AND METHODS: At least one cortical onlay allograft was used in 40 elective total hip arthroplasty revisions (40 patients) to reconstruct femoral bone defects. The operations were performed between January 1999 and August 2010 in the Turku University Hospital, Finland. The mean follow-up time was 52 months (range: 12-125 months). RESULTS: The allografts were incorporated into the bone tissue in 37 of 40 (92.5%) patients. Cementless revision stems healed in 36 of 40 (90.0%) patients, but these patients were not exactly the same patients whose allografts were successfully incorporated. One or more surgical complications were experienced by 14 of 40 (35.0%) patients during follow-up. In all, 4 of 40 (10.0%) patients (all women) had hip infections during follow-up. Of the 7 patients with rheumatoid arthritis, 4 (57.1%) had at least one complication. CONCLUSIONS: The use of the cortical onlay allografts provides a feasible option for restoring the integrity of the proximal femur in revision total hip arthroplasty, but the complication rate is high, particularly in female patients with rheumatoid arthritis.
24656864 Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA 2014 Apr 3 Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DRβ1 (p = 1.4 × 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 × 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1(∗)03 (encoding serine at 11) and HLA-B(∗)08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DRβ1 Ser11+Leu11: p = 5.8 × 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 × 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DRβ1 position 11 were distinct (p < 2.9 × 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 × 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.
23263277 Role of FK506 binding protein 5 (FKBP5) in osteoclast differentiation. 2013 Nov OBJECTIVES: We previously disclosed the enhanced expression of FK506 binding protein 5 (FKBP5) messenger RNA (mRNA) in bone marrow (BM) CD34(+) cells in rheumatoid arthritis (RA), in which systemic osteoporosis takes place. Since BM CD34(+) cells are precursors of osteoclasts, it is possible that FKBP5 overexpression might lead to osteoporosis by affecting osteoclastogenesis. We therefore explore the influences of FKBP5 in osteoclast differentiation. METHODS: Stable transfectants of RAW264.7 overexpressing murine FKBP5 gene were established. Osteoclast differentiation was induced by receptor activator of nuclear factor kappa B (NF-κB) ligand and was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assay. RESULTS: FKBP5 transfectants of RAW264.7 generated higher numbers of TRAP-positive multinucleated cells with increased activity of pit formation on calcium phosphate-coated culture slides than mock transfectants. The enhancement of osteoclast differentiation of FKBP5 transfectants was only partially inhibited by N-acetyl L-cysteine. Finally, glucocorticoid enhanced FKBP5 mRNA expression as well as osteoclast differentiation of RAW264.7 cells in a dose-dependent manner. CONCLUSIONS: These results indicate that FKBP5 promotes osteoclast differentiation by a mechanism distinct from NF-κB activation. Moreover, the data suggest that FKBP5 might play a role in bone destruction and development of osteoporosis in RA as well as in glucocorticoid-induced osteoporosis.
25231203 Developing the Polish Educational Needs Assessment Tool (Pol-ENAT) in rheumatoid arthritis 2015 Mar OBJECTIVES: To undertake cross-cultural adaptation and validation of the educational needs assessment tool (ENAT) for use with people with rheumatoid arthritis (RA) and systemic sclerosis (SSc) in Poland. METHODS: The study involved two main phases: (1) cross-cultural adaptation of the ENAT from English into Polish and (2) Cross-cultural validation of Polish Educational Needs Assessment Tool (Pol-ENAT). The first phase followed an established process of cross-cultural adaptation of self-report measures. The second phase involved completion of the Pol-ENAT by patients and subjecting the data to Rasch analysis to assess the construct validity, unidimensionality, internal consistency and cross-cultural invariance. RESULTS: An adequate conceptual equivalence was achieved following the adaptation process. The dataset for validation comprised a total of 278 patients, 237 (85.3 %) of which were female. In each disease group (145, RA and 133, SSc), the 7 domains of the Pol-ENAT were found to fit the Rasch model, X (2)(df) = 16.953(14), p = 0.259 and 8.132(14), p = 0.882 for RA and SSc, respectively. Internal consistency of the Pol-ENAT was high (patient separation index = 0.85 and 0.89 for SSc and RA, respectively), and unidimensionality was confirmed. Cross-cultural differential item functioning (DIF) was detected in some subscales, and DIF-adjusted conversion tables were calibrated to enable cross-cultural comparison of data between Poland and the UK. CONCLUSION: Using a standard process in cross-cultural adaptation, conceptual equivalence was achieved between the original (UK) ENAT and the adapted Pol-ENAT. Fit to the Rasch model, confirmed that the construct validity, unidimensionality and internal consistency of the ENAT have been preserved.
23292520 A predictive model for remission and low disease activity in patients with established rhe 2013 May The objective of this study was to identify predictors for remission or low disease activity (LDA) in established rheumatoid arthritis (RA) at 12 months of anti-TNF-α therapy. We have performed a prospective observational study in 90 consecutive patients with active RA receiving TNF-α inhibitors. Baseline and standard assessments were done every 3 months, including individual parameters (clinical and biological) and composite activity scores (28-joint disease activity score, DAS28). The primary outcome measure was DAS28-based EULAR response criteria. The multivariate logistic regression was used to analyze the association between disease activity and several RA baseline characteristics. Of the RA, 78.8 % was classified as good responders based on the EULAR-DAS28 criteria, 44.4 % RA achieving remission (DAS28 ≤ 2.6) and 34.4 %, LDA (DAS28 ≤ 3.2). Parameters associated with an increased likelihood of remission and LDA were initial DAS28-erythrocyte sedimentation rate ≤ 7 (odds ratio (OR) 3.3, 95 % confidence interval (CI) 2.03-5.81; OR 1.8, 95 % CI 1.09-6.68), Health Assessment Questionnaire Disability Index ≤  2 (OR 7.0, 95 % CI 1.56-31.91; OR 1.3, 95 % CI 1.03-5.79), C-reactive protein level ≤ 20 mg/l (OR 1.5, 95 % CI 0.29-8.22; OR 0.5, 95 % CI0.08-2.97), rheumatoid factor ≤ 20 IU/ml (OR 18.9, 95 % CI 10.79-38.36; OR 32.9, 95 % CI 4.03-269), anti-cyclic citrullinated peptide antibodies ≤ 40 IU/ml (OR 3.5, 95 % CI 0.67-18.19; OR 1.2, 95 % CI 1.02-1.59), concurrent prednisolone (OR 0.2, 95 % CI 0.05-0.36; OR 0.2, 95 % CI 0.06-0.63), methotrexate or leflunomide (OR 1.6, 95 % CI 1.2-13.53; OR 2.9, 95 % CI 1.20-4.36). A predictive matrix for remission and LDA in established active RA patients receiving TNF-α inhibitors was proposed. Further studies are necessary to confirm the value of such matrix in particular RA settings, leading to optimization of the use of anti-TNF-α therapy.
23990969 Prosthetic joint infection in patients with rheumatoid arthritis: an outcome analysis comp 2013 BACKGROUND: Patients with rheumatoid arthritis (RA) have been shown to have an increased susceptibility to the development of prosthetic joint infection (PJI) after hip or knee replacement. However, little information is available on the demographic data, outcome of treatment and prognostic factors in RA patients when compared to those in non-RA patients. METHODS/PRINCIPAL FINDINGS: We performed a retrospective cohort analysis of all cases of PJI that were treated at our institution between 2002 and 2008. Of 346 episodes of PJI during the study period, 46 (13.3%) occurred in patients with RA. Compared to the non-RA cohort, RA patients with PJI were female predominant (74% vs 27%, p<0.001), younger (median age, 51 vs 63 years, p<0.001) and developed infection earlier (median joint age, 72 vs 128 days, p<0.001). The 2-year survival rate free of treatment failure was lower in RA patients with PJI episodes either treated with débridement (22% vs 52%, p = 0.002) or two-stage exchange (78% vs 95%, p = 0.004). A longer duration of symptoms before débridement surgery (median, 11 vs 5 days, p = 0.015), and absence of antibiotics in bone cement for two-stage exchange (relative risk, 8.0; p = 0.02) were associated with treatment failure in patients with RA. DISCUSSION: The outcome of PJI in RA patients was generally worse than that in non-RA patients. Risk of treatment failure increased in the setting of delayed débridement and two-stage exchange without the use of antibiotic-impregnated bone cement. These findings highlight the importance of vigilant monitoring and aggressive treatment for PJI in RA patients.
23415134 Efficacy of the switch to modified-release prednisone in rheumatoid arthritis patients tre 2013 Jul OBJECTIVES: In rheumatoid arthritis (RA), low-dose glucocorticoids (GCs) demonstrate disease-modifying potential when added to DMARDs. Modified-release (MR) prednisone taken at bedtime (released 2am) is more effective than immediate-release (IR) GC taken in the morning. METHODS: In an open-label observational study, 950 RA outpatients (mean age 57 ± 13 years; 75% females) treated with GCs and DMARDs (83.7% methotrexate, 10.5% leflunomide; 15.8% biologics) were switched from IR-prednisone or 6-methyl (6M)-prednisolone to low-dose MR-prednisone and followed for 4 months. Morning stiffness duration (MS), pain intensity (numerical rating scale [NRS], 0-10), patient and physician global assessment (GA, 0-10 scale) and disease activity score (DAS28) were assessed at baseline, 2 and 4 months. RESULTS: 513 patients were switched to MR-prednisone from IR-prednisone (9.4±5.4 mg) and 437 from 6M-prednisolone (6.7±3.7 mg). Among 920 patients (96.8%) completing 4-months' MR-prednisone treatment, MS decreased from 58±37 min at T1 to 32±24 min at endpoint (p<0.001); NRS pain intensity reduced from 5.4±1.8 to 3.5±1.4 (p<0.001), and patient and physician GA scores improved from 5.4±1.7 to 3.5±1.4 and 5.1±1.7 to 3.3±1.4, respectively (p<0.001). DAS28 score decreased from 4.2±1.4 to 3.3±1.2 (p<0.001). Mean daily MR-prednisone dosage decreased from 8.2mg to 6.7mg between baseline and endpoint and significantly higher improvements in MS, NRS pain and GA scores were seen in patients switched from 6M-prednisolone versus IR-prednisone. MR-prednisone was well tolerated. CONCLUSIONS: Switching GC-treated RA patients to low-dose MR-prednisone significantly improved outcomes over 4 months.
23951149 HLA-DRB1 shared epitope-dependent DR-DQ haplotypes are associated with both anti-CCP-posit 2013 The association between Human Leukocyte Antigen (HLA) class II and rheumatoid arthritis (RA) has been extensively studied, but few reported DR-DQ haplotype. Here we investigated the association of HLA-DRB1, DQA1, DQB1, and DR-DQ haplotypes with RA susceptibility and with anti-CCP antibodies in 281 RA patients and 297 control in Han population. High-resolution genotyping were performed. The HLA-DRB1 shared epitope (SE)-encoding allele *0405 displayed the most significant RA association (P = 1.35×10(-6)). The grouped DRB1 SE alleles showed great association with RA (P = 3.88×10(-13)). The DRB1 DRRAA alleles displayed significant protective effects (P = 0.021). The SE-dependent DR-DQ haplotype SE-DQ3/4/5 remained strong association with both anti-CCP -positive (P = 3.71×10(-13)) and -negative RA (P = 3.89×10(-5)). Our study revealed that SE alleles and its haplotypes SE-DQ3/4/5 were highly associated with RA susceptibility in Han population. The SE-DQ3/4/5 haplotypes were associated with both anti-CCP positive RA and -negative RA.
24130267 AMPA/kainate glutamate receptors contribute to inflammation, degeneration and pain related 2015 Jan OBJECTIVES: Synovial fluid glutamate concentrations increase in arthritis. Activation of kainate (KA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (GluRs) increase interleukin-6 (IL-6) release and cause arthritic pain, respectively. We hypothesised that AMPA and KA GluRs are expressed in human arthritis, and that intra-articular NBQX (AMPA/KA GluR antagonist) prevents pain and pathology in antigen-induced arthritis (AIA). METHODS: GluR immunohistochemistry was related to synovial inflammation and degradation in osteoarthritis (OA) and rheumatoid arthritis (RA). A single intra-articular NBQX injection was given at induction, and knee swelling and gait of AIA and AIA+NBQX rats compared over 21 days, before imaging, RT-qPCR, histology and immunohistochemistry of joints. Effects of NBQX on human primary osteoblast (HOB) activity were determined. RESULTS: AMPAR2 and KA1 immunolocalised to remodelling bone, cartilage and synovial cells in human OA and RA, and rat AIA. All arthritic tissues showed degradation and synovial inflammation. NBQX reduced GluR abundance, knee swelling (p<0.001, days 1-21), gait abnormalities (days 1-2), end-stage joint destruction (p<0.001), synovial inflammation (p<0.001), and messenger RNA expression of meniscal IL-6 (p<0.05) and whole joint cathepsin K (p<0.01). X-ray and MRI revealed fewer cartilage and bone erosions, and less inflammation after NBQX treatment. NBQX reduced HOB number and prevented mineralisation. CONCLUSIONS: AMPA/KA GluRs are expressed in human OA and RA, and in AIA, where a single intra-articular injection of NBQX reduced swelling by 33%, and inflammation and degeneration scores by 34% and 27%, respectively, exceeding the efficacy of approved drugs in the same model. AMPA/KA GluR antagonists represent a potential treatment for arthritis.
24988902 Comparative efficacy of biologics as monotherapy and in combination with methotrexate on p 2014 Jul 3 OBJECTIVE: To compare biologics as monotherapy or in combination with methotrexate (MTX) in terms of patient reported outcomes (PROs) in RA patients with an inadequate response to conventional DMARDs (DMARD-IR). METHODS: With a systematic literature review 17 RCTs were identified that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, abatacept, anakinra or tocilizumab. Treatment effects in terms of pain (0-100 mm), patient's global assessment of disease activity (PGA; 0-100 mm), Health Assessment-Questionnaire (HAQ) disability index (DI; 0-3), and the physical component summary (PCS) of the SF36 Health Survey (0-100) at 24 weeks were combined by means of Bayesian network meta-analyses. RESULTS: With tocilizumab monotherapy, greater improvements in pain (difference = -11.1; (95% Credible Interval -21.3, -0.1)) and PGA (-10.3 (-20.4, 0.8)) were observed than with aTNF monotherapy. Tocilizumab was at least as efficacious as aTNF in HAQ-DI improvements (-0.16; (-0.37, 0.05)). aTNF + MTX (-17.9 (-23.1, -13.0) & -19.1 (-24.2, -14.4)), abatacept + MTX (-23.0 (-47.3, 1. 5) & -13.6 (-28.4, 2.0)) and tocilizumab + MTX (-16.0 (-26.3, -6.3) & -15.1 (-25.1, -5.7)) showed comparable reductions in pain and PGA relative to MTX. Efficacy of anakinra + MTX was much smaller as compared to other biologics. The greatest improvements in HAQ-DI relative to MTX were observed with aTNF + MTX (-0.30 (-0.37, -0.22)) and tocilizumab + MTX (-0.27 (-0.42, -0.12)), followed by abatacept + MTX (-0.21 (-0.37, -0.05)) and anakinra + MTX (-0.11 (-0.26, 0.05)). The improvements in SF36-PCS with abatacept + MTX, aTNF + MTX and tocilizumab + MTX were comparable. There is a >90% probability that aTNF + MTX results in a greater improvement in pain (-12.4), PGA (-16.1) and HAQ-DI (-0.21) than aTNF as monotherapy. Efficacy of tocilizumab + MTX showed comparable improvements in PROs as tocilizumab monotherapy. CONCLUSIONS: Based on a network meta-analysis involving indirect comparison of trial findings, the following observations were made for DMARD-IR patients. In monotherapy, tocilizumab was associated with a greater improvement in pain and self-reported disease activity than aTNF, and was at least as efficacious regarding functional ability. The improvements in PROs with aTNF, abatacept and tocilizumab in combination with MTX were comparable. Improvements in PROs with tocilizumab as monotherapy were similar to that of tocilizumab + MTX, whereas aTNF as monotherapy was likely to be less efficacious than aTNF + MTX.
24504798 Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in r 2014 Feb OBJECTIVE: To delineate daily and cumulative glucocorticoid dose thresholds associated with increased mortality rates in rheumatoid arthritis (RA). METHODS: We studied RA patients recruited from rheumatology clinics. Annually, we assessed the glucocorticoid dose, demographic, socioeconomic, clinical, and laboratory features of RA, cardiovascular (CV) risk factors, and vital status. We used Cox proportional hazards regression to assess associations between the daily or cumulative glucocorticoid dose and death, adjusting for potential confounders and for the propensity to receive glucocorticoids. We tested strata of the glucocorticoid dose to delineate the threshold associated with death. RESULTS: We studied 779 RA patients with a total of 7,203 person-years of observation, during which 237 of them died, yielding a mortality rate of 3.2 per 100 person-years (95% confidence interval [95% CI] 2.8-3.7). One hundred twenty of the deaths were due to CV causes, yielding a CV mortality rate of 1.8 (95% CI 1.5-2.1). Exposure to glucocorticoids was associated with a dose-dependent increase in death from all causes, with a ratio (HR) of 1.07 per mg of prednisone per day (95% CI 1.05-1.08). Compared to patients who were not receiving corticosteroids, the minimum daily prednisone dose threshold associated with an increase in all-cause mortality was 8-15 mg, with an adjusted HR of 1.78 (95% CI 1.22-2.60). For the cumulative dose of glucocorticoids, the minimum dosage associated with all-cause mortality was 40 gm (HR 1.74 [95% CI 1.25-2.44]). CONCLUSION: Glucocorticoid use in RA is associated with a dose-dependent increase in mortality rates, with a daily threshold dose of 8 mg, at which the number of deaths increased in a dose-dependent manner. These findings may assist clinicians in selecting the appropriate glucocorticoid dosage for RA patients who require these agents.