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ID PMID Title PublicationDate abstract
23415051 Does early arthritis clinic organisation improve outcomes? What evidence is there? A syste 2013 May OBJECTIVES: To perform a systematic review aimed to identify studies addressing the effect of the establishment of a structured organisation programme, named early arthritis clinic (EAC), finalized to manage patients with early arthritis (EA) or suspected early rheumatoid arthritis (ERA). METHODS: A literature search was performed until May 2012 using electronic databases. Additional information was obtained through a hand and grey literature search. Primary and secondary outcomes and eligibility criteria have been defined. RESULTS: The search provided a total of 3367 citations and, after the selection process, 11 non randomised controlled trials were selected, including a total of 8240 participants. The efficacy of EAC did clearly emerge with regard to reduction of the referral lag time and of the time to treatment (secondary outcomes). Only two studies met the primary outcomes: one study demonstrated that the EAC contributed to reducing disease activity and radiographic progression but not functional disability, while another reported a reduction of pain after a 6-12-month period of follow-up. CONCLUSIONS: Whether the establishment of EAC would improve the prognosis of EA in terms of primary outcomes such as clinical, functional and radiologic progression compared to patients managed outside from EAC does appear a still poorly addressed issue in the literature, which should be recognised as an urgent unmet need by the rheumatology community to gain more evidence-based information on this topic.
24503194 Performance characteristic of anti-cyclic citrullinated peptide (CCP) assay on Korean rheu 2014 Apr The objective of this study was to evaluate the performance of the established anti-cyclic citrullinated peptide (anti-CCP) enzyme-linked immunosorbent assay (ELISA) compared to Rheumatoid Factor-Immunoglobulin M (RF-IgM) and C - reactive protein (CRP). Serum samples of 176 patients were analyzed with the anti-CCP ELISA assay method established in our laboratory. The results of rheumatoid arthritis (RA) patients, the other inflammatory patients, and healthy controls were compared using MedCalc (version 7.0). The anti-CCP assay results were compared with RF-IgM and CRP concentration analyzed in Catholic University. The specificity of ELISA test results of RA patients showed 91% and 87%, when healthy controls or osteoarthritis patients were considered as negative. Thus, the established ELISA method was RA specific, but its sensitivity was low. To see the low sensitivity may from aging effect, the concentration of anti-CCP was analyzed for different aging group. We tested 110 healthy controls' sera using the same method. The statistical results of young subjects (<45 years old) showed significantly lower anti-CCP concentrations than those of older subjects (>65 years old, p<0.0001). The citrullination might also be occurring during aging process in healthy populations. The validation results imply that the established method could be used as a clinical diagnostic for RA together with RF-IgM.
24057144 Barriers to accessing biologic treatment for rheumatoid arthritis in Greece: the unseen im 2014 Jan The latest regulatory change in the distribution system of biologic disease-modifying, antirheumatic drugs limited their sale only through the designated pharmacies of the National Organization for Healthcare Services Provision (EOPYY) or the National Health System (NHS) hospitals, adding to the complexity of access to effective treatment for rheumatoid arthritis (RA) in Greece. The aim of this paper was to assess the barriers to access RA treatment, by recording patients', rheumatologists' and EOPYY pharmacists' experiences. One twenty-three patients, 12 rheumatologists and 27 pharmacists from Athens and other urban areas in Greece participated in the study. Three types of standardized questionnaires were used to elicit information from each group of respondents using the method of personal interview for patients and the method of postal survey for doctors and pharmacists. During the last year, 26% of patients encountered problems in accessing their rheumatologist and 49% of patients experienced difficulties in accessing their medication. Ninety-two percent of rheumatologists and 96% of pharmacists confirmed that patients experience difficulties in accessing RA medication. The most commonly reported reasons for reduced access to medical treatment were travel difficulties and long distance from doctor's clinic, as well as delays in booking an appointment. The most frequently reported barriers to access pharmaceutical treatment were difficulties in the prescription process, distance from EOPYY pharmacies and medicine shortages in NHS hospitals. The study showed that RA patients are facing increased barriers to access timely and effective treatment. Redesign of the current system of distribution ensuring the operation of additional points of sale is deemed necessary.
23364395 Exome sequencing identifies novel rheumatoid arthritis-susceptible variants in the BTNL2. 2013 Apr The butyrophilin-like protein 2 gene (BTNL2) within the class III region of the major histocompatibility complex genomic region was identified as a rheumatoid arthritis (RA) susceptibility gene by exome sequencing (19 RA cases) with stepwise filtering analysis, and then validated by Sanger sequencing and association analysis using 432 cases and 432 controls. Logistic regression of the Sanger-sequenced single-nucleotide variants in an association study of 432 cases and 432 controls showed that 12 non-synonymous single-nucleotide polymorphisms (SNPs) in BTNL2 were significantly associated with RA. The lowest P-values were obtained from three SNPs, rs41521946, rs28362677 and rs28362678, which were in absolute linkage disequilibrium: P=4.55E-09, odds ratio=1.88, 95% confidence interval=1.52-2.33. The BTNL2 locates on chromosome 6 between HLA-DRB1 and NOTCH4, and is 170 kb apart from these two genes. Although DRB1 and NOTCH4 were reported to be RA-susceptible, the three BTNL2 SNPs retained significant association with RA when evaluated by the logistic regression with the adjustment for RA-susceptible HLA-DRB1 alleles in Japanese or rs2071282-T in NOTCH4: P=0.0156 and P=0.00368, respectively. These results suggest that the three non-synonymous SNPs in BTNL2 confer RA risk independently from HLA-DRB1 and NOTCH4.
22447331 Tacrolimus treatment increases bone formation in patients with rheumatoid arthritis. 2013 Aug Tacrolimus is a calcineurin inhibitor, and it is used for the treatment of rheumatoid arthritis (RA). It works by inhibiting nuclear factor of activated T cells and inducting immunosuppression. This study aims to evaluate the influence of tacrolimus on the bone metabolism of patients with RA. Twenty-eight RA patients in three centers received tacrolimus 3 mg once daily for 24 weeks. Blood samples for evaluating bone metabolism and cytokines were collected at Weeks 0 and 24. We measured the serum C-telopeptide of type I collagen (sCTx-I), osteocalcin and inflammatory cytokines. We analyzed the data using the Kruskal-Wallis test and Spearman's correlation. IL-2 and IL-6 were significantly decreased after the administration of tacrolimus (p = 0.027 and p = 0.024). There was no significant difference in the serum level of sCTx-I before and after treatment. The level of serum osteocalcin at Week 24 was significantly increased compared to the level at Week 0 (p = 0.002). The increase of osteocalcin was correlated with the reductions of IL-2 and IFN-γ (r = 0.405, p = 0.033 and r = 0.380, p = 0.046, respectively). Tacrolimus treatment increased bone formation markers in RA patients. This suggests that tacrolimus may play a role to inhibit bone erosion by increasing bone formation as well as improving the clinical symptoms of RA.
24349530 Cytosolic phospholipase A2 regulates TNF-induced production of joint destructive effectors 2013 INTRODUCTION: Rheumatoid arthritis (RA) is an inflammatory disease of the joint characterized by chronic synovitis causing pain, swelling and loss of function due to destruction of cartilage and bone. The complex series of pathological events occurring in RA is largely regulated via excessive production of pro-inflammatory cytokines, the most prominent being tumor necrosis factor (TNF). The objective of this work was to elucidate possible involvement of group IVA cytosolic phospholipase A2 (cPLA2α) in TNF-induced regulation of synovitis and joint destructive effectors in RA, to evaluate the potential of cPLA2α as a future therapeutic target. METHODS: The involvement of cPLA2α in tumor necrosis factor (TNF)-induced intracellular signaling cascades in synoviocytes (synovial fibroblast-like cells) was analyzed by arachidonic acid (AA) release assay, synoviocyte enzyme activity assay, gene expression analysis by real-time PCR and ELISA immunoassay for the detection of prostaglandin E2 (PGE2), interleukin 8 (IL8) and stromelysin-1 (MMP3), respectively. RESULTS: Inhibitors of cPLA2α enzyme activity (AVX002, ATK) significantly reduced TNF-induced cellular release of AA, PGE2, IL8 and MMP3. This reduction was evident both at transcriptional, protein or metabolite levels. Interestingly, cPLA2α inhibition affected several key points of the arachidonyl cascade; AA-release, cyclooxygenase-2 (COX2) expression and PGE2 production. Furthermore, the results suggest that cPLA2α is subject to transcriptional auto-regulation as inhibition of cPLA2α resulted in reduced PLA2G4A gene expression in TNF-stimulated synoviocytes. CONCLUSIONS: cPLA2α appears to be an important regulator of central effectors of inflammation and joint destruction, namely MMP3, IL8, COX2, and PGE2. Decreased transcription of the PLA2G4A and COX2 genes in response to cPLA2α enzyme inhibition further suggest a self-reinforcing effect of cPLA2α inhibition in response to TNF. Collectively, these results support that cPLA2α is an attractive therapeutic target candidate as its inhibition reduces the production of multiple key pro-inflammatory factors involved in RA pathogenesis.
24310226 Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid a 2014 Feb Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and bone resorption. The proinflammatory cytokine interleukin 17 (IL-17), primarily produced by Th17 cells, has been shown to be involved in all stages of the disease and to be an important contributor of RA chronicity. Three major processes drive the IL-17-mediated chronicity. Several epigenetic events, enhanced in RA patients, lead to the increased production of IL-17 by Th17 cells. IL-17 then induces the production of several inflammatory mediators in the diseased synovium, which are further synergistically enhanced via combinations of IL-17 with other cytokines. IL-17 also promotes the survival of both the synoviocytes and inflammatory cells and promotes the maturation of these immune cells. This leads to an increased number of synoviocytes and inflammatory cells in the synovial fluid and in the synovium leading to the hyperplasia and exacerbated inflammation observed in joints of RA patients. Furthermore, these IL-17-driven events initiate several feedback-loop mechanisms leading to increased expansion of Th17 cells and thereby increased production of IL-17. In this review, we aim to depict a complete picture of the IL-17-driven vicious circle leading to RA chronicity and to pinpoint the key aspects that require further exploration.
24276366 Environmental and genetic factors in the development of anticitrullinated protein antibodi 2015 Feb OBJECTIVE: To investigate the role of genetic and environmental factors in the development of anticitrullinated protein antibodies (ACPA) and ACPA-positive rheumatoid arthritis (RA) in a twin cohort. METHODS: A total of 12 590 twins were analysed for the presence of ACPAs (CCP2 ELISA), HLA-DRB1 shared epitope (SE) gene alleles, and exposure to smoking. Twins with established RA were identified in national public care registers. Antibody reactivities against citrullinated and native forms of α-enolase, vimentin, fibrinogen and type II collagen peptides were tested by ELISA in anti-CCP2-positive subjects and their cotwins. Structural equation models and ORs for the development of ACPA and ACPA-positive RA were computed for smokers and SE carriers. RESULTS: A total of 2.8% (350/12 590) of the twins were ACPA positive, and 1.0% (124/12 590) had ACPA-positive RA. Most of the variability in the ACPA status was accounted for by non-shared environmental or stochastic factors (78%, 95% CI 55% to 100%) rather than shared environmental and genetic factors. Analysis of specific risk factors revealed an association between smoking and SE and the presence of ACPAs. Twins with ACPA-positive RA were more frequently SE positive than twins with ACPAs without RA. Reactivities against multiple citrullinated peptides were present in most twins with ACPA-positive RA but in fewer twins with ACPAs without RA. CONCLUSIONS: Environment, lifestyle and stochastic factors may be more important than genetics in determining which individuals develop ACPAs. Genetic factors (particularly SE) may have a relatively larger role in determining which ACPA-positive individuals will ultimately develop arthritis.
24445240 Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide 2 antibody and ant 2014 Jun The aim of this work was to assess the diagnostic value of anti-CCP-3 and anti-CCP-2 for the diagnosis of rheumatoid arthritis (RA) and determine whether anti-CCP-3 more accurately identifies patients with rheumatoid arthritis than anti-CCP-2. PubMed and CNKI databases were searched for studies published in English and Chinese that examined the use of anti-CCP-3 and anti-CCP-2 in the diagnosis of known or suspected rheumatoid arthritis from January 2006 to July 2013. Seventeen included studies of methodological quality were rated by using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tools A random-effects method was used to summarize sensitivities, specificities, positive and negative likelihood ratio (LR+ and LR-, respectively), and diagnostic odds ratio from 17 studies. The pooled sensitivity, specificity, LR+, LR- and diagnostic odds ratio for anti-CCP-3 were 0.737 (95% CI, 0.717-0.757), 0.933 (95% CI, 0.924-0.942), 11.096 (95% CI, 8.876-13.870), 0.274 (95% CI, 0.231-0.326), and 42.908 (95% CI, 33.828-54.426), respectively. For anti-CCP-2, the values were 0.719 (95% CI, 0.699-0.739), 0.960 (95% CI, 0.953-0.966), 17.485 (95% CI, 11.960-25.562), 0.294 (95% CI, 0.258-0.335) and 63.458 (95% CI, 44.214-91.078), respectively. With high specificity and moderate sensitivity, anti-CCP-2 and anti-CCP-3 played an important role in confirming the diagnosis of RA. Anti-CCP-3 did not have better diagnostic performances than anti-CCP-2, but anti-CCP-2 had evident heterogeneity compared to anti-CCP-3, especially in American patients.
24081426 Demonstrating disease activity in patients with rheumatoid arthritis. Is 18F FDG PET a sen 2013 Dec 13 AIM: We aimed to investigate the relationship of fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F FDG PET/CT) with clinical, laboratory parameters and conventional radiographs in patients with rheumatoid arthritis (RA). PATIENTS, MATERIAL, METHODS: 25 patients with RA diagnosis were evaluated by sociodemographic, clinical [duration of disease (year), the joints in which the complaints started, most recent joint involvement]; other parameters used in RA-specific clinical assessment [Steinbocker functional staging, disease activity score 28 (DAS 28 score), health assessment questionnaire score (HAQ score), general RA assessment (patients' and physicians' global assessment), patients' assessments of pain and general health condition (visual analog scale)], laboratory, radiological [conventional radiology of hand and foot joints], positron emission tomography [18F FDG PET visual total score and maximum standardized uptake value (SUVmax) total score] parameters. RESULTS: No significant correlation was detected between the 18F FDG PET total score and SUVmax total score of the patients and clinical, laboratory, and radiological parameters (p > 0.05). There was no relationship between the cut-off values determined according to the disease activity and 18F FDG PET/SUVmax total values (p > 0.05). CONCLUSIONS: In our study, no relationship was found between disease activity demonstrated by 18F FDG PET/CT in RA patients and clinical, laboratory, and radiological parameters. 18F FDG PET/CT appears to be a more sensitive method in demonstrating disease activity compared to other evaluated methods.
24863714 Value of ultrasonography for diagnosis of synovitis associated with rheumatoid arthritis. 2014 Sep AIM: To investigate the value of ultrasonography (US) for diagnosing synovitis associated with rheumatoid arthritis (RA). METHOD: Bilateral metacarpophalangeal (MCP), proximal interphalangeal (PIP) II-V and wrist joints of 46 RA patients and 35 healthy controls were evaluated by quantitative and semiquantitative US. Wrists on more severely affected sides of 20 of the 46 patients also underwent magnetic resonance imaging (MRI). The MRI and US results were compared. The US cutoff to distinguish pathology was calculated. The two US methods were compared and the correlation between quantitative methods and clinical serologic markers was analyzed. RESULTS: The imaging techniques (US and MRI) for detecting synovitis produced consistent results (γ = 0.70-0.77, P < 0.001). When the cutoffs for the MCP and PIP joints were 2.5 and 2.6 mm, respectively; the sensitivities/specificities were 82.8%/85.8% and 98.2%/84.8%, respectively. When the cutoff for the wrist was 5.2 mm, the sensitivity/specificity was 93.4%/93.4%. The average synovial membrane thickness was positively related to biochemical markers erythrocyte sedimentation rate, C-reactive protein, anticyclic citrullinated peptide antibody, and Disease Activity Index of 28 joints (γ = 0.307-0.614; P = 0.020, 0.038, 0.01, < 0.001, respectively) but was poorly related to rheumatoid factor immunoglobulin A (RF-IgA), RF-IgM, and RF-IgG (γ = 0.06-0.115; P = 0.45, 0.45, 0.62, respectively). CONCLUSIONS: US is a valid method for diagnosing early-stage synovitis, with high-accuracy cutoffs for MCP, PIP and wrist joints set at 2.5, 2.6 and 5.2 mm. The mean synovial thicknesses of the bilateral wrist, MCP II-IV and PIP II-IV joints can be used to assess disease activity.
22935203 Ultrasonographic predictors for the development of joint damage in rheumatoid arthritis pa 2013 Jan OBJECTIVES: This paper aims to evaluate if any ultrasonographic aspect of metacarpo-phalangeal (MCP) joint can be predictors for the development of new joint damage, at single joint level, in rheumatoid arthritis (RA) patients. METHODS: Two hundred and forty MCP joints of 24 patients with RA were prospectively evaluated both clinically and by ultrasound (US) at time 0, at six months and 12 months, in order to collect the following variables: presence of synovial hypertrophy and power-Doppler (PD) vascularisation both graded on a semiquantitative (0-3) scale, and the number and dimension of bone erosions. X-ray examinations were carried out at time 0 and at 12 months and lesions were graded using the Sharp/van der Heijde (S/vdH) method at single joint level. Potential prognostic determinants for joint damage obtained at the first examination and during follow-up were entered in a conditional logistic regression analysis. RESULTS: Fifteen out of seventeen (88%) of the new eroded joints on x-rays examination had persistent PD vascularity and 14/17 (82%) had persistent synovial thickening (p=0.001 and p=0.02, vs. non-eroded joints, respectively). In multiple conditional logistic regression analysis, the most important factor associated with the development of radiological joint damage was the presence of a synovial PD score ≥2 on two or more US evaluations (OR 8.51 [95%CI 1.84-39.48] for Rx new erosions and OR 8.30 [95%CI 1.97-38.9] for increased S/vdH local joint score). Both baseline synovial score ≥2 and presence of Rx erosions were also significantly associated with the development of radiological joint damage. Two predictive models for x-ray erosions and total single joint level S/vdH damage score were constructed consisting of 2 baseline plus one longitudinal variable with a ROC AUC of 0.916 (95%CI 0.867-0.965) and 0.886 (95%CI 0.814-0.957). CONCLUSIONS: At the single joint level, the presence of US determined synovial thickness and PD signal at baseline and the persistent PD signal over time have relevant prognostic value for the development of articular damage in the same MCP joints of RA patients.
25433529 Inhibition of PCSK6 may play a protective role in the development of rheumatoid arthritis. 2015 Feb OBJECTIVE: To assess the effect of proprotein convertase subtilisin/kexin type 6 (PCSK6) in the synovial fibroblasts of rheumatoid arthritis (RA). PCSK6 is a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of protein maturation. METHODS: PCSK6 expression was detected in the synovial tissue of 10 patients with RA, 10 controls with osteoarthritis, and 10 controls with ankylosing spondylitis using Western blotting and quantitative real-time PCR. Genotyping of 67 tag single-nucleotide polymorphisms (SNP) was performed using an Illumina VeraCode (Illumina) microarray in a case-control study including 267 patients with RA and 160 healthy controls. Genotyping of 4 other tag SNP was performed using a TaqMan probe genotyping assay in 1056 healthy controls and 1151 patients with RA. Cultured RA synovial fibroblasts (RASF) were transfected with PCSK6 small interfering RNA to study changes in the proliferation, invasion, migration capacity, secretion of inflammatory cytokines, cell cycle, and expression profiles of the RASF. RESULTS: Expression of PCSK6 mRNA and protein was significantly higher in the synovial tissues of individuals with RA than in control tissues. One SNP, rs8029797, was significantly associated with RA (p = 0.011). Knockdown of PCSK6 by RNA interference significantly decreased proliferation, invasion, and migration of RASF. These changes in RASF appeared to be related to reduced tumor necrosis factor-α secretion, G0/G1 arrest, and altered expression of various proteins including those involved in angiogenesis (matrix metalloproteinase 9, nitric oxide synthase trafficking), hypoxia (hypoxia-inducible factor-α, thioredoxin domain containing 5), proliferation (chromosome 10 open reading frame 116), and inflammation [CCL7, chemokine (C-X-C motif) ligand 9, interleukin 26]. CONCLUSION: PCSK6 is upregulated in the synovial tissues of patients with RA and has a genetic effect on the risk of RA. Inhibition of PCSK6 may play a protective role in the development of RA.
24782115 Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation 2014 Jul BACKGROUND: We investigated the effects of anakinra, an interleukin-1 receptor antagonist, on coronary and left ventricular function in coronary artery disease (CAD) patients with rheumatoid arthritis. METHODS AND RESULTS: In a double-blind crossover trial, 80 patients with rheumatoid arthritis (60 with CAD and 20 without) were randomized to a single injection of anakinra or placebo and after 48 hours to the alternative treatment. At baseline and 3 hours after treatment, we assessed (1) flow-mediated dilation of brachial artery; (2) coronary flow reserve, ejection fraction, systemic arterial compliance, and resistance by echocardiography; (3) left ventricular global longitudinal and circumferential strain, peak twisting, untwisting velocity by speckle tracking; and (4) interleukin-1β, nitrotyrosine, malondialdehyde, protein carbonyl, and Fas/Fas ligand levels. At baseline, patients with CAD had 3-fold higher interleukin-1β, protein carbonyl, higher nitrotyrosine, malondialdehyde, and Fas/Fas ligand than non-CAD (P<0.05). After anakinra, there was a greater improvement of flow-mediated dilation (57±4% versus 47±5%), coronary flow reserve (37±4% versus 29±2%), arterial compliance (20±18% versus 2±17%), resistance (-11±19% versus 9±21%), longitudinal strain (33±5% versus 18±2%), circumferential strain (22±5% versus 13±5%), peak twisting (30±5% versus 12±5%), untwisting velocity (23±5% versus 13±5%), ejection fraction (12±5% versus 0.5±5%), apoptotic and oxidative markers, and, in particular, of protein carbonyl (35±20% versus 14±9%) in CAD than in non-CAD patients (P<0.01). No changes in the examined markers were observed after placebo. CONCLUSIONS: Interleukin-1 inhibition causes a greater improvement in endothelial, coronary aortic function in addition to left ventricular myocardial deformation and twisting in rheumatoid arthritis patients with CAD than in those without. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01566201.
24560656 Comparison of anti-CCP autoantibodies measurement by ELISA and a bead-based assay in a lar 2014 Apr OBJECTIVES: The aims of our study were to compare in a cohort of 705 patients the diagnostic performance of two tests to detect autoantibodies to cyclic citrullinated peptides (CCP) and to determine whether a bead-based assay within a multiplex flow immunoassay (MFA) can be used instead of an enzyme linked immunosorbent assay (ELISA) technique in routine practice. DESIGN AND METHODS: Six hundred and thirty patients with rheumatic symptoms and 75 patients with systemic lupus erythematosus (SLE) were tested for anti-CCP autoantibodies using two techniques: ELISA (Inova) and MFA (BioPlex, Bio-Rad). RESULTS: Using kappa coefficient, there was an excellent agreement between ELISA and MFA when comparing 630 patients with rheumatic symptoms (κ coefficient, 0.82). In this cohort 174 patients were identified as suffering from RA, while 456 patients suffered from other diseases. Sensitivity and specificity values of anti-CCP autoantibodies for RA were 70.7% and 92.3% for ELISA and 64.4% and 92.8% for MFA. The positive and negative predictive values were 77.4% and 89.2% for ELISA and 77.2% and 87.2% for MFA, respectively. There were no differences in the diagnostic performances between the two assays (Z=0.67). The specificity values of anti-CCP autoantibodies analysing patients with SLE were 97.3% with MFA and 96% with ELISA with an excellent agreement between the methods (98.7%; κ coefficient, 0.79). CONCLUSION: Concordance between ELISA and MFA is high in routine practice. Overall, MFA is a powerful tool for rapid assessment of anti-CCP autoantibodies and can replace the ELISA technique, which could be used as a second-line test in some cases.
24394199 Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine c 2014 Aug Sulphasalazine (SSA) is a disease modifying anti-rheumatic drug (DMARD) that is commonly used to treat rheumatoid arthritis (RA). Plasma levels of SSA and its metabolite sulphapyridine are influenced by common polymorphisms in genes that encode N-acetyl transferase 2 (NAT2) and ATP-binding cassette protein G2 (ABCG2). Study participants had early RA that was treated with a combination DMARD regimen that included SSA. Toxicity was defined by cessation of SSA due to adverse effects and response as remission after 12 months of treatment. The effect of variables on toxicity was assessed by a Cox-proportional Hazard model and response by logistic regression. After correction for conventional variables, toxicity in 229 participants was influenced by NAT2 phenotype (hazard ratio=1.74 (95% confidence interval (CI) 1.01-3.21), P=0.044) and remission in 141 participants was associated with ABCG2 genotype (odds ratio=3.34 (95% CI 1.18-9.50), P=0.024). In our sample of early RA patients who were primarily treated with a combination of DMARDs, common variants in genes that encode NAT2 and ABCG2 were associated respectively with toxicity and response to SSA.
23899235 Lung involvement and drug-induced lung disease in patients with rheumatoid arthritis. 2013 Jul Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and a significant cause of morbidity and mortality. Usual interstitial pneumonia and nonspecific interstitial pneumonia seem to be the most frequent patterns in RA patients with ILD, although the proportion of patients with usual interstitial pneumonia is higher than among patients with other systemic rheumatic autoimmune diseases. RA patients with ILD most frequently present with chronic symptoms of cough and dyspnea when climbing stairs or walking uphill. A physical examination may reveal inhalatory crackles and a pulmonary function test demonstrates restrictive physiology, often with reduced diffusing capacity. High-resolution computed tomography is generally sufficient to confirm a diagnosis of ILD, although a minority of cases may require a surgical lung biopsy. Conventional disease-modifying antirheumatic drugs such as methotrexate (MTX) or leflunomide (LEF) and biological agents such as TNF-blocking agents or rituximab may trigger or aggravate ILD in RA patients, and infections may contribute to increased mortality in such patients. LEF should not be used in patients with a history of MTX pneumonitis. The prevalence of interstitial pneumonia among RA patients treated with anti-TNF agents ranges from 0.5 to 3%; however, as the evidence that anti-TNF increases or decreases the risk of ILD is controversial, it is not clear whether this indicates more severe RA requiring biological therapy or the effect of exposure to potentially toxic drugs such as MTX or LEF. The development of treatment-related ILD is a paradoxical adverse event, and patients should be warned about this rare but serious complication of biological or disease-modifying antirheumatic drug therapy.
23415907 Reduced hepatotoxicity by total glucosides of paeony in combination treatment with lefluno 2013 Mar Combination use of methotrexate (MTX) and leflunomide (LEF) has been proved effective in the treatment of active rheumatoid arthritis (RA). However, previous trials have documented that both are associated with increased incidence of liver toxicity. As active compounds extracted from the roots of the traditional Chinese herb Paeonia lactiflora Pall, total glucosides of paeony (TGP) have been shown to have anti-inflammatory, hepatoprotective and immuno-regulatory activities, without evident toxicity or side effects. In this 24-week, open label, randomized multicenter clinical trial, we investigated the efficacy of TGP and the protective effect on hepatotoxicity in the combination treatment with LEF and MTX for patients with active RA. A total of 204 patients with active RA (DAS28>3.2) recruited from 3 regional referral centers were enrolled and received MTX and LEF combination therapy (MTX 10 mg/week plus LEF 20 mg/day) with or without TGP for up to 24 weeks by randomization. Hepatotoxicity was defined as an increase of at least 1.5-fold the upper limits of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Significantly less frequent hepatotoxicity was observed in patients with TGP than those without (9.5% vs 34.8%, p < 0.001) at 12 weeks. The proportion of patients whose ALT or AST levels were > 1.5 to ≤2 times and >2 to ≤3 times the ULN were lower in TGP group than the control (1.9% vs 10.1%, 2.9% vs 12.4%, p < 0.05 respectively). More patients in the TGP group achieved a European League Against Rheumatism (EULAR) good response or moderate response at 12 weeks, although there is no statistical significance. Similar results were observed at 24 weeks. Our preliminary study demonstrates the hepatoprotective and additive role of TGP in combination with MTX and LEF in the treatment of active RA.
23290983 Rheumatoid arthritis-associated corneal ulceration: mortality and graft survival. 2013 Apr PURPOSE: To investigate mortality and graft survival in patients undergoing penetrating keratoplasty (PKP) for rheumatoid arthritis-associated corneal ulceration (RACU), Fuchs' endothelial dystrophy (FED), and pseudophakic bullous keratopathy (PBK). DESIGN: Case-control study. PARTICIPANTS AND CONTROLS: Patients listed on the UK Transplant Registry who had undergone a PKP for RACU, FED, or PBK between January 4, 1999, and January 4, 2006. Comparative standardized mortality ratios (SMRs) and causes of death were obtained from the Office for National Statistics. METHODS: Outcome data were collected from the UK Ocular Tissue National Transplant database and supplementary questionnaires at transplantation and at 1, 2, and 5 years. Institutional review board approval for the National Health Service Blood and Transplant to undertake the study was obtained. MAIN OUTCOME MEASURES: Mortality and graft survival. RESULTS: A total of 3665 patients were included: RACU (117), PBK (1701), and FED (1847). Five-year survival of patients with RACU was 42% (95% confidence interval [CI], 26-56) compared with 76% (95% CI, 72-78) for FED and 55% for PBK (95% CI, 50-60; P < 0.01). The SMRs for female and male patients with RACU were 43.5 (95% CI, 19.5-63.3) and 12.2 (95% CI, 7.1-19.5), respectively, in comparison with 1.84 and 1.45 for patients with RA, respectively (P < 0.01). There were no significant differences in the causes of death among patients with RACU, FED, or PBK (P > 0.9), with infection the most common cause. The 5-year graft survival rate was 48% (95% CI, 32-62) for RACU, 59% (95% CI, 56-62) for PBK, and 84% (95% CI, 82-86) for FED (P < 0.01). CONCLUSIONS: Mortality and ocular morbidity were significantly increased in patients with RACU. Accelerated immunosenescence should be considered in the differential diagnosis of patients presenting with RACU, and a multidisciplinary approach to management is required.
23764034 Rheumatoid arthritis vs osteoarthritis in patients receiving total knee arthroplasty: peri 2014 Feb There is a paucity of data available on perioperative outcomes of patients undergoing total knee arthroplasty (TKA) for rheumatoid arthritis (RA). We determined differences in demographics and risk for perioperative adverse events between patients suffering from osteoarthritis (OA) versus RA using a population-based approach. Of 351,103 entries for patients who underwent TKA, 3.4% had a diagnosis of RA. RA patients were on average younger [RA: 64.3 years vs OA: 66.6 years; P<0.001] and more likely female [RA: 79.2% vs OA: 63.2%; P<0. 001]. The unadjusted rates of mortality and most major perioperative adverse events were similar in both groups, with the exception of infection [RA: 4.5% vs. OA: 3.8%; P<0.001]. RA was not associated with increased adjusted odds for combined adverse events.