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ID PMID Title PublicationDate abstract
23342796 [Clinical result of forefoot correction by the first ray stabilization combined with resec 2012 Oct OBJECTIVE: To introduce the procedure of the 1st ray stabilization combined with resection of the lesser metatarsal heads for patient with severe forefoot deformity caused by rheumatoid arthritis (RA) and evaluate the short to mid-term clinical results. METHODS: From Oct. 2006 to Aug. 2010,97 patients (129 feet) aged from 36 to 67 years (average 54), with forefoot deformity caused by rheumatoid arthritis were reviwed. There were 88 males and 9 females,65 single lateral involved and 32 bilateral involved, the average duration of disease was 17 years (6 to 32 years). The 1st ray instability and lesser metatarsophalangeal (MTP) joint stiff dislocation were found in all cases. The first ray stabilization combined with resection of the lesser metatarsal head procedure were performed for all cases. The radiographic Hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measurde and the JSSF (Japanese Society for Surgery of the Foot) score were evaluated before operation and every follow up. RESULTS: The average followed-up was 37 months (6 to 52 months) for all patients except 5 (7 feet) and 1 died for acute cardiac infarction 1 year after operation. The average JSSF score improved from (33.2 +/- 8.2) points preoperative to (67.3 +/- 3.1) points at final followed-up (P < 0.01); the average HVA was corrected from (50.0 +/- 11.8) degrees preoperative to (21.2 +/- 3.2) degrees at final follow up (P < 0.01); the average IMA was corrected from (15.5 +/- 3.6) degrees preoperative to (9.7 +/- 6.6) degrees at final follow up (P < 0.01). MTP joint nonunion was found in 4 feet. A radiographic high density mass was found in the 1st cuneiform bone during 8 to 11 months followed-up in 3 feet; delayed wound healing was happened in 9 feet; MTP joint infection was happened in 2 feet; tarsometatarsal joint infection was happened in 1 foot; lesser MTP joints deformity recurrence were found in 16 feet. CONCLUSION: The characters of forefoot with RA in later stage are the 1st ray deformity and instability compound with the lesser toes deformity. The 1st ray stability procedure which include the 1st MTP arthrodesis and the Lapidus procedure can correct the 1st ray deformities and rebuilt its stability. The lesser toes metatarsal head resection is effective in correct their deformity. This combined procedure is reliable. It is suitable for patients with severe Hallux valgus, increased IMA, tarsometatarsal joint instability and the lesser MTP joint stiff dislocation.
23196701 Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to m 2013 Dec OBJECTIVE: To compare EuroQol 5-Dimensions (EQ-5D) utility and quality-adjusted life-years (QALYs) in patients with early, methotrexate (MTX) refractory rheumatoid arthritis (RA), randomised to addition of infliximab (IFX) or sulfasalazine and hydroxychloroquine (SSZ+HCQ). METHODS: RA-patients with symptoms <1 year were enrolled between 2002 and 2005 at 15 Swedish centres. After 3-4 months of MTX monotherapy, patients with a remaining DAS28>3.2 were randomised to addition of IFX or SSZ+HCQ and followed for 21 months. EQ-5D profiles were collected every 3 months. Between-group comparisons of utility change and accumulated QALYs were performed, using last observation carried forward (LOCF) following protocol breach. Missing data were imputed by linear interpolation or LOCF. Sensitivity analyses applying baseline observation carried forward (BOCF) or restricted to completers were conducted. RESULTS: Of 487 patients initially enrolled, 128 and 130 were randomised to IFX or SSZ+HCQ, respectively. Mean utility in the IFX and SSZ+HCQ groups increased from 0.52 (SD 0.27) and 0.55 (SD 0.27) at randomisation to 0.66 (SD 0.25) and 0.63 (SD 0.27) at 21 months (adjusted mean difference favouring IFX 0.04; 95% CI -0.01, 0.09; p=0.15). Average accumulated QALYs were 1.10 (SD 0.37) and 1.07 (SD 0.42) in the IFX and SSZ+HCQ groups, respectively (adjusted mean difference favouring IFX 0.07; 95%CI -0.01, 0.14; p=0.07). BOCF analysis showed similar results, while differences were reversed, though remained statistically non-significant among completers. Dropout rates in the IFX/SSZ+HCQ groups were 30%/43% (p=0.01). CONCLUSIONS: Comparing addition of IFX or SSZ+HCQ to MTX in active early RA, no statistically significant differences in utility or QALY gain could be detected over 21 months. TRIAL REGISTRATION: Registered in WHO database at the Karolinska University Hospital, number CT20080004.
22647483 Treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine restores endothelial funct 2012 May 30 INTRODUCTION: Endothelial dysfunction (ED) participates to atherogenesis associated to rheumatoid arthritis. We recently reported increased arginase activity/expression in vessels from adjuvant-induced arthritis (AIA) rats. In the present study, we investigated the effects of a curative treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine (nor-NOHA) on vascular dysfunction in AIA rats. METHODS: AIA rats were treated with nor-NOHA (40 mg/kg/d, ip) for 21 days after the onset of arthritis. A group of untreated AIA rats and a group of healthy rats served as controls. ED was assessed by the vasodilatory effect of acetylcholine (Ach) on aortic rings. The role of superoxide anions, prostanoids, endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide synthase (NOS) pathway was studied. Plasma levels of IL-6 and vascular endothelial growth factor (VEGF) were determined by ELISA kits. Arthritis severity was estimated by a clinical, radiological and histological analysis. RESULTS: Nor-NOHA treatment fully restored the aortic response to Ach to that of healthy controls. The results showed that this beneficial effect is mediated by an increase in NOS activity and EDHF and reduced superoxide anion production as well as a decrease in the activity of cyclooxygenase (COX)-2, thromboxane and prostacyclins synthases. In addition, nor-NOHA decreased IL-6 and VEGF plasma levels in AIA rats. By contrast, the treatment did not modify arthritis severity in AIA rats. CONCLUSIONS: The treatment with an arginase inhibitor has a potent effect on ED in AIA independently of the severity of the disease. Our results suggest that this new pharmacological approach has the potential as a novel add-on therapy in the treatment of RA.
21954100 Atlantoepistrophic magnetic resonance imaging involvement in early rheumatoid arthritis: a 2011 Nov OBJECTIVE: Rheumatoid arthritis (RA) is the most common inflammatory disorder affecting the cervical spine. The purpose of this study was to characterize the atloaxial involvement with magnetic resonance imaging (MRI) in patients with early RA at the moment of diagnosis and after 18 months of a tight control therapy. METHODS: Twenty consecutive patients with early RA without cervical symptoms and 20 healthy controls were enrolled. The patients underwent unenhanced and enhanced gadolinium MRI study of the upper cervical spine at diagnosis and after 18 months of therapy. The presence of pannus tissue at MRI was considered active synovitis. RESULTS: Five (25%) of the 20 patients presented craniocervical involvement with active synovitis at MRI. At onset, patients with cervical involvement presented higher levels of erythrocyte sedimentation rate, a higher swollen joint count, and a higher Disease Activity Score in 44 joints level. All 5 patients (100%) with cervical involvement presented already peripheral erosions. After 18 months, 1 of 5 patients with atloepistrophic synovial involvement at baseline presented complete regression of the enhancement of synovial periodontoid process, and 1 presented a decrease of this enhancement. None of the patients developed erosive process at the odontoid. The only patient with complete regression of the enhancement presented a very early disease (<3 months). CONCLUSION: Our study demonstrates involvement of the atloaxial junction in 25% of early RA patients, in particular in patients with active and erosive arthritis. An early diagnosis and aggressive treatment with a combination therapy, aiming for remission, does not always reduce atlantoaxial synovitis.
23053688 A multicenter, randomized, double-blind clinical trial of combination therapy with Anbainu 2013 Jan This study aims to evaluate the clinical and radiological efficacy as well as safety profiles of Anbainuo, a recombinant human TNFRII:Fc fusion protein, combined with methotrexate (MTX) versus MTX alone or Anbainuo alone in the treatment of Chinese patients with moderate to severe rheumatoid arthritis (RA). In this 24-week, multicenter, double-blind, active comparator-controlled study, 396 RA patients were randomized into combination therapy group (Anbainuo plus MTX), Anbainuo group, or MTX group. Clinical response was assessed using the American College of Rheumatology (ACR)-N, ACR20, ACR50, ACR70, and van der Heijde modification of Sharp score, among which ACR-N and ACR20 were defined as primary major endpoints. After 24 weeks of treatment, the ACR-N in the combination therapy group (12.79 ± 9.24 %) was significantly higher than that in Anbainuo group (9.56 ± 11.16 %) and in MTX group (5.08 ± 11.1 %) (p = 0.00 and p = 0.00, respectively). Patients in Anbainuo group had significantly higher ACR-N than those in MTX group (p = 0.02). More patients in the combination therapy group (53.6 %) achieved ACR50 improvement response than those in the MTX group (30.8 %). ACR70 of combination therapy group (27.7 %) was significantly higher than that of Anbainuo group (15.8 %) and MTX group (7.70 %), with no significant difference between Anbainuo group and MTX group. DAS28-ESR in the combination therapy group was significantly reduced compared to either monotherapy groups. Moreover, DAS28-ESR was significantly lower in Anbainou group than in MTX group. The combination therapy group also showed significantly less radiographic progression than the MTX group (p = 0.03). The total adverse events (AE) in the combination group (40.9 %) was significantly higher than those in the MTX group (28.8 %) (p < 0.05). Anbainuo combined with MTX therapy can effectively control the disease activity and radiographic progression of RA, while the incidence of AE also increased compared to either Anbainuo or MTX.
22294625 A comparative effectiveness study of adalimumab, etanercept and infliximab in biologically 2012 Jul PURPOSE: To compare the effectiveness of anti-tumour necrosis factor (TNF) agents in biologically naive and 'switched' rheumatoid arthritis (RA) patients. METHODS: RA patients enrolled in the CORRONA registry newly prescribed adalimumab (n=874), etanercept (n=640), or infliximab (n=728) were stratified based on previous anti-TNF use. Clinical effectiveness at 6, 12 and 24 months was examined using the modified American College of Rheumatology response criteria (mACR20/50/70) and achievement of remission (28-joint disease activity score (DAS28) and clinical disease activity index (CDAI)) in unadjusted and adjusted analyses. The persistence of anti-TNF treatment was examined using Cox proportional hazard models. RESULTS: Among 2242 patients (1475 biologically naive, 767 switchers), mACR20, 50 and 70 responses were similar (p>0.05) for adalimumab, etanercept and infliximab at all time points, as were rates of CDAI and DAS28 remission (p>0.05). Response and remission outcomes were consistently inferior for switched versus biologically naive patients. The adjusted OR for achieving an mACR20 response was 0.54 (95% CI 0.38 to 0.76) in first-time switchers and 0.42 (95% CI 0.23 to 0.78) in second-time switchers versus biologically naive patients at 6 months. The adjusted OR for achieving DAS28 remission were 0.29 (95% CI 0.15 to 0.58) for first-time switchers and 0.26 (95% CI 0.08 to 0.84) for second-time switchers. Persistence was higher in biologically naive patients, for whom persistence was highest with infliximab. CONCLUSIONS: No differences in rates of drug response or remission were observed among the three anti-TNF. Infliximab was associated with greater persistence in biologically naive patients. Response, remission and persistence outcomes were diminished for patients who switched anti-TNF.
23233654 Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid art 2013 Aug BACKGROUND: Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach. METHODS: We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity. RESULTS: 772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. CONCLUSIONS: Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.
22532637 Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progr 2012 Jul OBJECTIVE: To identify a specific pattern of serum cytokines that correlates with the diagnosis, activity and severity of rheumatoid arthritis (RA) in patients with early RA as well as with the level of serum markers of B cell activation. METHODS: Serum interleukin (IL)-1β, IL-1 receptor antagonist (IL1-Ra), IL-2, IL-4, IL-6, IL-10, IL-17, IL-21, monocyte chemotactic protein 1 (MCP-1), tumour necrosis factor α and interferon γ levels were measured in the (ESPOIR) Etude et Suivi des POlyarthrites Indifférenciées Récentes early arthritis cohort, which included patients with at least two swollen joints for >6 weeks and <6 months, and no previous corticosteroids or disease-modifying antirheumatic drugs. Serum cytokine levels were compared between patients who met the 1987 American College of Rheumatology criteria for RA (n=578) or had undifferentiated arthritis (UA, n=132) at the 1-year follow-up visit. RESULTS: Serum IL-6 and IL-21 were the only cytokines that discriminated RA from UA on univariate analysis. IL-6 level was associated with RA, whereas erythrocyte sedimentation rate and C-reactive protein were not. Higher proportions of rheumatoid factor and anticyclic citrullinated protein (CCP) positivity, levels of markers of B cell activation, and a higher frequency of rapid radiographic progression were observed in patients with RA with detectable IL-6 or IL-21. Multivariate analysis associated IL-6 and anti-CCP levels with radiographic erosions at enrolment with 1-year radiographic progression. CONCLUSION: Serum IL-6 concentration is greater in RA than in UA. Increase in serum IL-6 and IL-21 levels is associated with markers of B cell activation, and IL-6 is associated with radiographic progression in patients with RA.
22721819 Reliability study of tibialis posterior and selected leg muscle EMG and multi-segment foot 2012 Jul OBJECTIVE: To determine within- and between-day reliability characteristics of electromyographic (EMG) activity patterns of selected lower leg muscles and kinematic variables in patients with rheumatoid arthritis (RA) and pes planovalgus. METHODS: Five patients with RA underwent gait analysis barefoot and shod on two occasions 1 week apart. Fine-wire (tibialis posterior [TP]) and surface EMG for selected muscles and 3D kinematics using a multi-segmented foot model was undertaken barefoot and shod. Reliability of pre-determined variables including EMG activity patterns and inter-segment kinematics were analysed using coefficients of multiple correlation, intraclass correlation coefficients (ICC) and the standard error of the measurement (SEM). RESULTS: Muscle activation patterns within- and between-day ranged from fair-to-good to excellent in both conditions. Discrete temporal and amplitude variables were highly variable across all muscle groups in both conditions but particularly poor for TP and peroneus longus. SEMs ranged from 1% to 9% of stance and 4% to 27% of maximum voluntary contraction; in most cases the 95% confidence interval crossed zero. Excellent within-day reliability was found for the inter-segment kinematics in both conditions. Between-day reliability ranged from fair-to-good to excellent for kinematic variables and all ICCs were excellent; the SEM ranged from 0.60° to 1.99°. CONCLUSION: Multi-segmented foot kinematics can be reliably measured in RA patients with pes planovalgus. Serial measurement of discrete variables for TP and other selected leg muscles via EMG is not supported from the findings in this cohort of RA patients. Caution should be exercised when EMG measurements are considered to study disease progression or intervention effects.
22833339 Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap 2012 Nov OBJECTIVE: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes a chronic debilitating polyarthralgia/polyarthritis, for which current treatments are often inadequate. To assess whether new drugs being developed for rheumatoid arthritis (RA) might find utility in the treatment of alphaviral arthritides, we sought to determine whether the inflammatory gene expression signature of CHIKV arthritis shows any similarities with RA or collagen-induced arthritis (CIA), a mouse model of RA. METHODS: Using a recently developed animal model of CHIKV arthritis in adult wild-type mice, we generated a consensus CHIKV arthritis gene expression signature, which was used to interrogate publicly available microarray studies of RA and CIA. Pathway analyses were then performed using the overlapping gene signatures. RESULTS: Gene set enrichment analysis showed that there was a highly significant overlap in the differentially expressed genes in the CHIKV arthritis model and in RA. This concordance also increased with the severity of RA, as measured by the inflammation score. A highly significant overlap was also seen between CHIKV arthritis and CIA. Pathway analysis revealed that the overlap between these arthritides was spread over a range of different inflammatory processes. Involvement of T cells and interferon-γ (IFNγ) in CHIKV arthritis was confirmed in studies of MHCII-deficient mice and IFNγ-deficient mice, respectively. CONCLUSION: These results suggest that RA, a chronic autoimmune arthritis, and CHIKV disease, usually a self-limiting viral arthropathy, share multiple inflammatory processes. New drugs and biologic therapies being developed for RA may thus find application in the treatment of alphaviral arthritides.
22821856 Navigating motherhood choices in the context of rheumatoid arthritis: women's stories. 2013 Jun OBJECTIVE: Planning a family is a complex decision. For women with chronic conditions such as rheumatoid arthritis (RA), there are additional concerns about their own and their baby's health. This qualitative study examined women's experiences of negotiating their family decisions in the context of RA. METHODS: A qualitative study was conducted in 14 women who provided a written account of their motherhood decisions and experiences. Those 'stories' were then thematically analysed. RESULTS: RA was found to affect women's motherhood decisions and experiences. Three key themes were identified for both the process of decision making and the experience of that decision: capacity, uncertainty and acceptance. Only two of the women decided not to have children, while for others the decision centred on changing expectations from the number of children they planned to have, to parenting within the restrictions of their physical abilities. CONCLUSION: While many women struggled through the negotiations of their motherhood choices, those who chose to have children reported great joy in that experience. The challenges faced by women with RA contemplating motherhood, however, highlight the need for understanding and support from health professionals and the provision of resources so that women can make informed choices.
22325059 Proteins related to the functions of fibroblast-like synoviocytes identified by proteomic 2012 Mar OBJECTIVES: It is well known that the fibroblast-like synoviocytes (FLS) play a key role in pathogenesis of rheumatoid arthritis (RA). This study was performed to separate the differentially expressed proteins of FLS from the patients with RA or osteoarthritis (OA) by two-dimensional electrophoresis (2-DE), and found proteins associated with the functions of FLS by mass spectrometry (MS). METHODS: Total proteins were extracted and quantified from the primary cultured FLS from patients of RA (n=8) or OA (n=6). Proteins were separated by high-resolution 2-DE, and identified the differentially expressed proteins by MS. Western blot analyses was used to validated the expression of candidate proteins. The mRNA of these proteins was detected by semi-quantitative fluorescent PCR. RESULTS: There are 1147 protein spots from RA and 1324 protein spots from OA showed on 2-DE graphs, respectively. We have selected 84 protein spots for MS analysis, and 27 protein spots were successfully identified. We have found that protein isoaspartyl methyltransferase (PIMT) and pirin (iron-binding nuclear protein, PIR) with lower expression in RA, and thioredoxin 1(Trx-1) only expressed in RA may be associated with functions of FLS. Western Blot confirmed the expression of PIMT and pirin lower in RA, and Trx-1 expressed only in RA. The results of semi-quantitative fluorescent PCR are also consistent with 2-DE graphs. CONCLUSIONS: PIMT, pirin and Trx-1 affect the functions of FLS in some style and can be the drug targets of RA.
22027617 Thymus, innate immunity and autoimmune arthritis: interplay of gene and environment. 2011 Dec 1 A hypomorphic mutation of the gene encoding zeta-associated protein-70 (ZAP-70), a signaling molecule in T cells, produces autoimmune arthritis in mice under a microbially conventional condition but not in a clean environment. The genetic anomaly alters thymic selection of self-reactive T cells as well as natural regulatory T cells and their respective functions. Highly self-reactive polyclonal T cells, including arthritogenic ones, thus produced by the thymus strongly recognize self-antigens presented by antigen-presenting cells, stimulate them to up-regulate co-stimulatory molecules and secrete cytokines that drive naïve self-reactive T cells to differentiate into autoimmune effector Th17 cells. Administration of microbial products and activation of complement can facilitate the differentiation, evoking clinically overt arthritis in a microbially clean environment. Furthermore, mutation-dependent graded attenuation of T cell receptor signaling alters disease phenotypes and the dependency of disease occurrence on the environment. These findings provide a model of how genetic and environmental factors, in association, cause autoimmune diseases such as rheumatoid arthritis.
22686732 Therapeutic effect of an altered peptide ligand derived from heat-shock protein 60 by supp 2012 Sep Rheumatoid arthritis is a systemic autoimmune disease mediated by T cells. Productive engagement of T cell receptors by major histocompatibility complex-peptide leads to proliferation, differentiation and the definition of effector functions. Altered peptide ligands (APL) generated by amino acid substitutions in the antigenic peptide have diverse effects on T cell response. We predicted a novel T cell epitope from human heat-shock protein 60, an autoantigen involved in the pathogenesis of rheumatoid arthritis. Three APLs were designed from this epitope and it was demonstrated that these peptides induce the activation of T cells through their ability to modify cell cycle phase's distribution of CD4+T cells from RA patients. Also, IL-17, TNF-α and IL-10 levels were determined in PBMC from these patients. Unlike the wild-type peptide and the other two APLs, APL2 increased the IL-10 level and suppressed IL-17 secretion in these assays. Therapeutic effect of this APL in adjuvant arthritis (AA) and collagen-induced arthritis (CIA) models was also evaluated. Clinical score, histopathology, inflammatory and regulatory cytokine concentration were monitored in the animals. APL2 efficiently inhibited the progression of AA and CIA with a significant reduction of the clinical and histopathologic score. Therapeutic effect of APL2 on CIA was similar to that obtained with MTX; the standard treatment for RA. This effect was associated with a decrease of TNF-α and IL-17 levels. These results suggest that the therapeutic effect of APL2 is mediated in part by down-regulation of inflammatory cytokines and support the potential use of APL2 as a therapeutic drug in RA patients.
22152098 A short-chain methotrexate polyglutamate as outcome parameter in rheumatoid arthritis pati 2012 Mar OBJECTIVES: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis (RA). Although in general MTX is very effective, the major drawback is the large inter-patient variability in clinical response. The circulating levels of MTX polyglutamates (MTXPGs) are supposed to correlate with clinical efficacy, therefore having a potential role in drug monitoring. However, there is a controversial discussion about the importance of methotrexate polyglutamates as outcome parameters in the therapy of rheumatoid arthritis. The aim of the present study was to investigate the formation and pharmacokinetics of MTXPGs and to correlate their concentration with clinical response in MTX-naïve patients. METHODS: The pharmacokinetics of erythrocyte MTXPGs was determined in samples of nineteen MTX-naïve patients by high pressure liquid chromatography (HPLC) using post-column photo-oxidation and fluorimetric detection. The relationship between erythrocyte concentrations of MTXPGs and the primary outcome parameter DAS-28 was assessed using the Spearman's correlation coefficient. RESULTS: The short-chain polyglutamate MTXPG2 revealed to be a potential marker for clinical outcome in rheumatoid arthritis with a statistically significant positive correlation of MTXPG2 Cmax levels and improvement in DAS-28 (+0.518, p=0.023) over 16 weeks. Furthermore, Cmax levels of MTXPG2 negatively correlated with basophils (-0.478, p=0.038) and eosinophils (-0.531, p=0.019), both pro-inflammatory cells involved in the disease. CONCLUSIONS: MTXPG2 seems to be a potential indicator for clinical response and may serve as a marker for drug monitoring.
22488116 Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in pa 2012 Aug OBJECTIVE: From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA. METHODS: Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg). RESULTS: Compared to controls, levels of Th17 cells (CD4+IL-17+) were increased and Treg cells (CD4+CD25(high) FoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients. CONCLUSION: This study demonstrates for the first time that inhibition of IL-6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA.
22161761 Down-regulation of microRNA-34a* in rheumatoid arthritis synovial fibroblasts promotes apo 2012 Jun OBJECTIVE: To investigate the expression and effect of the microRNA-34 (miR-34) family on apoptosis in rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Expression of the miR-34 family in synovial fibroblasts with or without stimulation with Toll-like receptor (TLR) ligands, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), hypoxia, or 5-azacytidine was analyzed by real-time polymerase chain reaction (PCR). Promoter methylation was studied by combined bisulfite restriction analysis. The effects of overexpression and silencing of miR-34a and miR-34a* on apoptosis were analyzed by annexin V/propidium iodide staining. Production of X-linked inhibitor of apoptosis protein (XIAP) was assessed by real-time PCR and immunohistochemistry analysis. Reporter gene assay was used to study the signaling pathways of miR-34a*. RESULTS: Basal expression levels of miR-34a* were found to be reduced in synovial fibroblasts from RA patients compared to osteoarthritis patients, whereas levels of miR-34a, miR-34b/b*, and miR-34c/c* did not differ. Neither TNFα, IL-1β, TLR ligands, nor hypoxia altered miR-34a* expression. However, we demonstrated that the promoter of miR-34a/34a* was methylated and showed that transcription of the miR-34a duplex was induced upon treatment with demethylating agents. Enforced expression of miR-34a* led to an increased rate of FasL- and TRAIL-mediated apoptosis in RASFs. Moreover, levels of miR-34a* were highly correlated with expression of XIAP, which was found to be up-regulated in RA synovial cells. Finally, we identified XIAP as a direct target of miR-34a*. CONCLUSION: Our data provide evidence of a methylation-specific down-regulation of proapoptotic miR-34a* in RASFs. Decreased expression of miR- 34a* results in up-regulation of its direct target XIAP, thereby contributing to resistance of RASFs to apoptosis.
20552328 Osteoporosis in inflammatory joint diseases. 2011 Feb Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are two inflammatory joint diseases characterized by bone complications including osteoporosis. In RA, periarticular bone loss, bone erosions, and systemic osteoporosis are observed, with an increased risk of fractures. Determinants of fractures are underlying conditions (as RA has a female preponderance and an increased prevalence with age), severity of the disease, and use of glucocorticoids. However, bone loss can occur even in glucocorticoid-naive patients. Prospective data show that the optimal control of inflammation in RA is associated with decrease in structural damage and bone loss. RA illustrates the role of inflammation on bone resorption. In AS, osteoporosis is an early event and vertebral fracture risk is increased. Bone loss is related mainly to inflammation, as the disease can occur in young male adult populations, and glucocorticoids are not used in this disease. However, AS is characterized by progressive stiffness and ankylosis of the spine and illustrates also the potential role of inflammation on local bone formation.
20012960 Report of anti-CCP antibody positive paraneoplastic polyarthritis and review of the litera 2011 Dec A 45-year-old female presented to the rheumatology clinic with complaint of pain and swelling of multiple small joints of the hands and feet. She also complained of cough and shortness of breath onset around the same time. Since her cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor tests were positive, rheumatoid arthritis (RA) was diagnosed and she was started on prednisone with plans for additional disease modifying therapy. Chest X-ray showed a small right pleural effusion. While additional pulmonary evaluation was being planned, a few weeks later she presented with dyspnea, fever and tachycardia. Spiral CT showed pulmonary emboli and increased pleural effusion and patient was started on anticoagulation. A chest tube was placed and exudative pleural effusion was drained. Cytology sample from bronchoscopy raised concerns for adenocarcinoma. Open lung biopsy confirmed moderately differentiated adenocarcinoma. The patient died of lung cancer in the hospital 8 weeks from her diagnosis of RA. We describe a case of paraneoplastic polyarthritis with positive anti-CCP antibody test which has not been reported before. We also review the literature on paraneoplastic arthritis which has been described in association with various other malignancies besides lung cancer.
21604972 Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid ar 2011 Sep Current treatments for rheumatoid arthritis (RA) have long-term side effects such that new treatments are needed that can safely help manage the disease. There is a growing appreciation that GABA receptors (GABA-Rs) on immune cells provide new targets that can be used to modulate immune cell activity. Here, we show for the first time that activation of peripheral GABA-Rs can inhibit the development of disease in the collagen-induced arthritis (CIA) mouse model of RA. Mice that received oral GABA had a reduced incidence of CIA, and those mice that did develop CIA had milder symptoms. T cells from GABA-treated mice displayed reduced proliferative responses to collagen and their APC had a reduced ability to promote the proliferation of collagen-reactive T cells. Thus, GABA downregulated both T-cell autoimmunity and APC activity. Collagen-reactive T cells from GABA-treated mice displayed reduced recall responses in the presence of GABA ex vivo, indicating that GABA consumption did not desensitize these cells to GABA. GABA-treated mice had reduced collagen-reactive IgG2a, but not IgG1 antibodies, consistent with reduced Th1 help. The levels of serum anti-collagen IgG2a antibodies were correlated significantly with the CIA disease scores of individual mice. Our results suggest that activation of peripheral GABA-Rs may provide a new modality to modulate T cell, B cell, and APC activity and help ameliorate RA and other inflammatory diseases.