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ID PMID Title PublicationDate abstract
23819992 Epistasis with HLA DR3 implicates the P2X7 receptor in the pathogenesis of primary Sjögre 2013 Jun 2 INTRODUCTION: The aim of this study was to examine the association between functional polymorphisms in the pro-inflammatory P2X7 receptor and the Ro/La autoantibody response in primary Sjögren's syndrome (pSS). METHODS: Twelve functional P2RX7 polymorphisms were genotyped in 114 pSS patients fulfilling the Revised American-European Consensus Criteria for pSS, and 136 controls. Genotyping of the A1405G (rs2230912) polymorphism was performed on a replication cohort consisting of 281 pSS patients and 534 controls. P2X7 receptor function in lymphocytes and monocytes was assessed by measurement of ATP-induced ethidium+ uptake. Serum IL-18 levels were determined by ELISA. RESULTS: The minor allele of P2RX7 A1405G is a tag for a common haplotype associated with gain in receptor function, as assessed by ATP-induced ethidium+ uptake. A positive association between 1405G and anti-Ro±La seropositive pSS patients was observed in Cohort 1. Although not replicated in Cohort 2, there was a consistent, significant, negative epistatic interaction effect with HLA-DR3 in seropositive pSS patients from both cohorts, thereby implicating this gain of function variant in the pathogenesis of pSS. Serum IL-18 was elevated in seropositive pSS patients, but was not influenced by P2RX7 A1405G. CONCLUSIONS: The P2RX7 1405G gain-of-function haplotype may be a risk factor for seropositive pSS in a subset of subjects who do not carry HLA risk alleles, but has no effect in subjects who do (epistasis). Potential mechanisms relate to autoantigen exposure and inflammatory cytokine expression. The observed elevation of IL-18 levels is consistent with P2X7 receptor activation in seropositive pSS patients. Collectively these findings implicate P2X7 receptor function in the pathogenesis of pSS.
23504381 Gene expression of catalytic proteasome subunits and resistance toward proteasome inhibiti 2013 May OBJECTIVE: Dysregulation of proteasome subunit β1i expression has been shown in total blood mononuclear cells (PBMC) from patients with primary Sjögren syndrome (pSS), a B cell-driven systemic autoimmune disorder. METHODS: Proteasome activation was investigated in sorted blood cells from patients with pSS and controls by measuring transcript levels of constitutive (β1/β2/β5) and corresponding immunoproteasome catalytic subunits (β1i/β2i/β5i) using real-time PCR. At protein level, β1i protein expression was analyzed by immunoblotting. Functional effects of proteasome inhibition on proteolytic activity and induction of apoptosis were also evaluated in cellular subsets. RESULTS: The proteasome was found to be activated in pSS, with upregulation of gene expression of catalytic proteasome subunits. Western blot analysis revealed decreased β1i protein expression in pSS B lymphocytes, with decreased protein despite increased messenger RNA (mRNA) levels. After proteasome inhibition in vitro, proteolytic activity was less reduced and resistance to apoptosis was increased in B lymphocytes compared to other cells. CONCLUSION: In pSS, catalytic subunits of the proteasome are upregulated at the mRNA level, while dysregulation of subunit β1i is attributed to B lymphocytes. B cell resistance after proteasome inhibition differs from the classical concept of increased susceptibility toward inhibition in activated cells, supporting the novel notion that susceptibility depends on cellular intrinsic factors and on proteasome activation.
23400265 Electrolyte imbalances and nephrocalcinosis in acute phosphate poisoning on chronic type 1 2013 Feb Although renal calcium crystal deposits (nephrocalcinosis) may occur in acute phosphate poisoning as well as type 1 renal tubular acidosis (RTA), hyperphosphatemic hypocalcemia is common in the former while normocalcemic hypokalemia is typical in the latter. Here, as a unique coexistence of these two seperated clinical entities, we report a 30-yr-old woman presenting with carpal spasm related to hypocalcemia (ionized calcium of 1.90 mM/L) due to acute phosphate poisoning after oral sodium phosphate bowel preparation, which resolved rapidly after calcium gluconate intravenously. Subsequently, type 1 RTA due to Sjögren's syndrome was unveiled by sustained hypokalemia (3.3 to 3.4 mEq/L), persistent alkaline urine pH (> 6.0) despite metabolic acidosis, and medullary nephrocalcinosis. Through this case report, the differential points of nephrocalcinosis and electrolyte imbalances between them are discussed, and focused more on diagnostic tests and managements of type 1 RTA.
23674818 Characterization of a new regulatory CD4+ T cell subset in primary Sjögren's syndrome. 2013 Aug OBJECTIVE: CD4(+)CD25(low)GITR(+) T lymphocytes expressing FoxP3 and showing regulatory function have been recently described in healthy donors (HD). The objective of the study was to investigate their presence and role in patients with primary SS (pSS). METHODS: CD4(+)CD25(low)GITR(+) cells circulating in peripheral blood (PB) of patients with pSS were isolated by MACS technique, their phenotype was studied by flow cytometry and real-time PCR, and their function was studied by in vitro co-culture. CD4(+)CD25(low)GITR(+) cells infiltrating salivary glands (SGs) were revealed by immunohistochemistry. RESULTS: Results indicated that conventional CD4(+)CD25(high) regulatory T cells (Tregs) are decreased, whereas CD4(+)CD25(low)GITR(+) cells are expanded in the PB of pSS as compared with HD. Phenotypic analysis demonstrated that CD4(+)CD25(low)GITR(+) cells display Treg markers, including FoxP3, TGF-β and IL-10, and functional experiments demonstrated that they exert a strong inhibitory activity against autologous effector cells. CD4(+)CD25(low)GITR(+) cells were detectable in great number in the SG inflammatory infiltrate. Interestingly, PB CD4(+)CD25(low)GITR(+) cell expansion was evident only in patients with inactive disease, while conventional CD4(+)CD25(high) Treg number was not associated with disease activity. CONCLUSION: The present data demonstrate that circulating CD4(+) cells expressing GITR, but with low levels of CD25 (CD4(+)CD25(low)GITR(+)), are detectable in pSS patients. These cells, displaying Treg phenotype and function, are present in SG inflamed tissues and are expanded in the PB of subjects with inactive disease. Data suggest that the expansion of CD4(+)CD25(low)GITR(+) cells in pSS may represent a counter-regulatory attempt against autoimmune-driven inflammation and may provide a new target for future treatment strategies.
24183073 Immunomodulation by dietary long chain omega-3 fatty acids and the potential for adverse h 2013 Nov Recommendations to consume fish for prevention of cardiovascular disease (CVD), along with the U.S. Food and Drug Administration-approved generally recognized as safe (GRAS) status for long chain omega-3 fatty acids, may have had the unanticipated consequence of encouraging long-chain omega-3 (ω-3) fatty acid [(eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] supplementation and fortification practices. While there is evidence supporting a protective role for EPA/DHA supplementation in reducing sudden cardiac events, the safety and efficacy of supplementation with LCω-3PUFA in the context of other disease outcomes is unclear. Recent studies of bacterial, viral, and fungal infections in animal models of infectious disease demonstrate that LCω-3PUFA intake dampens immunity and alters pathogen clearance and can result in reduced survival. The same physiological properties of EPA/DHA that are responsible for the amelioration of inflammation associated with chronic cardiovascular pathology or autoimmune states, may impair pathogen clearance during acute infections by decreasing host resistance or interfere with tumor surveillance resulting in adverse health outcomes. Recent observations that high serum LCω-3PUFA levels are associated with higher risk of prostate cancer and atrial fibrillation raise concern for adverse outcomes. Given the widespread use of supplements and fortification of common food items with LCω-3PUFA, this review focuses on the immunomodulatory effects of the dietary LCω-3PUFAs, EPA and DHA, the mechanistic basis for potential negative health outcomes, and calls for biomarker development and validation as rational first steps towards setting recommended dietary intake levels.
24012618 The association between galactosylation of immunoglobulin G and body mass index. 2014 Jan 3 OBJECTIVE: Obesity is becoming a fast-growing health problem worldwide. Glycosylation of proteins and their variations significantly affect protein structure and function, thus altering numerous physiological and pathophysiological cellular processes. Since plasma glycans were significantly associated with body mass index (BMI) in both Croatian and Chinese populations, the study evaluated the association between immunoglobulin G (IgG) glycome, which is closer to biological function, and BMI. METHOD: The study included individuals from two Croatian Adriatic islands, Vis and Korčula, and individuals from Northern Scottish Orkney Islands. A hydrophilic interaction chromatography on Waters BEH Glycan chromatography column was used to analyze N-glycans attached to IgG in plasma samples from a total of 3515 individuals. RESULTS: A small but significant positive correlation between BMI and the level of neutral glycans without galactoses was detected. After taking into account the influence of age and gender, correlation coefficients indicated that BMI was responsible for up to 2.0% of variation in the level of neutral glycans without galactoses. Furthermore, after adjusting the effects of age and gender, the level of neutral glycans with two terminal galactoses was negatively associated with BMI in analyzed sample groups, suggesting that BMI could be responsible for up to 3.2% of variation in this glycan feature. CONCLUSION: Our study is the first large-scale study to indicate the association of BMI and changes in IgG galactosylation. The observed loss of galactose which is associated with increased BMI might be related to chronic inflammation that accompanies the development of obesity.
23902301 Influence of periodontal disease, Porphyromonas gingivalis and cigarette smoking on system 2013 Oct BACKGROUND: Anti-citrullinated protein antibody (ACPA) responses may precede clinical onset of rheumatoid arthritis. Porphyromonas gingivalis peptidylarginine deiminase can citrullinate proteins possibly inducing autoimmunity in susceptible individuals. AIM: To determine whether periodontitis, carriage of P. gingivalis, smoking and periodontal therapy influence ACPA titres. METHODS: Serum and plaque samples were collected from 39 periodontitis patients before and after non-surgical periodontal treatment, and from 36 healthy subjects. Carriage of P. gingivalis was determined by PCR of plaque DNA. ACPA was determined by anti-cyclic citrullinated peptide (CCP) enzyme-linked immunosorbent assay (ELISA). Anti-P. gingivalis titres were determined by ELISA. RESULTS: Untreated periodontitis patients had higher anti-CCP antibody titres than healthy controls [three patients (8%) greater than manufacturer suggested assay diagnostic threshold (5 Assay Units/AU) versus none (0%); mean ± SEM: 1.37 ± 0.23 versus 0.40 ± 0.10 AU, p < 0.0001]. Periodontitis patients who smoked demonstrated lower anti-P. gingivalis (15956 ± 4385 versus 2512 ± 1290 Units/ml, p < 0.05), but similar anti-CCP than non-smoking periodontitis patients (smokers: 1.31 ± 0.35; non-smokers: 1.41 ± 0.32 AU). Healthy smokers demonstrated elevated anti-CCP titres (0.75 ± 0.19 AU), at levels between healthy non-smokers (0.15 ± 0.05 AU) and non-smoker periodontitis patients. Six months after periodontal treatment, there were significant reductions in anti-CCP (non-smokers p < 0.05) and anti-P. gingivalis (all participants p < 0.01). CONCLUSION: In subjects with periodontitis, P. gingivalis infection may be responsible for inducing autoimmune responses that characterize rheumatoid arthritis.
23573834 Risk factors for superficial wound complications in hip and knee arthroplasty. 2014 Feb Superficial wound complications have been consistently implicated in the development of prosthetic joint infection. This cohort study aimed to determine perioperative risk factors associated with superficial wound complications. The study was performed over an 18-month period (January 2011 to June 2012) and included 964 patients undergoing prosthetic hip or knee replacement surgery. The factors associated with superficial wound complication differed according to arthroplasty site. In the combined cohort the following factors were associated with superficial wound complications: the use of 0.5% chlorhexidine in 70% alcohol for surgical skin preparation compared with 1% iodine in 70% alcohol (odds ratio (OR) 4.75; 95% confidence interval (CI) 1.42, 15.92; p = 0.012); increasing age (OR, 1.13; 95% CI, 1.06,1.19; p 0.18); increasing body mass index (BMI) (OR, 1.08; 95% CI, 1.05,1.12; p < 0.001); rheumatoid arthritis (OR, 2.56; 95% CI, 1.17, 5.58; p 0.018); and increasing blood transfusions (OR, 1.26; 95% CI, 1.06,1.49; p 0.008). In the hip arthroplasty cohort, the use of 0.5% chlorhexidine in 70% alcohol for surgical skin preparation (OR, 13.35; 95% CI, 2.11, 84.29; p 0.006), increasing BMI (OR, 1.13; 95% CI, 1.06, 1.19; p < 0.001) and increasing blood transfusions (OR, 1.26; 95% CI, 1.06, 1.49; p 0.008) were associated with superficial wound complications. In the knee arthroplasty cohort rheumatoid arthritis (OR, 2.75; 95% CI, 1.03, 7.33; p 0.043) and increasing tourniquet time (OR, 1.01; 95% CI, 1.00, 1.02; p = 0.029) were independent predictors of superficial wound complications. Further research is warranted to assess the impact of modification of these factors on the subsequent development of wound complications and prosthetic joint infection.
25076823 Peripheral Quantitative CT (pQCT) Using a Dedicated Extremity Cone-Beam CT Scanner. 2013 Mar 29 PURPOSE: We describe the initial assessment of the peripheral quantitative CT (pQCT) imaging capabilities of a cone-beam CT (CBCT) scanner dedicated to musculoskeletal extremity imaging. The aim is to accurately measure and quantify bone and joint morphology using information automatically acquired with each CBCT scan, thereby reducing the need for a separate pQCT exam. METHODS: A prototype CBCT scanner providing isotropic, sub-millimeter spatial resolution and soft-tissue contrast resolution comparable or superior to standard multi-detector CT (MDCT) has been developed for extremity imaging, including the capability for weight-bearing exams and multi-mode (radiography, fluoroscopy, and volumetric) imaging. Assessment of pQCT performance included measurement of bone mineral density (BMD), morphometric parameters of subchondral bone architecture, and joint space analysis. Measurements employed phantoms, cadavers, and patients from an ongoing pilot study imaged with the CBCT prototype (at various acquisition, calibration, and reconstruction techniques) in comparison to MDCT (using pQCT protocols for analysis of BMD) and micro-CT (for analysis of subchondral morphometry). RESULTS: The CBCT extremity scanner yielded BMD measurement within ±2-3% error in both phantom studies and cadaver extremity specimens. Subchondral bone architecture (bone volume fraction, trabecular thickness, degree of anisotropy, and structure model index) exhibited good correlation with gold standard micro-CT (error ~5%), surpassing the conventional limitations of spatial resolution in clinical MDCT scanners. Joint space analysis demonstrated the potential for sensitive 3D joint space mapping beyond that of qualitative radiographic scores in application to non-weight-bearing versus weight-bearing lower extremities and assessment of phalangeal joint space integrity in the upper extremities. CONCLUSION: The CBCT extremity scanner demonstrated promising initial results in accurate pQCT analysis from images acquired with each CBCT scan. Future studies will include improved x-ray scatter correction and image reconstruction techniques to further improve accuracy and to correlate pQCT metrics with known pathology.
24352336 Noxa in rheumatic diseases: present understanding and future impact. 2014 Sep Impaired programmed cell death is an important contributing mechanism in the development of chronic inflammatory and autoimmune diseases. Overexpression of Bcl-2 family proteins in such diseases has led to the concept of targeted suppression of these proteins as a primary therapeutic strategy. However, limited success with this approach has prompted pharmacologists to look at the other side of the coin, with the aim of reactivating jeopardized pro-apoptotic proteins that may neutralize Bcl-2 or other anti-apoptotic molecules. In this effort, BH3-only proteins have gained recent attention as endogenous molecules for the sensitization of resistant cells to undergo apoptosis. Among the BH3-only family, Noxa stands out as exceptional for its specificity to bind Mcl-1 and Bcl-2 and blunt their biological properties. Noxa is now being tested as a promising therapeutic target in cancer biology. Nonetheless, its role and clinical application still lack validation in autoimmune diseases, including rheumatic conditions. This is partly attributed to the significant gap in our understanding of its regulatory role and how either overexpression of Noxa or delivery of BH3 mimetics could be therapeutically exploited. In this review we highlight some recent studies in RA, OA, SLE and SS suggesting that Noxa may be used as a potential therapeutic target to circumvent invasive and tissue destructive processes in these rheumatic diseases.
23364320 Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety 2013 Jan 29 INTRODUCTION: Cyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects. Data from randomised and observational studies suggest that celecoxib has similar cardiovascular toxicity to traditional NSAIDs. The overall safety balance of a strategy of celecoxib therapy versus traditional NSAID therapy is unknown. The European Medicines Agency  requested studies of the cardiovascular safety of celecoxib within Europe. The Standard care versus Celecoxib Outcome Trial (SCOT) compares the cardiovascular safety of celecoxib with traditional NSAID therapy in the setting of the European Union healthcare system. METHODS AND ANALYSIS: SCOT is a large streamlined safety study conducted in Scotland, England, Denmark and the Netherlands using the Prospective Randomised Open Blinded Endpoint design. Patients aged over 60 years with osteoarthritis or rheumatoid arthritis, free from established cardiovascular disease and requiring chronic NSAID therapy, are randomised to celecoxib or their previous traditional NSAID. They are then followed up for events by record-linkage within their normal healthcare setting. The hypothesis is non-inferiority with a confidence limit of 1.4. The primary endpoint is the first occurrence of hospitalisation or death for the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are (1) first hospitalisation or death for upper gastrointestinal ulcer complications (bleeding, perforation or obstruction); (2) first occurrence of hospitalised upper gastrointestinal ulcer complications or APTC endpoint; (3) first hospitalisation for heart failure; (4) first hospitalisation for APTC endpoint plus heart failure; (5) all-cause mortality and (6) first hospitalisation for new or worsening renal failure. ETHICS AND DISSEMINATION: SCOT has been approved by the relevant ethics committees. The trial results will be published in a peer-reviewed scientific journal. CLINICAL TRIALS REGISTRATION NUMBER: Clinicaltrials.gov (NCT00447759).
24651914 Intra-articular and soft tissue injections, a systematic review of relative efficacy of va 2014 Dec The comparative efficacy of various Corticosteroid (CS) injections commonly used to treat musculoskeletal conditions has not been systematically studied. Our objective is to synthesize data about comparative efficacy of various CS used for intra-articular and periarticular soft tissue injections. Online databases were searched including MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effectiveness, and bibliographies of studies till November 2013. We included all randomized controlled trials comparing two CS for intra-articular and periarticular injections, selected according to Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology. Seven good quality trials were selected for qualitative data synthesis. Two trials comparing triamcinolone hexacetonide (TH) and methylprednisolone (MP) for knee arthritis suggested faster pain relief with TH for rheumatoid arthritis (RA) at day 7 (p < 0.05) and osteoarthritis (OA) at week 3 (visual analogue scale, 33 mm vs 14 mm, p < 0.01) but a similar long-term efficacy. One trial suggested faster pain relief with MP compared to triamcinolone acetonide (TA) for rotator cuff tendonitis at 2 weeks (percentage of patients improving 92 % vs. 50 %; p = 0.02) but similar long-term efficacy, while another trial suggested no difference between TA and MP for knee OA. Two trials for knee arthritis suggested a substantially better efficacy for TH than TA (response rate at 24 months 77 % vs 39 %; p = 0.001) and betamethasone (BM) at day 42 (p < 0.01). There is paucity of data regarding comparative efficacy of various CS injections. Limited number of studies favored TH over other CS (TA, MP, BM).
24594197 The human peptidylarginine deiminases type 2 and type 4 have distinct substrate specificit 2014 Apr Human peptidylarginine deiminases (hPADs) have been implicated in several diseases, particularly in rheumatoid arthritis. Since hPAD2 and hPAD4 are the isotypes expressed in the inflamed joints of RA patients and protein citrullination by PADs has been proposed to play a pathophysiological role, they represent unique therapeutic targets. To facilitate the development of substrate-based PAD inhibitors the substrate specificity of hPAD2 and hPAD4 was determined. Recombinant hPADs were expressed in bacteria or mammalian cell lines and allowed to citrullinate proteins in cell lysates, as well as a series of synthetic peptides. The citrullinated residues in proteins and the efficiency of peptide citrullination were determined by mass spectrometry. In total 320 hPAD2 and 178 hPAD4 citrullination sites were characterized. Amino acid residues most commonly found in citrullination sites for both isotypes are Gly at +1 and Tyr at +3 relative to the target arginine. For hPAD4 several additional amino acids were observed to be preferred at various positions from -4 to +4. The substrate motifs determined by amino acid substitution analysis partially confirmed these preferences, although peptide context dependent differences were also observed. Taken together, our data show that the enzyme specificity for cellular substrates and synthetic peptides differs for hPAD2 and hPAD4. hPAD4 shows more restrictive substrate specificity compared to hPAD2. Consensus sequences, which can be used as the basis for the development of PAD inhibitors, were derived for the citrullination sites of both hPAD2 and hPAD4.
24618265 Risk of high-grade cervical dysplasia and cervical cancer in women with systemic inflammat 2015 Jul BACKGROUND: Previous studies have suggested a potential risk of cervical cancer in patients with systemic inflammatory diseases (SID) such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). OBJECTIVES: To assess the risk of high-grade cervical dysplasia, a surrogate endpoint for cervical cancer and cervical cancer, in women with SID, including IBD, psoriasis, rheumatoid arthritis (RA) or SLE, compared with the risk in women without SID. METHODS: Using US insurance data (2001-2012), we conducted a cohort study of 133,333 women with SID, based on two or more diagnoses and one or more dispensed prescription for disease-specific treatment, and 533,332 women without SID. High-grade cervical dysplasia and cervical cancer was defined by a validated algorithm with a positive predictive value of ≥81%. RESULTS: Over the mean follow-up of 2.1 years, the crude incidence rate of high-grade cervical dysplasia and cervical cancer per 100,000 person-years was the highest at 141.1 in SLE and the lowest at 82.2 in psoriasis among women with SID, and 73.4 in women without SID. The multivariable HR adjusted for potential confounders was 1.07 (95% CI 0.79 to 1.45) in IBD, 0.96 (95% CI 0.73 to 1.27) in psoriasis, 1.49 (95% CI 1.11 to 2.00) in RA and 1.53 (95% CI 1.07 to 2.19) in SLE. Multivariable HRs were increased, but not statistically significant, in IBD, RA and SLE with baseline use of systemic immunosuppressive drugs or steroids. CONCLUSIONS: The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in women with RA and SLE than in those without SID. The risk may be increased in IBD with use of systemic immunosuppressive drugs or steroids.
24654562 Efficacy and safety of etanercept in chronic immune-mediated disease. 2014 May INTRODUCTION: TNF-α inhibitors have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or disease-modifying antirheumatic drugs in the treatment of chronic inflammatory immune-mediated diseases. Etanercept is a fusion protein that acts as a 'decoy receptor' for TNF-α. AREAS COVERED: This paper evaluates the efficacy and safety of etanercept in patients with chronic inflammatory immune-mediated diseases. EXPERT OPINION: Etanercept was first approved for the treatment of rheumatoid arthritis (RA) and subsequently of chronic plaque psoriasis, psoriatic arthritis, ankylosing spondylitis and juvenile RA. Etanercept as other TNF-α inhibitors, particularly infliximab, may be administered off-label to treat other chronic inflammatory immune-mediated diseases such as systemic sclerosis, Behcet disease, systemic lupus erythematosus, polymyositis, dermatomyositis and mixed connective tissue disease. Early etanercept treatment prevents joint damage and helps to avoid long-term disability in arthritis. Etanercept administered at a dose of 50 mg once weekly is effective in inducing an earlier remission of RA, and etanercept 50 mg twice weekly may favor a more rapid improvement of psoriasis and psoriatic arthritis. Etanercept and adalimumab may exert beneficial effects on lipid profile and improve endothelial dysfunction. Appropriate screening tests for latent tuberculosis, hepatitis B virus and hepatitis C virus should be performed before starting etanercept. TNF-α inhibitors including etanercept are contraindicated in patients with demyelinating diseases.
23488692 IL-1β/HMGB1 complexes promote The PGE2 biosynthesis pathway in synovial fibroblasts. 2013 May PGE2 is a potent lipid mediator of pain and oedema found elevated in RA. Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme of the PGE2 pathway inducible by proinflammatory cytokines. mPGES-1 is markedly upregulated in RA synovial tissue despite antirheumatic treatments, suggesting that multiple inflammatory stimuli contribute to its induction. High-mobility group box chromosomal protein 1 (HMGB1) is known to induce inflammation both by direct interaction with TLR4 and by enhancement of other proinflammatory molecules signalling, through complex formation. The high expression of extracellular HMGB1 within the inflamed synovium, implies its pro-arthritogenic role in RA. We aimed to investigate the effects of IL-1β/HMGB1 complexes on mPGES-1 and other enzymes of the PGE2 pathway in synovial fibroblasts (SFs) from patients with arthritis. Furthermore, we studied the effect of COX-2 inhibition and IL-1RI antagonism on prostanoid and cytokine production by SFs. Stimulation of SFs with HMGB1 in complex with suboptimal amounts of IL-1β significantly increased mPGES-1 and COX-2 expressions as well as PGE2 production, as compared to treatment with HMGB1 or IL-1β alone. Furthermore, NS-398 reduced the production of IL-6 and IL-8, thus indicating that IL-1β/HMGB1 complexes modulate cytokine production in part through prostanoid synthesis. Treatment with IL-1RA completely abolished the induced PGE2 and cytokine production, suggesting an effect mediated through IL-1RI. IL-1β/HMGB1 complexes promote the induction of mPGES-1, COX-2 and PGE2 in SF. The amplification of the PGE2 biosynthesis pathway by HMGB1 might constitute an important pathogenic mechanism perpetuating inflammatory and destructive activities in rheumatoid arthritis.
24548461 A rice-based soluble form of a murine TNF-specific llama variable domain of heavy-chain an 2014 Apr 10 Tumor necrosis factor alpha (TNF) plays a pivotal role in chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although anti-TNF antibody therapy is now commonly used to treat patients suffering from these inflammatory conditions, the cost of treatment continues to be a concern. Here, we developed a rice transgenic system for the production of a llama variable domain of a heavy-chain antibody fragment (VHH) specific for mouse TNF in rice seeds (MucoRice-mTNF-VHH). MucoRice-mTNF-VHH was produced at high levels in the rice seeds when we used our most recent transgene-overexpression system with RNA interference technology that suppresses the production of major rice endogenous storage proteins while enhancing the expression of the transgene-derived protein. Production levels of mTNF-VHH in rice seeds reached an average of 1.45% (w/w). Further, approximately 91% of mTNF-VHH was released easily when the powder form of MucoRice-mTNF-VHH was mixed with PBS. mTNF-VHH purified by means of single-step gel filtration from rice PBS extract showed high neutralizing activity in an in vitro mTNF cytotoxicity assay using WEHI164 cells. In addition, purified mTNF-VHH suppressed progression of collagen-induced arthritis in mice. These results show that this rice-expression system is useful for the production of neutralizing VHH antibody specific for mTNF.
24357062 Inhibition of arthritis in the Lewis rat by apolipoprotein A-I and reconstituted high-dens 2014 Mar OBJECTIVE: This study questions whether high-density lipoproteins (HDLs) and apolipoprotein A-I inhibit joint inflammation in streptococcal cell wall peptidoglycan-polysaccharide (PG-PS)-induced arthritis in female Lewis rats. APPROACH AND RESULTS: Administration of PG-PS to female Lewis rats caused acute joint inflammation after 4 days, followed by remission by day 8. The animals subsequently developed chronic joint inflammation that persisted until euthanasia at day 21. Treatment with apolipoprotein A-I 24 hours before and 24 hours after PG-PS administration reduced the acute and chronic joint inflammation. Treatment with apolipoprotein A-I at days 7, 9, and 11 after PG-PS administration reduced the chronic joint inflammation. Treatment with apolipoprotein A-I or reconstituted HDLs consisting of apolipoprotein A-I complexed with phosphatidylcholine 24 hours before and at days 1, 7, 9, and 11 after PG-PS administration reduced acute and chronic joint inflammation. Treatment with apolipoprotein A-I also reduced the inflammatory white blood cell count, synovial fluid proinflammatory cytokine levels, synovial tissue macrophage accumulation, as well as toll-like receptor 2, and inflammatory cytokine expression. At the molecular level, preincubation of human monocyte-derived macrophages with apolipoprotein A-I or reconstituted HDLs before PG-PS stimulation inhibited the PG-PS-induced increase in toll-like receptor 2 and myeloid differentiation primary response gene (88) mRNA levels, nuclear factor-κB activation, and proinflammatory cytokine production. The effects of apolipoprotein A-I and reconstituted HDLs were abolished by transfecting the human monocyte-derived macrophages with ATP-binding cassette transporter A1 or G1 siRNA. CONCLUSIONS: Apolipoprotein A-I and reconstituted HDLs attenuate PG-PS-induced arthritis in the rat. Studies in human monocyte-derived macrophages indicate that this benefit may be because of the inhibition of toll-like receptor 2 expression and decreased nuclear factor-κB activation in macrophages.
25373902 Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. 2014 Oct 23 Different subsets and/or polarized phenotypes of monocytes and macrophages may play distinct roles during the development and resolution of inflammation. Here, we demonstrate in a murine model of rheumatoid arthritis that nonclassical Ly6C(-) monocytes are required for the initiation and progression of sterile joint inflammation. Moreover, nonclassical Ly6C(-) monocytes differentiate into inflammatory macrophages (M1), which drive disease pathogenesis and display plasticity during the resolution phase. During the development of arthritis, these cells polarize toward an alternatively activated phenotype (M2), promoting the resolution of joint inflammation. The influx of Ly6C(-) monocytes and their subsequent classical and then alternative activation occurs without changes in synovial tissue-resident macrophages, which express markers of M2 polarization throughout the course of the arthritis and attenuate joint inflammation during the initiation phase. These data suggest that circulating Ly6C(-) monocytes recruited to the joint upon injury orchestrate the development and resolution of autoimmune joint inflammation.
24932752 Eponyms in cardiothoracic radiology: part III--interstitium. 2014 Sep Eponyms serve the purpose of honoring individuals who have made important observations and discoveries. As with other fields of medicine, eponyms are frequently encountered in radiology, particularly in chest radiology. However, inappropriate use of an eponym may lead to potentially dangerous miscommunication. Moreover, an eponym may honor the incorrect person or a person who falls into disrepute. Despite their limitations, eponyms are still widespread in the medical literature. Furthermore, in some circumstances, more than one individual may have contributed to the description or discovery of a particular anatomical structure or disease, whereas in others, an eponym may have been incorrectly applied initially and propagated for years in the medical literature. Nevertheless, radiologic eponyms are a means of honoring those who have made lasting contributions to the field of radiology, and familiarity with these eponyms is critical for proper reporting and accurate communication. In addition, the acquisition of some historical knowledge about those whose names are associated with various structures or pathologic conditions conveys a sense of humanity in the science of medicine. In this third installment of this series, the authors discuss a number of chest radiology eponyms as they relate to the pulmonary interstitium, including relevant clinical and imaging features, as well biographical information of the respective eponym's namesake.