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ID PMID Title PublicationDate abstract
23239179 Measuring methotrexate polyglutamates in red blood cells: a new LC-MS/MS-based method. 2013 Feb The folate antagonist methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis. The therapeutic effects of MTX are attributed to the intracellular levels of MTX, present in the cell as polyglutamates (MTXPGn). We developed a new liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS)-based assay to separately quantitate MTXPGn in red blood cells using stable-isotope-labelled internal standards. Samples were analyzed by LC-ESI-MS/MS using a Waters Acquity UPLC BEH C18 column with a 5-100% organic gradient of 10 mM ammonium bicarbonate (pH 10) and methanol. The analysis consisted of simple sample preparation and a 6-min run time. Detection was done using a Waters Acquity UPLC coupled to a Waters Quattro Premier XE with electrospray ionization operating in the positive ionization mode. Assay validation was performed following recent Food and Drug Administration guidelines. The method was linear from 1-1,000 nM for all MTXPGn (R(2) > 0.99). The coefficient of variation ranged from 1-4% for intraday precision and 6-15% for interday precision. Samples were stable for at least 1 month at -80 °C. Recovery ranged from 98-100%, and the relative matrix-effect varied from 95-99%. The lower limit of quantitation was 1 nM for each MTXPGn. Fifty patient samples from the tREACH study were analyzed. The MTXPGn concentration and distribution of these samples were comparable with values reported in literature. The developed LC-ESI-MS/MS method for the quantitative measurement of MTXPGn in red blood cells is both sensitive and precise within the clinically relevant range. The method can be easily applied in clinical laboratories due to the combination of simple pre-treatment with robust LC-ESI-MS/MS.
23723316 Biologic discontinuation studies: a systematic review of methods. 2014 Mar OBJECTIVES: We conducted a systematic review to assess the design and 'failure definition' in studies of biologic discontinuation in rheumatoid arthritis (RA). METHODS: We found 403 studies on PubMed, and included nine published papers and five abstracts from scientific meetings. We used a structured extraction form to collect information regarding study design and outcome (failure) definition. RESULTS: Three types of studies were found: randomised controlled trials, long-term extension studies of clinical trials and prospective discontinuation studies. The largest study had 196 subjects in the discontinuation arm. Most studies allowed concomitant use of non-biologic drugs at biologic discontinuation. Heterogeneity was also found in the failure definition. Although all studies used measures of disease activity, the threshold for failure and the time point of assessment differed among studies. Few studies incorporated changing use of non-biologic drugs or glucocorticoids into the failure definition. CONCLUSIONS: Although many studies have examined the outcome of biologic discontinuation, they have all been relatively small. Typical practice studies from registries may add important information but will likely need to rely on a broader failure definition.
24754275 Association of polymorphisms in SPARC and NLRP2 genes with rheumatoid arthritis in a Chine 2015 Jan OBJECTIVES: To investigate the association of the polymorphisms in SPARC and NLRP2 with rheumatoid arthritis (RA) in a Chinese Han population. METHODS: Four single nucleotide polymorphisms (SNPs) covering SPARC and three SNPs covering NLRP2 were investigated in 624 Chinese Han RA patients and 1920 healthy controls. RESULTS: The A allele at SPARC rs3210714, SPARC rs11950384, NLRP2 rs2217659, and NLRP2 rs703468 were linked to reduced risk of RA (p = 0.0016, p = 0.0051, p < 0.0001, and p = 0.0033, respectively). Under the recessive model, the A/A genotype of rs3210714, rs11950384, rs2217659, and rs703468 were relevant with RA (p = 0.0071, p = 0.017, p < 0.0001 and p = 0.0066, respectively). Haplotype analysis identified the SPARC GGCG haplotype, AAAA haplotype were associated with the risk for RA (p < 0.0001 and p = 0.0015, respectively), while the risk of RA was lower for carriers of the GAAA haplotype (p < 0.0001), AACG haplotype (p < 0.0001), and the AGCG haplotype (p < 0.0001). The NLRP2 GG haplotype was a risk factor (p < 0.0001), while the GA haplotype and the AG haplotype were associated with lower risk of RA (p < 0.0001 and p = 0.0017, respectively). There was no significant difference between the RA patients and the controls in polymorphisms of rs7719521, rs1978707, and rs269913. CONCLUSION: This study indicates that polymorphisms in SPARC and NLRP2 are related to RA susceptibility in a Chinese Han population.
23981748 Interferon-gamma release assays versus tuberculin skin testing in patients with rheumatoid 2013 Jun OBJECTIVE: The aim of this study was to analyze the results of interferon-gamma release assays (IGRAs) and tuberculin skin tests (TST) performed to detect latent tuberculosis infection (LTBI) in patients with rheumatoid arthritis (RA). METHODS: Interferon-γ release assays and TST test results were summarized and systematically reviewed. RESULTS: Four hundred and five RA patients and 339 controls that underwent IGRA and/or TST were identified in seven studies. Five studies were case-control studies and two were cross-sectional studies. Among RA patients, the IGRA positivity rate was 31.6% (89/282; range 11.4%-44.6%), and the TST positivity rate was 23.0% (78/339; range from 14.60% to 45%). Concordance rates ranged from 40% to 76% and discordance rates from 24% to 29.7%. Agreement between IGRAs and TST in RA was poor (69.6%, k = 0.33, 95% CI 0.188-0.478). The IGRA positivity rate was 31.0% in RA and 40.0% in controls, which was not significant (relative risk [RR] 0.802, 95% CI 0.629-1.023, P = 0.075). The TST positivity rate was 24.7% in RA and 50.5% in controls, and this difference was not significant (RR 0.680, 95% CI 0.331-1.339, P = 0.295). CONCLUSIONS: Positivity rates of IGRA and TST were 31.6 and 23.0%, respectively, in RA patients. Agreement between IGRA and TST results in RA was poor. Our data suggest that both IGRA and TST are needed to detect LTBI in RA.
25283012 [A case of esophageal and intestinal tuberculosis that occurred during treatment of rheuma 2014 Aug An 88-year-old woman with rheumatoid arthritis who had started etanercept treatment in July 2011 was referred to our hospital in February 2012 for right-sided pleural effusion. Chest computed tomography showed right pleural effusion, partial swelling of a calcified mediastinal lymph node, and mid-esophageal thickening of the mucosal wall. Gastroendoscopy showed mid-esophageal ulceration. Histological examination of biopsy specimens from this ulceration revealed noncaseating granulomas with Langhans giant cells. Ziehl-Neelsen staining of this section was positive for acid-fast bacilli. Polymerase chain reaction analysis of gastric juice was positive for Mycobacterium tuberculosis; we therefore diagnosed the patient with esophageal tuberculosis. However, since abdominal computed tomography showed swelling of mesenteric lymph nodes, we also suspected intestinal tuberculosis. Colonoscopy showed multiple ileal erosions; histological analyses of biopsied specimens revealed granulomas with Langhans giant cells, similar to the esophageal findings. We finally diagnosed the patient with both esophageal and intestinal tuberculosis. After anti-tuberculosis treatment, the right pleural effusion disappeared and the abdominal lesions improved. Although mycobacterial involvement of both the esophagus and intestine is rare in immunocompromised and immunocompetent hosts, differential diagnosis of these diseases is likely to become more important.
24010689 [Adalimumab versus etanercept in the treatment of active rheumatoid arthritis: cost-effect 2013 Jul PURPOSE: To assess the effectiveness and efficiency of the two alternatives mainly used in our area, etanercept (ETN) and adalimumab (ADA), for the treatment of rheumatoid arthritis (RA) patients under real clinical practice. MATERIAL AND METHODS: We performed a retrospective observational study, where the time horizon was 12 months referred to the year 2012. We analyzed the characteristics of patients, and the effectiveness and efficiency of ETN and ADA in our study population. INCLUSION CRITERIA: patients over 18 years, diagnosed with RA treated at the outpatient clinic of the Rheumatology Health Sector of Teruel. We determined the mean decrease in DAS28 value (DAS28r) of each drug and we defined as a unit of effectiveness in pharmacoeconomic study, a DAS28 value at baseline (DAS28a) less than 3.2 points and DAS28r greater than 1.2 points. As parameter to determine the cost-effectiveness of both alternatives we used net health benefits (NHB). RESULTS: The average value of DAS28a was 2,25 and 2,72 points for ETN and ADA respectively, with a value of DAS28r 1,01 points higher for ETN, although not statistically significant (p> 0.05). NHB obtained a value of -0.121, 95% CI (-0.951 to 0.709). CONCLUSIONS: Both alternatives are effective in the treatment of RA, although it seems to be a trend in favor of ETN in cost-effectiveness degree.
25070946 Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphis 2014 Dec 20 Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.
25430645 Synthesis of some CC chemokines and their receptors in the synovium in rheumatoid arthriti 2014 Dec We studied the expression of some CC chemokines and their receptors in the synovium of patients with rheumatoid arthritis, osteoarthrosis, and a history of joint injury. In patients with rheumatoid arthritis, the levels mRNA for some angiogenic and proinflammatory chemokines (CCL5/RANTES, CCL11/eotaxin, CCL24/eotaxin-2, and CCL26/eotaxin-3) and their receptors (CCR1, CCR2, CCR3, CCR4, and CCR5) was elevated. mRNA expression correlated with activity, stage, and serological status of rheumatoid arthritis. Obtained data confirm the importance of CC chemokines as mediators of angiogenesis and inflammation in the synovium in rheumatoid arthritis.
24609058 Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. 2014 Jul OBJECTIVES: Reports on the regulation of neutrophil function by IL-6 are often conflicting. Therapeutic inhibition of IL-6 in RA is associated with occasional neutropenia, but the mechanisms underlying this observation are poorly understood. This study investigated interactions between IL-6, the anti-IL-6 receptor agent tocilizumab (TCZ) and neutrophils in vitro and in vivo. METHODS: Neutrophils were isolated from healthy controls and incubated in vitro with pharmacologically relevant concentrations of IL-6 or TCZ. Neutrophils were also isolated from RA patients, including a cohort following TCZ therapy. Apoptosis was measured by annexin V/propidium iodide (PI) flow cytometry; phagocytosis was measured by incubating apoptotic neutrophils with THP-1-derived macrophages; chemotaxis was measured using cell migration through hanging-cell inserts towards IL-8 and cell surface proteins, including adhesion molecules CD11b (αMβ2 integrin) and CD62L (L-selectin) were measured by flow cytometry. RESULTS: IL-6 (10-100 ng/ml) did not affect the rate of neutrophil apoptosis, priming of the respiratory burst or adhesion molecule expression nor act as a neutrophil chemoattractant. However, IL-6 enhanced signal transducer and activator of transcription 3 (STAT3) activation and neutrophil migration towards IL-8. TCZ in vitro did not induce apoptosis or phagocytosis of neutrophils, nor did it have a significant effect upon apoptosis or cell surface molecule expression. Neutrophil functions in ex vivo neutrophils from RA patients receiving TCZ treatment were unaffected. CONCLUSION: Therapeutic blockade of IL-6, while inducing a transient neutropenia, does not directly affect neutrophil functions associated with host defence. TCZ-associated neutropenia cannot be explained by direct induction of apoptosis by TCZ, induction of apoptosis following depletion of IL-6, nor increased phagocytosis of neutrophils.
24656275 Lack of information in current guidelines regarding systemic corticosteroids in inflammato 2014 Mar 17 The use of systemic steroids for inflammatory diseases is a controversial issue-one that continuously invites disagreement throughout the healthcare community. However, there is little, if any, mention of systemic steroid recommendations among widely used rheumatoid arthritis, psoriasis, and psoriatic arthritis guidelines. This relative dearth of information is contrasted by the pervasive systemic steroid use for decades both domestically and abroad. The European League Against Rheumatism (EULAR) guidelines for rheumatoid arthritis discuss systemic steroid use, though relatively briefly. The most recent American Academy of Dermatology (AAD) psoriasis and American College of Rheumatology (ACR) rheumatoid arthritis guidelines fail to make any recommendations regarding systemic steroid use. Currently, there is a void in guidelines regarding when and how (if at all) to use systemic steroids in psoriasis and there are minimal recommendations regarding psoriatic and rheumatoid arthritis. Considering how often primary care physicians, dermatologists, and rheumatologists prescribe systemic steroids for rheumatic diseases and psoriasis, this void must be filled.
23877549 [Cardiovascular risk in systemic inflammatory diseases]. 2013 Jul Systemic inflammatory diseases are associated with increased cardiovascular morbidity and mortality. The link between inflammatory and cardiovascular diseases can be attributed to the coexistence of classical risk factors and inflammatory mechanisms activated during systemic inflammatory diseases involving the immune system. Unfavorable metabolic effects of anti-inflammatory drugs can also contribute to increase cardiovascular risk. Yet, clinical implications of these findings are not entirely clear, and deeper knowledge and awareness of cardiac involvement in inflammatory diseases are necessary. The aim of this review is to summarize cardiac involvement in systemic inflammatory diseases and to identify aspects where evidence is currently lacking that would deserve further investigation in the future.
24428959 Reduction of peripheral blood T cells producing IFN-γ and IL-17 after therapy with abatac 2014 Mar OBJECTIVES: Abatacept (ABA), a molecule used in the treatment of rheumatoid arthritis (RA), competes with the engagement of CD28, a T-cell receptor for co-stimulatory signals. CD28-mediated signalling regulates several T-cell functions, including inflammatory cytokine production and regulatory T cells (Treg) differentiation. Therefore, our objective was to evaluate the effects of ABA on peripheral blood T-lymphocyte cytokine production and on the number of circulating Treg. METHODS: In 24 RA patients treated with ABA for at least 6 months the proportions and absolute numbers of peripheral blood T cells producing interferon-gamma (IFN-γ) and interleukin-17 (IL-17) after in vitro stimulation, as well as those of Treg were longitudinally evaluated by flow cytometry. RESULTS: At baseline, compared with 16 healthy controls, RA patients had a higher percentage of CD4+ and CD8+ T cells producing IL-17 (p=0.021, and p=0.006, respectively), as well as of circulating Treg (p=0.041). After 6 months of therapy with ABA, there was a decrease of the percentage of IFN-γ- and IL-17-producing CD8+ T cells (p=0.033 and p=0.035, respectively), and of Treg (p=0.008), while that of IL-17-producing CD4+ T cells decreased after 12 months of treatment (p=0.005). The number of IL-17-producing T cells and of Treg, higher than in controls at baseline, normalised after ABA therapy. All these variations were statistically significant only in RA patients with EULAR good clinical response (n=17). CONCLUSIONS: The blockade of CD28 signal caused by ABA induces the decrease in peripheral blood of IL-17- and IFN-γ-producing T cells.
24340045 B cells contribute to heterogeneity of IL-17 producing cells in rheumatoid arthritis and h 2013 Secretion of the proinflammatory cytokine Interleukin-17A (IL-17A) is the hallmark of a unique lineage of CD4 T cells designated Th17 cells, which may play a crucial role in the pathogenesis of rheumatoid arthritis (RA) and many autoimmune diseases. Recently, IL-17-producing cells other than T cells have been described, including diverse innate immune cells. Here, we show that the cellular sources of IL-17A in RA include a significant number of non-T cells. Multicolour fluorescence analysis of IL-17-expressing peripheral blood mononuclear cells (PBMC) revealed larger proportions of IL-17(+)CD3(-) non-T cells in RA patients than in healthy controls (constitutive, 13.6% vs. 8.4%, and after stimulation with PMA/ionomycin 17.4% vs. 7.9% p < 0.001 in both cases). The source of IL-17 included CD3(-)CD56(+) NK cells, CD3(-)CD14(+) myeloid cells as well as the expected CD3(+)CD4(+) Th17 cells and surprisingly a substantial number of CD3(-)CD19(+) B cells. The presence of IL-17A-expressing B cells was confirmed by specific PCR of peripheral MACS-sorted CD19(+) B cells, as well as by the analysis of different EBV-transformed B cell lines. Here we report for the first time that in addition to Th17 cells and different innate immune cells B cells also contribute to the IL-17A found in RA patients and healthy controls.
24593170 Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patie 2014 Sep OBJECTIVES: To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. METHODS: J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. RESULTS: The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. CONCLUSIONS: Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules.
24584918 Vaccine responses in patients with rheumatoid arthritis treated with certolizumab pegol: r 2014 Apr OBJECTIVE: To evaluate the humoral immune response to pneumococcal and influenza vaccination in adults with rheumatoid arthritis (RA) receiving certolizumab pegol (CZP). METHODS: In this 6-week, single-blind, placebo-controlled trial with optional 6-month open-label extension (NCT00993668), patients were stratified by concomitant methotrexate (MTX) use and randomized to receive CZP 400 mg (loading dose; according to CZP label) or placebo at weeks 0, 2, and 4. Pneumococcal (polysaccharide 23) and influenza vaccines were administered at Week 2. Satisfactory humoral immune response, defined as ≥2-fold titer increase in ≥3 of 6 pneumococcal antigens and ≥4-fold titer increase in ≥2 of 3 influenza antigens, were assessed independently 4 weeks after vaccination. RESULTS: Following pneumococcal vaccination, 62.5% of placebo patients and 54.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions was -8.0 percentage points; 95% CI -22.5 to 6.6%). Following influenza vaccination, 61.4% of placebo and 53.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions: -8.0 percentage points; 95% CI -22.9 to 7.0%). In all patients, including those with effective titers at baseline, 58.2% of placebo and 53.3% of CZP patients developed satisfactory pneumococcal titers, and 54.1% of placebo and 50.5% of CZP patients developed satisfactory influenza antibody titers. Vaccine responses to pneumococcal and influenza antigens were reduced similarly in both treatment groups with concomitant MTX use. CONCLUSION: Humoral immune responses to pneumococcal and influenza vaccination are not impaired when given during the loading phase of CZP treatment in patients with RA. (ClinicalTrials.gov NCT00993668).
23726309 [Corneal chrysiasis. Gold salt deposits in the cornea in a patient with rheumatoid arthrit 2013 Jun CASE REPORT: A 60-year-old woman with rheumatoid arthritis of 20 years onset, on treatment with monthly intramuscular gold salts (GS) for the last 7 years. She complained of suffering from halo vision, and the examination showed a visual acuity of 0.6 in both eyes (BE). The slit lamp showed some deposits in the stroma with scattered golden granulated, without any further inflammatory reaction. DISCUSSION: GS deposits are dose-dependent and reversible, although very slowly. In this article, we introduce, for the first time, evidence of deposits of GS in all layers of the cornea, predominantly in the corneal stroma and in the endothelium.
23505273 Disseminated Mycobacterium haemophilum infection in a 72-year-old patient with rheumatoid 2013 Mar 15 Mycobacterium haemophilum is a slow growing, aerobic, fastidious mycobacterium requiring hemin and a temperature of 30-32° C for optimal growth that is ubiquitous in nature. Disease in immunocompromised adults typically manifests as skin lesions such as papules, pustules and ulcerations. This organism also causes lymphadenitis in immunocompetent children. Antitumour necrosis factor-α (anti-TNF-α) therapy with agents such as infliximab, etanercept and adalimumab is increasingly being used for immunosuppression in patients with various autoimmune conditions. These agents are known to place patients at increased risk for tuberculosis and other granulomatous diseases. However, little is known about illness caused by M haemophilum in patients on immunosuppression with anti-TNF-α therapy. We describe a case of disseminated M haemophilum manifesting as skin lesions in a 72-year-old man with rheumatoid arthritis on infliximab and methotrexate.
24938203 Costs of pain in rheumatology. 2014 Jun 6 Chronic pain has been identified as an important issue related to various rheumatic diseases. At the time of a major government spending review, it is appropriate to discuss the pain characterising rheumatic diseases and its related costs. It is clearly essential for healthcare authorities to rationalise their policies on the basis of the increasing expectations of the users of healthcare services while simultaneously balancing their books. There are few published studies concerning the costs of pain of any kind, and the same is true of the costs of the chronic pain associated with diseases such as rheumatoid arthritis, osteoarthritis, and fibromyalgia.
23203906 Abatacept (CTLA-4IG) treatment reduces the migratory capacity of monocytes in patients wit 2013 Mar OBJECTIVE: The binding of abatacept (CTLA-4Ig) to the B7 ligands CD80 and CD86 prevents the engagement of CD28 on T cells and thereby prevents effector T cell activation. In addition, a direct effect of CTLA-4Ig on antigen-presenting cells (APCs) could contribute to the therapeutic effect. To further elucidate the mechanism of CTLA-4Ig, we performed phenotype and functional analyses of APCs in patients with rheumatoid arthritis (RA) before and after the initiation of CTLA-4Ig therapy. METHODS: Peripheral blood mononuclear cells were analyzed before and at 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of APCs were determined by flow cytometry. CD14+ monocytes were further analyzed for the expression of costimulatory and adhesion molecules and for their transendothelial migratory capacity in vitro. In addition, CD14+ monocytes from healthy controls were analyzed for their migratory and spreading capacity. RESULTS: Proportions and absolute numbers of monocytes were significantly increased in RA patients treated with CTLA-4Ig. The expression of several adhesion molecules was significantly diminished. In addition, monocytes displayed a significant reduction in their endothelial adhesion and transendothelial migratory capacity upon treatment with CTLA-4Ig. Likewise, isolated monocytes from healthy controls revealed a significant reduction in their migratory and spreading activity after preincubation with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. CONCLUSION: We describe direct effects of CTLA-4Ig therapy on phenotype and functional characteristics of monocytes in RA patients that might interfere with the migration of monocytes to the synovial tissue. This additional mechanism of CTLA-4Ig might contribute to the beneficial effects of CTLA-4Ig treatment in RA patients.
23861949 Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte in 2013 Invasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway play a critical role in RA-FLS invasion induced by lipopolysaccharide (LPS). The present study aimed to explore the anti-invasive activity of celastrol on LPS-stimulated human RA-FLSs, and to elucidate the mechanism involved. We investigated the effect of celastrol on LPS-induced FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Results showed that celastrol suppressed LPS-stimulated FLS migration and invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppressing the binding activity of NF-κB in the MMP-9 promoter, and suppressed the TLR4/MyD88/NF-κB pathway. Administration of celastrol (0.5 mg/kg and 1 mg/kg, intraperitoneally) daily for 3 weeks in a collagen-induced arthritis rat model markedly alleviated the clinical signs, synovial hyperplasia and inflammatory cell infiltration of joints. In conclusion, celastrol might inhibit FLS migration and invasion induced by LPS by suppressing TLR4/NF-κB-mediated MMP-9 expression, providing a theoretical foundation for the clinical treatment of RA with celastrol.