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ID PMID Title PublicationDate abstract
24073556 [Etanercept therapy in rheumatoid arthritis: efficacy and safety]. 2013 Jul INTRODUCTION: Etanercept, tumor necrosis factor (TNF-alpha) antagonist, lowers the disease activity level in patients with rheumatoid arthritis (RA), reduces joint destruction saving physical functions and improving life quality. OBJECTIVE: The aim of this study was to establish efficacy and safety of etanercept in combination with disease modifying antirheumatic drugs (DMARDs) in the treatment of RA. METHODS: To patients with active RA, who were on therapy with DMARD, etanercept was introduced in weekly doses of 50 mg, with continuation of DMARD. Efficacy of this form of treatment was evaluated in the 12th week. Maintenance of the effect of treatment was also evaluated during 24, 48 and 96 weeks. Long-term evaluation of etanercept safety was assessed by registering all unwanted events during a two-year period. RESULTS: After 12 weeks of treatment with etanercept, 80% of patients had ACR20 response, while 85% showed clinically significant decrease of DAS28 index. We achieved remission in five patients (12.5%) and low activity of RA in 17 patients (42.5%). During a 96-week of follow-up period, achieved therapy effects were maintained. In four patients (10%) etanercept therapy was interrupted after 24 weeks because of inadequate response. In one of them (2.5%) we recorded a cardiovascular incident. Acute infections were registered in 47 cases. Four of those were severe infections. Neither cases of malignancy development were noted, nor were there any lethal disease outcomes. CONCLUSION: Etanercept in combination with DMARD shows a high level of efficacy in the treatment of RA. The safety profile of the drug is satisfactory.
23739258 Proteomic analysis of synovial fibroblast-like synoviocytes from rheumatoid arthritis. 2013 Jul OBJECTIVES: The purpose of this study was to identity protein expression patterns of fibroblast-like synoviocytes (FLSs) derived from the synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis. METHODS: Two-dimensional gel electrophoresis (2-DE) in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) was used to visualise and identify differential cellular protein expression profiles in FLSs between RA and control groups. Western-blot analysis was performed to further verify selected differentially-expressed proteins. RESULTS: A total of 1633 and 1603 protein spots were examined in synovial FLSs of RA patients and controls, respectively. Ninety-two spots in the RA group were statistically over- or under-expressed compared with controls. Among them, 33 proteins over-expressed by more than 3-fold were then identified by MALDI-TOF-MS analysis. These proteins included enzymatic and structural proteins (e.g. PKM1/M2, α-enolase, ERp60, lamin-A/C), signal transduction proteins (e.g. annexin 11, peroxiredoxin 1, TrpRS), heat-shock/chaperone proteins (e.g. TCP-1, GRP75, HspB5, Bip) and some unknown protein species. Three proteins, namely α-enolase, GRP75 and PKM2, were verified by Western blot and the results were found to be consistent with proteomic analysis. CONCLUSIONS: The differentially expressed proteins identified in RA synovial FLSs might be candidate RA-associated proteins and may prove to be promising diagnostic indicators or new therapeutic targets for RA.
23317890 Correlation between single nucleotide polymorphism of rs3811047 in IL-1 F7 gene and rheuma 2013 Jan OBJECTIVE: To discuss the association between single nucleotide polymorphism (SNP) of rs3811047 in IL-1 F7 gene and rheumatoid arthritis (RA) susceptibility among the Han population in central plains of China. METHODS: A total of 276 RA patients admitted to our hospital from December 2009 to December 2011 together with 276 healthy physical examinees in the same period were chosen as the subjects. The typing for rs3811047 SNP in IL-1 F7 gene was carried out by using ligase detection reaction and polymerase chain reaction technique. And the frequency of each allele and genotypes distribution was calculated so as to evaluate the association between genotype distribution and RA susceptibility. RESULTS: The frequency of A allele of rs3811047 in IL-1 F7 gene in RA group and control group was 16.27% and 17.68%, respectively, and that of G allele in two groups was 83.73% and 82.32%, respectively. The difference between two groups wasn't statistical significant (P >0.05). The frequency of genotype AA, AG and GG in RA group was 2.19%, 27.84% and 69.97%, respectively, while that in control group was 2.94%, 29.78% and 67.28%, respectively. The difference of distribution of three genotypes was not statistically significant (P >0.05). RA patients with A allele were better than those without A allele in joint swelling index, rest pain, HAQ scoring and blood sedimentation. There was significant difference between two groups in above indexes (P<0.05/P<0.01). CONCLUSIONS: No significant correlation between RA susceptibility among the Han population in central plains of China and rs3811047 SNP inIL-1 F7 gene is observed. However, A allele of rs3811047 has certain influence on the condition of RA patients.
23280345 Synergistic effects of interleukin-1β and interleukin-17A antibodies on collagen-induced 2013 Feb Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that mainly causes the synovial joint inflammation and cartilage destruction. Both interleukin-1β (IL-1β) and Interleukin-17 (IL-17) are important proinflammatory cytokines involved in the pathogenesis of RA. We investigated whether combination therapy with IL-1β and IL-17A antibodies would generate the potential for synergistic effects on a collagen-induced arthritis (CIA) mouse model. Mice with CIA were subcutaneously injected with humanized IL-1β antibody, IL-17A antibody, or combination treatment. The effects of treatment were determined by arthritis severity score, histological damage and bone destruction, autoreactive humoral and cellular immune responses and cytokine production. Treatment with IL-1β antibody or IL-17A antibody alone resulted in beneficial effects on clinical and histological parameters of CIA mice. Compared with the single antibody treatments, the combination therapy resulted in a more significant effect in alleviating the severity of arthritis by preventing bone damage and cartilage destruction, reducing humoral and cellular immune responses, and down-regulating the expression of IL-1β, IL-6, IL-17A, IFN-γ, RANKL and MMP-3 in inflammatory tissue. In conclusion, combination treatment with humanized IL-1β and IL-17A antibodies demonstrates synergistic beneficial effects for preventing joint inflammation and cartilage destruction and bone damage in CIA mice model. These studies also provide evidence that combination with IL-1β and IL-17A antibodies may lead to a new combinatorial therapy for RA patients.
24689997 The apoB/apoA1 ratio predicts future cardiovascular events in patients with rheumatoid art 2014 OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased mortality and morbidity due to cardiovascular disease (CVD). A high apolipoprotein (apo)B/apoA1 ratio is known to predict cardiovascular events (CVEs) in the population. apoA1 has, besides anti-atherogenic effects, anti-inflammatory properties. The importance of apolipoproteins in the development of CVEs, in the context of lipids, haemostatic factors, and inflammation, was evaluated over 18 years in patients with RA. METHOD: Seventy-four patients with inflammatory active RA (61 females/13 males, mean age 63.6 years, disease duration 22.1 years) had been previously investigated in a study of haemostatic factors [tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI)-1, von Willebrand factor (vWF)], lipids (cholesterol and triglycerides), apolipoproteins (apoA1 and apoB), lipoprotein(a) [Lp(a)], and markers of inflammation [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and haptoglobin]. After 18 years, the first CVE during follow-up and the presence of traditional CV risk factors, extra-articular disease, and pharmacological treatment were registered. Cox proportional hazards regression was used to identify predictors of a new CVE. RESULTS: A new CVE (n = 34) was predicted by the apoB/apoA1 ratio (p < 0.01), the triglyceride level (p < 0.01), PAI-1 (p < 0.01) and tPA (p < 0.01) activities, vWF (p < 0.001), ESR (< 0.001), CRP (< 0.05), and haptoglobin (p < 0.05). apoA1 (p = 0.056) and apoB (p < 0.05) correlated weakly and inversely with haptoglobin and CRP, respectively. In a multiple Cox regression model, adjusted for gender and previous CVD, the apoB/apoA1 ratio significantly predicted a new CVE, as did vWF, PAI-1, and ESR. CONCLUSIONS: The apoB/apoA1 ratio was a good predictor of CVE during 18 years of follow-up in patients with active RA. Apolipoproteins correlated negatively with inflammation.
25286687 [The change of CD4+ CD25+ regulatory T cells in patients with rheumatoid arthritis]. 2014 Jul OBJECTIVE: To investigate the change of CD4+ CD25+ FoxP3+ regulatory T cells (Treg)in peripheral blood (PB)and synovial fluid (SF) in patients with rheumatoid arthritis (RA) and its role in RA immune tolerance imbalance. METHODS: The frequency of CD4+ CD25+ FoxP3+ Treg in PB and SF cells in active RA patients and healthy volunteers were determined using flow cytometry. The expression of FoxP3 gene in mononuclear cells was analyzed by real-time PCR. The correlation between the frequency of CD4+ CD25+ FoxP3+ Treg in PB cells and disease activity indices was evaluated. RESULTS: (1) Active RA patients had a higher level of CD4+ CD25+ FoxP3+ Treg in SF cells (7.56% +/- 2.89%) than in PB cells (1.84% +/- 0.97%). Their level of CD4+ CD25+ FoxP3+ Treg in SF cells was also higher than that of healthy volunteers (2.19% +/- 0.54%). Anti-CCP antibody (ACPA) positive RA patients had a lower level of CD4+ CD25+ FoxP3+ Treg (1.40% +/- 0.63%) in PB cells compared with the ACPA negative RA patients (2.85 +/- 0.87%). (2) Active RA patients had a higher mRNA level of FoxP3 in SF mononuclear cells than those inactive RA patients and healthy volunteers (P < 0.01). (3) The frequency of CD4+ CD25+ FoxP3+ Treg in PB cells in active RA patients had no correlation with disease activity indices (P > 0.05). CONCLUSION: Altered frequency of CD4+ CD25+ FoxP3+ Treg in SF cells of RA patients might contribute to RA immune tolerance imbalance in inflammatory joints.
25045250 Drug delivery options to increase patient adherence and satisfaction in the management of 2014 Rheumatoid arthritis (RA) is a chronic, progressive, inflammatory disease associated with joint destruction. Tocilizumab (TCZ) is a humanized monoclonal anti-interleukin-6 receptor antibody that was initially developed for use as an intravenous (IV) infusion. Previous studies have shown that TCZ-IV is an important treatment option in patients with moderate-to-severe RA. A subcutaneous (SC) formulation of 162 mg TCZ that was recently developed and approved provides an additional treatment option for RA patients. In the present review, we provide an update on the efficacy and safety of TCZ-SC, compared with TCZ-IV. The TCZ-SC doses of 162 mg every 2 weeks (q2w) or weekly (qw) were selected based on pharmacokinetic and pharmacodynamic studies. Both TCZ-SC q2w and qw regimens showed equivalent effects to TCZ-IV in most patients; however, the TCZ-SC qw regimen consistently showed a more rapid effect in terms of C-reactive protein normalization. Randomized controlled studies showed that TCZ-SC monotherapy or combined with disease-modifying antirheumatic drugs demonstrated comparable efficacy to TCZ-IV in patients who were both biologic-naïve and refractory to tumor necrosis factor inhibitors. TCZ-SC at both qw and q2w were generally well-tolerated for up to 24 weeks. There was a low rate of withdrawal due to adverse events, and their incidence was comparable with that seen with TCZ-IV. An injection site reaction was seen in approximately 10% of patients who received the subcutaneous formulation. In conclusion, although clinical results are still limited, the currently available evidence suggests that TCZ-SC is a promising treatment for moderate-to-severe RA, both as monotherapy and combination therapy. More data is needed to determine the optimal dosing schedule.
24832838 Acceptability of less than perfect health states in rheumatoid arthritis: the patients' pe 2014 May Some health problems are considered by many individuals as a 'normal' part of ageing. Our aim was to investigate whether patients with rheumatoid arthritis (RA) consider different types and levels of health losses as acceptable beyond a certain age. A multicenter cross-sectional survey was performed involving RA patients at the initiation of the first biological therapy. The EQ-5D and the Health Assessment Questionnaire Disability Index (HAQ-DI) questionnaires were used to describe domain-specific health states. Patients were asked to indicate for each domain from what age and onward (between ages 30 and 80 years in 10 year intervals) they considered moderate and severe problems acceptable or alternatively never acceptable. Seventy-seven RA patients (females 86%, mean age 50.3, disease duration 9.1 years) completed the questionnaire. Disease activity (DAS28), EQ-5D and HAQ-DI scores were mean 6.00 (SD 0.85), 0.35 (SD 0.36), 1.48 (SD 0.66), respectively. The majority of the patients considered age 70 and beyond as acceptable to have some health problems (EQ-5D: self-care 42%, pain/discomfort 34%, mobility 33%, usual activities 33%, anxiety/depression 27%), whilst at ages 30 and 40 as not acceptable. Severe health problems were mostly (57-69%) considered never acceptable, except the 'Usual activities' domain (acceptable from age 80 by 50.6%). The great majority of the patients (77-96%) were younger than what they indicated as the acceptability age limit. Similar results were found for the HAQ-DI. This small experimental study suggests that RA patients consider some health problems acceptable. This acceptability is age related and varies by health areas. Further larger studies are needed to explore explanatory variables and to compare with other diseases. Owing to the impact acceptability might have on RA patients' self-evaluation of current health state and decision-making, the topic deserves methodological improvement and further investigation.
23321589 Association study of TRAF1/C5 polymorphism (rs10818488) with susceptibility to rheumatoid 2013 Mar 15 To determine whether the tumor necrosis factor (TNF)-receptor associated factor 1/complement component 5 (TRAF1/C5) polymorphism (rs10818488) confers susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematous (SLE), a meta-analysis was performed. A total of 11 studies with 17 comparisons (11 for RA, 6 for SLE) were available for this meta-analysis, which consisted of 13,456 patients, 12,259 controls for RA and 1,894 patients, 6,729 controls for SLE. A significant association of the A allele of TRAF1/C5 polymorphism (rs10818488) with RA susceptibility was detected in the North Africa population (OR=1.557, 95% CI: 1.225-1.977). Furthermore, the association between this allelic variant and SLE risk was additionally found in population of European (OR=1.247, 95% CI: 1.060-1.466). Analysis also showed the A/G allelic frequency of TRAF1/C5 variant (rs10818488), in different healthy populations, had a different distribution (χ(2)=269.41, P<0.001). Taken together, our study demonstrates that the TRAF1/C5 polymorphism (rs10818488) may confer susceptibility to RA in North Africa population, and in European population, it might be a contributory factor towards SLE.
24432364 Effect of sclerostin-neutralising antibody on periarticular and systemic bone in a murine 2013 INTRODUCTION: Patients with chronic inflammatory diseases have increased bone loss and bone fragility and are at increased risk of fracture. Although anti-resorptive drugs are effective in blocking inflammation-induced bone loss, they are less effective at rebuilding bone. We have previously shown that treatment with sclerostin antibody (Scl-AbI) builds bone and can prevent or restore bone loss in a murine model of inflammatory bowel disease. In this study, we tested the effect of Scl-AbI in a murine model of rheumatoid arthritis (the collagen-induced arthritis model, CIA). We hypothesised that sclerostin blockade can protect and restore bone both locally and systemically without affecting progression of inflammation. METHODS: CIA was induced in male DBA/1 mice, which were treated with either PBS or Scl-AbI (10 mg/kg, weekly) prophylactically for 55 days or therapeutically for 21 days (starting 14 days post onset of arthritis). Systemic inflammation was assessed by measuring the serum concentration of anti-CII IgG1, IgG2a and IgG2b by ELISA. Changes in bone mass and structure, either at sites remote from the joints or at periarticular sites, were measured using DEXA and microCT. Bone focal erosion was assessed in microCT scans of ankle and knee joints. RESULTS: Circulating anti-CII immunoglobulins were significantly elevated in mice with CIA and there were no significant differences in the levels of anti-CII immunoglobulins in mice treated with PBS or Scl-ABI. Prophylactic Scl-AbI treatment prevented the decrease in whole body bone mineral density (BMD) and in the bone volume fraction at axial (vertebral body) and appendicular (tibial proximal metaphysis trabecular and mid-diaphysis cortical bone) sites seen in PBS-treated CIA mice, but did not prevent the formation of focal bone erosions on the periarticular bone in the knee and ankle joints. In the therapeutic study, Scl-AbI restored BMD and bone volume fraction at all assessed sites but was unable to repair focal erosions. CONCLUSIONS: Sclerostin blockade prevented or reversed the decrease in axial and appendicular bone mass in the murine model of rheumatoid arthritis, but did not affect systemic inflammation and was unable to prevent or repair local focal erosion.
25490986 Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn? 2015 Feb There is increasing scientific interest in the field of vitamin D research, moving the focus beyond bone health to other disease processes. Low circulating vitamin D levels have been reported as a risk factor for several pathophysiologically divergent diseases, including cancers, diabetes, CVD, multiple sclerosis and inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD). But, therein, remains the challenge: can any single nutrient contribute to multiple complex disease mechanisms and, ultimately, have therapeutic potential? The aim of this review is to critically evaluate several strands of scientific evidence surrounding vitamin D and inflammation, primarily focusing on IBD. Epidemiological studies suggest an increased incidence of IBD and rheumatoid arthritis in countries of more northern latitudes, mirroring sunlight patterns. A considerable body of evidence supports the anti-inflammatory effects of vitamin D, at least in animal models of IBD. Although it is accepted that suboptimal vitamin D status is common in IBD, some studies suggest that this associates with more severe disease. With regard to treatment, the data are only beginning to emerge from randomised controlled trials to suggest that people with IBD may remain in remission longer when treated with oral vitamin D. In conclusion, several strands of evidence suggest that vitamin D may modify the immune response in IBD. There is a continued need for large well-designed clinical trials and mechanistic studies to determine if, and how, this emerging promise translates into tangible clinical benefits for people with chronic debilitating diseases such as IBD.
24574207 Increased surgeon experience with rheumatoid arthritis reduces the risk of complications f 2014 Mar OBJECTIVE: To determine the relationship between surgeon experience with, and complications following, total joint arthroplasty (TJA) in patients with rheumatoid arthritis (RA). METHODS: Using administrative data, we assembled a cohort of patients with RA who had undergone at least 1 elective primary hip or knee replacement procedure between 2002 and 2009. Cox proportional hazards, censored on death and accounting for clustering of patients within surgeons, were used to determine the relationship between overall and "RA-specific" surgeon TJA volume and the occurrence of a composite "complication" outcome (revision, infection, dislocation, or periprosthetic fracture within 2 years of the initial TJA), controlling for potential confounders (patient age, sex, comorbidity, and disease severity). RESULTS: We identified 4,762 patients with RA who were eligible for TJAs (1,515 total hip arthroplasties and 3,247 total knee arthroplasties). Among these patients, 152 (3.2%) experienced a surgical complication within 2 years of the procedure. After controlling for patient and hospital factors, greater surgeon TJA volume in patients with RA (RA TJA), but not overall TJA volume (all TJA), was associated with a reduced risk of complications (for surgeon RA TJA volume per 10 cases, adjusted hazard ratio [HR] 0.81, 95% confidence interval [95% CI] 0.71-0.93, P = 0.002; for surgeon all TJA volume, adjusted HR 0.98, 95% CI 0.97-1.00, P = 0.09). CONCLUSION: In a cohort of patients with RA who underwent hip or knee TJA, increased surgeon experience performing TJA in patients with RA, irrespective of their overall TJA experience and hospital factors, was associated with a decreased risk of surgical complications. These findings have potential implications for surgeon training and the referral practices of rheumatologists.
23280360 Circulating citrullinated vimentin fragments reflect disease burden in ankylosing spondyli 2013 Apr OBJECTIVE: Ankylosing spondylitis (AS) has been considered a seronegative rheumatic disease based on absent or low levels of antibodies against citrullinated proteins. The present study was undertaken to evaluate whether a citrullinated and matrix metalloproteinase-degraded fragment of vimentin (VICM) could be a prognostic biomarker in AS. METHODS: VICM was measured in serum samples from healthy controls (n=35), control patients with rheumatoid arthritis (RA) (n=47), and patients with AS (n=201). The optimal cutoff for diagnostic sensitivity and specificity was determined by receiver operating characteristic curve analysis. Baseline and 2-year spine radiographs were available from 118 AS patients, and were scored using the modified Stoke AS Spine Score (mSASSS). We assessed correlations with patient demographic characteristics (age, disease duration), disease activity (Bath AS Disease Activity Index [BASDAI], C-reactive protein level), and disease severity (mSASSS) using Spearman's rho. The independent association of VICM with 2-year radiographic progression, defined as a change of >0 in the mSASSS or the development of a new syndesmophyte, was analyzed by multivariate regression. RESULTS: Levels of degraded VICM were significantly higher in both RA patients and AS patients than in healthy controls (both P<0.001). AS patients with the highest levels of VICM had the largest burden of disease (P<0.01), i.e., highest mSASSS score and BASDAI. VICM levels were significantly and independently associated with radiographic progression after 2 years (β=0.69, P=0.0005). Patients with both a high VICM level and a high baseline mSASSS had the highest risk of radiographic progression (odds ratio 13 for mSASSS change, 32 for new syndesmophytes), with progression occurring in 67% of these patients. CONCLUSION: The present findings show that serum VICM may be of prognostic value in AS. The data also suggest that citrullination may be relevant in AS pathogenesis.
22380574 An in vitro and in vivo investigation into the suitability of compression coated tablets o 2013 Mar OBJECTIVE: The aim of this study was to develop chronotherapeutic drug delivery system of indomethacin using polyethylene oxide (PEO) with a predetermined lag time of 6 h by compression coating technique. MATERIALS AND METHODS: Solid dispersions (SD) of indomethacin were prepared using novel carrier sucrose fatty acid ester (SFE 1815) to increase the in vitro dissolution. The optimized SD was formulated as immediate release core tablet which were further coated with PEO (WSR Coagulant or WSR N12 K) using compression coating technique. Compression coated tablets formulated with PEO WSR Coagulant in 1:1.7 ratio of core tablet weight and coating polymer was considered as optimized formulation, which was further characterized by differential scanning calorimetry, X-ray diffractometry, Fourier transformed infrared spectroscopy, and scanning electron microscopy. RESULTS: The results indicated that there was no chemical incompatibility and slight change in surface properties. C(max), area under the curve (AUC(0-t)), and T(max) following oral ingestion of commercial capsule (Indocap) and optimized formulation (CT 4) were found to be 1973.18 ± 36.89 ng/mL, 11090.09 ± 131.21 ng/mL/h, 0.99 ± 0.02 h and 2115.46 ±6 2.61, 10413.14 ± 299.66 ng/mL/h, 7.00±0.02 h, respectively. CONCLUSION: Unaltered AUC(0-t) and C(max), but delayed T(max) indicated clear lag time before immediate release of drug which is suitable for treating rheumatoid arthritis following circadian rhythm.
23558031 p38 inhibition and not MK2 inhibition enhances the secretion of chemokines from TNF-α act 2013 Jul OBJECTIVES: For many years the p38 MAP kinase (MAPK) has been a major anti-inflammatory target for the development of an oral therapy for rheumatoid arthritis (RA). However, disappointing results from Phase II clinical studies suggest that adaptations may occur, which allow escape from blockade of the p38 pathway. In this study we investigated whether p38 inhibition mediated JNK activation represents such an escape mechanism. METHODS: Interaction between the JNK and p38 pathways was studied in TNF-α stimulated THP-1 monocytes, primary macrophages and fibroblast-like synoviocytes from OA and RA patients using pharmacological inhibitors and siRNAs. RESULTS: TNF-α induced phosphorylation of JNK and c-Jun was sustained by p38 inhibitors in monocytes, primary macrophages and FLS. Upregulation of Mip1α, Mip1β and IL-8 mRNAs and protein were observed upon p38 inhibition. More importantly, inhibition of MK2, the substrate of p38 did not sustain JNK activation upon TNF-α activation and did not elevate Mip1α, Mip1β and IL-8 chemokines as compared to TNF-α alone. In this study, TNF-α or IL-1β induced JNK activation is sustained by p38 inhibition, resulting in enhanced chemokine secretion. CONCLUSIONS: Based on the suggested role of these chemokines in RA pathogenesis, the upregulation of these chemokines may provide an explanation for the lack of efficacy of p38 inhibitors in Phase II. The absence of any effect of MK2 inhibition in our models on this mechanism, while coming with similar efficacy on blocking p38, provides support for further investigations to reveal the potential of MK2 inhibition as a novel treatment of RA.
25112157 Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed 2014 Aug 12 INTRODUCTION: A major subset of patients with rheumatoid arthritis (RA) is characterized by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPAs). These autoantibodies, which are commonly detected by using an enzyme-linked immunosorbent assay (ELISA) based on synthetic cyclic citrullinated peptides (CCPs), predict clinical onset and a destructive disease course. In the present study, we have used plasma and synovial fluids from patients with RA, for the affinity purification and characterization of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be used in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPAs that bind to autoantigens expressed in vivo in the major inflammatory lesions of RA (that is, in the rheumatoid joint). METHODS: Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels of above 300 AU/mL. Total IgG was isolated on Protein G columns and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analyzed for reactivity and specificity by using the CCPlus® ELISA, in-house peptide ELISAs, Western blot, and immunohisto-/immunocytochemistry. RESULTS: Approximately 2% of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from α-enolase, vimentin, fibrinogen, and collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but, more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from patients with RA. CONCLUSIONS: We have isolated ACPAs from plasma and synovial fluid and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISAs, de facto act as surrogate antigens for at least four different, well-characterized, largely non-cross-reactive, ACPA fine specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPAs can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs.
24739090 Vitamin D, steroid hormones, and autoimmunity. 2014 May The endogenous serum metabolite of vitamin D (calcitriol, 1,25(OH)2 D3 ) is considered a true steroid hormone (D hormone), and like glucocorticoids (GCs) and gonadal hormones, may exert several immunomodulatory activities. Serum vitamin D deficiency (25(OH) D), and therefore reduced 1,25(OH)2 D3 availability, is considered a risk factor for several chronic/inflammatory or autoimmune conditions, including infectious diseases, type 1 diabetes, multiple sclerosis, and especially autoimmune rheumatic diseases (ARD). In ARD in particular, 1,25(OH)2 D3 regulates both innate and adaptive immunity, potentiating the innate response (antimicrobial activity) but reducing adaptive immunity (antigen presentation, T and B cell activities). Regarding a possible synergism between vitamin D and GCs, several studies show that 1,25(OH)2 D3 has significant additive effects on dexamethasone-mediated inhibition of human lymphocyte and monocyte proliferation. Conversely, vitamin D deficiency seems to play a role in increasing autoantibody production by B cells, and seasonal vitamin D declines may trigger flares in ARD, as recently shown. Finally, 1,25(OH)2 D3 seems to reduce aromatase activity and limit the negative effects related to increased peripheral estrogen metabolism (cell proliferation, B cell overactivity).
25339568 [Acute interstitial pneumonia in patient with rheumatoid arthritis treated with leflunomid 2014 Leflunomide (LEF) is an isoxazole derivative used as disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA). It is effective and safe in patients with active RA, in whom standard treatment is insufficient or contraindicated, but it can cause interstitial lung disease (ILD). Identified risk factors for LEF-induced ILD include pre-existing ILD, cigarette smoking, low body weight, and use of loading dose. LEF should be avoided in patients with pre-existing ILD. We present a case of 59-year-old male with RA and a history of smoking and methotrexate (MTX) treatment, who developed dyspnoea, non-productive cough, and fever about two months after the administration of LEF. The clinical and radiological presentation was of acute pneumonia. The patient was treated with methylprednisolone pulse, prednisone, and cyclophosphamide, but he died of respiratory failure.
24408079 EBV-positive MTX-diffuse large B cell lymphoma in a rheumatoid arthritis patient. 2014 Mar Methotrexate (MTX)-associated lymphoproliferative disorders have received much attention from rheumatologists, and early diagnosis is very important for reducing mortality. There are several reports of radiologic findings in patients with pulmonary malignant lymphoma, mainly consisting of masses, nodules, and lymphadenopathy. Computed tomography has rarely detected necrosis in the masses. In this article, we report a case of MTX-associated Epstein-Barr virus-positive diffuse large B-cell lymphoma characterized by a very large lung mass with prominent areas of central necrosis. The disease regressed after withdrawal of MTX.
23280344 Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduc 2013 Mar We previously established an IgG Fc receptor IIB (FcγRIIB)-deficient C57BL/6 (B6)-congenic mouse strain (KO1), which spontaneously develops rheumatoid arthritis (RA), but not systemic lupus erythematosus (SLE). Here, we show that when Y chromosome-linked autoimmune acceleration (Yaa) mutation was introduced in KO1 strain (KO1.Yaa), the majority of KO1.Yaa mice did not develop RA, but instead did develop SLE. This phenotype conversion did not depend on autoantibody specificity, since KO1.Yaa mice, compared with KO1, showed a marked increase in serum levels of both lupus-related and RA-related autoantibodies. The increase in frequencies of CD69(+) activated B cells and T cells, and the spontaneous splenic GC formation with T follicular helper cell generation were manifest early in life of KO1.Yaa, but not KO1 and B6.Yaa, mice. Activated CD4(+) T cells from KO1.Yaa mice showed upregulated production of IL-21 and IL-10, compared with the finding in KO1 mice, indicating the possibility that this aberrant cytokine milieu relates to the disease phenotype conversion. Thus, our model is useful to clarify the shared and the disease-specific mechanisms underlying the clinically distinct systemic autoimmune diseases RA and SLE.