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ID PMID Title PublicationDate abstract
28314444 PDK1 promotes the inflammatory progress of fibroblast-like synoviocytes by phosphorylating 2017 May This study investigated the role of PDK1 in inflammatory response which is initiated by TNF-α and analyzed the association between PDK1 and RSK2. TNF-α were added into MH7A cells to induce inflammation condition. Through overexpressing or suppressing PDK1 in MH7A cells, the role of PDK1 in cell invasiveness and inflammatory factors was determined. Levels of MMPs protein and inflammatory cytokines were assessed with PDK1 siRNA and TNF-α treatment. Inhibition of RSK2 was used to investigate the function of RSK2 on PDK1-induced inflammation. The phosphorylation of RSK2 was detected when PDK1 was inhibited. Luciferase reporter assay was performed to detect the transcriptional activity of NF-κB. We found highly expressed PDK1 could promote cell invasion and secretion of IL-1β and IL-6 in MH7A cells. Inhibition of RSK2 reduced the PDK1-induced cell invasion and cytokines secretion in MH7A cells. In response to TNF-α, PDK1 could phosphorylate RSK2 and activated RSK2, then promoting the activation of NF-κB. This may be a possible therapeutic option of rheumatoid arthritis.
26783341 Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th 2016 Feb 15 The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The K/BxN autoimmune arthritis model is dependent on the microbiota, and particularly on segmented filamentous bacteria, for the autoimmune phenotype. The mechanisms of how the gut microbiota affects arthritis development are not well understood. In this study, we investigate the contribution of two T cell subsets, Th17 and follicular helper T (Tfh), to arthritis and how microbiota modulates their differentiation. Using genetic approaches, we demonstrate that IL-17 is dispensable for arthritis. Antibiotic treatment inhibits disease in IL-17-deficient animals, suggesting that the gut microbiota regulates arthritis independent of Th17 cells. In contrast, conditional deletion of Bcl6 in T cells blocks Tfh cell differentiation and arthritis development. Furthermore, Tfh cell differentiation is defective in antibiotic-treated mice. Taken together, we conclude that gut microbiota regulates arthritis through Tfh but not Th17 cells. These findings have implications in our understanding of how environmental factors contribute to the development of autoimmune diseases.
26866293 Generalizability of Patients With Rheumatoid Arthritis in Biologic Agent Clinical Trials. 2016 Oct OBJECTIVE: Randomized controlled trials (RCTs) have consistently demonstrated the efficacy of biologic agents in treating patients with rheumatoid arthritis (RA) who satisfy strict eligibility criteria, yet studies report that a majority of RA patients in the US have had biologic treatment exposure. We identified the proportion of RA patients in clinical practice satisfying entry criteria for biologic agent RCTs. METHODS: Eligibility criteria of 30 RCTs of 10 Food and Drug Administration-approved biologic agents to treat RA were reviewed, summarized, and applied to 2 observational clinical cohorts: the Veterans Affairs Rheumatoid Arthritis registry (VARA; n = 1,523) and the Rheumatology and Arthritis Investigational Network Database (RAIN-DB; n = 1,548). Patients at a single clinical encounter were assessed for overall trial eligibility as well as eligibility across 3 domains: demographics, disease activity, and medication exposure. RESULTS: The mean percentage of patients that satisfied eligibility criteria was 3.7% (interquartile range [IQR] 1.5-3.1) in VARA and 7.1% (IQR 4.4-7.7) in RAIN-DB. Ineligibility was most often due to low disease activity, specifically low joint counts. The mean Disease Activity Score in 28 joints at enrollment was 6.59 (range 6.1-7.1) across RCTs versus 3.87 (0.07-8.69) in VARA and 3.65 (0.49-7.21) in RAIN-DB. RCTs for non-tumor necrosis factor (TNF) inhibitor biologic agents were more restrictive than RCTs for TNF inhibitors. There was no trend in eligibility by RCT study publication or drug approval date. CONCLUSION: The vast majority of RA patients from our clinical cohorts did not satisfy criteria for participation in biologic agent RCTs. These findings underscore the need for caution in extrapolating trial results to day-to-day management of RA patients and may provide insight into the differential responses to biologic agents reported in prior observational studies.
26866428 Stopping Tumor Necrosis Factor Inhibitor Treatment in Patients With Established Rheumatoid 2016 Aug OBJECTIVE: Tumor necrosis factor inhibitor (TNFi) biologic agents are an effective treatment for rheumatoid arthritis (RA). It is unclear whether patients whose disease is in remission or who have stable low disease activity need to continue use of TNFi or can stop this treatment. This study was undertaken to assess whether patients with established RA who are in remission or have stable low disease activity can effectively and safely stop their TNFi therapy. METHODS: The study was designed as a pragmatic multicenter, open-label randomized controlled trial. Inclusion criteria were a diagnosis of RA according to the American College of Rheumatology 1987 classification criteria, as well as use of a TNFi for at least 1 year along with a stable dose of disease-modifying antirheumatic drugs and a Disease Activity Score in 28 joints (DAS28) of <3.2 over the 6 months preceding trial inclusion. Patients were randomized in a 2:1 ratio to either stop or continue treatment with their current TNFi. Flare was defined as a DAS28 of ≥3.2 during the 12-month follow-up period and an increase in score of ≥0.6 compared to the baseline DAS28. RESULTS: In total, 531 patients were allocated to the stop group and 286 to the TNFi continuation group. At 12 months, more patients had experienced a flare in the stop group (272 [51.2%] of 531) than in the continuation group (52 [18.2%] of 286; P < 0.001). The hazard ratio for occurrence of a flare after stopping TNFi was 3.50 (95% confidence interval [95% CI] 2.60-4.72). The mean DAS28 in the stop group was significantly higher during the follow-up period compared to that in the continuation group (P < 0.001). Of the 195 patients who restarted TNFi treatment after experiencing a flare and within 26 weeks after stopping, 165 (84.6%) had regained a DAS28 of <3.2 by 6 months later, and the median time to a regained DAS28 of <3.2 was 12 weeks (95% Cl 10.7-13.3). There were more hospitalizations in the stop group than in the continuation group (6.4% versus 2.4%). CONCLUSION: Stopping TNFi treatment results in substantially more flares than does continuation of TNFi in patients with established RA in remission or with stable low disease activity.
27580766 [A case of anti-cyclic citrullinated peptides antibody positive rheumatoid meningitis with 2016 Sep 29 We report an 84-year-old woman with rheumatoid meningitis. She developed weakness in her muscles and became cognitively impaired. However, physical examination revealed no evidence of rheumatoid arthritis. Levels of anti-cyclic citrullinated peptide antibodies were elevated. Brain magnetic resonance imaging (MRI) showed hyperintense lesions in the frontotemporoparietal subarachnoid space on fluid attenuated inversion recovery (FLAIR) images. Leptomeningeal enhancement was also evident on gadolinium-enhanced T1-weighted images. We suspected rheumatoid meningitis. A brain biopsy was performed and methylprednisolone pulse therapy was started. Subsequently, her symptoms and MRI findings rapidly improved.
25365778 Mindfulness and cognitive-behavioral interventions for chronic pain: differential effects 2015 Feb OBJECTIVE: This study compared the impact of cognitive-behavioral therapy for pain (CBT-P), mindful awareness and acceptance treatment (M), and arthritis education (E) on day-to-day pain- and stress-related changes in cognitions, symptoms, and affect among adults with rheumatoid arthritis (RA). METHOD: One hundred forty-three RA patients were randomized to 1 of the 3 treatment conditions. CBT-P targeted pain-coping skills; M targeted awareness and acceptance of current experience to enhance coping with a range of aversive experiences; E provided information regarding RA pain and its management. At pre- and posttreatment, participants completed 30 consecutive evening diaries assessing that day's pain, fatigue, pain-related catastrophizing and perceived control, morning disability, and serene and anxious affects. RESULTS: Multilevel models compared groups in the magnitude of within-person change in daily pain and stress reactivity from pre- to posttreatment. M yielded greater reductions than did CBT-P and E in daily pain-related catastrophizing, morning disability, and fatigue and greater reductions in daily stress-related anxious affect. CBT-P yielded less pronounced declines in daily pain-related perceived control than did M and E. CONCLUSIONS: For individuals with RA, M produces the broadest improvements in daily pain and stress reactivity relative to CBT-P and E. These findings also highlight the utility of a diary-based approach to evaluating the treatment-related changes in responses to daily life.
26271620 Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. 2015 Aug 15 INTRODUCTION: Patients with rheumatoid arthritis (RA) are at an increased risk of malignancies compared with the general population. This has raised concerns regarding these patients, particularly with the widespread use of immunomodulating therapies, including biologic disease-modifying antirheumatic drugs (DMARDs). We performed a systematic literature review and analysis to quantify the incidence of malignancies in patients with RA and the general population to update previously published data. METHODS: A literature search was conducted that was consistent with and similar to that in a meta-analysis published in 2008. MEDLINE, BIOSIS Previews, Embase, Derwent Drug File and SciSearch databases were searched using specified search terms. Predefined inclusion criteria identified the relevant observational studies published between 2008 and 2014 that provided estimates of relative risk of malignancy in patients with RA compared with the general population. Risk data on overall malignancy and site-specific malignancies (lymphoma, melanoma and lung, colorectal, breast, cervical and prostate cancer) were extracted. The standardized incidence ratios (SIRs; a measure of risk) relative to the general population were evaluated and compared with published rates. RESULTS: A total of nine publications met the inclusion criteria. Seven of these reported SIRs for overall malignancy; eight for lymphoma, melanoma, and lung, colorectal and breast cancer; seven for prostate cancer; and four for cervical cancer. Compared with those in the general population, the SIR estimates for patients with RA suggest a modest increased risk in overall malignancy, as previously observed. Patients with RA continued to show an increased risk of lymphoma and lung cancer compared with the general population. Overall, SIR estimates for colorectal and breast cancers continued to show a decrease in risk, whereas cervical cancer, prostate cancer and melanoma appeared to show no consistent trend in risk among patients with RA compared with the general population. CONCLUSIONS: The additional data evaluated here are consistent with previously reported data. Patients with RA are at an increased risk of lung and lymphoma malignancies compared with the general population. Quantifying differences in malignancy rates between non-biologic and biologic DMARD-treated patients with RA may further highlight which malignancies may be related to treatment rather than to the underlying disease.
27578615 Identifying significant gene-environment interactions using a combination of screening tes 2016 Nov Although gene-environment (G× E) interactions play an important role in many biological systems, detecting these interactions within genome-wide data can be challenging due to the loss in statistical power incurred by multiple hypothesis correction. To address the challenge of poor power and the limitations of existing multistage methods, we recently developed a screening-testing approach for G× E interaction detection that combines elastic net penalized regression with joint estimation to support a single omnibus test for the presence of G× E interactions. In our original work on this technique, however, we did not assess type I error control or power and evaluated the method using just a single, small bladder cancer data set. In this paper, we extend the original method in two important directions and provide a more rigorous performance evaluation. First, we introduce a hierarchical false discovery rate approach to formally assess the significance of individual G× E interactions. Second, to support the analysis of truly genome-wide data sets, we incorporate a score statistic-based prescreening step to reduce the number of single nucleotide polymorphisms prior to fitting the first stage penalized regression model. To assess the statistical properties of our method, we compare the type I error rate and statistical power of our approach with competing techniques using both simple simulation designs as well as designs based on real disease architectures. Finally, we demonstrate the ability of our approach to identify biologically plausible SNP-education interactions relative to Alzheimer's disease status using genome-wide association study data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
26011852 Long-term results of cruciate-retaining total knee replacement in patients with rheumatoid 2015 Jun BACKGROUND: There is controversy about whether to retain or excise the posterior cruciate ligament in rheumatoid knees because attenuation of the ligament is often present in this subgroup of patients. We reviewed more than 15 years of results of cruciate-retaining total knee replacements (TKRs) in patients with rheumatoid arthritis. METHODS: We reviewed patients' charts and radiographs to evaluate knee range of motion and flexion contractures, component loosening and osteolysis at the bone-cement interface. Our primary outcome was revision of a femoral or tibial component for any reason, and the secondary outcome was revision for any reason and periprosthetic fracture during the follow-up period. RESULTS: Our study included 112 patients (7 men, 105 women, 176 knees). Their mean age was 49.3 (range 33-64) years. Twenty-one patients died and 16 were lost to follow-up, leaving 75 patients (119 knees) with a minimum follow-up of 15 (mean 16.1) years for our analysis. Of these, 61 patients (101 knees) were available for clinical and radiological evaluation at the final follow-up assessment. At a mean of 12.2 (range 6-16) years, revision was necessary in 14 patients (19 knees), including 1 patient with an infection. Eleven patients (11 knees) had periprosthetic fractures at a mean of 11.4 (range 5-14) years after the index operation. The survival rate, with the end point being revision of the femoral or tibial component for any reason, was 98.7% at 10 years and 83.6% at 17 years. The survival rate of revision and periprosthetic fracture was 97.6% at 10 years and 76.9% at 17 years. CONCLUSION: Special attention should be paid to component loosening or periprosthetic fracture after more than 10 years of follow-up in this subgroup of patients.
26758438 Evaluation of the effects of different supplementation on oxidative status in patients wit 2016 Aug Rheumatoid arthritis is a chronic inflammatory disease. Reactive oxygen species have been considered as aggravating factors for autoimmune diseases. Fatty acids had been linked in reduction of various diseases by augment of their antioxidant potential and antiinflammatory mechanisms. The aim of this study was to assess the oxidative status in patients with rheumatoid arthritis who used concentrated fish oil only or concentrated fish oil in combination with evening primrose oil in a period of 3 months. Subjects were divided into three groups. The group I consists of patients who had been taking only their regular rheumatologic therapy; group II, patients who had been taking concentrated fish oil; and group III, patients who had been taking concentrated fish oil and evening primrose oil. Peripheral blood samples were used for all the assays. We assessed the following oxidative stress markers: index of lipid peroxidation (thiobarbituric acid-reactive substances (TBARS)), hydrogen peroxide (H2O2), superoxide anion radical (O2 (-)), nitric oxide (NO), superoxide dismutase activity (SOD), catalase activity (CAT), and glutathione levels (GSH) in erythrocytes. There were no statistically significant changes for any of the oxidative stress parameters in group I. In group II, levels of TBARS, NO2 (-), and GSH were increased, while levels of H2O2 decreased. Increased values of TBARS, NO2 (-), and SOD were found in group III. Our findings indicate that intakes of fish oil and evening primrose oil may be of importance in mitigation of inflammation, disease activity, and oxidative stress biomarkers, through increased activities of antioxidant enzymes.
25496464 Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumat 2015 Jul OBJECTIVES: To evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease-modifying antirheumatic drugs. METHODS: In this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID). PRIMARY ENDPOINT: response rate by American College of Rheumatology (ACR) ≥ 20% improvement criteria (ACR20) at week 12. RESULTS: ACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p < 0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p < 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment-related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-cholesterol levels increased with tofacitinib. CONCLUSIONS: Tofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profile was consistent with that reported from global monotherapy trials.
27434862 Resistin Gene Expression is Downregulated in CD4(+) T Helper Lymphocytes and CD14(+) Mono 2016 Oct Rheumatoid arthritis (RA) is caused by complex interactions between immune cells and sustained by Th1 response cytokines. Resistin [resistance to insulin; (RETN)] is an inflammatory cytokine, first discovered in murine adipocytes. In man, RETN is mainly secreted by monocytes. The distinct role of RETN in the immune reaction is uncertain; however, RETN has pro-inflammatory, pro-fibrotic and possibly tolerogenic properties. The aim was to assess the reaction of RETN gene expression to TNF-α inhibition (I) in pathogenetic immune cell subsets in RA, in the context of Th1, inflammatory and regulatory cytokine gene expressions. Accordingly, we measured RETN, IFN-γ, TNF-β, IL-1β, TNF-α, TGF-β and IL-10 gene expressions in CD14(+) monocytes, CD4(+) T helper (Th) lymphocytes (ly), CD8(+) T cytotoxic (Tc) ly and CD19(+) B ly in active RA before and 3 months after start of TNF-αI. Leucocyte subsets were separated by specific monoclonal antibody-covered beads, RNA extracted and levels of RETN, Th1 response, inflammatory and regulatory cytokine mRNAs measured by quantitative reverse transcription-polymerase chain reaction technique. We found that TNF-αI caused a significant downregulation of RETN gene expression in CD14(+) monocytes and CD4(+) Th ly and was unchanged in CD8(+) Tc ly and CD19(+) B ly. Both in active RA and during TNF-αI, RETN mRNA levels were significantly higher in CD14(+) monocytes than in all other examined cell types. In monocytes, fold change in RETN and TGF-β gene expressions upon TNF-αI correlated significantly. Our findings indicate that RETN has pro-inflammatory as well as proresolving roles in active RA.
27080691 Adipokines in bone disease. 2016 May Adipose tissue secretes highly bioactive factors, the adipokines. Systemic levels of adipokines are often altered in the presence of inflammation. In turn, adipokines affect different tissues and cells systemically as well as locally, contributing to immunomodulatory and bone remodelling mechanisms. The role of adipokines has been evaluated in chronic inflammatory diseases, such as rheumatoid arthritis, as well as in primarily degenerative joint diseases, such as osteoarthritis, particularly with regard to their levels of expression and their effects on joint tissues including synovial membrane, cartilage and bone. Distinct adipokines have been found to modulate matrix remodelling as well as inflammatory responses. In this Review, we summarize current knowledge relating to adipokines in rheumatic diseases, with a particular focus on the effects of adipokines on bone remodelling.
27059535 Quantification and Impact of Secondary Osteoarthritis in Patients With Anti-Citrullinated 2016 Sep OBJECTIVE: To search for evidence of secondary osteoarthritis (OA) in patients with rheumatoid arthritis (RA) in a cross-sectional and longitudinal setting, and to relate osteophyte formation to functional outcome. METHODS: Anti-citrullinated protein antibody (ACPA)-positive RA patients underwent high-resolution peripheral quantitative computed tomography of the hand. Cross-sectional and longitudinal measurements were performed. The number and size (volume) of osteophytes as well as bone erosions were documented. The relationship of osteophytes to bone erosions and to demographic and disease-specific data was evaluated by multiple logistic regression models. RESULTS: A total of 202 ACPA-positive RA patients were enrolled in the cross-sectional part of the study, and a total of 77 ACPA-positive RA patients were enrolled in the longitudinal analysis (interval of 1.5 years between baseline and follow-up assessment). The mean ± SD number of osteophytes per patient was 1.3 ± 2.3, and the mean ± SD osteophyte volume per patient was 2.6 ± 4.9 mm(3) . The total number of erosions was significantly correlated with the total number of osteophytes (P < 0.001), and the total volume of erosions was significantly correlated with the total volume of osteophytes (P < 0.001). Moreover, the number of osteophytes was related to age (P < 0.001) and disease duration (P = 0.001), while the volume of osteophytes was related to age (P = 0.001), disease duration (P < 0.001), and function as measured by the Health Assessment Questionnaire (P = 0.013). Multivariate regression analyses showed an independent association between osteophytes and erosions. In the longitudinal analysis, the mean number (P = 0.033) and volume (P < 0.001) of osteophytes increased significantly in RA patients during their disease course. CONCLUSION: Age, disease duration, and bone erosions are associated with osteophytes, indicating development of secondary OA in patients with RA.
27648996 Total elbow arthroplasty following complex fractures of the distal humerus: results in pat 2016 Sep 13 BACKGROUND: The treatment of complex distal humerus fractures is challenging and is often associated with unsatisfactory results. Anatomic reduction and stable internal fixation is difficult to obtain, especially in elderly osteoporotic patients. For these reasons, total elbow arthroplasty (TEA) has recently evolved as a valid procedure in selected cases following these injuries. The aim of this study was to analyze outcomes of TEA for the treatment of complex distal humerus fractures in 20 low-demanding patients over 65 years of age. MATERIALS AND METHODS: All patients, at a mean follow-up of 60 months, were evaluated clinically using the Mayo Elbow Performance Score (MEPS) and radiographically in order to assess the positioning of the prosthetic components and signs of loosening. Statistical analyses investigated the presence of clinical and radiographic variables as predictive factors of poor functional outcomes. RESULTS: Similar MEPSs were observed in the affected and unaffected arm. Results were good or excellent in 90% of the patients, even if a high rate of complications (35%) was encountered. The development of postoperative complications and concomitant cognitive impairment and rheumatoid arthritis were predictive factors of unsatisfactory outcomes. CONCLUSIONS: According to the results observed, TEA can be considered as a valid treatment for complex fractures of the distal humerus in low-demanding patients older than 65 years of age, in which a stable fixation is difficult to obtain. Several variables may influence the final outcomes.
25681343 Cutting edge: circulating plasmablasts induce the differentiation of human T follicular he 2015 Mar 15 B cells require CD4(+) T follicular helper (Tfh) cells to progress through the germinal center and provide protective Ab responses. In this article, we reveal a reciprocal interaction whereby circulating human plasmablasts are potent inducers of the Tfh cell-differentiation program, including the expression of their key transcription factor Bcl-6. The markedly increased propensity of plasmablasts, compared with naive B cells, to induce Tfh cell differentiation was due to their increased production of IL-6. Specific targeting of IL-6 using tocilizumab therapy in patients with rheumatoid arthritis led to a significant reduction in circulating Tfh cell numbers and IL-21 production, which was correlated with reduced plasmablast formation. Our data uncover a positive-feedback loop between circulating plasmablasts and Tfh cells that could sustain autoimmunity and spread Ab-driven inflammation to unaffected sites; this represents an important therapeutic target, as well as reveals a novel mechanism of action for tocilizumab.
25956216 Serologic profile and clinical markers of Sjögren syndrome in patients with rheumatoid ar 2015 Jun OBJECTIVE: The aim of this study was to evaluate the clinical relevance of rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) in patients with Sjögren syndrome (SS) secondary to rheumatoid arthritis (RA). METHODS: The study included 118 individuals, and the subjects were divided into three groups: rheumatoid arthritis (RA; n = 46), RA with secondary Sjögren syndrome (RA/SS; n = 20) and healthy controls (C; n = 52). Clinical and laboratory characteristics, including ocular, oral, and serum markers, anti-CCP, and rheumatoid factor (RF), were compared in addition to biopsy of labial minor salivary glands. RESULTS: The RA group exhibited unstimulated salivary flow rate, and Schirmer test results were similar to those for C and higher than those for RA/SS (P < .05). Furthermore, the frequency of xerophthalmia and xerostomia was similar among the RA and C groups, and much higher in the RA/SS group (P < .05). Anti-CCP positivity and serum levels were similar in both RA groups, irrespective of SS diagnosis (RA × RA/SS; P > .05). RF presented a similar frequency and serum level between the RA and RA/SS groups (P > .05). CONCLUSIONS: Secondary SS seems to be a cluster of oral and ocular symptoms among patients with RA. Anti-CCP and RF are not relevant to evaluate the presence of SS among these patients.
26155788 Rheumatoid arthritis-associated autoantibodies in non-rheumatoid arthritis patients with m 2015 Jul 9 INTRODUCTION: Rheumatoid arthritis-associated autoantibodies (RA-AAB) can be present in serum years before clinical onset of rheumatoid arthritis (RA). It has been hypothesized that initiation of RA-AAB generation occurs at inflamed mucosal surfaces, such as in the oral cavity or lungs. The aim of this study was to assess systemic presence of RA-AAB in patients without RA who had oral or lung mucosal inflammation. METHODS: The presence of RA-AAB (immunoglobulin A [IgA] and IgG anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), IgM and IgA rheumatoid factor (RF), IgG anti-carbamylated protein antibodies and IgG and IgA anti-citrullinated peptide antibodies against fibrinogen, vimentin and enolase) were determined in sera of non-RA patients with periodontitis (PD, n = 114), bronchiectasis (BR, n = 80) or cystic fibrosis (CF, n = 41). Serum RA-AAB levels were compared with those of periodontally healthy controls (n = 36). Patients with established RA (n = 86) served as a reference group. Association of the diseases with RA-AAB seropositivity was assessed with a logistic regression model, adjusted for age, sex and smoking. RESULTS: Logistic regression analysis revealed that IgG anti-CCP seropositivity was associated with BR and RA, whereas the association with PD was borderline significant. IgA anti-CCP seropositivity was associated with CF and RA. IgM RF seropositivity was associated with RA, whereas the association with BR was borderline significant. IgA RF seropositivity was associated with CF and RA. Apart from an influence of smoking on IgA RF in patients with RA, there was no influence of age, sex or smoking on the association of RA-AAB seropositivity with the diseases. Anti-CarP levels were increased only in patients with RA. The same held for IgG reactivity against all investigated citrullinated peptides. CONCLUSION: Although overall levels were low, RA-AAB seropositivity was associated with lung mucosal inflammation (BR and CF) and may be associated with oral mucosal inflammation (PD). To further determine whether mucosal inflammation functions as a site for induction of RA-AAB and precedes RA, longitudinal studies are necessary in which RA-AAB of specifically the IgA isotype should be assessed in inflamed mucosal tissues and/or in their inflammatory exudates.
26941025 Biosimilar DMARDs: What Does the Future Hold? 2016 Apr Biological medicinal products, albeit fundamental in unresponsive inflammatory rheumatic diseases, represent a significant economic burden to healthcare systems worldwide. A new landmark in the treatment of these conditions was achieved with the European Medicines Agency's endorsement of CT-P13, the first biosimilar of a monoclonal antibody, infliximab. The main driving force behind biosimilar development is to improve accessibility at lower costs, provided the quality, efficacy and safety of the biosimilar is similar to that of the reference drug. Many other biosimilar candidates are currently under development and will probably be approved in the near future, posing complex prescribing decisions for rheumatologists. In this article, biosimilar disease-modifying anti-rheumatic drugs (DMARDs) are put into perspective: what they are, the stepwise manufacturing process and the available mechanisms that regulate the thorough comparability exercise. Non-clinical and clinical data leading to CT-P13 approval are briefly reviewed, and current clinical data on upcoming biosimilars are also addressed. Other matters covered include extrapolation of clinical indications, interchangeability and automatic substitution. As cumulative evidence on the use of biosimilars grows, controversies abate and patients and physicians become reassured. However, adequate answers to the uncertainties still surrounding biosimilar agents are necessary to ensure the trust of rheumatologists and, on a larger scale, to guarantee their widespread use and success.
25672758 Positional identification of RT1-B (HLA-DQ) as susceptibility locus for autoimmune arthrit 2015 Mar 15 Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.