Production and characterization of an Fv-clasp of rheumatoid factor, a low-affinity human autoantibody.

Rheumatoid factor (RF) is an autoantibody against IgG that affects autoimmune diseases and inhibits the effectiveness of pharmaceuticals and diagnostic agents. Although RFs derived from various germline genes have been identified, little is known about their molecular recognition mechanisms. In this study, the Fv-clasp format was used to prepare YES8c, an RF. We developed an Escherichia coli secretion expression system capable of producing milligram-scale of YES8c Fv-clasp per 1 L of culture. Although YES8c is an autoantibody with very low affinity, the produced Fv-clasp maintained specific binding to IgG. Interestingly, the molecules prepared by E. coli secretion had a higher affinity than those prepared by refolding. In the structure of the YES8c-Fc complex, the N-terminus of the light chain is close to Fc; therefore, it is suggested that the addition of the N-terminal methionine may cause collisions with Fc, resulting in reduced affinity. Our findings suggest that the Fv-clasp, which provides sufficient stability and a high bacterial yield, is a useful format for studying RFs with very low affinity. Furthermore, the Fv-clasp produced from a secretion expression system, which can properly process the N-terminus, would be suitable for analysis of RFs in which the N-terminus may be involved in interactions.

IgA rheumatoid factor in rheumatoid arthritis.

OBJECTIVES: Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context. METHODS: An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available. RESULTS: The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjögren's syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies. CONCLUSIONS: IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity.

Proteogenomic analysis of the autoreactive B cell repertoire in blood and tissues of patients with Sjögren's syndrome.

OBJECTIVE: To comparatively analyse the aberrant affinity maturation of the antinuclear and rheumatoid factor (RF) B cell repertoires in blood and tissues of patients with Sjögren's syndrome (SjS) using an integrated omics workflow. METHODS: Peptide sequencing of anti-Ro60, anti-Ro52, anti-La and RF was combined with B cell repertoire analysis at the DNA, RNA and single cell level in blood B cell subsets, affected salivary gland and extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) of patients with SjS. RESULTS: Affected tissues contained anti-Ro60, anti-Ro52, anti-La and RF clones as a small part of a polyclonal infiltrate. Anti-Ro60, anti-La and anti-Ro52 clones outnumbered RF clones. MALT lymphoma tissues contained monoclonal RF expansions. Autoreactive clones were not selected from a restricted repertoire in a circulating B cell subset. The antinuclear antibody (ANA) repertoires displayed similar antigen-dependent and immunoglobulin (Ig) G1-directed affinity maturation. RF clones displayed antigen-dependent, IgM-directed and more B cell receptor integrity-dependent affinity maturation. This coincided with extensive intra-clonal diversification in RF-derived lymphomas. Regeneration of clinical disease manifestations after rituximab coincided with large RF clones, which not necessarily belonged to the lymphoma clone, that displayed continuous affinity maturation and intra-clonal diversification. CONCLUSION: The ANA and RF repertoires in patients with SjS display tissue-restricted, antigen-dependent and divergent affinity maturation. Affinity maturation of RF clones deviates further during RF clone derived lymphomagenesis and during regeneration of the autoreactive repertoire after temporary disruption by rituximab. These data give insight into the molecular mechanisms of autoreactive inflammation in SjS, assist MALT lymphoma diagnosis and allow tracking its response to rituximab.

Regulatory and other rheumatoid factors in rheumatoid arthritis patients with active disease or in remission.

BACKGROUND: Previously, we identified a regulatory rheumatoid factor (regRF), the production of which provides rats with resistance to collagen-induced arthritis (CIA). Immunization with conformers of IgG Fc fragments carrying epitopes specific to regRF reduces symptoms of CIA. The aim of this study was to determine whether there is a link between regRF levels and rheumatoid arthritis (RA) activity in humans in order to assess the potential of regRF as a therapeutic biotarget in RA. The variability of rheumatoid factor (RF) specificities present in the blood of RA patients was also studied. METHODS: The regRF were studied in RA patients with active disease and in remission. Variability in the specificities of RF associated with RA was studied by concurrent inhibition of RF latex fixation by variants of modified IgG. RESULTS: Patients in remission had regRF levels higher than in healthy subjects. The regRF in remission was characterized by tight binding to its antigen, as in healthy subjects. The regRF levels in patients with active RA varied dramatically, and regRF binding to its antigen was weak. The exacerbation of Still's disease coincided with low regRF levels and affinity, while an improvement in patient condition was associated with an increase in regRF levels and affinity. The RF specific to RA, which was detected by the RF latex-fixation method, was a nonhomogeneous population of antibodies that included RF to lyophilized IgG, to IgG immobilized on polystyrene, and to rabbit IgG. CONCLUSION: Stimulating regRF production might enable improved RA therapy.

Ultrasonographic characteristics of major salivary glands in anti-centromere antibody-positive primary Sjögren's syndrome.

PURPOSE: To investigate salivary gland ultrasonography (SGUS) findings in primary Sjögren's syndrome (pSS) patients positive for the anti-centromere antibody (ACA) and compare these with those in ACA-negative pSS patients. METHODS: We analyzed demographic, clinical, laboratory, and SGUS data of pSS patients who fulfilled the 2002 American-European Consensus Group classification criteria for pSS. SGUS findings of four major salivary glands (bilateral parotid and submandibular glands) were scored in five categories and compared between ACA-positive and ACA-negative pSS patients. Linear regression analysis was performed to elucidate the factors associated with SGUS score. RESULTS: In total, 121 pSS patients were enrolled (19, ACA-positive). The ACA-positive patients were older (67.0 vs 58.0 years, P = 0.028), whereas anti-Ro/SSA and anti-La/SSB positivity was more prevalent in the ACA-negative group (89.2% vs 21.1%, P < 0.001, and 47.1% vs 10.5%, P = 0.007, respectively). The total SGUS and hypoechoic area scores were lower in ACA-positive patients (16.0 vs 23.0, P = 0.027, and 4.0 vs 7.0, P = 0.004, respectively). In univariate regression analysis, being positive for unstimulated salivary flow rate (USFR < 1.5 ml/15 min), anti-Ro/SSA, and rheumatoid factor were positively associated whereas ACA positivity was negatively associated with the SGUS score. In multivariate regression analysis, being positive for USFR, anti-Ro/SSA, and rheumatoid factor showed significant association with the SGUS score. CONCLUSIONS: ACA-positive pSS patients showed a lower SGUS score than ACA-negative patients, which was especially prominent in the hypoechoic area component.

Effect of celecoxib combined with glucosamine hydrochloride in promoting the functional recovery and decreasing the inflammatory factor levels in patients with knee osteoarthritis.

To explore the role of celecoxib with glucosamine hydrochloride on functional recovery and reduction of inflammatory factors in patients with knee osteoarthritis. Altogether 128 patients with knee osteoarthritis in the middle and early stage admitted to our hospital from January 2018 to July 2019 were selected and grouped into the control group (CG) (celecoxib tablet therapy) and the combination group (ComG) (celecoxib combined with glucosamine hydrochloride therapy). Blood routine indexes and inflammatory factor levels before and after intervention, Lequesne score, VAS pain and adverse reactions of the two groups of patients before and after intervention were explored. Before intervention, there was no evident difference between the two groups in each index (P>0.05). After intervention, the blood routine index IgM rheumatoid factor, albumin/globulin, erythrocyte sedimentation rate and inflammatory factors TNF-α, IL-6, IL-1ß, hs-CRP levels in the ComG were evidently better than those in the CG, while Lequesne score and VAS pain score were lower than those in the CG (P<0.01). The total incidence of adverse reactions in the ComG was evidently lower than that in the CG. Celecoxib combined with glucosamine hydrochloride is effective in the treatment of knee osteoarthritis and has little adverse reactions.

The Prevalence of Sjögren's Syndrome in Rheumatoid Arthritis Patients and Their Clinical Features.

BACKGROUND: To estimate the prevalence of Sjögren's syndrome (SS) in patients with rheumatoid arthritis (RA) and to compare the clinical features of RA patients with and without SS. METHODS: We conducted a retrospective study of RA patients who visited a rheumatology clinic in a tertiary referral hospital in Korea between May 20 and July 22, 2016. All patients fulfilled the classification criteria for RA, and the diagnosis of SS was made clinically by rheumatologists and according to the 2002 American-European Consensus Group (AECG), 2012 American College of Rheumatology (ACR), and 2016 ACR/European League Against Rheumatism (EULAR) classification criteria. The prevalence was estimated as the number of SS patients within the total number of RA patients. The disease activity and treatment pattern of RA were compared between patients with and without SS. RESULTS: Among 827 RA patients, 72 patients (8.7%) were diagnosed with SS by a rheumatologist, though only 60 patients (7.3%) satisfied the 2002 AECG classification criteria for SS. Fifty-two patients (6.3%) and 56 patients (6.8%) fulfilled the 2012 ACR and 2016 ACR/EULAR classification criteria, respectively. The prevalence of SS in RA patients was 10.5%, 17.0%, and 67.6% in rheumatoid factor, antinuclear antibody (≥ 1:80), and anti-Ro antibody positive patients, respectively. CONCLUSION: The prevalence of SS among RA patients was 8.7% according to rheumatologists' diagnosis. The presence of SS did not affect the treatment patterns of RA patients. However, the autoantibody profiles and demographics of RA patients with SS differed from those of patients without SS.

Screen the Effective Components of Lycopodii herba on Rheumatoid Arthritis with the Aid of Spectrum-Effect Relationship and Uncover its Potential Mechanism.

Lycopodii herba (SJC), a traditional Chinese medicine, has the effect of dispelling wind and eliminating dampness (a therapeutic principle and method of traditional Chinese medicine for rheumatoid arthritis), relaxing tendon and activating collaterals. However, the major effective components and its therapeutic mechanism were unclear. In this study, different SJC samples with slightly different compositions were prepared by extracting with different concentrations of ethanol. Then, the therapeutic effects on rheumatoid arthritis (RA) of different SJC samples were evaluated. Finally, the spectrum-effect relationship between UPLC-Q-TOF/MS fingerprints and the effect of RA was explored to screen the effective components. Western blotting was used to study the potential mechanism. The volume of hind paw and the level of RF, TNF-α, and IL-1ß were lower after administrating with different SJC samples, compared with the model group. Histopathological findings also confirmed that SJC could relieve the symptoms of RA. Combined with identification of the components in plasm from SJC, lycojaponicumin C, des-N-methyl-α-obscurine, 8ß-acetoxy-12ß-hydroxy-lycopodine or 8ß-acetoxy-11α-hydroxy-lycopodine or 8ß-hydroxy-11α-acetoxylycopodine were considered to be the major effective components. The mechanism may be related to AChE/NF-κB signaling pathway. This work provides a general method to screen the potential effective components of herb medicines and would be benefit to understand the mechanism of SJC for the treatment of RA.

The Impact of Cigarette Smoking on Risk of Rheumatoid Arthritis: A Narrative Review.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent proliferation of synovial tissues, which eventually leads to cartilage and bone destruction without effective treatments. Anti-citrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) are two main characteristic autoantibodies found in RA patients and are associated with unfavorable disease outcomes. Although etiologies and causes of the disease have not been fully clarified yet, it is likely that interactive contributions of genetic and environmental factors play a main role in RA pathology. Previous works have demonstrated several genetic and environmental factors as risks of RA development and/or autoantibody productions. Among these, cigarette smoking and HLA-DRB1 are the well-established environmental and genetic risks, respectively. In this narrative review, we provide a recent update on genetic contributions to RA and the environmental risks of RA with a special focus on cigarette smoking and its impacts on RA pathology. We also describe gene-environmental interaction in RA pathogenesis with an emphasis on cigarette smoking and HLA-DRB1.

The etiology of rheumatoid arthritis.

Rheumatoid arthritis is a heterogeneous disease, which can be, based on data combining genetic risk factors and autoantibodies, sub-classified into ACPA-positive and -negative RA. Presence of ACPA and RF as well as rising CRP-levels in some patients years before onset of clinical symptoms indicate that relevant immune responses for RA development are initiated very early. ACPA are highly specific for RA, whereas RF can also be found among healthy (elderly) individuals and patients with other autoimmune diseases or infection. The most important genetic risk factor for RA development, the shared epitope alleles, resides in the MHC class II region. Shared epitope alleles, however, only predispose to the development of ACPA-positive RA. Smoking is thus far the most important environmental risk factor associated with the development of RA. Studies on synovitis have shown the importance not only of adaptive but also of innate immune responses. In summary of the various results from immunological changes in blood and synovial tissue, the extension of the immune response from a diffuse myeloid to a lympho-myeloid inflammation appears to be associated with a more successful therapeutic response to biologics. With respect to advances in synovitis research, new targets for treatment against pathological subsets of immune cells or fibroblasts are already on the horizon. However, alternative strategies involving the microbiome may play an important role as well and research in this field is growing rapidly.

The association of choroidal thickness with rheumatoid factor and anti-cyclic citrullinated peptide in rheumatoid arthritis.

PURPOSE: To measure ocular vascular parameters in rheumatoid arthritis patients and compare with those of controls and to evaluate the association of rheumatoid factor and anti-cyclic citrullinated peptide antibody with the choroidal thickness. METHODS: Superficial foveal vessel density, superficial and deep foveal avascular zone area, and subfoveal choroidal thickness were measured using the swept-source optical coherence tomography angiography. Multivariate linear regression was used to assess the correlation of subfoveal choroidal thickness with serological markers in patients with rheumatoid arthritis. RESULTS: Choroidal thickness in patients was significantly thinner than that in healthy controls (278.87 ± 59.54 µm vs. 323.94 ± 98.02 µm, p = 0.03). Despite the weak positive correlations between rheumatoid factor/anti-cyclic citrullinated peptide and choroidal thickness, these relationships were not statistically significant (p > 0.05). CONCLUSIONS: In patients with rheumatoid arthritis, subfoveal choroid was thinner than controls. There were similar correlations between choroidal thickness and rheumatoid factor and anti-cyclic citrullinated peptide antibody.

Prevention and cure: The major unmet needs in the management of rheumatoid arthritis.

The outcome of treatment of patients with rheumatoid arthritis (RA) has qualitatively improved in recent years due to better and earlier treatment approaches, and new drugs. It is now generally accepted that the phenotype of RA is the end-point of a disease continuum. Large retrospective studies have identified anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor in the stored serum of patients, years before the development of clinical RA. Recent data suggest mucosal sites such as the oral mucosa (in particular the periodontium), lung and gut may be the sites where auto-immunity is initiated. The role of bacteria at these sites is reviewed. Much recent work has focussed on the role of high resolution imaging namely ultrasound and magnetic resonance imaging in identifying subclinical inflammation in at-risk individuals with early musculoskeletal symptoms (e.g. arthralgia) but without clinical synovitis. Importantly, the first musculoskeletal site involved is usually not the joint (synovium). Sub-clinical disease predicts the onset of clinical arthritis, and its timing, in symptomatic at-risk individuals. These and other predictive markers will be described. The ability to identify patients at-risk of RA before joint involvement has led to interventions aimed at preventing/delaying disease. Once arthritis occurs, rapid remission is the target of therapy. The percentage of patients with RA achieving clinical remission has improved markedly compared with a few decades ago. The optimum outcome is to induce remission sufficiently profound so that therapy can be stopped, without flare, that is drug-free remission, which is effectively cure. Limitations of the tools used to measure remission, the outcome of tapering therapy, and new approaches to achieve successful drug cessation are described. Overall, this article reviews progress towards meeting the unmet needs of prevention/cure.

Does the nitrogen single-breath washout test contribute to detecting pulmonary involvement in rheumatoid arthritis? A pilot study.

OBJECTIVE: There has been growing interest in studying small airway disease through measures of ventilation distribution, thanks to the resurgence of the nitrogen single-breath washout (N2SBW) test. Therefore, this study evaluated the contribution of the N2SBW test to the detection of pulmonary involvement in patients with rheumatoid arthritis (RA). RESULTS: Twenty-one patients with RA underwent clinical evaluation, pulmonary function tests (PFTs), including the N2SBW test, and computed tomography (CT). The main tomographic findings were air trapping and bronchiectasis (57.1% and 23.8% of cases, respectively). According to the phase III slope of the N2SBW (phase III slope), 11 and 10 patients had values < 120% predicted and > 120% predicted, respectively. Five patients with limited involvement on CT had a phase III slope > 120%. The residual volume/total lung capacity ratio was significantly different between patients with phase III slopes < 120% and > 120% (P = 0.024). Additionally, rheumatoid factor positivity was higher in patients with a phase III slope > 120% (P = 0.021). In patients with RA and airway disease on CT, the N2SBW test detects inhomogeneity in the ventilation distribution in approximately half of the cases, even in those with normal conventional PFT results.

Tobacco-Derived Lipopolysaccharide, Not Microbial Translocation, as a Potential Contributor to the Pathogenesis of Rheumatoid Arthritis.

Microbial lipopolysaccharides (LPS) have been implicated in the pathogenesis of rheumatoid arthritis (RA), possibly driving a systemic inflammatory response that may trigger the development and/or exacerbation of the disease. To explore the existence of this mechanism in African RA patients, we have measured systemic levels of LPS and its surrogate, LPS-binding protein (LBP), as well as those of intestinal fatty acid-binding protein (I-FABP), pulmonary surfactant protein D (SP-D), and cotinine in serum to identify possible origins of LPS, as well as associations of these biomarkers with rheumatoid factor (RF) and anticitrullinated peptide (aCCP) autoantibodies and the DAS 28-3 clinical disease severity score. A cohort of 40 disease-modifying antirheumatic drug-naïve, black South African RA patients rated by compound disease scores and 20 healthy subjects and 10 patients with chronic obstructive pulmonary disease (COPD) as controls were included in this study. Levels of the various biomarkers and autoantibodies were measured using a combination of ELISA and immunofluorimetric and immunoturbidometric procedures. LPS levels were lowest in the RA group compared to the healthy controls (p = 0.026) and COPD patients (p = 0.017), while LBP levels were also significantly lower in RA compared to the healthy individuals (p = 0.036). Levels of I-FABP and SP-D were comparable between all three groups. Categorisation of RA patients according to tobacco usage revealed the following significant positive correlations: LBP with C-reactive protein (p = 0.0137); a trend (p = 0.073) towards an association of LBP with the DAS 28-3 disease severity score; RF-IgG antibodies with both LPS and LBP (p = 0.033 and p = 0.041, respectively); aCCP-IgG antibodies with LPS (p = 0.044); and aCCP-IgG with RF-IgM autoantibodies (p = 0.0016). The findings of this study, several of them novel, imply that tobacco products, as opposed to microbial translocation, represent a potential source of LPS in this study cohort of RA patients, again underscoring the risks posed by tobacco usage for the development and severity of RA.

Use of Rheumatologic Testing in Patients Who Eventually Receive a Diagnosis of Rheumatoid Arthritis.

OBJECTIVES: Anti-cyclic citrullinated peptide antibody (ACPA) has excellent specificity and prognostic value in patients with early rheumatoid arthritis (RA). The American College of Rheumatology included ACPA in their 2010 classification criteria for RA, but we hypothesize that primary care physicians (PCPs) underuse ACPA, even when clinical suspicion for RA is high. We aimed to describe their use of diagnostic testing in patients who were referred to a rheumatologist and eventually diagnosed as having RA. METHODS: In this retrospective cohort study, a systematic abstraction tool was used to review the medical records of patients seen between January 1, 2010 and June 15, 2014 in two rheumatology clinics: one private practice and one community health center associated with an academic medical center. For purposes of hypothesis generation, we compared the characteristics of patients with and without testing using unpaired t tests or Fisher exact tests. RESULTS: We identified 173 patients with RA referred from 141 different PCPs: 82.7% were women with a mean ± standard deviation age of 55.5 ± 18.6 years. ACPA and rheumatoid factor were ordered in 28.9% (95% confidence interval 22.6-36.2) and 41.0% (95% confidence interval 33.9-48.6) of patients, respectively. Imaging was underused. Almost half (45.7%, or 37/81) of the patients with documented symptom duration had a delay of at least 1 year before referral; however, ACPA utilization was not associated with the delay to treatment initiation. CONCLUSIONS: Most PCPs failed to order diagnostic tests for RA before referring a patient with polyarthritis who eventually received a diagnosis of RA. We also observed delays in diagnosis, with half of the patients waiting >1 year from symptom onset to diagnosis. These findings suggest educational efforts for PCPs should focus on emphasizing earlier diagnostic workups, especially ACPA, in patients suspected to have RA.

Beyond the antibodies: serum metabolomic profiling of myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) is a chronic, potentially debilitating autoimmune disease characterized by weakness and rapid fatigue of the voluntary muscles that worsens on exertion. Left untreated, MG symptoms may cause significant morbidity or even death. To date, no robust biological marker is available to follow the course of the disease. Therefore, new diagnostic approaches and biological markers are essential not only for improved diagnosis of the disease but for improved outcomes. OBJECTIVES: The present study applied a two-control, multi-label metabolomics profiling approach as a potential strategy for the identification of biomarkers unique to myasthenia gravis (MG). METHODS: Metabolic analyses using acid- and dansyl-labelled serum from seropositive MG (n = 46), rheumatoid arthritis (RA) (n = 23) and healthy controls (HC) (n = 49) were performed on samples from adult patients presenting to the University of Alberta Hospital neuromuscular and rheumatology clinics. Comparisons between patients with MG vs. HC, and RA vs. HC were made using univariate and multivariate statistics. RESULTS: Serum biomarker patterns were statistically significantly different between groups. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models exhibited considerable distinction between all groups. Metabolites were then filtered to remove peak pairs common to both disease cohorts. Combined metabolite panels revealed clear separation between MG and HC for both library-matched (AUROC: 0.92 ± 0.03) and highest AUC patients (AUROC: 0.94 ± 0.05). CONCLUSION: In patients presenting to the clinic with seropositive MG, metabolomic profiling is capable of distinguishing patients with disease from those without. These results provide an important first step towards a potential biomarker for improving MG identification.

IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis.

Objective: Animal models for human diseases are especially valuable for clarifying molecular mechanisms before or around the onset. As a model for rheumatoid arthritis (RA), we utilise knock-in mice gp130F759. They have a Y759F mutation in gp130, a common receptor subunit for interleukin 6 (IL-6) family cytokines. Definitive arthritis develops around 8 months old and the incidence reaches 100% around 1 year old. Careful examination in the clinical course revealed very subtle resistance in flexibility of joints at 5 months old. Therefore, pathophysiological changes in gp130F759 were examined to dissect molecular mechanisms for preclinical phase of RA. Methods: Severity of arthritis in gp130F759 was evaluated with a clinical score system and histological quantification. Serum cytokines, autoantibodies and C reactive protein (CRP) were measured. Changes in the synovium were analysed by real-time PCR, flow cytometry and immunohistochemistry. Results: Around 5 months old, various types of cytokines, rheumatoid factor (RF), anti-circular citrullinated peptide IgM and CRP increased in the sera of gp130F759. Enhancement of neovascularisation, synovial hyperplasia and fibrosis was observed. Also, increases in haematopoietic cells dominated by innate immune cells and gene expression of Il6 and Padi4 were detected in the joints. Il6 was expressed by non-haematopoietic synovial cells, whereas PAD4 protein was detected in the synovial neutrophils. Padi4 is induced in neutrophils in vitro by IL-6. Increases of phospho-STAT3 and PAD4 protein were detected in the synovium. Deletion of IL-6 in gp130F759 normalised the amount of PAD4 protein in the joints. Conclusion: The IL-6-PAD4 axis operates in the earliest phase of arthritis in gp130F759, implicating it in early RA.

Dose-response associations between metabolic indexes and the risk of comorbid type 2 diabetes mellitus among rheumatoid arthritis patients from Northern China: a case-control study.

OBJECTIVE: To investigate whether there were any differences in the patterns of metabolic abnormalities between patients with rheumatoid arthritis (RA) with comorbid type 2 diabetes mellitus (T2DM) and other populations, and to plot the dose-response relationships between metabolic indexes and the risk of comorbid T2DM among patients with RA. DESIGN AND SETTING: This is a retrospective case-control study using electronic medical records (EMRs). Patients with RA and/or T2DM or controls who were admitted to the First Affiliated Hospital of China Medical University between April 2008 and December 2016 were retrospectively recruited through the EMR system. After age-matching and sex-matching, 261 controls, 274 patients with T2DM, 276 patients with RA and 151 patients with RA+T2DM were eventually recruited. RESULTS: Patients with RA+T2DM exhibited higher levels of systolic blood pressure (SBP), fasting plasma glucose (FPG) and triglyceride (TG) than the RA only patients. Moreover, the proportions of impaired fasting glucose (IFG), and total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) dyslipidaemia in the RA+T2DM group were higher than those in the RA alone group (for IFG: 28.48% vs 18.84%, p=0.02; for TC: 25.17% vs 15.22%, p=0.01; for LDL-C: 25.83% vs 17.03%; p=0.03). Rheumatoid factor (RF) positivity and IFG were independent risk indicators for comorbid T2DM among patients with RA (for RF positivity: OR=0.45; 95% CI: 0.29 to 0.69; p<0.001; for IFG: OR=1.70; 95% CI: 1.04 to 2.76; p=0.03). CONCLUSION: Linear dose-response associations between SBP, TC, TG and the risk of comorbid T2DM among patients with RA were observed, whereas a non-linear dose-response association between FPG and the risk of comorbid T2DM was found. Patients with RA+T2DM were more likely to exhibit metabolic abnormalities than RA only patients. Patients with RA+T2DM with metabolic abnormalities deserve more attention from rheumatologists and endocrinologists.