Novel and unique rheumatoid factors cross-react with viral epitopes in COVID-19.

Rheumatoid factors (RFs), polyreactive antibodies canonically known to bind two conformational epitopes of IgG Fc, are a hallmark of rheumatoid arthritis but also can arise in other inflammatory conditions and infections. Also, infections may contribute to the development of rheumatoid arthritis and other autoimmune diseases. Recently, RFs only in rheumatoid arthritis were found to bind novel linear IgG epitopes as well as thousands of other rheumatoid arthritis autoantigens. Specific epitopes recognized by infection-induced polyreactive RFs remain undefined but could provide insights into loss of immune tolerance. Here, we identified novel linear IgG epitopes bound by RFs in COVID-19 but not rheumatoid arthritis or other conditions. The main COVID-19 RF was polyreactive, binding two IgG and multiple viral peptides with a tripeptide motif, as well as IgG Fc and SARS-CoV-2 spike proteins. In contrast, a rheumatoid arthritis-specific RF recognized IgG Fc, but not tripeptide motif-containing peptides or spike. Thus, RFs have disease-specific IgG reactivity and distinct polyreactivities that reflect the broader immune response. Moreover, the polyreactivity of a virus-induced RF appears to be attributable to a very short peptide motif. These findings refine our understanding of RFs and provide new insights into how viral infections may contribute to autoimmunity.

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.

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.

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.

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 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.

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.

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.

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.

Structure-function analyses of a stereotypic rheumatoid factor unravel the structural basis for germline-encoded antibody autoreactivity.

Rheumatoid factors (RFs) are autoantibodies against the fragment-crystallizable (Fc) region of IgG. In individuals with hematological diseases such as cryoglobulinemia and certain B cell lymphoma forms, the RFs derived from specific heavy- and light-chain germline pairs, so-called "stereotypic RFs," are frequently produced in copious amounts and form immune complexes with IgG in serum. Of note, many structural details of the antigen recognition mechanisms in RFs are unclear. Here we report the crystal structure of the RF YES8c derived from the IGHV1-69/IGKV3-20 germline pair, the most common of the stereotypic RFs, in complex with human IgG1-Fc at 2.8 Å resolution. We observed that YES8c binds to the CH2-CH3 elbow in the canonical antigen-binding manner involving a large antigen-antibody interface. On the basis of this observation, combined with mutational analyses, we propose a recognition mechanism common to IGHV1-69/IGKV3-20 RFs: (1) the interaction of the Leu432-His435 region of Fc enables the highly variable complementarity-determining region (CDR)-H3 to participate in the binding, (2) the hydrophobic tip in the CDR-H2 typical of IGHV1-69 antibodies recognizes the hydrophobic patch on Fc, and (3) the interaction of the highly conserved RF light chain with Fc is important for RF activity. These features may determine the putative epitope common to the IGHV1-69/IGKV3-20 RFs. We also showed that some mutations in the binding site of RF increase the affinity to Fc, which may aggravate hematological diseases. Our findings unravel the structural basis for germline-encoded antibody autoreactivity.

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.

CD4+CXCR5+PD-1+ T Follicular Helper Cells Play a Pivotal Role in the Development of Rheumatoid Arthritis.

BACKGROUND T follicular helper (Tfh) cells are a subgroup of activated CD4+ T cells in the germinal centers of secondary lymphoid organs, they play critical roles in the development of many chronic autoimmune inflammatory diseases. The aim of this study was to investigate whether circulating Tfh cells contribute to the development of rheumatoid arthritis (RA). MATERIAL AND METHODS Thirty patients fulfilled the diagnosis criteria that was established by the American College of Rheumatology and 30 healthy controls were recruited. The frequency of Tfh cells in patients and collagen-induced arthritis (CIA) in DBA/1J mice were analyzed by flow cytometry. The serum IL-21 level was examined by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of Blimp-1 and Bcl-6 were detected by qRT-PCR. RESULTS RA patients had more CD4⁺PD-1⁺CXCR5⁺ Tfh cells in peripheral blood compared with healthy controls, and CIA in DBA/1J mice showed similar results. Higher mRNA expression of Bcl-6 and lower Blimp-1 mRNA expression were observed in patients with RA compared to healthy controls, and the expression level of IL-21 was higher in RA patients, which was also seen in CIA mice. Furthermore, the spleen CD4⁺ICOS⁺CXCR5⁺ Tfh cells in CIA mice show significantly higher frequency than that in the control mice. The percentage of CD4⁺PD-1⁺CXCR5⁺ Tfh cells was correlated positively with the values of erythrocyte sedimentation rate (ESR) (r=0.968, P<0.001), rheumatoid factor (RF) (r=0.962, P<0.001), C-reactive protein (CRP) (r=0.953, P<0.001), and anti-cyclic citrullinated peptide antibodies (ACPA) (r=0.966, P<0.001), and the level of serum interleukin (IL)-21 in RA patients showed positive correlation with ESR (r=0.982, P<0.001), RF (r=0.959, P<0.001), CRP (r=0.951, P<0.001), and ACPA (r=0.971, P<0.001) as well. CONCLUSIONS The activated Tfh cells in the peripheral blood may be responsible for the development of RA.

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.

Influence of baseline modified Rheumatic Disease Comorbidity Index (mRDCI) on drug survival and effectiveness of biological treatment in patients affected with Rheumatoid arthritis, Spondyloarthritis and Psoriatic arthritis in real-world settings.

AIM: To assess the impact of baseline modified Rheumatic Disease Comorbidity Index (mRDCI) a simple comorbidity count, on overall survival of treatments with biological drugs in patients affected with Rheumatoid Arthritis (RA), Spondyloarthritis (SpA) and Psoriatic Arthritis (PsA) in real-world settings. METHODS: Patients (nr. 635) with RA (nr. 214), SpA (nr. 213) and PsA (nr. 208) starting a first biological drug were retrospectively analysed. mRDCI was scored at baseline, and disease characteristics were recorded at entry and at last observation. Drug retention was analysed using Kaplan-Meier curves. Cox regression models were used to estimate the association of baseline mRDCI with drug discontinuation and clinical outcomes, the achievement of clinical remission based on 28 joint-Disease Activity Score (DAS28) <2.6 for RA and PsA, and on Ankylosing Spondylitis-C-reactive protein Disease Activity Score (ASDAS-CRP) <1.3 for SpA. RESULTS: Baseline mRDCI significantly correlated with the number of biological drug switches (rho 0.26). Persistence on biologic therapy was significantly higher in patients with mRDCI=0 (96.4%), than in those with mRDCI ≥2 (83.9%). Patients without comorbidities showed significantly higher drug survival rate in PsA (P = 0.0001) or SpA (P = 0.02), but not in RA. mRDCI was also found to be a predictor of definitive drug discontinuation (HR: 1.53) and of failure to achieve remission in RA (HR: 0.66) or PsA (HR: 0.77), and in SpA (HR: 0.43). CONCLUSIONS: This study provided evidence that baseline mRDCI negatively impacts the persistence on biologic treatments and clinical outcomes in patients with RA, SpA and PsA in real-life settings.

HIF-1A gene polymorphisms and its protein level in patients with rheumatoid arthritis: a case-control study.

OBJECTIVES: The aim of the study was to identify HIF-1A genetic variants and their possible association with HIF-1α, VEGF, KDR, RORc and Foxp3 protein levels, and susceptibility to and severity of RA. METHODS: The HIF-1A gene polymorphisms were genotyped for 587 RA patients and 341 healthy individuals. The HIF-1α, VEGF, KDR, RORc and Foxp3serum levels were evaluated. RESULTS: Under the codominant model, the frequency of the rs12434438 GG genotype was lower in RA patients than in controls (P = 0.02). Under the recessive model (AA + AG vs GG), the association was also significant (OR 3.32; CI 1.19-9.24; P = 0.02). Overall, rs12434438 A/G and rs1951795 A/C are in almost completed linkage disequilibrium with D' = 0.96 and r2 = 0.85. The HIF-1A rs1951795 A allele was associated with rheumatoid factor (P = 0.02) and mean value of erythrocyte sedimentation rate (ESR) (P = 0.05). In RA patients with HIF-1A rs12434439 GG genotype, the parameters of disease activity such as DAS-28, VAS score, Larsen score or HAQ score were lower compared to RA patients with the HIF-1A rs12434439 AA genotype. Moreover, we also observed that Foxp3 serum levels were higher, and RORc2 serum levels were lower in RA patients with rs12434439 GG. CONCLUSION: The polymorphic HIF-1A rs12434439 GG genotype may play a protective role for RA development.

Therapeutic plasma exchange for hyperviscosity syndrome secondary to high rheumatoid factor.

Hyperviscosity syndrome (HVS) is most commonly associated with Waldenstrom's macroglobulinemia, where it may be life-threatening. HVS may also occur in autoimmune diseases; data pertaining to efficacy of therapeutic plasma exchange (TPE) in HVS arising in non-malignant gammopathy are limited. We report a case of 71-year-old female with erosive rheumatoid arthritis with profoundly elevated rheumatoid factor (57,400 IU/ml; normal <35) who presented with findings consistent with HVS: profound weakness, headache, epistaxis and plasma viscosity (8.5 centipoise). She was successfully treated with pulsed high-dose steroids and TPE. Her symptoms of HVS have not recurred and the plasma viscosity has remained less than 3 centipoise. Given a slow onset of non-specific symptoms, HVS may be missed, incurring high risk of adverse effect. In symptomatic patients with high RF activity, a high index of suspicion for HVS is necessary to ensure timely identification and treatment with TPE, a safe and effective therapy.

Rheumatoid factors do not preferentially bind to ACPA-IgG or IgG with altered galactosylation.

Objectives: Recent reports describe interactions between the two most prominent RA-related autoantibodies, RFs and ACPAs. The main aim of the present study was to investigate whether RFs preferentially interact with ACPA-IgG over non-ACPA IgG. Additionally, interactions of RFs with IgG with altered galactose content in the Fc domain were examined, since ACPA-IgGs have been shown to have decreased Fc galactose content in RF+ patients. Methods: (Auto)antibody interactions were studied in a surface plasmon resonance imaging assay and with ELISA. Target antibodies were isolated from RA patient plasma (polyclonal ACPA- and non-ACPA-IgG) or recombinantly produced to obtain monoclonal IgG with well-defined Fc galactose content. Interacting autoantibodies were studied using autoantibody positive patient sera and two recombinantly produced IgM-RFs. Results: The sera from 41 RF+ RA patients showed similar RF binding to ACPA- and non-ACPA-IgG and no differences in binding to IgG with normal, high or low levels of Fc galactosylation. Two monoclonal IgM-RFs, one interacting with the CH2-CH3 interface and one binding close to the C-terminal end of the CH3 domain showed no influence of the Fc glycan on IgG binding by IgM-RF. Conclusion: Although interactions between RF and ACPA may play a role in inflammatory processes in RA, RFs do not preferentially interact with ACPA-IgG over non-ACPA-IgG nor with agalatosylated IgG over IgG with normal or high galactosylation.

The effect of rheumatoid arthritis-associated autoantibodies on the incidence of cardiovascular events in a large inception cohort of early inflammatory arthritis.

Objective: . RA is associated with an increased risk of cardiovascular events (CVEs). The objective was to estimate independent effects of RA autoantibodies on the incident CVEs in patients with early RA. Methods: Patients were enrolled in the Canadian Early Inflammatory Arthritis Cohort, a prospective multicentre inception cohort. Incident CVEs, including acute coronary syndromes and cerebrovascular events, were self-reported by the patient and partially validated by medical chart review. Seropositive status was defined as either RF or ACPA positive. Multivariable Cox proportional hazards survival analysis was used to estimate the effects of seropositive status on incident CVEs, controlling for RA clinical variables and traditional cardiovascular risk factors. Results: . A total of 2626 patients were included: the mean symptom duration at diagnosis was 6.3 months ( s . d . 4.6), the mean age was 53 years ( s . d . 15), 72% were female and 86% met classification criteria for RA. Forty-six incident CVEs occurred over 6483 person-years [incidence rate 7.1/1000 person-years (95% confidence interval 5.3, 9.4)]. The CVE rate did not differ in seropositive vs seronegative subjects and seropositivity was not associated with incident CVEs in multivariable Cox regression models. Baseline covariates independently associated with incident CVEs were older age, a history of hypertension and a longer duration of RA symptoms prior to diagnosis. Conclusion: The rate of CVEs early in the course of inflammatory arthritis was low; however, delays in the diagnosis of arthritis increased the rate of CVEs. Hypertension was the strongest independent risk factor for CVEs. Results support early aggressive management of RA disease activity and co-morbidities to prevent severe complications.

The association between insulin-like growth factor 1 (IGF-1), IGF-binding proteins (IGFBPs), and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis.

OBJECTIVES: To assess the association between plasma levels of the insulin-like growth factor (IGF) system including IGF-1, IGF-binding proteins (IGFBPs) including IGFBP-1, total (t-)IGFBP-3 and functional (f-)IGFBP-3, and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis (RA). METHOD: Plasma concentrations of IGF-1, IGFBP-1, t-IGFBP-3, f-IGFBP-3, and PICP were measured by immunoassay. RESULTS: No significant difference was observed in plasma IGF-1 levels between pre- and postmenopausal subjects. Plasma levels of IGFBP-1 were elevated in RA. PICP and f-IGFBP-3 were greatly affected by menopausal status. Of the three IGFBPs tested, only f-IGFBP-3 plasma levels in RA women correlated negatively with age and disease duration. A positive correlation was demonstrated between PICP and erythrocyte sedimentation rate (ESR) in RA. Moreover, there was no correlation between PICP and IGF-1 and any of the IGFBPs in RA women. CONCLUSIONS: Considerable disruption of the IGF system in RA was found to be related to disease activity and duration. Changes in the IGF-IGFBP axis and PICP levels were different in pre- and postmenopausal women with RA. Elevated plasma PICP concentrations may indicate an increased rate of bone formation in postmenopausal RA women. Additionally, the observed changes in the IGF/IGFBP system did not affect bone formation during RA.