Serological and Molecular Characterization of Hepatitis C Virus-Related Cryoglobulinemic Vasculitis in Patients without Cryoprecipitate.

Prolonged B cells stimulation due to the Hepatitis C virus (HCV) can result in autoimmunity, stigmatized by rising levels of cryoglobulins (CGs), the rheumatoid factor (RF), and free light chains (FLC) of immunoglobulins (Ig) associated with a range of symptoms, from their absence to severe cryoglobulinemic vasculitis and lymphoma. Here, we aimed to identify an immunological signature for the earliest stages of vasculitis when cryoprecipitate is still not detectable. We firstly analyzed the IgG subclasses, FLC, and RF in 120 HCV-RNA-positive patients divided into four groups according to the type of cryoprecipitate and symptoms: 30 asymptomatic without cryoprecipitate (No Cryo), 30 with vasculitis symptoms but without CGs that we supposed were circulating but still not detectable (Circulating), 30 type II and 30 type III mixed cryoglobulinemia (Cryo II and Cryo III, respectively). Our results revealed that patients with supposed circulating CGs displayed a pattern of serological parameters that closely resembled Cryo II and Cryo III, with a stronger similarity to Cryo II. Accordingly, we analyzed the groups of Circulating and Cryo II for their immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements, finding a similar mixed distribution of monoclonal, oligoclonal, and polyclonal responses compared to a control group of ten HCV-RNA-negative patients recovered from infection, who displayed a 100% polyclonal response. Our results strengthened the hypothesis that circulating CGs are the origin of symptoms in HCV-RNA-positive patients without cryoprecipitate and demonstrated that an analysis of clonal IGH and TCR rearrangements is the best option for the early diagnosis of extrahepatic complications.

Asociaciones de hallazgos diagnósticos con actividad de la enfermedad en el síndrome de Sjogren primario: un análisis de conglomerados / Associations of diagnostic findings with disease activity in primary Sjogren's syndrome: a cluster analysis

Objective The diagnosis of primary Sjӧgren's syndrome still relies upon a constellation of clinical, laboratory, imaging, and pathological findings. We aimed to evaluate the relation of the disease activity with the results of diagnostic tests for primary Sjӧgren's syndrome. Methods A principal component with cluster analysis was performed to classify 69 patients with primary Sjӧgren's syndrome based on the results of diagnostic evaluations. Results Anti-SSA autoantibody was the most represented feature on the principal components. The anti-SSA and ultrasound score were positively correlated (p=0.001). We identified two distinct clusters of low or high disease activity (p<0.001). Except for disease duration and serum beta2-microglobulin, the clusters were significantly different in salivary flow (p= 0.004), ultrasound findings (p<0.001), IgG (p= 0.001), and salivary beta2-microglobulin (p= 0.048). Also, positive findings were significantly different between the clusters in rheumatoid factor, antinuclear antibody, anti-SSA, and anti-SSB (all p≤0.013). Conclusion Patients with higher syndrome activity were best recognized with serological and ultrasound assessments. However, patients with lower syndrome activity had a longer disease duration, higher stimulated salivary flow rate, and a positive biopsy of minor salivary glands (56%) (AU)

Objetivo El diagnóstico del síndrome de Sjӧgren primario todavía se basa en una constelación de hallazgos clínicos, de laboratorio, de imagen y patológicos. Nuestro objetivo fue evaluar la relación de la actividad de la enfermedad con los resultados de las pruebas diagnósticas para el síndrome de Sjӧgren primario. Métodos Se realizó un análisis de componentes principales mediante conglomerados para clasificar a 69 pacientes con síndrome de Sjӧgren primario en función de los resultados de las evaluaciones de diagnóstico. Resultados El autoanticuerpo anti-SSA fue la característica más representada en los componentes principales. El anti-SSA y la puntuación de ultrasonido se correlacionaron positivamente (p=0,001). Identificamos dos grupos distintos de baja o alta actividad de la enfermedad (p<0,001). Excepto por la duración de la enfermedad y la microglobulina beta2 sérica, los grupos fueron significativamente diferentes en el flujo salival (p=0,004), los hallazgos de ultrasonido (p<0,001), IgG (p=0,001) y microglobulina beta2 salival (p=0,048). Además, los hallazgos positivos fueron significativamente diferentes entre los grupos en factor reumatoide, anticuerpo antinuclear, anti-SSA y anti-SSB (todos p≤0,013). Conclusión Los pacientes con mayor actividad del síndrome se reconocieron mejor con evaluaciones serológicas y ecográficas. Sin embargo, los pacientes con menor actividad del síndrome tenían una mayor duración de la enfermedad, mayor tasa de flujo salival estimulado y una biopsia productiva de glándulas salivales menores (56%) (AU)

ASSOCIATION OF SOME IMMUNOLOGICAL BIOMARKERS WITH RHEUMATOID ARTHRITIS PATIENTS IN THI-QAR PROVINCE.

OBJECTIVE: The aim: The aim of this research is to evaluate some immunological biomarkers in cases of Rheumatoid arthritis and to verify their correlation with activity of disease among the population of Thi-Qar province. PATIENTS AND METHODS: Matherials and methods: This study included 45 cases of rheumatoid arthritis and 45 healthy subjects. All cases underwent complete history taking, thor¬ough clinical examination, and laboratory tests including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Anti-citrulline antibody (Anti-CCP) and rheumatoid factor (RF). IL-17and TNF-α blood level was measured by Enzyme Linked Immunosorbent Assay (ELISA) method. DAS-28 (Disease activity score 28) was evaluated. RESULTS: Results: Serum levels TNF-α was higher in Rheumatoid arthritis patients (424.3±19.46 pg/ml) than in healthy individuals (112.7±4.73 pg/ml), and IL-17 blood levels were higher in Rheumatoid arthritis patients (233.5±241.4 pg/ml) than the healthy individuals group (47.24±49.7 pg/ml). There was significant association found among IL-17, DAS-28, CRP and hemoglobin levels. CONCLUSION: Conclusions: In conclusion, IL-17 blood levels were significantly increased in peoples with rheumatoid arthritis than in healthy individuals. Its significant relationship with DAS-28 suggested that the level of IL-17 in serum could be important immunological biomarker for activity of disease in disease of Rheumatoid arthritis.

Correlation of serum citrullinated histone H3 levels with disease activity in patients with rheumatoid arthritis.

OBJECTIVES: Serum citrullinated histone H3 (CitH3) levels in humans with rheumatoid arthritis (RA) were examined and the associations between CitH3 levels and disease variables were investigated. METHODS: Serum CitH3 levels were measured using an enzyme-linked immunosorbent assay in 151 RA patients (69 with highly, 32 with moderately, and 20 with mildly active RA and 30 with RA in remission) and 56 healthy controls. Receiver operating characteristic curve analysis was performed to evaluate the discriminant capacity of CitH3 between highly/moderately active RA and RA in remission/mild activity. Furthermore, machine-learning methods were applied to construct a predictive model. RESULTS: CitH3 concentration was more upregulated in patients with highly and moderately active RA than in those with mild activity and remission. The area under the curve for CitH3 was 0.825 for discriminating between highly and mildly active RA, 0.840 for discriminating between highly active RA and RA in remission, 0.789 for discriminating between moderately and mildly active RA, and 0.829 for discriminating between moderately active RA and RA in remission. The correlation analysis revealed that serum CitH3 levels were positively associated with Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR), ESR, C-reactive protein, rheumatoid factor, and some routine blood parameters (WBC, RDW, PLT, N, and N%), while negatively associated with haemoglobin, lymphocyte percentage, and thyroid-stimulating hormone. Through machine learning, the optimal predictive model was selected and had high performance. CONCLUSIONS: CitH3 is significantly associated with disease activity and could serve as a useful candidate biomarker to assess disease activity in patients with RA.

Impact of lifestyle and comorbidities on seropositive rheumatoid arthritis risk from Korean health insurance data.

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis in which primary prevention is key. However, the impact of lifestyle and comorbidities on RA development is unknown. Data from the Korean National Health Insurance Service (NHIS)-national sample cohort from 2002 to 2016 were used. At baseline, demographic characteristics, socioeconomic status, type of residential area, lifestyle behaviours (including exercise), and comorbidities (including the Charlson Comorbidity Index, CCI) were included. Cox regression analysis and Kaplan-Meier curves were used to evaluate the impact of lifestyle and comorbidities on seropositive RA occurrence. A total of 517,053 participants were included in the analysis for seropositive RA occurrence. Mean follow up duration was 71.5 and 142.3 person-month for seropositive RA occurrence group and non-occurrence group, respectively. Seropositive RA was diagnosed in 1,948 participants (0.37%) during follow-up. Cox regression analysis revealed that being aged between 40 and 79, a higher CCI, and hyperlipidemia resulted in elevated hazard ratios (HRs) for seropositive RA, whereas male gender, city residence, moderate alcohol consumption, high regular exercise and a BMI between 23 and 34.9 kg/m2 resulted in lower HRs. Using Korean NHIS data, the present study demonstrates that high-intensity regular physical exercise and moderate alcohol consumption are negatively associated with seropositive RA occurrence, which are modifiable lifestyle habits that might aid the primary prevention of seropositive RA.

Lower baseline autoantibody levels are associated with immune-related adverse events from immune checkpoint inhibition.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are a novel cancer therapeutic that have been successful in treating advanced malignancies; however, they also cause immune-related adverse events (irAE). Given that some irAE are clinically similar to traditional autoimmune diseases, autoantibodies have been suggested as possible biomarkers of irAE. However, there are very little data on autoantibody investigation prior to ICI. Our aim was to determine if specific baseline autoantibodies were associated with irAE and see if changes in autoantibody concentration corresponded with irAE development. METHODS: This study used data from an oncologic clinical trial of adaptive dosing combination ICI therapy in patients with advanced melanoma. Plasma was collected at baseline and 6 weeks after ICI initiation and tested in a microarray of 120 autoantigens commonly associated with autoimmune disease, as well as antinuclear antibody (ANA), rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibody (anti-CCP). Autoantibody concentrations were compared between patients experiencing an organ-specific event versus not. Heatmaps, volcano plots and hierarchical clustering were used to determine autoantibody concentration differences among irAE patient clusters as defined by signal intensity of autoantibodies. Kaplan-Meier curves were created and a log-rank test was performed to assess differences in survival. RESULTS: The microarray analysis demonstrated that patients who experienced specific irAE had fewer differentially expressed autoantibodies at baseline than those that did not have those specific irAE, and a greater fold change (FC) in antibody concentration from baseline to 6 weeks corresponded with specific irAE development. However, no autoantibodies were identified as being predictive of specific events. Time to first irAE was less than 6 weeks in 69% of patients, and these patients had less autoantibodies at baseline. Considering ANA, RF and CCP autoantibodies, there were no significant differences between the seropositive and seronegative patients in irAE development, severity, timing or survival. CONCLUSION: Patients with low autoantibody concentrations at baseline as well as a greater FC in autoantibody concentration over 6 weeks developed more distinct organ-specific irAE. This may suggest differences in the balance of cellular immunity and humoral pathways that are relevant in the pathogenesis of irAE, though further investigation is needed.

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.

Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis.

OBJECTIVES: The human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis. METHODS: We performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA). RESULTS: Meta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not. CONCLUSIONS: HLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.

Pulmonary fibrosis in relation to genetic loci in an inception cohort of patients with early rheumatoid arthritis from northern Sweden.

OBJECTIVES: Pulmonary manifestations in RA are common comorbidities. Interstitial lung disease (ILD), both idiopathic and in RA, has been associated with several genetic variants. We assessed pulmonary fibrosis (PF) in an inception cohort of RA patients in relation to genetic variants and disease-related factors. METHODS: A total of 1466 early RA patients were consecutively included and followed prospectively from the index date until death or 31 December 2016. Clinical and laboratory data and treatment were continuously registered according to the Swedish Rheumatology Quality Register. DNA was available from 1184 patients and 571 151 genome-wide single-nucleotide polymorphisms (SNPs) were analysed. Thirteen identified genetic variants were extracted. At follow-up, the patients answered a questionnaire regarding disease progression and lung involvement that was validated by reviewing medical records and analysing radiological examinations. RESULTS: The prevalence of PF was 5.6% and the annualized incidence rate was 5.0/1000 (95% CI 3.80, 6.54). Four SNPs were associated with PF in RA: rs35705950 [MUC5B; OR 2.5 (95% CI 1.5, 4.0), adjusted P-value = 0.00016, q-value = 0.0021]; rs111521887 [TOLLIP; OR 1.9 (95% CI 1.3, 2.8), adjusted P-value = 0.0014, q-value = 0.0092]; rs2609255 [FAM13A; OR 1.7 (95% CI 1.1, 2.5), adjusted P-value = 0.013, q-value = 0.055] and rs2736100 [TERT; OR 1.5 (95% CI 1.0, 2.2), adjusted P-value = 0.046, q-value = 0.15]. Older age and RF positivity were associated with increased risk, while MTX treatment was associated with a lower risk of PF. CONCLUSIONS: Development of PF in an inception cohort of RA patients was associated with 4 of 12 ILD risk genes. RA-related factors except for age at diagnosis and RF positivity were of limited importance in PF development.

The relationship between serum rheumatoid factor level and SYNTAX score I in patients with acute myocardial infarction.

OBJECTIVE: Rheumatoid factor (RF) has been associated with an increased likelihood of developing coronary artery disease and cardiovascular mortality. This study aimed to evaluate the relationship between serum RF levels and SYNTAX score I (SSI) in patients with acute myocardial infarction. METHODS: This study included 418 consecutive patients who were diagnosed with acute myocardial infarction and underwent coronary angiography. The baseline serum RF levels of all patients were measured. The study population was divided into 2 groups, namely, ST-segment elevation myocardial infarction (STEMI) group (218 patients) and non-ST-segment elevation myocardial infarction (NSTEMI) group (200 patients). Each group was further divided into 2 subgroups, namely, SSI ≤22 group and SSI >22 group. RESULTS: In the STEMI group, RF levels were significantly higher in the SSI >22 group than that in the SSI ≤22 group (13.0 IU/mL [7.0-51.0 IU/mL] versus 11.0 IU/mL [4.0-37.0 IU/mL], respectively, p=0.002). In the NSTEMI group, RF levels were significantly higher in the SSI >22 group than that in the SSI ≤22 group (15.5 IU/mL [8.0-69.5 IU/mL] versus 13.0 IU/mL [4.0-36.0 IU/mL, respectively], p<0.001). Forward conditional logistic regression analysis demonstrated that neutrophil-to-lymphocyte ratio, total cholesterol level, positive RF, and left ventricular ejection fraction were independently associated with intermediate and high SSI in patients with STEMI. Furthermore, cardiac troponin T levels and positive RF were independently associated with intermediate and high SSI in patients with NSTEMI. CONCLUSION: Serum RF concentrations are independently associated with SSI in patients with acute myocardial infarction.

Perceptions of Rheumatologists on Diagnosis of Psoriatic Arthritis in China.

Objective: High prevalence of undiagnosed psoriatic arthritis (PsA) and prolonged diagnostic delay are key troubles in the appropriate management of PsA. To analyze the possible causes for this phenomenon, a web-based nationwide survey was conducted to investigate rheumatologists' perceptions on PsA diagnosis in China. Methods: The electronic questionnaire consisting of 38 questions were designed by an expert panel and distributed with the online survey tool Sojump, which is a professional online survey platform. The completed questionnaires by real-name rheumatologists were collected. Results: A total of 1594 valid questionnaires were included. More than half of Chinese rheumatologists reported it was challenging to make a diagnosis of PsA. The four major challenges were "Difficulties in identification of atypical or hidden psoriasis", "Absence of diagnostic biomarkers", "No active self-report of history or family history of psoriasis" and "Various musculoskeletal manifestations". In diagnosing PsA, minor participants had incorrect knowledge of inflammatory arthropathy (13.7%), acute phase reactant (23.8%), and rheumatoid factor (28.7%). There were no significant differences in the knowledge of PsA and practice habits in diagnosing PsA between modern western medicine (WM)- and traditional Chinese medicine (TCM)-rheumatologists. The part-time rheumatologists were not as good as full-time rheumatologists in diagnosing PsA. Conclusions: About three quarters of Chinese rheumatologists are familiar with the elements in PsA diagnosis and have good practice habits in diagnosing PsA. Four main challenges in making PsA diagnosis are revealed. There was no significant difference in the knowledge of PsA between WM- and TCM-rheumatologists.

Therapeutic Potential of a Novel Bifidobacterium Identified Through Microbiome Profiling of RA Patients With Different RF Levels.

The potential therapeutic effects of probiotic bacteria in rheumatoid arthritis (RA) remain controversial. Thus, this study aimed to discover potential therapeutic bacteria based on the relationship between the gut microbiome and rheumatoid factor (RF) in RA. Bacterial genomic DNA was extracted from the fecal samples of 93 RA patients and 16 healthy subjects. Microbiota profiling was conducted through 16S rRNA sequencing and bioinformatics analyses. The effects of Bifidobacterium strains on human peripheral blood mononuclear cells and collagen-induced arthritis (CIA) mice were assessed. Significant differences in gut microbiota composition were observed in patients with different RF levels. The relative abundance of Bifidobacterium and Collinsella was lower in RF-high than in RF-low and RF-negative RA patients, while the relative abundance of Clostridium of Ruminococcaceae family was higher in RF-high than in RF-low and RF-negative patients. Among 10 differentially abundant Bifidobacterium, B. longum RAPO exhibited the strongest ability to inhibit IL-17 secretion. Oral administration of B. longum RAPO in CIA mice, obese CIA, and humanized avatar model significantly reduced RA incidence, arthritis score, inflammation, bone damage, cartilage damage, Th17 cells, and inflammatory cytokine secretion. Additionally, B. longum RAPO significantly inhibited Th17 cells and Th17-related genes-IL-17A, IRF4, RORC, IL-21, and IL-23R-in the PBMCs of rheumatoid arthritis patients. Our findings suggest that B. longum RAPO may alleviate RA by inhibiting the production of IL-17 and other proinflammatory mediators. The safety and efficacy of B. longum RAPO in patients with RA and other autoimmune disorders merit further investigation.

High-titer rheumatoid factor seropositivity predicts mediastinal lymphadenopathy and mortality in rheumatoid arthritis-related interstitial lung disease.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a common connective tissue disease-related ILD (CTD-ILD) associated with high morbidity and mortality. Although rheumatoid factor (RF) seropositivity is a risk factor for developing RA-ILD, the relationship between RF seropositivity, mediastinal lymph node (MLN) features, and disease progression is unknown. We aimed to determine if high-titer RF seropositivity predicted MLN features, lung function impairment, and mortality in RA-ILD. In this retrospective cohort study, we identified patients in the University of Chicago ILD registry with RA-ILD. We compared demographic characteristics, serologic data, MLN size, count and location, and pulmonary function over 36 months among patients who had high-titer RF seropositivity (≥ 60 IU/ml) and those who did not. Survival analysis was performed using Cox regression modeling. Amongst 294 patients with CTD-ILD, available chest computed tomography (CT) imaging and serologic data, we identified 70 patients with RA-ILD. Compared to RA-ILD patients with low-titer RF, RA-ILD patients with high-titer RF had lower baseline forced vital capacity (71% vs. 63%; P = 0.045), elevated anti-cyclic citrullinated peptide titer (122 vs. 201; P = 0.001), CT honeycombing (50% vs. 80%; P = 0.008), and higher number of MLN ≥ 10 mm (36% vs. 76%; P = 0.005). Lung function decline over 36 months did not differ between groups. Primary outcomes of death or lung transplant occurred more frequently in the high-titer RF group (HR 2.8; 95% CI 1.1-6.8; P = 0.028). High-titer RF seropositivity was associated with MLN enlargement, CT honeycombing, and decreased transplant-free survival. RF titer may be a useful prognostic marker for stratifying patients by pulmonary disease activity and mortality risk.

Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B. In order to identify relevant autoantigens, we screened a random peptide library (RPL) with pooled IgGs obtained from 50 patients with seronegative RA. Patients' sera were then used in an ELISA test to identify the most frequently recognized peptide among those obtained by screening the RPL. Sera from age- and sex-matched healthy subjects were used as controls. We identified a specific peptide (RA-peptide) recognized by RA patients' sera, but not by healthy subjects or by patients with other immune-mediated diseases. The majority of sera from seronegative and seropositive RA patients (73.8% and 63.6% respectively) contained IgG antibodies directed against the RA-peptide. Interestingly, this peptide shares homology with some self-antigens, such as Protein-tyrosine kinase 2 beta, B cell scaffold protein, Liprin-alfa1 and Cytotoxic T lymphocyte protein 4. Affinity purified anti-RA-peptide antibodies were able to cross react with these autoantigens. In conclusion, we identified a peptide that is recognized by seropositive and, most importantly, by seronegative RA patients' sera, but not by healthy subjects, conferring to this epitope a high degree of specificity. This peptide shares also homology with other autoantigens which can be recognized by autoantibodies present in seronegative RA sera. These newly identified autoantibodies, although present also in a percentage of seropositive RA patients, may be considered as novel serum biomarkers for seronegative RA, which lacks the presence of RF and/or ACPAs.

ACPA Antibodies Titer at the Time of Rheumatoid Arthritis Diagnosis Is Not Associated with Disease Severity.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease with the presence of autoantibodies, rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA). The presence of RF or ACPA predicts RA severity. Data on the influence of ACPA titer on RA course are limited. OBJECTIVES: To determine the correlation between ACPA titers at the time of RA diagnosis to RA features and severity during 3 years of follow-up. METHODS: We performed a retrospective study of RA patients treated at our institution during the years 2006-2015 with known ACPA titers at RA diagnosis who completed at least 3 years of follow-up. Patients (N=133) were divided according to ACPA titer: seronegative (< 15 U/ml, n=55), weakly positive (15-49 U/ml, n=18), moderately positive (50-300 U/ml, n=29), and strongly positive (> 300 U/ml, n=31). Patient data, including disease activity score (DAS28), bone erosion on hand and/or foot X-rays, treatments with corticosteroids and disease-modifying-anti-rheumatic drugs (DMARDs), and hospitalizations, were recorded. Chi-square and Mann-Whitney method were used for statistical analysis. P < 0.05 was considered as statistically significant. RESULTS: Male gender, smoking, and RF positivity correlated with ACPA positivity and higher ACPA titers. There was no correlation between ACPA titer and the variables defined as representing RA severity: higher DAS28, bone erosions, hospitalizations, need for corticosteroids, and conventional and biological DMARDs. CONCLUSIONS: Titer of ACPA was not identified as a predictive factor for RA severity.

Prevalence and relevant factors of positive RF in brucellosis patients with arthralgia.

BACKGROUND: Brucellosis is a critical zoonotic disease in the world, it is the non-specific arthralgia that make brucellosis patients easily misdiagnosed as rheumatoid arthritis (RA) in endemic regions. Elevated rheumatoid factor (RF) is an essential indicator of RA, and the RF in brucellosis patients is significantly higher than healthy people. Therefore, this study further explored the distribution of RF and the relevant factors of the RF positivity in brucellosis patients with arthralgia, in order to strengthen the recognition of physicians for brucellosis patients with RF positivity, especially in brucellosis-endemic areas, so as to avoid misdiagnosis and untimely treatment that may lead to malignant outcomes. METHODOLOGY AND PRINCIPAL FINDINGS: The medical records of all 572 brucellosis inpatients were collected in the Sixth People's Hospital of Shenyang, China from 2015 to 2016. After excluding 106 patients without arthralgia, 5 patients who unwilling to perform RF testing and 16 patients with diseases that may affect RF, 445 brucellosis inpatients with arthralgia were involved in this retrospective cross-sectional study. 143 (32.1%) patients with RF >10 IU/ml were classified into the RF positive group, with an average level of 16.5[12.2, 34.7] IU/ml, of which 45 (10.1%) patients were high-positive with RF >30 IU/ml. Multivariate logistic regression model was used to further analyze the relevant factors of the RF positivity and found that age, wrist joint pain and elevated C-reactive protein (CRP) were positively associated with RF positivity, with OR of 1.02 (P = 0.024), 8.94 (P = 0.008) and 1.79 (P = 0.019), respectively. CONCLUSION: The prevalence of positive RF in brucellosis patients with arthralgia was critical, nearly one-third of patients had RF positive. Elderly men brucellosis patients with arthralgia, wrist joint pain and elevated CRP were at high risk of positive RF. It is reminded that physicians should focus on differential diagnosis during clinical diagnosis and treatment, especially in brucellosis-endemic regions.

Definition and Validation of the American College of Rheumatology 2021 Juvenile Arthritis Disease Activity Score Cutoffs for Disease Activity States in Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate new Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) cutoffs to separate the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with oligoarthritis and with rheumatoid factor-negative polyarthritis, based on subjective disease assessment by the treating pediatric rheumatologist. METHODS: The cutoffs definition cohort was composed of 1,936 patients included in the multinational Epidemiology, Treatment and Outcome of Childhood Arthritis (EPOCA) study. Using the subjective physician rating as an external criterion, 4 methods were applied to identify the cutoffs: mapping, Youden index, 90% specificity, and maximum agreement. The validation cohort included 4,014 EPOCA patients, patients from 2 randomized trials, and 88 patients from the PharmaChild registry. Cutoff validation was conducted by assessing discriminative and predictive ability. RESULTS: The JADAS10 cutoffs were 1.4, 4, and 13, respectively, for oligoarthritis and 2.7, 6, and 17, respectively, for polyarthritis. The cJADAS10 cutoffs were 1.1, 4, and 12, respectively, for oligoarthritis and 2.5, 5, and 16, respectively, for polyarthritis. The cutoffs discriminated strongly among different levels of pain and morning stiffness, between patients who were and those who were not prescribed a new medication, and between different levels of improvement in clinical trials. Achievement of ID and MiDA according to the new JADAS cutoffs at least twice in the first year of disease predicted better outcome at 2 years. CONCLUSION: The 2021 JADAS and cJADAS cutoffs revealed good metrologic properties in both definition and validation samples, and are therefore suitable for use in clinical trials and routine practice.

Correlations between autoantibodies and the ATR-FTIR spectra of sera from rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide. Due to high heterogeneity in disease manifestation, accurate and fast diagnosis of RA is difficult. This study analyzed the potential relationship between the infrared (IR) spectra obtained by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and the presence of autoantibodies and antibodies against urease in sera. Additionally, the wave number of the IR spectrum that enabled the best differentiation between patients and healthy blood donors was investigated. Using a mathematical model involving principal component analysis and discriminant analysis, it was shown that the presence of anti-citrullinated protein antibody, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, and anti-nuclear antibodies correlated significantly with the wave numbers in the IR spectra of the tested sera. The most interesting findings derived from determination of the best predictors for distinguishing RA. Characteristic features included an increased reaction with urease mimicking peptides and a correspondence with particular nucleic acid bands. Taken together, the results demonstrated the potential application of ATR-FTIR in the study of RA and identified potential novel markers of the disease.

Differences in autoimmunity factors based on the activity of thromboangiitis obliterans.

OBJECTIVE: The treatment of Buerger's disease (BD) presents a medical problem as its etiology is still unclear. In this study, our objective was to evaluate the serum levels of autoimmune markers in patients with different clinical features of BD. METHODS: In this study, 80 BD patients were categorized in three groups using a cross-sectional design: migratory thrombophlebitis, cold sensitivity, and skin discoloration (mild symptoms); chronic ulcers, claudication, and burning pain of the feet at night (moderate symptoms); pain at rest and spontaneous gangrene (severe symptoms). Enzyme-linked immunosorbent assay was performed to measure antibodies against immunoglobulin M rheumatoid factor (IgM RF), anti-nuclear antibodies (ANA), antibodies against cyclic citrullinated peptide (anti-CCP), antiphospholipid antibodies (APA), anti-cardiolipin antibodies (ACLA), anti-double stranded DNA (anti-dsDNA), and extractable nuclear antigen (ENA) profile. RESULTS: Patients with severe symptoms showed the lowest age (p=0.031), ESR (p<0.001), and highest prevalence of ischemia (p<0.001). In all the patients, the serum levels of ANA and IgM RF were higher than 1 U and 15 IU/mL, respectively. However, the progression of the disease from mild to moderate did not affect these markers significantly (p>0.05). Other markers were negative in patients with BD. CONCLUSION: The findings of this study indicate that BD may closely be correlated to transient autoimmune phenomena, despite the fact that further research is required to investigate how transient unspecific autoimmune reactions contribute to the BD pathogenesis.

Assessment of genetic polymorphisms within nuclear factor-κB signaling pathway genes in rheumatoid arthritis: Evidence for replication and genetic interaction.

OBJECTIVE: This study was performed to replicate the associations of genetic polymorphisms within nuclear factor-κB (NF-κB) signaling pathway genes with rheumatoid arthritis (RA), and to further examine genetic interactions in a Chinese population. METHODS: A total of eleven single-nucleotide polymorphisms (SNPs) were genotyped in 594 RA patients and 604 healthy controls. RESULTS: Genetic association analysis revealed that NFKBIE rs2233434, TNIP1 rs10036748 and BLK rs13277113 were significantly associated with RA, cyclic citrullinated peptide (CCP)-positive RA and rheumatoid factor (RF)-positive RA, and TNFAIP3 rs2230926 was significantly associated with CCP-positive RA. Significant additive interaction was observed between NFKB1 rs28362491 and IKBKE rs12142086 (RERI = 0.76, 95% CI 0.13-1.38; AP = 0.57, 95% CI 0.11-1.03), NFKBIE rs2233434 and BLK rs13277113 (RERI = 1.41, 95% CI 0.88-1.94; AP = 0.85, 95% CI 0.50-1.20), NFKBIL rs2071592 and TNIP1 rs10036748 (RERI = 0.59, 95% CI 0.17-1.02; AP = 0.46, 95% CI 0.05-0.87), UBE2L3 rs5754217 and TNFSF4 rs2205960 (RERI = 0.50, 95% CI 0.16-0.84; AP = 0.57, 95% CI 0.09-1.05). Significant multiplicative interaction was detected between BLK rs13277113 and UBE2L3 rs5754217 (p = 0.02), BLK rs13277113 and TNFSF4 rs2205960 (p = 0.03). CONCLUSIONS: Our results lent further support to the role of NF-κB signaling pathway in the pathogenesis of RA from a genetic perspective.