Differences in referral path, clinical and radiographic outcomes between seronegative and seropositive rheumatoid arthritis Mexican Mestizo patients: A cohort study.

BACKGROUND: The study compared the referral path, the first two-year clinical outcomes, and the first five-year radiographic outcomes between seronegative patients (SNPs) from a recent-onset rheumatoid arthritis dynamic cohort initiated in 2004 and seropositive patients (SPPs). Predictors of incidental erosive disease were investigated. PATIENTS AND METHODS: Up to March 2023, one independent observer reviewed the charts from 188 patients with at least two years of clinical assessments and up to five years of annual radiographic assessments. SNPs were defined when baseline RF and ACPA serum titers were within local normal ranges. The erosive disease was defined on hand and/or foot radiographs when at least one unequivocal cortical bone defect was detected. The incidental erosive disease was defined in baseline erosive disease-free patients who developed erosions at follow-ups. Multivariate Cox regression analyses identified hazard ratios (95% confidence interval) for factors to predict incidental erosive disease. RESULTS: There were 17 (9%) SNPs, and they had a shorter time from symptoms onset to first physician evaluation, visited a lower number of physicians, and received less intensive treatment at referral and during the first years of follow-up than SPPs. Also, they had fewer 0-66 swollen joints and were less frequently persistent on therapy. The erosive disease was detected only in SPPs, and its frequency increased from 10.1% at baseline to 36.1% at the five-year radiographic assessment. There were 53 (31.4%) patients with incidental erosive disease, and differences between SPPs and SNPs were statistically significant at the feet location. Incidental erosive disease was predicted by baseline ACPA, ESR, substantial morning stiffness, and cumulative CRP. CONCLUSIONS: SNPs showed mild differences in their referral path and clinical outcomes compared to SPPs. However, erosive disease was detected only in SPPs and was predicted by baseline and cumulative clinical and serologic variables.

Effect of Disease-related Variables on Bone Mineral Density in Patients with Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the bony architecture. Nevertheless, it remains uncertain whether these effects are due to disease progression, limited mobility, or medication. We conducted this study to analyze changes in bone mineral density (BMD) in patients with RA and its relationship with various disease parameters, such as demographic factors, disease activity, functional disability, duration since onset of symptoms, cumulative steroid dose, and titers of rheumatoid factor (RF). MATERIALS AND METHODS: This cross-sectional study was conducted at the Rheumatology Clinic of the Tertiary Care Hospital of Mumbai. We included 96 consecutive patients diagnosed with RA using the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. Demographic, clinical, and biochemical data were also collected. Disease severity was assessed using the Disease Activity Score 28 with Erythrocyte Sedimentation Rate (DAS28-ESR) score, and physical disability was assessed using the Health Assessment Questionnaire (HAQ) score. BMD was calculated using dual-energy X-ray absorptiometry (DEXA). Significant variations among continuous variables were examined using the t-test, while disparities between categorical variables were evaluated using the Chi-squared test. Statistical significance was set at p < 0.05 within the 95% confidence interval (CI) range. RESULTS: Of the 96 patients, 77 were female, and 19 were male. The mean age of the study population was 45.28 ± 10.15 years. As the age of patients increased, BMD was found to decrease in the total lumbar spine, neck of the femur, and total hip region (p < 0.05). Sex did not seem to affect BMD. In all three regions, a decrease in BMD with increasing duration since the onset of RA symptoms was observed. Disease severity, measured using the DAS28-ESR score, did not decrease BMD. There was an increase in functional disability, calculated using the HAQ score, with a decrease in BMD at all sites. RF positivity was associated with decreased BMD at the neck of the femur and total hip region but not the total lumbar spine. Long-term use of steroids (≥30 days) decreased BMD at all three sites. CONCLUSION: Our study reiterates the effect of RA on the BMD of patients. Advanced age, duration since symptom onset, physical disability, RF positivity, and long-term corticosteroid use are disease-related factors affecting BMD in patients with RA.

Increased Rheumatoid Factor production in patients with severe COVID-19.

BACKGROUND: Searching for Rheumatoid Factors (RF) in patients with coronavirus disease (COVID-19) has rarely been described. OBJECTIVES: To investigate the association between RF isotypes (IgM, IgA, and IgG) and different clinical presentations of COVID-19 in a series of Tunisian patients. STUDY DESIGN: Eighty-two COVID-19 patients were enrolled in this study. Symptomatic cases were recruited from the Department of COVID-19 and the intensive care unit (ICU) of the University Hospital of Mahdia, Tunisia, from January 2021 to March 2021. Different RF isotypes were assessed using a commercial enzyme-linked immunosorbent assay (ELISA). RESULTS: Forty-one patients (50%) had RF of any isotype. Thirty-two patients (39%) were tested positive for RF-IgM. Symptomatic forms of the disease were associated with RF-IgM positivity (p = 0.005). The mean concentration of RF-IgM was higher in the severe form than in the moderate and asymptomatic forms (p = 0.006). CONCLUSIONS: Our study suggests that the production of RF-IgM isotype is increased in patients with severe COVID-19.

Immune Checkpoint Inhibitor-Associated Remitting Seronegative Symmetrical Synovitis With Pitting Edema: Description of a New Entity by CanRIO.

OBJECTIVE: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is characterized by symmetrical synovitis with pitting edema and negative rheumatoid factor (RF). It has been described in a setting of malignancy, suggesting a paraneoplastic association. With the increasing use of immune checkpoint inhibitors (ICIs) for the treatment of cancers and emergence of immune-related adverse events (irAEs), our objective was to identify and describe cases of ICI-associated RS3PE (ICI-RS3PE) and compare them to non-ICI-RS3PE. METHODS: The Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) network is a collaboration of Canadian rheumatologists with experience in the management of patients with rheumatic irAEs (Rh-irAEs). Standardized data on adult patients with Rh-irAE have been collected as part of retrospective and prospective cohorts. In this study, detailed information on all cases of ICI-RS3PE from both cohorts were extracted and analyzed. RESULTS: We identified 11 cases of ICI-RS3PE. The most frequently observed malignancy was nonsmall cell lung cancer (4 of 11), followed by malignant melanoma (2 of 11) and cutaneous squamous cell carcinoma (2 of 11). The median time to onset of ICI-RS3PE was 26 weeks from ICI start and 52 weeks from diagnosis of malignancy. Seven patients had stable cancer prior to onset of ICI-RS3PE, 3 had partial response, and 1 had complete response. All patients received glucocorticoids. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) were needed in 10 patients. CONCLUSION: ICI-RS3PE may be an independent Rh-irAE, separate from paraneoplastic RS3PE. The symptoms of ICI-RS3PE responded well to glucocorticoids, but concomitant treatment with csDMARDs may be necessary.

Hypothyroidism and autoimmune thyroid disorders in rheumatoid arthritis: relationship with disease activity.

Background and aims: Thyroid function abnormalities and thyroid autoantibodies have previously been described in rheumatoid arthirits (RA) with limited data. In some studies, a relationship was found between thyroid autoantibodies and RA disease activity. However, there are not strong studies in the literature indicating the relationship between thyroid diseases and RA. The aim of this study was to determine the frequency of hypothyroidism and to investigate the relationship between thyroid hormone levels, autoantibodies and disease activity in patients with rheumatoid arthritis (RA). Methods : 1017 patients with the diagnosis of RA were recruited. This observational study was conducted between January 2014 and July 2015. Demographic variables were recorded. Anti-nuclear antibodies (ANA), anti-cyclic citrulli-nated peptide antibody (anti-CCP), Rheumatoid Factor (RF), C reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), anti-microsomal antibody (anti-TPO )and anti-thyroglobulin antibody (anti-TG) were determined. Visual analog score and Disease Activiy Score 28 (DAS-28) ESR and DAS-28 CRP were recorded. The relationship between thyroid hormone levels and thyroid antibodies and disease activity parameters were determined. Results: 98 (%9,7) patients had hypothyroidism and 61 (%6) patients had hyperthyroidism. 210 (20,7%) patients with RA was positive for TPOAb and 165(16,3%) for anti-TG. Positive correlation was detected between anti-TPO positivity and anti-CCP levels (p:0.005, r:0,274). In anti-TG antibody positive patients, there was a significant positive correlation of thyroid hormone levels with CRP and DAS 28-CRP (p:0.01, r:0,120; p:0.01, r:0,169). Conclusion: Thyroid autoantibodies were found to be positive in 16-21% of patients with RA. Though hypothyroidism is not very frequent in RA patients, autoimmune thyroid disease is quite common, which may be related to disease activity.

Elevated serum soluble CD27 levels are associated with both disease activity and humoral immune activity in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the serum level of soluble CD27 (sCD27) and its potential clinical significance in rheumatoid arthritis (RA). METHODS: Serum sCD27 levels in RA patients, idiopathic inflammatory myopathy (IIM) patients, systemic lupus erythematosus (SLE) patients and healthy controls (HCs) were detected by enzyme-linked immunosorbent assay. The medical information and laboratory data of the patients were collected. Serum sCD27 levels in RA patients with different clinical features were analysed, as was the correlation between the clinical data and serum sCD27 levels. Independent samples t test, the Mann-Whitney U-test or Wilcoxon signed-rank test, and Spearman correlation were used for statistical analysis. RESULTS: Levels of sCD27 were elevated in RA patients (3898 [2525, 5834] pg/mL) compared with IIM patients (2467 [1939, 3324] pg/mL) or HCs (1659 ± 648 pg/mL) (p 0.001). In addition, serum sCD27 levels correlated with age, erythrocyte sedimentation rate, C-reactive protein (CRP), rheumatoid factor (RF), immunoglobulin A, immunoglobulin G, complement 4 and disease activity score in 28 joints in RA patients. Levels of sCD27 were higher in RF-positive RA patients (6054 ± 5842 pg/mL) than in RF-negative patients (3902 ± 2098 pg/mL), and a similar finding was also observed in anti-cyclic citrullinated peptide (anti-CCP) antibody-positive (5810 ± 5671 pg/mL) and anti-CCP-negative (4183 ± 2187 pg/mL) RA patients. Serum ESR, RF, IgA, IgG levels and DAS28-CRP were elevated in RA patients with higher sCD27 levels than in those with lower sCD27 levels (p<0.01). CONCLUSIONS: Serum sCD27 might be a promising biomarker that reflects both disease activity and humoral immunity activity in RA.

Influence of rheumatoid factor on serum drug levels of TNF inhibitors with different structures in rheumatoid arthritis.

OBJECTIVES: Certolizumab pegol (CZP), an Fc-free antibody fragment, has shown stable serum levels and steady efficacy in the treatment of RA patients, irrespective of RF levels at baseline. Here, we examine, in clinical practice, the effect of baseline RF and ACPA levels on serum drug levels of IFX, ADL and CZP an Fc-free antibody fragment. METHODS: This is a retrospective study performed in real-world patients. We assessed 170 patients with RA: 90 (53%) received IFX, 48 (28%) ADL and 32 (19%) CZP. Demographic and clinical variables, RF and ACPA levels were obtained at the baseline visit (T0), and patients were stratified based on negative, low, medium, or high levels. After 6 months (T6) serum drug levels and anti-drug antibodies (ADAb), were computed. RESULTS: While CZP serum levels did not differ across RF groups at T6, high baseline RF was linked to lower serum drug levels compared to RF negative status in treatment with complete monoclonal antibodies IFX and ADL. No differences in disease activity measured by DAS28 at baseline were observed across RF quartiles in patients treated with IFX or ADL. ADAb was observed in 26 patients with IFX, 3 with ADL and 1 with CZP, following 6 months of treatment. Patients with high baseline RF levels dropped out more frequently by secondary non-response in IFX or ADL than CZP (80% vs. 75% vs. 33%, p=0.002). CONCLUSIONS: In this real word data evaluation, CZP serum levels were independent of RF levels in patients however patients with high baseline RF levels who obtained IFX or ADL had lower serum drug levels at 6 months than baseline RF-negative patients. In addition, secondary non-response was more frequent in patients with high RF levels treated with IFX and ADL.

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.

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.

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.

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.

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.

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.

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.