RF-negative Patients Research Articles

Clinical and laboratory pattern of patients with systemic lupus erythematosus seropositive for rheumatoid factor.

The aim of the study was to investigate the associations between the presence and level of rheumatoid factor (RF) in the blood serum and the clinical and laboratory characteristics of patients with systemic lupus erythematosus (SLE). This retrospective tricentric cross-sectional study analyzed a Ukrainian contingent of SLE patients. Medical records of 495 patients were evaluated. Rheumatoid factor serum concentration was tested in 206 of them (41.6%) using turbidimetry technique. Clinical manifestations, routine laboratory parameters, specific immunological tests, disease activity (SLEDAI-2K), and damage indices (SLICC/ACR DI) were evaluated. Our study revealed that RF was elevated in 27.7% of patients. The RF-positive patients experienced a longer delay in SLE diagnosis (2.0 vs. 0.5 years, p = 0.046), less frequent kidney involvement (42.1% vs. 59.4%, p = 0.045) and fever (42.1% vs. 59.2%, p = 0.046), and more frequent lymphadenopathy (59.6% vs. 42.3%, p = 0.039) compared to RF-negative patients. Patients with RF positivity had higher levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and antinuclear antibody (ANA) titer, and were more frequently positive for antibodies to Ro/SSA and La/SSB. Rheumatoid factor concentration directly correlated with CRP (r = 0.318; p < 0.01) and ESR (r = 0.228; p = 0.04) levels. However, no associations were found between RF levels and SLEDAI-2K, joint involvement frequency, SLICC/ACR DI or drug therapy content. Univariate logistic regression analysis showed that RF positivity was independently associated with lymphadenopathy, presence of anti-Ro/SSA and anti-La/SSB antibodies, and negatively associated with kidney involvement. In RF-seropositive SLE patients (approximately 28%), the diagnosis is established later compared to RF-seronegative ones; kidney involvement and fever are less common, while lymphadenopathy develops more frequently. Rheumatoid factor seropositivity is associated with higher levels of ESR, CRP, ANA, and the presence of antibodies to Ro/SSA and La/SSB. According to the results of univariate logistic regression analysis, an independent association with RF positivity was confirmed only for kidney involvement, lymphadenopathy, and antibodies to Ro/SSA and La/SSB.

Anti-carbamylated Protein Antibodies Positivity in Rheumatoid Arthritis and Its Association With Rheumatoid Factor and Anti-cyclic Citrullinated Protein Antibodies.

Background Rheumatoid arthritis (RA) is a widespread autoimmune disease affecting millions of people worldwide. The current markers include anti-cyclic citrullinated peptide (anti-CCP) antibodiesand rheumatoid factor (RF), which are nonspecific and elevated in variousconditions and do not have a prognostic value. They are also elevated in the later stages of the disease. Anti-carbamylated protein (anti-CarP) antibodies have been reported to be associated with joint damage in RA. Therefore, this study aimed to evaluate the sensitivity and specificity of anti-CarP antibodies in individuals with RA and their relationship with inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Methods This was a cross-sectional case-control study conducted from April 2020 to March 2021 at the Saveetha Medical College, Chennai, India. The age makeup of the three groups was evaluated: Group 1 comprised anti-CCP and RF-positive patients; Group 2 comprised anti-CCP and RF-negative patients; and Group 3 was the control group, which comprised healthy volunteers. Patient samples, including blood and serum, have been utilized to conduct various assessments aimed at evaluating biomarkers such as CRP, ESR, RF, and autoantibodies like anti-CCP and anti-CarP. Results This study examined the role of various autoantibodies and biomarkers in RA across three distinct groups. Group 1 predominantly consisted of middle-aged individuals, and women constituted the majority in both Group 1 and Group 2, consistent with higher RA prevalence among females. In Group 1, 65.7% of patients tested positive for anti-CarP, while in Group 2, 48.6% tested positiveeven when RF and anti-CCP antibodies were absent. This suggests a potential diagnostic role for anti-CarP antibodies in identifying RA patients early. CRP and ESR levels were significantly elevated in RA patients (Groups 1 and 2) compared to healthy controls (Group 3), indicating higher inflammatory activity in affected individuals. We also observed that anti-CarPantibodies had a specificity of 69.1% and a sensitivity of 78.2%. Positive correlations between the diagnosis of RA and anti-CarP antibody positivity were observed across the groups and correlated well with the inflammatory markers and signs such as joint damage. The data were found to be statistically significant. Conclusions Our study showed a significant correlation between joint damage and CRP levels and a positive correlation between anti-CarP antibodies and ESR and CRP values. These findings suggest that anti-CarP antibodies can offer certain advantages over RF and anti-CCP antibodies in RA diagnosis due to their early detection potential, higher specificity, complementary diagnostic role, and predictive value for disease severity.

The impact of autoantibodies on the efficacy of biological disease-modifying anti-rheumatic drugs in rheumatoid arthritis: meta-analysis of randomized controlled trials.

To investigate the efficacy of bDMARDs in patients with RA with RF/ACPA compared with patients without these autoantibodies. Previous systematic literature reviews performed by EULAR RA management task forces were searched for qualifying RCTs. RCTs investigating the efficacy of bDMARDs and including both autoantibody-positive (≤80% of total population) and -negative RA patients were eligible. For trials comparing bDMARD+csDMARD vs csDMARD, relative risks (RR) comparing two groups (RF + vs RF-, ACPA+ vs ACPA-) were calculated for efficacy outcomes for each arm. Subsequently, relative risk ratios (RRRs) were computed, as the ratio of RR of the bDMARD-arm and the RR from the non-bDMARD-arm. Pooled effects were obtained with random effect meta-analyses. Data from 28 eligible RCTs were analyzed, pooling 23 studies in three subgroups: 6 including csDMARD-naïve patients, 14 csDMARD-IR, and 3 TNFi-IR patients. In csDMARD-naïve and csDMARD-IR patients, seropositivity was not associated with a better response to bDMARDs: pooled 6-month ACR20 RRRs 1.02 (0.88-1.18) and 1.09 (0.90-1.32), respectively. Other outcomes showed no difference between groups either. In TNFi-IR patients, based on 3 trials, the 6-month ACR20 RRR was 2.28 (1.31-3.95), favoring efficacy in seropositive patients. Other outcomes mostly showed no significant difference between the groups. Based on the mode of action, efficacy was comparable between RF-positive and RF-negative patients for both TNFi and non-TNFi treatment and also for the individual bDMARDs. The effect of bDMARDs is generally comparable in patients with and without RF/ACPA, regardless of the patient population, the mechanism of action or individual drug used.

Correlation Between Rod Fracture and Shear Stress: A Novel Parameter

We sought to assess the accuracy of a novel parameter proportional to the rod shear stress (RSS) in identifying patients at risk of rod fracture (RF) after surgery for correction of adult spinal deformity. We performed a retrospective medical record review of patients aged ≥18 years treated for adult spinal deformity between 2004 and 2014 with ≥24 months of follow-up. The primary outcome was RFs identified radiographically. Patient weight (w), number of instrumented levels (N), and minimum rod diameter (d) were recorded and used to calculate the RSS parameter (RSS=Nwd2). Receiver operating characteristic curves were produced and the area under the curve (AUC ± 95% confidence interval [CI]) was calculated to compare this parameter's discriminative accuracy to that of its constituent variables. The sensitivity, specificity, and likelihood ratios (LRs) were calculated. A total of 28 RF-positive and 154 RF-negative patients were included. The average age was 59.2 ± 9.6 years, and 93.4% were women. The RSS parameter produced the greatest AUC (0.73 ± 0.11). At an RSS cutoff of 30.1, it achieved a sensitivity of 71.4% and specificity of 71.4% (LR, 2.5; 95% CI, 1.8-3.5). The number of instrumented levels produced the next-greatest AUC (0.65 ± 0.12), with a sensitivity of 78.6% and specificity of 50.0% at a cutoff of 15 (LR, 1.6; 95% CI, 1.2-2.0). The RSS is calculated using easily obtainable information and shows potential as a tool for predicting patient-specific risk of RF after spinal fusion. The number of instrumented levels also correlates strongly with the occurrence of RFs and is not significantly less accurate than the RSS. A larger sample size and prospective validation would be useful in determining with greater confidence which parameter is superior for predicting RFs after spinal fusion.

In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation

ObjectivesTo investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis.MethodsIgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide...

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

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. 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. 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). 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.

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

To investigate the serum level of soluble CD27 (sCD27) and its potential clinical significance in rheumatoid arthritis (RA). 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. 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). Serum sCD27 might be a promising biomarker that reflects both disease activity and humoral immunity activity in RA.

Rheumatoid factor is associated with severe COVID-19.

Coronavirus disease 2019 (COVID-19) has been proposed as triggering autoimmunity. The aim of this study was to evaluate the presence and clinical significance of autoantibodies in patients with COVID-19. We retrospectively collected data from 245 patients who were hospitalized for COVID-19. All patients were tested for the presence of antinuclear antibody (ANA), rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), and anti-cytoplasmic neutrophil antibody (ANCA). Risk factors for death and critical COVID-19, defined as the need for invasive mechanical ventilation or extracorporeal membrane oxygenation, were analyzed. Ninety (36.7%) patients tested positive for ANA, and 51 (20.8%) patients tested positive for RF. Three patients each (1.2%) tested positive for ACPA and ANCA. RF-positive patients had higher rates of invasive mechanical ventilation and death than RF-negative patients (70.6% vs 28.4%, P < 0.001 and 45.1% vs 18.6%, P < 0.001, respectively). Underlying lung disease, kidney disease, heart disease, quick COVID severity index (qCSI), and lactate dehydrogenase (LDH) were associated with in-hospital death. RF (odds ratio [OR] 7.31, 95% CI 2.50-21.37, P < 0.001), qCSI (OR 1.42, 95% CI 1.19-1.69, P < 0.001), and LDH (OR 1.004, 95% CI 1.002-1.005, P < 0.001) were associated with critical COVID-19. Combination of RF, qCSI, and LDH showed good prognostic value (area under the curve=0.903, P < 0.001) for critical COVID-19. ANA and RF were frequently detected in COVID-19 patients. RF could be a risk factor for critical COVID-19. The results of this study suggest immune dysfunction contributes to the complications of COVID-19.

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.

IgA rheumatoid factor is associated with bone mineral density preservation in rheumatoid arthritis

Autoantibodies such as IgM rheumatoid factor (RF) and anti-citrullinated proteins/peptides antibodies (ACPA) have previously been incriminated in systemic bone loss in rheumatoid arthritis (RA). There are, however, no data describing association of IgA RF and IgG RF with systemic bone loss. This study was aimed to investigate the association of RF isotypes with systemic bone loss among patients with RA. RF isotypes and ACPA were measured by enzyme-linked immunosorbent assay among 153 patients with RA. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry. Ninety-four (61.4%) patients had positive IgA RF, 89 (58.2%) had positive IgG RF, 109 (71.2%) had positive IgM RF, whereas 122 (80.3%) RA patients tested positive for ACPA. Compared to the IgA RF-negative patients, IgA RF-positive patients exhibited higher disease activity and had higher RF titers. Seven (4.6%) patients had low BMD at femoral neck, 12 (7.8%) at total femur, and 47 (30.7%) at lumbar spine. IgA RF was found to be associated with protection against low BMD at spine (OR = 0.47, 95% CI = 0.23-0.95, p = 0.034). This association was further confirmed in the multivariate regression analysis taking into account several potential confounding factors(OR = 0.21, 95% CI = 0.06-0.65, p = 0.039). No association between low BMD and the presence of IgG RF or IgM RF or ACPA was found. IgA RF for the first time ever was shown to be associated with BMD preservation at spine in RA. Key points • IgA RF was associated with protection against low spinal BMD. • No association between low BMD and the presence of IgG RF or IgM RF was found.

14-3-3η Protein as a Potential Biomarker in Juvenile Idiopathic Arthritis.

The 14-3-3η (eta) protein was evaluated as a biomarker in a cohort of patients with juvenile idiopathic arthritis (JIA), as well as disease- and healthy-controls, to determine its potential clinical utility. In this case-control study, levels of 14-3-3η protein were evaluated in archival specimens from patients with JIA, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), as well as healthy pediatric controls. Just over 200 patients were evaluated, using specimens banked between 1990 and 2011. Comparisons were made to complete blood cell count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and anti-nuclear antibody (ANA) positivity. 14-3-3η at levels 0.2 ng/mL or higher was considered positive. Fisher’s exact tests, odds ratios, 95% confidence intervals, and p-values were reported. 14-3-3η positivity was seen in all included JIA subtypes. The rate of positivity was the highest in RF-positive (pos) polyarticular JIA. In the disease and healthy controls, lower rates of positivity were observed. The frequency of 14-3-3η positivity among RF-positive and RF-negative (neg) polyarticular JIA patients, especially at values ≥0.5 ng/mL (associated with poor outcomes in adults), was also highest. Several JIA patients with 14-3-3η positivity developed RF and anti-CCP positivity later in their disease. Significant levels of 14-3-3η can be found in approximately 30% of RF-pos and RF-neg patients with polyarticular JIA. This protein may represent a new biomarker for polyarticular JIA, particularly RF-neg polyarticular JIA.

Plasma micro-RNA-22 is associated with disease activity in well-established rheumatoid arthritis.

Micro-RNAs (miRNAs) are an endogenous small, single-stranded, non-coding RNAs with a 18-25 nucleotide long and have been reported as potential extracellular biomarkers of various diseases. They mainly decrease the gene expression by inhibiting the translation or cause mRNA destabilisation. The aim of our study was to identify miRNAs whose concentration may be associated with severity of rheumatoid arthritis (RA). A total of 74 unrelated individuals, 50 with RA and 24 in a control group were enrolled to the study. Real-time PCR was used to evaluate the plasma concentration levels of 8 miRNAs: miR-26a, miR-125b, miR-20b, miR-22, miR-221, miR-17, miR-93, miR-106b. The logistic regression results showed that miR-22 (p=0.0003) and miR-26a (p=0.049) may be the most important molecules distinguishing RA patients and healthy controls. Moreover, the quantity of miR-22 was different between rheumatoid factor (RF)-positive and RF-negative patients (p=0.04). In this study we demonstrated for the first time that plasma concentration of miR-22 may be considered as a potential molecular marker associated with disease activity.

THU0181 SOLUBLE VASCULAR BIOMARKERS IN RHEUMATOID ARTHRITIS AND ANKYLOSING SPONDYLITIS: EFFECTS OF ONE-YEAR ANTI-TNF-Α THERAPY

Background:Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with inflammatory atherosclerosis, increased cardiovascular (CV) morbidity and mortality. Numerous proteins may serve as biomarkers of inflammatory atherosclerosis. The treatment of arthritis by tumour necrosis factor α (TNF-α) inhibitors may decrease the serum concentrations of these biomarkers.Objectives:In this study we wished to determine circulating levels of oxidized LDL (oxLDL) - β2 glycoprotein I (β2GPI) complexes (AtherOx), anti-hsp60 antibodies, soluble urokinase plasminogen activator receptor (sUPAR) and N-terminal B-type natriuretic peptide (NT-proBNP) in sera of RA and AS patients. We also wished to assess the effects of anti-TNF treatment on these biomarkers.Methods:Altogether 53 arthritis patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study.Circulating oxLDL/β2gpI complexes, anti-human Hsp60 immunoglobulin G (IgG) levels and BNP8-29fragment levels were assessed by ELISA. suPAR levels were assessed by suPARnostic®Quick Triage test. All laboratory assessments were performed at baseline, as well as 6 and 12 months after treatment initiation. Results were associated with DAS28, BASDAI, CRP.Results:In the mixed cohort of 53 arthritis patients, the circulating levels of oxLDL/β2gpI significantly decreased after 12 months of anti-TNF therapy (0.20±0.11 U/ml) compared to baseline (0.24±0.10 U/ml; p=0.014). There was a tendency of non-significant decrease after 6 months (0.23±0.14 U/ml) versus baseline. Anti-Hsp60 antibody levels did not change after 6 months (158.6±138.6 AU/ml) and 12 months (167.3±143.3 AU/ml) compared to baseline (170.3±140.4 AU/ml). Among the patients, 21.2% had low, 36.4% “observe”, 9.1% high and 33.3% critical suPAR levels. suPAR levels showed a tendency of non-significant decrease after 6 months (11.3±17.7 ng/ml) and 12 months (10.3±15.3 ng/ml) versus baseline (11.5±16.4 ng/ml). However, when the four serum level categories described above were considered, suPAR concentrations exerted significant decrease in RA patients with critical suPAR levels (&gt;9ng/ml) (p=0.04). Similarly, BNP fragment levels showed only a tendency of decrease after 6 months (518.2±422.4 pmol/l) and 12 months (484.1±418.2 pmol/l) versus baseline (530.8±441.8 pmol/l). However, serum BNP levels at baseline and after 12 months were significantly increased in CCP positive compared to CCP negative RA patients (baseline: 670.6±323.0 versus 138.0±436.4 pmol/l; p=0.030 and 12 months: 652.9±283.2 versus 456.5±423.1 pmol/l; p=0.021), as well as in RF positive compared to RF negative RA patients (baseline: 680.6±381.6 versus 292.9±198.3 pmol/l; p=0.007 and 12 months: 668.9±346.5 versus 312.2±207.0 pmol/l; p=0.001).Conclusion:One-year anti-TNF therapy significantly decreased circulating oxLDL/β2gpI complex levels. This therapy also decreased suPAR levels in patients with critically high suPAR. BNP fragment levels were associated with seropositivity in RA. These vascular biomarkers may reflect the effects of TNF inhibition on endothelial activation.Acknowledgments:This study was sponsored by an investigator-initiated grant from Pfizer.Disclosure of Interests:Anita Pusztai: None declared, Attila Hamar: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Nóra Bodnár: None declared, György Kerekes: None declared, Monika Czókolyová: None declared, Szilvia Szamosi: None declared, Levente Bodoki: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Gábor Nagy: None declared, Ibolya Szöllösi: None declared, Luis Lopez Employee of: Retired employee of Corgenix Inc., Eiji Matsuura: None declared, Zoltán Prohászka: None declared, Sándor Szántó: None declared, Zoltán Nagy: None declared, Yehuda Shoenfeld: None declared, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen, Gabriella Szücs: None declared

Serum levels of 14-3-3η are associated with increased disease risk, activity and duration of rheumatoid arthritis in Chinese patients.

The aim of the present study was to determine the association between serum 14-3-3η expression levels and disease risk, inflammation level and disease duration in Chinese patients with rheumatoid arthritis (RA). A total of 45 Chinese patients with RA, 45 patients with osteoarthritis (OA) and 44 age- and sex-matched (with the RA group) healthy control (HC) subjects were consecutively recruited for the present case-controlled study. In addition, the demographic and clinicopathological characteristics of the patients with RA were collected. Serum samples were obtained from patients with RA, patients with OA and the HCs, and the serum levels of 14-3-3η were determined by ELISA. Compared with that in the OA patients (P=0.006) and HCs (P<0.001), 14-3-3η expression was significantly increased in RA patients, and receiver operating characteristics (ROC) analysis indicated that it served as a potential predictive marker for the risk of RA. In patients with RA, serum levels of 14-3-3η were positively correlated with disease duration (P=0.003), erythrocyte sedimentation rate (P=0.006) and disease activity score in 28 joints (P=0.025). The proportion of rheumatoid factor (RF)-positive patients (P=0.023) and anti-citrullinated protein antibody (ACPA)-positive patients (P=0.002) with RA was increased (when 14-3-3η expression was increased) compared with RF-negative patients or ACPA-negative patients, respectively. Of note, 14-3-3η serum levels were able to distinguish patients with established RA (disease duration, >2 years) from patients with early RA (disease duration, ≤2 years) with an AUC of 0.759 (95% CI, 0.612-0.905), and the sensitivity and the specificity at the best cut-off point (14-3-3η=0.613 ng/ml) were 79.3 and 75.0%, respectively. Furthermore, 14-3-3η was able to differentiate between RF-positive RA patients and RF-negative patients or HCs. In conclusion, circulating 14-3-3η expression may serve as a novel biomarker for disease risk and activity of RA in Chinese patients.

TGF-β1 +869C/T polymorphism increases susceptibility to rheumatoid arthritis in North Indian population.

Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease, characterized by chronic inflammation, hyperplasia (swelling), tenderness, erosion of cartilage and bones in synovial joints. Transforming growth factor-β1 (TGF-β1) is an important regulator of inflammation, and its polymorphism is implicated in several diseases. Therefore, the study was done to determine whether TGF-β1 C/T gene polymorphism was associated with RA in North Indian population. Eighty-seven (male/female: 29/58) healthy controls and 76 (male/female: 17/59) RA patients were recruited for association study between TGF-β1 +869C/T polymorphism. TGF-β1 +869C/T polymorphism was genotyped by allele specific amplification refractory mutation system polymerase chain reaction (ARMS-PCR) to test susceptibility to clinical presentation of RA patients in North Indian population by comparing RA genotypes with control groups. The genotypic association studies and dominant, recessive, and allelic models revealed that TGF-β1 +869C/T gene polymorphism is involved in the onset of RA. TGF-β1 +869 T (either TT or CT) allele and TT v/s CC (OR = 36.18, 95% CI = 11.98-109.31, P = 0.001); TT + CT v/s CC (OR = 0.16, 95% CI = 0.08-0.33, P = 0.001); TT v/s CC + CT (OR = 0.04, 95% CI = 0.1-0.09, P = 0.001); and T v/s C (OR = 0.12, 95% CI = 0.07-0.2, P = 0.001) show significant association with RA as compared with CC genotype or C alleles (P = 0.001). The patient carrying T alleles showed significant associations with increased ESR, uric acid, CRP, DAS28-ESR, and number of tender joints as compared to other genotypes. In the presence of RF, DAS-28-ESR was high in CT genotype. ESR, CRP, and swollen joint count were highest in TT genotype of RF negative patients. TGF-β1 polymorphism is associated with disease activity of RA. Disease activity is strongly modulated in the presence of serum RF and TGF-β1 polymorphism. Key Points •TGF-β1 +869C/T polymorphism was found to be associated with RA in the patients. •The polymorphism showed significant association with all inflammatory parameters as ESR, CRP, and DAS-28 in RA subjects. •RF negative patients showed high ESR, CRP, and swollen joint count with TT genotype. •TGF-β1 polymorphism and serum RF are modulating disease activity in RA.

Peptidylarginine deiminase 4 (PAD4) activity in early rheumatoid arthritis

Objectives: Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes catalysing the conversion of arginine residues to citrulline, which may constitute a risk factor in rheumatoid arthritis (RA) pathogenesis. We investigated PAD activation by serum (PADAct) in early RA, and the associations between PAD activation and disease characteristics, treatment response, and progression of radiographic damage.Method: Sera from disease-modifying anti-rheumatic drug (DMARD)-naïve early RA patients (n = 225), classified according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria, and healthy controls (n = 63) were analysed for PAD4 activating capacity at 0, 3, 12, and 24 months using a high-performance liquid chromatography fluorometric method. Associations for PADAct were evaluated by Mann–Whitney U and chi-squared tests. Changes in PADAct levels were compared using the Wilcoxon signed-rank test.Results: PADAct positivity occurred in 42% (n = 95) of the patients and was more prevalent in anti-citrullinated protein antibody (ACPA)-positive vs ACPA-negative patients (47% vs 20%, p = 0.002), but not in rheumatoid factor (RF)-positive vs RF-negative patients (44% vs 38%, p = 0.49). PADAct-positive were younger than PADAct-negative patients [mean ± sd 48.7 ± 13.5 vs 53.2 ± 13.7 years, p = 0.011]. Median [25th, 75th percentile] PADAct levels were higher in patients than in controls (8768 [7491, 11 393] vs 7046 [6347, 7906], p < 0.0001) and decreased after initiation of DMARD treatment, but were not associated with treatment response or progression of radiographic damage after 2 years of follow-up.Conclusion: Serum capacity to activate PAD4 was associated with ACPA and RF positivity and earlier disease onset in early RA patients, and decreased after initiation of DMARD treatment, indicating that anti-PAD treatment could potentially be beneficial in RA.

Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis: results from the SWEFOT trial population

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 μg/mL and ADA development in a randomized setting.Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 μg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 μg/mL or ADA positivity, using logistic regression.Results: Categorization of sIFX levels into < 0.2, 0.2–2.9, 3.0–7.0, and > 7.0 μg/mL showed a dose–response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 μg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 μg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up.Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 μg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders.Trial registration: SWEFOT NCT00764725 (https://clinicaltrials.gov/ct2/show/NCT00764725).

Anti-mutant citrullinated vimentin antibody in the diagnosis of rheumatoid arthritis

Objective This study aimed to assess the diagnostic value of anti-mutated citrullinated vimentin (MCV) antibodies in rheumatoid arthritis (RA) and its correlation with disease progression, extra-articular manifestations and overlap syndrome. Methods Retrospective Studies. Clinical data of 837 patients in PekingUnionMedicalCollegeHospitalfrom June to August 2017 were collected, including the result of anti-MCV, anti-cyclic citrullinated peptide (anti-CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR) and High-sensitivity-C-reactive protein (CRP). According to the 1987 American College of Rheumatology classification criteria for rheumatoid arthritis, there were 323 patients diagnosed with RA, including 59 males and 264 females with the average age of 51 years. According to whether the RA patients have overlap syndrome with other autoimmune disease (AID) or have extra-articular manifestations, 258 cases were categorized into RA group, including 47 males and 211 females with the average age of 50 years; 14 cases were categorized into the group of overlap syndrome, including 1 male and 13 females with the average age of 36 years; 51 cases were categorized into the group of extra-articular manifestations, including 11 males and 40 females with the average age of 59 years.According to 2010 rheumatoid arthritis classification criteria for destruction in joints, the radiographic changes were divided into 4 stages.There were 203 casesenrolled in our study, 88 caseswere fitted into early stage group (stage I)including 21 males and 67 females with the average age of 48 years; 115 caseswere fitted into progressive stage group, which compromisedstageⅡ (interim stage), stage Ⅲ (severe stage) and stage Ⅳ (final stage) cases, including 19 males and 96 females with the average age of 53 years. Mann-Whitney U test, χ2 test,Receiver operating characteristic (ROC) curves and Spearmancorrelation coefficientwere used in Statistical analysis. Results Ⅰ Amongdiagnosed RA patients, 199 (61.6%) cases were positive for anti-MCV, anti-CCP and RFsimultaneously, 42 (13%) cases were positive for anti-MCV, which was higher than anti-CCP positive (1 cases, 0.3%) or RF positive (7cases, 2.2%). The difference was statistically significant(P<0.001, P<0.001). Ⅱ ROC was calculated and MCV=35.95 U/ml was used as best-fit cut-off value. The AUC for anti-MCV was 0.867, while the sensitivity was 80.5% and specificity was 80.9%. Ⅲ The detection levels of anti-MCV (682.8 (106.4-1000.0)), anti-CCP (407 (4.0-1536.0)) and RF (82.8 (21.1-244.9)) in the group of progressive stage were higher than those in the group of early stage (114.5 (28.5-1000.0), 62.5 (5.0-1020.7), 50.1 (6.7-127.1)), which showed a significant difference (P<0.05, P<0.05, P<0.05). The anti-MCV, anti-CCP and RF were positively related to the degree of joint destruction (r=0.229, P<0.05; r=0.187, P<0.05; r=0.167, P<0.05); anti-MCV and anti-CCP were positively related to extra-articular manifestation (r=0.152, P<0.05; r=0.136, P<0.05). Conclusion Anti-MCV antibodies are more sensitive in patients with RA, and have complementary diagnostic value for anti-CCP and RF-negative patients; high levels of anti-MCV and anti-CCP in RA patients are associated with RA progression and extra-articular involvement. Key words: Arthritis, rheumatoid; Autoantibodies; Peptides, cyclic; Vimentin

Rheumatoid factor as predictor of response to treatment with anti-TNF alpha drugs in patients with rheumatoid arthritis

We determined whether rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) can predict remission or severe disability in rheumatoid arthritis (RA) patients treated with anti-tumor necrosis factor (TNF) alpha drugs.We performed a cohort study based on the clinical data from a referral center for the treatment of RA in Bogotá, Colombia, were included patients aged ≥18 years with diagnosis of RA with an active disease and for whom a treatment scheme was begun with anti-TNF alpha medication, with a minimum follow-up time of 12 months. Disease activity of Rheumatoid Arthritis was assessed through measurement of RF, ACPA, disease activity score (DAS28), and health assessment questionnaire (HAQ). We calculated the incidence rates (IRs) for remission and severe disability. We also calculated the incidence rate ratio (IRR) for each outcome by adjusting for possible confounders using the Poisson regression method. The hypothesis was tested with a P value of <.05. Statistical analysis was performed in Stata 15.We included 400 patients receiving an anti-TNF alpha agent. Median age was 60 years, and 322 patients were women (80.5%). RF was positive in 357 patients (89%), ACPA in 348 patients (87%), and co-positivity in 324 patients (81%). Median follow-up was 41 months (range, 12–79 months). The IR for remission was 23 per 100 person-years in RF-negative patients and 16 per 100 person-years in RF-positive patients. The adjusted IRR (age sex, treatment, and ACPA) was 1.51 (95%CI, 1.05–2.18). The IR for severe disability was 10.8 per 100 person-years in the RF-positive cohort and 2.3 per 100 person-years in the RF-negative cohort. The IRR adjusted for these factors was 4.37 (95%CI, 1.6–12). Co-positivity had a similar behavior to RF. No differences were recorded in the rates of remission or disability in ACPA-positive and ACPA-negative patients.Our findings suggest that remission is less frequent and severe disability more frequent in RF-positive patients treated with anti-TNF alpha agents than in RF-negative patients.

Frequency of CD19+CD24hiCD38hi regulatory B cells is decreased in peripheral blood and synovial fluid of patients with juvenile idiopathic arthritis: a preliminary study

BackgroundTo understand the relationship between regulatory B cells (Bregs) and juvenile idiopathic arthritis (JIA), we analyzed the percentages of Bregs and their function in peripheral blood (PB) and synovial fluid (SF) of JIA patients.MethodsTwenty-one JIA patients and 11 children with growing pain but without known rheumatic diseases as controls were included. The B cell phenotype and intracellular production of IL-10 of Bregs were assessed by flow cytometry. Mononuclear cells from PB and SF were stimulated to produce IL-10 in vitro for the identification of IL-10- producing regulatory B cells.ResultsThe percentage of CD24hiCD38hi Bregs in the PB of JIA patients was significantly decreased compared to that in controls, and it was even lower in the SF of JIA patients compared to that in the PB. CD24hiCD38hi Bregs frequency was significantly lower in the PB of RF-positive patients than in RF-negative patients. Frequency of IL-10-producing regulatory B cells (B10 cells) was significantly lower in active JIA patients than that in inactive patients.ConclusionsThe inability of the host to produce enough regulatory B cells in PB and especially in SF of JIA patients may contribute to the disease, especially the local inflammation.