Autoimmune diseases, autoantibody status and silicosis in a cohort of 1238 workers from the artificial stone benchtop industry.

OBJECTIVES: Autoimmune disorders are multifactorial but occupational exposures have long been implicated, including respirable crystalline silica (RCS). A modern epidemic of silicosis is emerging internationally, associated with dry processing of engineered stone with high (>90%) RCS content. We aimed to investigate the prevalence of clinical autoimmune disease and common autoantibodies in exposed workers. METHODS: Stone benchtop industry workers in Victoria, Australia were offered free screening for silicosis and related disorders. Symptoms or diagnoses of autoimmune disease were evaluated by questionnaire and blood tests taken for rheumatoid factor (RF), antinuclear antibodies (ANAs) and extractable nuclear antigens (ENAs). RESULTS: Among 1238 workers (93.3% male) screened from 2019 to 2021, 0.9% were confirmed with autoimmune disease. Among those without clinical disease, 24.6% had detectable ANAs (93.5% male), 4.6% detectable ENAs and 2.6% were positive for RF. Silicosis was diagnosed in 253 workers (24.3% of those with diagnostic information available). Of those with ANA readings, 54 (6.6%) had ANA titre >1:320. The likelihood of positive autoantibodies increased with age; smoking; higher exposure to RCS and silicosis diagnosis. CONCLUSION: The proportion of workers with detectable ANAs or ENAs was considerably higher than the 5%-9% expected in the general population. Some of the antibodies detected (eg, Scl-70, CENPB) have high sensitivity and specificity for systemic sclerosis. Long-term follow-up will be needed to estimate incidence. Rheumatologists should explore occupational history in new cases of autoimmune disease. Screening for autoimmune disease is indicated in workers exposed to RCS as these individuals need specialised management and may be entitled to compensation.

[High expression of anti-ß2 glycoprotein I (ß2GPI) autoantibody exacerbates inflammation and immune dysfunction in connective tissue disease].

Objective To observe the expression of anti-ß2 glycoprotein I (ß2GPI) autoantibody in connective tissue diseases and its relationship with the degree of inflammation and immune function. Methods Patients with broad connective tissue diseases including connective tissue disease (CTD), rheumatoid arthritis (RA), Sjogren's syndrome (SS), and systemic lupus erythematosus (SLE) were observed. ß2GPI was quantified by chemiluminescence, ESR was measured by Weil's method, and C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated polypeptide (CCP) antibody were measured by automatic biochemical analyzer. Results ß2GPI and their subtypes were significantly higher in RA patients compared with CTD, SS, and SLE patients. CRP was positively associated with anti-ß2GPI antibody and anti-ß2GPI antibody IgM in patients with connective tissue disease. ESR was positively associated with anti-ß2GPI antibody. Anti-ß2GPI antibody and anti-ß2GPI antibody IgM were elevated in the abnormal CRP group compared with the normal CRP group. Compared with the ESR normal group, anti-ß2GPI antibody and anti-ß2GPI antibody IgG were elevated in the ESR abnormal group. Anti-ß2GPI antibody was positively correlated with ESR and anti-CCP antibody in RA patients. Anti-ß2GPI antibody IgG was positively correlated with RF. Conclusion ß2GPI can be used as a predictor of the degree of inflammation and assessment of immune disorders in CTD.

Predictive factors and treatment outcomes associated with difficult-to-treat rheumatoid arthritis conditions: the ANSWER cohort study.

OBJECTIVES: To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biologic DMARDs (bDMARDs) and Janus kinase inhibitors (JAKi). METHODS: Retrospective analysis was conducted on data from the ANSWER cohort comprising 3623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention. RESULTS: Of the 3623 RA patients, 450 (12.4%) met the first two criteria of the EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared with those under 65, hazard ratio [HR] = 0.46; 95% CI: 0.31, 0.69), higher rheumatoid factor (RF) titres (HR = 1.005; 95% CI: 1.00, 1.01), higher clinical disease activity index (HR = 1.02; 95% CI: 1.01, 1.03), lower methotrexate dosage (HR = 0.97; 95% CI: 0.95, 0.99), and comorbidities like hypertension (HR = 1.53; 95% CI: 1.2, 1.95) and diabetes (HR = 1.37; 95% CI: 1.09, 1.73). Anti-IL-6 receptor antibodies (aIL-6R, HR = 0.53; 95% CI: 0.37, 0.75) and JAKi (HR = 0.64; 95% CI: 0.46, 0.90) were associated with fewer discontinuations due to ineffectiveness compared with TNF inhibitors. Oral glucocorticoid usage (HR = 1.65; 95% CI: 1.11, 2.47) was linked to increased discontinuation due to toxic adverse events. CONCLUSION: Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention.

Radiological insights into rheumatoid meningitis - a rare central nervous system manifestation of rheumatoid arthritis: a retrospective review of six cases.

BACKGROUND: The objective is to analyze and review the clinical, laboratory, and neuroimaging characteristics of rheumatoid meningitis (RM) in six patients with known rheumatoid arthritis (RA). METHODS: We performed a retrospective review of patients diagnosed with RM from August 2012 to June 2023. To identify the cases, we used medical term search engines and the hospital´s radiology case database. Clinical information and laboratory findings were gathered from the medical records. A neuroradiologist with five years of experience reviewed and analyzed the RM to determine the characteristics findings of RM. RESULTS: Six patients with RM are included. Seizures along with headaches were among the clinical signs that were documented. All the patients had high levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptides (ACPA) in the peripheral blood. Biopsy in two cases confirmed typical rheumatoid nodules. Leptomeningeal enhancement was found bilaterally in all cases and was predominantly found in the frontoparietal region. "Mismatch DWI/FLAIR" was found in five patients. Bilateral subdural collections could be found in two patients. Brain PET scan revealed increased metabolism in two cases. CONCLUSION: Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA) with challenging clinical diagnosis due to non-specific symptoms. This study highlights the importance of MR in detecting characteristic neuroimaging patterns, including "mismatch DWI/FLAIR", to aid in early diagnosis. Increased awareness of this condition may facilitate timely intervention and improve prognosis. These results still need to be verified by large studies.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Kynurenic Acid Analog Attenuates the Production of Tumor Necrosis Factor-α, Calgranulins (S100A 8/9 and S100A 12), and the Secretion of HNP1-3 and Stimulates the Production of Tumor Necrosis Factor-Stimulated Gene-6 in Whole Blood Cultures of Patients With Rheumatoid Arthritis.

Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with complex pathogenesis involving a variety of immunological events. Recently, it has been suggested that kynurenic acid (KYNA) might be a potential regulator of inflammatory processes in arthritis. KYNA has a definitive anti-inflammatory and immunosuppressive function. The aim of the present study is to investigate the complex effects of a newly synthesized KYNA analog-SZR72 on the in vitro production of tumor necrosis factor-α (TNF-α), tumor necrosis factor-stimulated gene-6 (TSG-6), calprotectin (SA1008/9), SA100 12 (EN-RAGE), and HNP1-3 (defensin-α) in the peripheral blood of patients with RA and the various effects of the disease. Methods: Patients with RA (n = 93) were selected based on the DAS28 score, medication, and their rheumatoid factor (RF) status, respectively. Peripheral blood samples from 93 patients with RA and 50 controls were obtained, and activated by heat-inactivated S. aureus. Parallel samples were pretreated before the activation with the KYNA analog N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride. Following the incubation period (18 h), the supernatants were tested for TNF-α, TSG-6, calprotectin, S100A12, and HNP1-3 content by ELISA. Results: SZR72 inhibited the production of the following inflammatory mediators: TNF-α, calprotectin, S100A12, and HNP1-3 in whole blood cultures. This effect was observed in each group of patients in various phases of the disease. The basic (control) levels of these mediators were higher in the blood of patients than in healthy donors. In contrast, lower TSG-6 levels were detected in patients with RA compared to healthy controls. In addition, the KYNA analog exerted a stimulatory effect on the TSG-6 production ex vivo in human whole blood cultures of patients with RA in various phases of the disease. Conclusion: These data further support the immunomodulatory role of KYNA in RA resulting in anti-inflammatory effects and draw the attention to the importance of the synthesis of the KYNA analog, which might have a future therapeutic potential.