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Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint damage and progressive destruction of adjacent cartilage and bones. Quick and accurate detection of rheumatoid factors (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) in serum is effective in diagnosing RA and preventing its progression. However, current methods for detecting these two biomarkers are costly, time-consuming, labor-intensive, and require specialized equipment. To address these limitations, a new microfluidic chip was developed to automatically conduct the dual-RA biomarker detection assay., Results: The integrated chip, which was equipped with micropumps, microvalves, and micromixers, was positioned underneath an optical detection module composed of a light-emitting diode, optical filters, condenser lenses, and a silicon photomultiplier to quantify the fluorescence signals of magnetic bead-bound analytes in two separate micro-chambers. The dual-target assay required only 5 μL of serum and took only 100 min to complete, accurately measuring RF and anti-CCP at concentrations ranging from 0.8 to 106.0 IU/mL and 6.0-59.0 U/mL, respectively. Compared with the gold standard, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the developed on-chip assays were 95.5 %, 94.4 %, 100.0 %, 100.0 %, 80.0 % for both RF and anti-CCP detection with 30 clinical samples., Significance: With its compact size of only 350 mm × 238 mm x 153 mm and low volumes of samples/reagents required, this system shows promise for point-of-care testing. The compact size, low sample volume requirement, and high performance of the developed system could significantly improve RA management and patient outcomes by providing rapid and accurate diagnostics in clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Current diagnosis and treatment of rheumatoid arthritis (RA) is still challenging. More than one-third of patients with RA could not be accurately diagnosed because of lacking biomarkers. Our recent study reported that scavenger receptor-A (SR-A) is a biomarker for RA, especially for anticyclic citrullinated peptide antibody (anti-CCP)-negative RA. Here, we further identified the B cell autoantigenic epitopes of SR-A. By a large-scale multicenter study including one training and three validation cohorts of 1954 participants, we showed that anticitrullinated SR-A peptide antibody (anti-CSP) was exclusively elevated in RA as a biomarker, particularly useful for seronegative RA. Combination of anti-CSP with anti-CCP demonstrated superior diagnostic value for RA, with sensitivity of 84.83% and specificity of 92.43%. Moreover, RA anti-CSP revealed distinct glycosylation patterns, capable of provoking inflammation in cartilage organoids and exacerbating disease progression in experimental arthritis. Together, these data identify anti-CSP as an RA autoantibody clinically applicable and actively involved in disease pathogenesis.

Objective: To analyze the diagnostic value of a combined test of anti-cyclic citrullinated peptide antibody (CCP), anti-keratin antibody (AKA), anti-carbamylated protein antibody (Carp antibody), and rheumatoid factor (RF) in the early diagnosis of rheumatoid arthritis (RA)., Methods: Sixty cases of RA admitted to our hospital from 2021 to 2022 (observation group) were selected, along with 50 cases of healthy physical examiners (control group). The results of CCP antibody, AKA antibody, Carp antibody, and rheumatoid factor in both groups were analyzed: the concentration of CCP antibody, AKA antibody, Carp antibody, and rheumatoid factor in each group at different levels; the comparison of various testing methods with the "gold standard" test; and the ROC curve analysis of CCP antibody, AKA antibody, Carp antibody, and rheumatoid factor in each group., Results: The concentrations of CCP antibody, AKA antibody, Carp antibody, and rheumatoid factor were significantly higher in the observation group than in the control group (p < 0.05). Furthermore, there was a significant increase in the concentrations of CCP antibody, AKA antibody, Carp antibody, and rheumatoid factor from the mild to moderate group (p < 0.05), as well as from the moderate to severe group (p < 0.05). Additionally, when comparing the mild and severe groups, there was a significant elevation in the concentrations of CCP antibody, AKA antibody, Carp antibody (p < 0.05), and rheumatoid factor (p < 0.05)., Conclusion: Anti-cyclic citrullinated peptide antibody, AKA antibody, Carp antibody, and rheumatoid factor combined tests have high sensitivity and specificity in the diagnosis of RA., (© 2025 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To identify differences in levels of serum biomarkers associated with atherosclerosis between anti-citrullinated protein antibodies (ACPA) positive groups., Methods: Cross-sectional data were used from the Dutch Lifelines Cohort Study combined with data derived from RA risk and early RA studies conducted at the University Medical Center Groningen (UMCG). Serum biomarkers of inflammation, endothelial cell activation, tissue remodeling and adipokine, which were previously associated with atherosclerosis, were measured with Luminex in four ACPA positive groups with different characteristics: without joint complaints, with joint complaints, RA risk and early RA groups., Results: Levels of C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor Receptor 1 (TNFR1) and vascular endothelial growth factor (VEGF) were significantly higher in the RA risk and early RA groups compared to the joint complaints and the no joint complaints groups. The difference remained statistically significant after correcting for renal function, smoking and hypertension in multivariate logistic regression analysis, with focus on ACPA positive with joint complaints group versus RA risk group: CRP OR = 2.67, p = 0.033; IL-6 OR = 3.73, p = 0.019; TNFR1 OR = 1.003, p < 0.001; VGEF OR = 8.59, p = 0.019., Conclusion: Individuals at risk for RA have higher levels of inflammatory markers and VEGF, which suggests that they might also have a risk of higher cardiovascular disease (CVD); however, this does not apply to individuals with ACPA positivity with self-reported joint complaints or without joint complaints only. Therefore, it is important that individuals with RA risk are referred to a rheumatologist to rule in or out arthritis/development of RA and discuss CVD risk., (© 2024. The Author(s).)

Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with increased cardiovascular disease (CVD) risk and mortality. This work aimed to evaluate the serum levels of the novel CV biomarkers fetuin-A (fet-A), Dickkopf-1 (DKK-1), galectin-3 (Gal-3), interleukin-32 (IL-32), and catestatin (CST) in RA patients and their associations with RA parameters and CVD markers. A cohort of 199 RA patients was assessed for traditional CVD risk factors, RA disease activity, and biomarker levels. Carotid ultrasound was used to measure carotid intima-media thickness (cIMT) and carotid plaque presence (cPP). Multivariate analyses examined correlations between biomarkers and RA parameters, serological markers, and CVD markers. Adjusted models showed that elevated CST expression levels were associated with rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity (OR = 2.45, p = 0.0001 and OR = 1.48, p = 0.04, respectively) in the overall cohort and for RF in men and women, respectively. In addition, fet-A concentration was inversely associated with the erythrocyte sedimentation rate (ESR) in the overall cohort (β = -0.15, p = 0.038) and in women (β = -0.25, p = 0.004). Fet-A levels were also negatively correlated with disease activity (DAS28-ESR) scores (β = -0.29, p = 0.01) and fibrinogen concentration (β = -0.22, p = 0.01) in women. No adjusted associations were observed for Gal-3, DKK-1 or IL32 concentration. The study revealed no significant associations between the biomarkers and cIMT or cPP. The measurement of CST and fet-A levels could enhance RA patient management and prognosis. However, the utility of biomarkers for evaluating CV risk via traditional surrogate markers is limited, highlighting the need for continued investigations into their roles in RA.

Background: Rheumatoid arthritis (RA) and periodontal disease (PD) are both characterized by an inflammatory reaction. Anti-cyclic citrullinated peptide (anti-CCP) is a common diagnostic test for RA. Anti-CCP is proposed to be used as a serological biomarker to detect PD in patients with RA. Methods: A case-control study was designed for 94 subjects; 42 patients with RA and 52 without RA. PD and its types were investigated among these subjects. An enzyme-linked immunosorbent assay (ELISA) test was used to measure anti-CCP levels in these subjects. Results: Subjects were recategorized into four groups after PD diagnosis: group 1 for RA with PD (34.04%); group 2 for RA only (10.63%); group 3 for PD only (30.85%); and group 4 for individuals without RA and PD (24.46%). Anti-CCP may be considered an effective biomarker for predicting the development of PD in RA patients based on five current results found in group 1 compared to other groups. These included the detection of significantly higher anti-CCP levels, a high sensitivity (63.15%), low specificity (50%), higher cut-off value (58.53 U/ml), high positive predictive value (94.73%), and low negative predictive value (8.69%) of anti-CCP. Chronic periodontitis is the most common and has a significant association with elevated levels of anti-CCP. Conclusion: Measuring the anti-CCP level in RA patients may be a good indicator for PD diagnosis based on the suggested cut-off value. The sensitivity of the test is sufficiently reliable to produce true positive results. Anti-CCP may also be useful in the diagnosis of PD type, especially chronic periodontitis., Competing Interests: Disclosures: The authors declare they have no funding or competing interests for the work described in this article. Ethical approval (IRB) was obtained from the ethical committee of the first author college with a No. 32 in June 2020., (Copyright © 2024 Marshfield Clinic Health System.)

Background: Hashimoto's thyroiditis (HT) is an autoimmune disease that is frequently associated with other autoimmune conditions., Objective: To perform serological screening for rheumatoid arthritis (RA) in patients with HT., Methods: Our study included 88 consecutive serum specimens of patients with confirmed HT and 88 sex- and age-matched healthy subjects. All study participants were tested for anti-cyclic citrullinated peptides antibodies (CCP-Ab) and rheumatoid factor (RF). CCP-Ab and RF were performed using ELISA commercial kits. Statistical analysis was conducted using Epi Info, version 3., Results: Out of 88 patients with HT, 15 (17.0%) had CCP-Ab or RF. The frequency of serological markers of RA was significantly higher in patients than in control individuals (17.0% vs 4.5%; P = .007). RF was more frequent in patients than in the control group, and the difference was statistically significant (13.6% vs 3.4%; P = .01). Isolated RF-IgM was absent in all controls and present in 6 patients with HT (6.8% vs 0%; P = .02). Out of 14 male patients, 3 (21.4%) had antibodies of RA. There was no significant difference in age between patients with CCP-Ab or RF and those without., Conclusion: A high frequency of serological markers of RA was highlighted in patients with HT., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Nephroblastoma overexpressed protein (NOV/CCN3), the early discovered member of the CCN family, has recently been suggested to be involved in a number of inflammatory processes, including wound healing, alveolar epithelial cell inflammation, cancer metastasis, and macrophage foam cell formation. However, the role of CCN3 in rheumatoid arthritis (RA), a classic autoimmune and inflammatory disease, remains elusive. RA is a chronic systemic autoimmune disease that eventually leads to cartilage and bone destruction and joint dysfunction. In this study, we investigated the potential of serum CCN3 as a biomarker for RA. The serum levels of CCN3 were measured by ELISA. The clinical and laboratory parameters were collected from a clinical record system, and disease activity was determined by joint disease activity score 28 (DAS28). Our results showed that the serum levels of CCN3 were significantly increased in RA patients compared to healthy controls. Furthermore, the CCN3 level was positively correlated with DAS28 (CRP), DAS28 (ESR), and the level of anti-CCP Ab, an autoantibody highly specific for RA. Furthermore, CCN3 showed a positive correlation with inflammatory cytokine IL-6, while no significant correlation with TNF- α was observed. These data suggest that CCN3 plays an important role in the development of RA and might be a potential disease activity biomarker for RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Yingying Wei et al.)

Introduction : Circulating markers of rheumatoid arthritis (RA) include the 14-3-3η protein, high-mobility group box-1 (HMGB1), anti-cyclic citrullinated peptide (anti-CCP) antibodies, anti-mutated citrullinated vimentin (anti-MCV) antibodies and rheumatoid factor (RF). We set out to determine which two markers in combination provided best discriminatory power for this disease. Methods : We recruited 108 RA patients, 102 non-RA patients (SLE, AS, Sjogren's syndrome, MCTD) and 90 healthy controls. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and the Youden index of each analyte were calculated and binary logistic regression analysis and receiver operating characteristic (ROC) curve were performed to evaluate their diagnostic value for RA alone and in paired combination. Results : As expected, all markers were elevated in RA patients ( P < 0.05). Binary logistic regression analysis showed that 14-3-3η had the highest odds ratio (95% CI) at 2.4 (1.9-2.8). Anti-CCP and anti-MCV had the highest areas under the curves [AUC (95% CI)] at 0.85 (0.78-0.90) and 0.85 (0.78-0.91) respectively (both P < 0.001). In serial detection (one marker followed by another), no combination had a Youden index >0.6. In parallel analysis (both considered together) several combinations had a Youden index >0.7, of which the highest (0.78) was anti-CCP with anti-MCV, with a sensitivity of 93.3% and specificity of 84.7%. Conclusions : Despite individual increases in serum 14-3-3η, HMGB1, anti-CCP, anti-MCV and RF, the combination of anti-CCP and anti-MCV might be of great help for diagnostic in RA, and so should be considered as routine tests for this disease.

Objective: Epidemiological studies suggest vitamin D deficiency as a potential risk factor for rheumatoid arthritis (RA) development, a chronic autoimmune disorder highly prevalent in indigenous North American (INA) population. We therefore profiled the circulating levels of 25-hydroxyvitaminD [25(OH)D], an active metabolite of vitamin D, in a cohort of at-risk first-degree relatives (FDR) of INA RA patients, a subset of whom subsequently developed RA (progressors)., Methods: 2007 onward, serum samples from INA RA patients and FDR were collected at the time of a structured baseline visit and stored at -20°C. Anti-citrullinated protein antibodies (ACPA), 25(OH)D, hs-CRP, vitamin-D binding protein (VDBP) and parathyroid hormone (PTH) levels were determined using ELISA and rheumatoid factor (RF) seropositivity was determined by nephelometry., Results: We demonstrate that 25 (OH) D concentrations were lower in winter than summer (P = 0.0538), and that serum 25(OH)D levels were higher in samples collected and stored after 2013 (P<0.0001). Analysis of samples obtained after 2013 demonstrated that 37.6% of study participants were 25(OH)D insufficient (<75nmol/L). Also, seropositive RA patients and FDR had lower 25(OH)D levels compared to ACPA-/FDR (P<0.05, P<0.01 respectively). Linear regression analysis showed 25(OH)D insufficiency was inversely associated with presence of RA autoantibodies. Longitudinal samples from 14 progressors demonstrated a consistent increase in 25(OH)D levels at the time they exhibited clinically detectable joint inflammation, without any significant change in VDBP or PTH levels. Spearman rank correlation analysis showed significant association between 25(OH)D and PTH levels, both in RA patients and progressors at RA onset time., Conclusion: We demonstrate that 25(OH)D levels in serum increased at RA onset in progressors. The potential role that vitamin D metabolites and their downstream effects play in RA transition requires further investigation., Competing Interests: The authors have declared that no competing interests exist.

(Gilles Boire): It was both a pleasure and an honor to present the 2019 Dunlop-Dottridge Lecture. My co-author and I will now discuss benefits and pitfalls of biomarkers developed through emerging techniques, evaluated through the experiential perspective of a seasoned clinician, as they apply to the quest for biomarker identification in rheumatic diseases.

Background: Disease-modifying antirheumatic drug (DMARD)-free remission, the sustained absence of synovitis after DMARD cessation, is increasingly achievable, especially in autoantibody-negative rheumatoid arthritis (RA). However, underlying mechanisms are unknown and patient subgroups that achieve this outcome are insufficiently characterized. We evaluated whether serological biomarkers at disease onset, as measured within the multi-biomarker disease activity (MBDA) score, are differently expressed in RA patients who achieve sustained DMARD-free remission., Methods: Two hundred ninety-nine RA patients were evaluated for achievement of sustained DMARD-free remission during a median follow-up of 4.3 years. Twelve biomarkers, as included in the MBDA score, were determined from the serum obtained at disease onset. Patients were categorized as having a low (< 30), moderate (30-44) or high (> 44) score. Analyses were stratified for anti-citrullinated protein antibodies (ACPA) based under the assumption that ACPA-positive and ACPA-negative RA are different disease entities., Results: Twenty percent achieved sustained DMARD-free remission. Overall, high MBDA scores were associated with achieving DMARD-free remission (high vs. low HR 3.8, 95% CI 1.2-12.2). Among ACPA-negative RA patients, moderate or high scores associated strongly with DMARD-free remission (moderate vs. low HR 9.4, 95% CI 1.2-72.9; high vs. low HR 9.7, 95% CI 1.3-71.1). This association was independent of age and other clinical factors (high vs. low HR 8.2, 95% CI 1.1-61.8). For ACPA-negative RA patients, the biomarkers C-reactive protein, serum amyloid A and matrix metalloproteinase-3 were individually associated with sustained DMARD-free remission. Among ACPA-positive RA patients, scores were not associated with DMARD-free remission., Conclusions: ACPA-negative RA patients who achieved sustained DMARD-free remission after treatment withdrawal were characterized by moderate to high MBDA scores at diagnosis. This is the first evidence that ACPA-negative RA can be subdivided in clinically relevant subsets at disease onset using a protein profile.

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We examined response to tofacitinib 5 or 10 mg two times a day in patients with seropositive vs seronegative RA., Methods: Data were pooled from five Phase III studies of conventional synthetic disease-modifying antirheumatic drug (csDMARD)- or biological DMARD-inadequate responders (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ORAL Standard [NCT00853385]). 'Serotype' subgroups were: anticyclic citrullinated peptide (CCP) and rheumatoid factor (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 response rates, Disease Activity Score (DAS28-4[ESR])-defined remission (DAS28-4[ESR]<2.6) and low disease activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36) physical functioning and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints were compared., Results: Baseline demographics/characteristics were similar across subgroups. Tofacitinib significantly improved ACR20/50/70 response rates, DAS28-4(ESR) LDA rates and CFB in HAQ-DI and FACIT-F vs placebo across subgroups. More anti-CCP+/RF+ than anti-CCP-/RF- patients had ACR20/50/70 responses (ACR20/50: both tofacitinib doses; ACR70: 10 mg two times a day). SF-36 physical functioning improved in anti-CCP+/RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both tofacitinib doses) and anti-CCP-/RF- patients (10 mg two times a day) vs placebo. More anti-CCP+/RF+ and anti-CCP+/RF- than anti-CCP-/RF- patients achieved DAS28-4(ESR) remission and LDA with tofacitinib 10 mg two times a day. Frequency of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across subgroups., Conclusion: Generally, tofacitinib efficacy (ACR20/50/70 responses) and safety were similar across subgroups. DAS28-4(ESR) remission rates and SF-36 physical functioning appeared lower in anti-CCP- patients., Competing Interests: Competing interests: PB has participated in advisory boards and received honoraria from AbbVie, BMS, Janssen, Pfizer Inc, Roche and UCB. SH has acted as a consultant for AbbVie, Celgene, Eli Lilly, Janssen, Pfizer Inc and Roche. PN has received funding for research and clinical trials, and honoraria for lectures and advice, from Pfizer Inc. CAC and KK are employees of Pfizer Inc and hold stock/stock options in Pfizer Inc. DW and KT are employees of Pfizer Australia Pty. Ltd and hold stock/stock options in Pfizer Inc.

Objective: Limited evidences are available on biomarkers to recognize Systemic Lupus erythematosus (SLE) patients at risk to develop erosive arthritis. Anti-citrullinated peptide antibodies (ACPA) have been widely investigated and identified in up to 50% of X-ray detected erosive arthritis; conversely, few studies evaluated anti-carbamylated proteins antibodies (anti-CarP). Here, we considered the application of machine learning models to identify relevant factors in the development of ultrasonography (US)-detected erosive damage in a large cohort of SLE patients with joint involvement., Methods: We enrolled consecutive SLE patients with arthritis/arthralgia. All patients underwent joint (DAS28, STR) and laboratory assessment (detection of ACPA, anti-CarP, Rheumatoid Factor, SLE-related antibodies). The bone surfaces of metacarpophalangeal and proximal interphalangeal joints were assessed by US: the presence of erosions was registered with a dichotomous value (0/1), obtaining a total score (0-20). Concerning machine learning techniques, we applied and compared Logistic Regression and Decision Trees in conjunction with the feature selection Forward Wrapper method., Results: We enrolled 120 SLE patients [M/F 8/112, median age 47.0 years (IQR 15.0); median disease duration 120.0 months (IQR 156.0)], 73.3% of them referring at least one episode of arthritis. Erosive damage was identified in 25.8% of patients (mean±SD 0.7±1.6), all of them with clinically evident arthritis. We applied Logistic Regression in conjunction with the Forward Wrapper method, obtaining an AUC value of 0.806±0.02. As a result of the learning procedure, we evaluated the relevance of the different factors: this value was higher than 35% for ACPA and anti-CarP., Conclusion: The application of Machine Learning Models allowed to identify factors associated with US-detected erosive bone damage in a large SLE cohort and their relevance in determining this phenotype. Although the scope of this study is limited by the small sample size and its cross-sectional nature, the results suggest the relevance of ACPA and anti-CarP antibodies in the development of erosive damage as also pointed out in other studies., Competing Interests: The authors have declared that no competing interests exist.

Background/purpose: Chronic periodontitis (CP) and rheumatoid arthritis (RA) are the most common chronic inflammatory diseases and their immunopathogenesis is similar. The aim of this study was to evaluate the effect of non-surgical periodontal treatment on the serum levels of RA-related inflammatory markers in patients with chronic periodontitis., Methods: Thirty-one Taiwanese adults with CP were included. Demographics and periodontal parameters, including probing depth, clinical attachment level, and number of remaining teeth in the oral cavity, were recorded. All subjects received non-surgical periodontal treatment such as scaling and subgingival root planing. Serum samples were collected before and after the treatment. Serum levels of anti-citrullinated protein antibodies (ACPA), rheumatoid factor, tumor necrosis factor-α (TNF-α), C-reactive protein, interleukin-1β (IL-1β), and Interleukin-6 (IL-6) were measured using an enzyme-linked immunosorbent assay., Results: Non-surgical periodontal treatment significantly reduced the serum ACPA (p = 0.015) and TNF-α levels (p = 0.026) in CP patients, particularly in patients with generalized CP. Furthermore, there was a significant and positive correlation between the number of extracted teeth and the reduction in the serum ACPA (p = 0.05) and IL-1β levels (p = 0.029) after non-surgical periodontal treatment., Conclusion: Non-surgical periodontal therapy may aid in the control of RA-related inflammatory markers in patients with CP. A large-scale study with well-defined populations is needed to clarify the benefit of non-surgical periodontal therapy., (Copyright © 2017. Published by Elsevier B.V.)

Background: The application of more sensitive imaging techniques, such as ultrasonography (US), changed the concept of non-erosive arthritis in systemic lupus erythematosus (SLE), underlining the need for biomarkers to identify patients developing the erosive phenotype. Anti-citrullinated peptide antibodies (ACPA), associated with erosions in inflammatory arthritis, have been identified in about 50% of patients with SLE with erosive arthritis. More recently, anti-carbamylated proteins antibodies (anti-CarP) have been associated with erosive damage in rheumatoid arthritis. We aimed to assess the association between anti-CarP and erosive damage in a large SLE cohort with joint involvement., Methods: We evaluated 152 patients (male/female patients 11/141; median age 46 years, IQR 16; median disease duration 108 months, IQR 168). All patients underwent blood draw to detect rheumatoid factor (RF) and ACPA (commercial enzyme-linked immunosorbent assay (ELISA) kit), and anti-CarP ("home-made" ELISA, cutoff 340 aU/mL). The bone surfaces of the metacarpophalangeal and proximal interphalangeal joints were assessed by US: the presence of erosions was registered as a dichotomous value (0/1), obtaining a total score (0-20)., Results: The prevalence of anti-CarP was 28.3%, similar to RF (27.6%) and significantly higher than ACPA (11.2%, p = 0.003). Erosive arthritis was identified in 25.6% of patients: this phenotype was significantly associated with anti-CarP (p = 0.004). Significant correlation between anti-CarP titer and US erosive score was observed (r = 0.2, p = 0.01)., Conclusions: Significant association was identified between anti-CarP and erosive damage in SLE-related arthritis, in terms of frequency and severity, suggesting that these antibodies can represent a biomarker of severity in patients with SLE with joint involvement.

Background: Anticitrullinated protein antibodies (ACPA) and citrullinated proteins play key roles in the pathogenesis of rheumatoid arthritis (RA). Many candidate citrullinated antigens have been identified in joints, but citrullinated proteins in sera are mostly uncertain in patients with RA. We explored the expression of citrullinated proteins in joints and sera of experimental arthritis, and we further investigated their specific expression correlated with the disease activity in patients with RA., Methods: Citrullinated protein expression in tissues was examined by IHC in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA). Serum citrullinated proteins from pGIA were examined by Western blotting, and the sequence was identified by MS. With the same methods, serum citrullinated proteins were analyzed in patients with RA, primary Sjögren's syndrome, systemic lupus erythematosus, and osteoarthritis as well as in healthy subjects, by Western blotting and MS. In patients with RA, the relationship between the expression of the identified protein (inter-alpha-trypsin inhibitor heavy chain 4 [ITIH4]) and clinical features was evaluated, and the levels of citrullinated ITIH4 were compared before and after biological treatment. The antibody response against citrullinated ITIH4 peptide was measured by enzyme-linked immunosorbent assay., Results: Citrullinated proteins were detected specifically in arthritic joints and sera from pGIA relative to controls. In sera, a common band of citrullinated protein at 120 kDa was revealed, and it fluctuated in parallel with arthritis score of pGIA by Western blotting. Interestingly, in 82% of RA patient sera, similar bands of citrullinated protein were specifically detected. These proteins were identified as citrullinated ITIH4, and especially the R438 site was commonly citrullinated between mice and humans. Citrullinated ITIH4 levels were associated with clinical parameters such as C-reactive protein (CRP), rheumatoid factor, and Disease Activity Score in 28 joints as measured by CRP in patients with RA. Its levels were decreased in correlation with the reduction of disease activity score after effective treatment in patients with RA. Moreover, antibody response to citrullinated epitope in ITIH4 was specifically observed in patients with RA., Conclusions: Our results suggest that serum citrullinated ITIH4 was specifically increased in patients with RA and could be a novel biomarker for assessing disease activity in patients with RA.

Background: The objective of the study was to compare the diagnostic yield of home-made ELISA tests based on synthetic chimeric fibrin/filaggrin citrullinated peptides (CFFCPs) with CCP3 and CCP3.1 commercial tests to detect anti-citrullinated protein/peptide antibodies (ACPAs) in rheumatoid arthritis (RA) patients. The prognostic value is also studied in a cohort of patients with early RA. Moreover, we transfer immunological assays from microtiter plates to microarray formats to allow the simultaneous analysis of several peptide sequences and reduce the volume of serum from patients., Methods: The diagnostic study includes: 100 RA patients who fulfilled the 1987 ACR criteria; 100 healthy blood donors; 35 patients with SLE according ACR criteria; 35 patients with PsA fulfilling the Wright and Moll criteria and 30 patients with HCV infection. The prognostic value study includes 50 patients with early RA with follow-up data available. All samples are from outpatients attending the Rheumatology Department of the Hospital Clinic of Barcelona., Results: Similar sensitivity, specificity and predictive values for the diagnosis of RA of CCFCPs compared to CCP3/CCP3.1 were obtained. Although a high concordance is observed between anti-CFFCPs and anti-CCP3/CCP3.1 in the early patients that rendered Larsen radiographic progression, CFFCPs could be a better marker of radiographic outcome. Strong correlations between the microarray and ELISA results were found for individual CFFCPs peptides., Conclusions: The development of multiplexing techniques combining a different spectrum of markers in a single analysis, including CFFCP peptides, could allow a more detailed analysis of the autoantibodies reactivity found in the sera of patients suffering of this heterogeneous disease.

Galectin-3 has been suggested as a pro-inflammatory mediator in animal arthritis and rheumatoid arthritis (RA). We aimed to study the serum level of galectin-3 in patients with newly diagnosed RA and associations with disease profile, Magnetic resonance imaging (MRI) findings and seromarkers of synovial matrix inflammation. One hundred and sixty DMARD naïve patients newly diagnosed with RA were included (CIMESTRA study). Clinical, serological and imaging data were recorded before treatment and at 6 weeks, 3 and 12 months. Galectin-3 and hyaluronan (HYA) were measured by ELISA (R&D and Corgenix, USA), and the N-terminal propeptide of type III collagen (PIIINP) by radioimmunoassay (Orion Diagnostica, Finland). One hundred and nineteen, 87 and 60 blood donors served as controls for galectin-3, HYA and PIIINP, respectively. Baseline galectin-3 was significantly elevated in anti-CCP positive (4.2 μg/l IQR [3.6;6.1]) patients as compared with anti-CCP negatives (4.0 μg/l [2.6;4.9], P = 0.05) and controls (3.8 μg/l [3.0;4.8], P < 0.01). During treatment, galectin-3 remained elevated, but increased transiently with peak values at 6 weeks. Galectin-3 correlated with baseline smoking, anti-CCP, and with MRI erosion score after 1 year of follow-up. HYA and PIIINP were elevated (P < 0.001) irrespective of anti-CCP status and correlated positively with synovitis assessed clinically and by MRI. HYA and PIIINP did not correlate with galectin-3. These observations indicate that HYA and PIIINP mainly reflect expansive synovitis proliferation while galectin-3 is more closely linked to autoimmunity, smoking and joint destructive processes., (© 2017 The Foundation for the Scandinavian Journal of Immunology.)