Diagnosis of rheumatoid arthritis: multivariate analysis of biomarkers

Objective. To test if a combination of biomarkers can increase the classification power of autoantibodies to cyclic citrullinated peptides (anti-CCP) in the diagnosis of rheumatoid arthritis (RA) depending on the diagnostic situation. Methods. Biomarkers were subject to three inclusion/exclusion criteria (discrimination between RA patients and healthy blood donors, ability to identify anti-CCP-negative RA patients, specificity in a panel with major non-rheumatological diseases) before univariate ranking and multivariate analysis was carried out using a modelling panel (n=906). To enable the evaluation of the classification power in different diagnostic settings the disease controls (n=542) were weighted according to the admission rates in rheumatology clinics modelling a clinic panel or according to the relative prevalences of musculoskeletal disorders in the general population seen by general practitioners modelling a GP panel. Results. Out of 131 biomarkers considered originally, we evaluated 32 biomarkers in this study, of which only seven passed the three inclusion/exclusion criteria and were combined by multivariate analysis using four different mathematical models. In the modelled clinic panel, anti-CCP was the lead marker with a sensitivity of 75.8% and a specificity of 94.0%. Due to the lack in specificity of the markers other than anti-CCP in this diagnostic setting, any gain in sensitivity by any marker combination is off-set by a corresponding loss in specificity. In the modelled GP panel, the best marker combination of anti-CCP and interleukin (IL)-6 resulted in a sensitivity gain of 7.6% (85.9% vs. 78.3%) at a minor loss in specificity of 1.6% (90.3% vs. 91.9%) compared with anti-CCP as the best single marker. Conclusions. Depending on the composition of the sample panel, anti-CCP alone or anti-CCP in combination with IL-6 has the highest classification power for the diagnosis of established RA.     

Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial

This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration–time curve (AUC) from time zero to last measurable concentration (AUC_0–last), AUC from time zero to infinity (AUC_0–∞), and maximum concentration (C_max) after two infusions. The primary efficacy endpoint was change from baseline to week 24 in Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP). Pharmacodynamics, immunogenicity, and safety were also assessed. 372 patients were randomly assigned to CT-P10 (n = 161) or RTX (n = 211 [US-RTX, n = 151; EU-RTX, n = 60]). For the co-primary pharmacokinetic endpoints, 90% confidence intervals (CI) for ratios of geometric means (CT-P10/US-RTX, CT-P10/EU-RTX or EU-RTX/US-RTX) all fell within the equivalence margin of 80–125%. Adjusted least squares (LS) mean (standard error) change from baseline in DAS28-CRP at week 24 was ?2.13 (0.175) for CT-P10 and ?2.09 (0.176) for RTX. The 95% CI (?0.29, 0.21) of the estimated treatment difference between CT-P10 and RTX (?0.04) was entirely within the efficacy equivalence margin of ±0.5. Pharmacodynamics, immunogenicity, and safety profiles were similar for CT-P10 and RTX. The pharmacokinetics of CT-P10, US-RTX, and EU-RTX were equivalent. CT-P10 and RTX were also equivalent in terms of efficacy and displayed similar pharmacodynamic, immunogenicity, and safety profiles up to week 24.     

The role of LAIR-1 (CD305) in T cells and monocytes/macrophages in patients with rheumatoid arthritis

The LAIR-1 receptor is expressed on a majority of mononuclear leukocytes. It is used as a biomarker when testing synovial fluid for evidence of rheumatoid arthritis (RA). The primary objective of this study was to measure T cell- and monocyte/macrophage-specific LAIR-1 expression in RA patients and compare this to LAIR-1 expression in osteoarthritis (OA) patients and healthy individuals. LAIR-1 expression was significantly decreased in circulating CD4⁺ T cells in RA patients compared to both OA patients and healthy individuals. In contrast, LAIR-1 is high in CD14⁺ monocytes and local CD68⁺ macrophages in synovial tissues from RA patients. Upon stimulation with TNF-α, LAIR-1 expression decreased in T-helper (Th)1 and Th2 CD4⁺ T cells from healthy donors. These results indicate that LAIR-1 may exert different functions on T cells and monocytes/macrophages and suggest that LAIR-1 may be a novel therapeutic target for the treatment of RA.     

Analysis of subgingival microbiome of periodontal disease and rheumatoid arthritis in Chinese: A case-control study

ObjectivePeriodontitis (PD) and rheumatoid arthritis (RA) share similar pathogenesis. Evidences indicated that oral bacteria play an important role in the etiology of both diseases. For example, Porphyromonas gingvialis connect the two diseases through immune responses. We designed this study to compare bacterial diversity in RA, PD and healthy subjects and to investigate whether there are other oral bacteria play an potential role in linking the two diseases.MethodsThis study included 3 groups of Chinese participants who visited Sichuan Provincial People’s Hospital during August 2018 and March 2019. Subgingival plaques were collected from RA group (n = 54), PD group (n = 45) and normal group (n = 44). Illumina MiSeq was used to compare the composition of subgingival microbiota and analyze correlations between oral bacteria and both diseases.ResultsAlpha diversity Analysis reflected similar microbiome profile in RA, PD and healthy groups. But we found Treponema was significantly more abundant in the PD and RA groups than healthy group at each taxonomic level from the phylum down to the genus level. Porphyromonas, Prevotella, and Veilonella were significantly more abundant in RA while Streptococcus, Gemella, Planobacterium were verified the opposite results.ConclusionsWe found no significant group differences referent to either microbial diversity or richness. But we picked out Spirochaetes which may link the two diseases. Upper/lower regulation of some microbia in RA may remind us a direction to explore the role they play in pathogenesis.     

Comparative modeling of TNFRSF25 (DR3) predicts receptor destabilization by a mutation linked to rheumatoid arthritis

We constructed a three-dimensional model of TNFRSF25 (death receptor-3; DR3), a tumor necrosis-receptor family member that is expressed on immune cells and on osteoblasts, to determine whether mutations that are linked to rheumatoid arthritis are likely to have effects on receptor function. Since the crystal structure of DR3 is not known, comparative modeling was used, aligning structural elements of the primary sequences of DR3 with TNFs which have been determined by crystallography, substituting the amino acids of the target protein for those in the known structure, introducing necessary deletions or insertions, followed by energy minimization to yield a putative structure. This approach has been validated by studies of other TNF-family receptors. The results show that the DR3 extracellular domain is comprised of four homologous cysteine-rich domains (CRDs), and that a mutation linked to rheumatoid arthritis is in a region critical for structural integrity of ligand-receptor complexes at the end of CRD3. Specifically, the D158G mutation eliminates two hydrogen bonds normally present in a N/D-T-V/D-C consensus motif typically found flanking the last cysteine of each CRD. This may cause aberrations in either T cell function or in response of bone cells to DR3 ligands, which may contribute to pathology in rheumatoid arthritis. Comparison of RA mutants to mutants in other TNFRSF receptors shows that these occur in homologous positions in CRDs, so that this site is proposed to be a 'hot spot' for mutations in TNFRSF family proteins.     

Breakdown of cartilage proteoglycan in a tissue culture model of rheumatoid arthritis

Proteoglycan breakdown was studied in a coculture model which mimics the confrontation between synovium and cartilage that occurs in rheumatoid arthritis. Bovine nasal-septum cartilage discs radioactively labeled (³⁵SO₄^2? with or without [³H]glucosamine) and ‘chased’ in non-radioactive medium were cultured in contact with minced rheumatoid synovial membranes for intervals up to 8 days. Synovium-stimulated (2–3 fold) cartilage breakdown was unaffected by ascorbate supplementation. Labeled products (small molecules plus proteoglycan complexes) in culture media were characterized by chromatographic, sedimentation and enzymic digestion methods. Breakdown was dominated by the release of a range of proteoglycan products, fully disaggregated and incapable of reaggregation with added hyaluronate. Because constituent glycosaminoglycans were of uniform size, proteoglycan polydispersity was attributed to differences in core protein length. Hydrocortisone inhibited degradation and partially prevented the shift of proteoglycans to lower average molecular weight. An additional breakdown pattern occasionally noted during the initial 48 h of coculture was characterized by release of a subpopulation of low charge-density proteoglycan bearing shortened glycosaminoglycan chains, consistent with glycosidase action. We conclude that rheumatoid synovia exhibit two distinct cartilage degradative potencies in vitro that may be important in vivo: (a) A variable hyaluronidase-like activity at early culture times, and (b) a dominant proteolytic activity generating an array of disaggregated proteoglycann products that differ largely on the basis of their core lengths. The response to hydrocortisone is consistent with inhibition of proteolysis through the stabilization of cellular membranes.     

Etiological role of cigarette smoking in rheumatoid arthritis: Nasal exposure to cigarette smoke condensate extracts augments the development of collagen-induced arthritis in mice

Cigarette smoking is a major environmental risk factor for rheumatoid arthritis (RA). However, the experimental bases supporting the etiological role of cigarette smoking in RA have not been fully provided. We have reported that cigarette smoke condensate (CSC), by means of subcutaneous injection into DBA/1J mice with collagen and complete Freund’s adjuvant or intraperitoneal injection one day before immunization, augmented the development of arthritis in the mouse model of collagen type II-induced arthritis (CIA). However, these experimental procedures may not be appropriate for cigarette smoking. In this study, we nasally exposed mice to mainstream CSC and found that CSC augmented the induction and development of arthritis and antibody level against collagen. Histological examination confirmed the augmenting effect of CSC. These findings provide experimental bases supporting the etiological role of cigarette smoking in RA.     

Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis

Most cell surface markers for CD4⁺CD25⁺ regulatory T cells (Tregs) are also expressed by activated non-regulatory T cells. Recently, CD127 down-regulation was found to identify functional Tregs in healthy individuals, but there are no data from patients with inflammatory conditions. We examined peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis patients with active inflammation and from healthy controls, and found that CD4⁺ T cells contained an equal proportion of CD25⁺CD127⁻/low cells in both groups. In patients, not all these cells expressed intracellular FOXP3. Upon activation by anti-CD3/anti-CD28, PBMC rapidly down-regulated CD127, while FOXP3 up-regulation was transitory and occurred in fewer cells. The activated cells were not anergic to restimulation and had no suppressive effects. The distinct kinetics indicate that the FOXP3⁻CD127⁻/low cells in rheumatoid arthritis patients most likely represent activated non-regulatory T cells. This complicates the use of CD127 for identification of Tregs in inflammatory diseases.     

Immunochemical and enzymatic study of ceruloplasmin in rheumatoid arthritis

Forty adult patients (30 women and 10 men) with rheumatoid arthritis (RA), treated with nonsteroidal anti-inflammatory drugs, were studied. Serum levels of immunoreactive ceruloplasmin, oxidase activity of the ceruloplasmin and total copper, as well as the specific oxidase activity (enzyme activity per unit of mass) and the copper/immunoreactive ceruloplasmin relationship were significantly higher in the group of patients than in the healthy control group (p < 0.001). However, no significant difference was found for the concentration of non-ceruloplasmin copper between both groups. A statistically significant negative correlation was obtained for the concentration of serum thiobarbituric acid-reacting substances with the immunoreactive ceruloplasmin and its oxidase activity in the group of patients (p < 0.005). These results suggest that in RA increases of serum copper are produced at the expense of the fraction linked to the ceruloplasmin, diminishing the proportion of apoceruloplasmin and other forms poor in copper. Although the increase in the serum concentration of ceruloplasmin might offer an additional safeguard against oxidative stress. it does not appear to have a beneficial effect upon the activity of the illness as evaluated by means the biological inflammation markers C-reactive protein, erythrocyte sedimentation rate and sialic acid.     

Genetic basis of rheumatoid arthritis: A current review

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. As with other complex traits, genome-wide association studies (GWASs) have tremendously enhanced our understanding of the complex etiology of RA. In this review, we describe the genetic architecture of RA as determined through GWASs and meta-analyses. In addition, we discuss the pathologic mechanism of the disease by examining the combined findings of genetic and functional studies of individual RA-associated genes, including HLA-DRB1, PADI4, PTPN22, TNFAIP3, STAT4, and CCR6. Moreover, we briefly examine the potential use of genetic data in clinical practice in RA treatment, which represents a challenge in medical genetics in the post-GWAS era.     

Levels of serum pentraxin 3, IL-6, fetuin A and insulin in patients with rheumatoid arthritis

ObjectiveThe aim of this study was to investigate the relationship between disease severity and biochemical parameters such as pentraxin-3, fetuin-A, IL-6, insulin and HOMA-IR levels in patients with rheumatoid arthritis.MethodsThis study included 60 patients with RA and 20 healthy controls. Serum pentraxin-3, fetuin-A, IL-6 and insulin concentrations were measured. Also, HOMA-IR values were calculated. Disease activity was assessed with Disease Activity Score (DAS28). To evaluate quality of life, the Health Assessment Questionnaire disability index was applied.ResultsThe serum values for ESR, CRP, pentraxin-3 and fetuin-A in patients with RA were found to be higher than control subjects (p values = 0.001, 0.001, 0.000, 0.000, 0.01, 0.02, respectively). A positive correlation was evident between the DAS 28 score and IL6 levels (r = 0.263, p = 0.045). We found no correlation between the DAS28 score and HOMA-IR, the levels of pentraxin 3, fetuin A, insulin (p < 0.05). Fetuin A levels were positively correlated with cumulative steroid dose (r = 0.382, p = 0.035). A statistically significant correlation was evident between presence of cardiovascular disease and HOMA-IR values in RA patients (r = 0.437, p = 0.032).ConclusionElevated levels of pentraxin-3, fetuin-A, CRP, ESR might play a role in the pathogenesis of RA. Levels of fetuin-A, insulin HOMA-IR, pentraxin-3, CRP and ESR were not associated with clinical severity of the RA.     

Emerging role of selenium in treatment of rheumatoid arthritis: An insight on its antioxidant properties

Rheumatoid Arthritis is an inflammatory disease primarily involves the inflamed synovium, affecting about 0.5–1 % population worldwide. It is the assumption from many years that oxidative stress is involved in the pathophysiology of inflammatory disorders like RA and many others. The significance of micronutrients in arthritis is linked to their role as a cofactor for the activation of selenoenzymes. Dietary interventions can manage the clinical symptoms of RA like pain, swelling and tenderness of joints and their associated disability along the progression of disease. This review highlights the antioxidant potential of selenium in treatment of RA along with the scientific evidence that Se supplementation can reduce disease progression by managing its clinical symptoms.     

A profile of immune response to herpesvirus is associated with radiographic joint damage in rheumatoid arthritis

Introduction  

Progression of joint damage despite appropriate therapy remains a significant problem for patients with rheumatoid arthritis (RA). This study was undertaken to identify profiles of immune response that correlate with radiographic joint damage as a first step toward the discovery of new pathogenic mechanisms of joint destruction in RA.     

益生菌治疗类风湿关节炎的meta分析和试验序贯分析

系统评价益生菌治疗类风湿关节炎的临床疗效。

检索中国生物医学数据库、中国知网、万方、维普、Embase、PubMed、the Cochrane Library、Web of Science数据库,时间均从建库至2021年7月,对公开发表的益生菌治疗类风湿关节炎的随机对照试验进行meta分析和试验序贯分析。

共纳入6项研究,总样本量242例。Meta分析显示,益生菌治疗类风湿关节炎能显著降低CRP[MD = ‒2.26,95% CI = （‒4.30,‒0.23）,P = 0.03]和TNF-α[MD = ‒1.78,95% CI = （‒2.73,0.83）,P＜0.01]水平,提高IL-10[MD = 3.80,95% CI = （0.40,7.19）,P = 0.03]水平,而ESR、IL-1β、IL-6、MDA、TAC、DAS28、TJC、SJC、HAQ和ACR20等水平均与安慰剂相当。敏感性分析显示结果较为稳健,试验序贯分析显示CRP的获益具有结论性,Egger检验显示不存在发表偏倚（P = 0.17）。

益生菌能够有效降低CRP和TNF-α水平,提高IL-10水平,具有治疗类风湿关节炎的潜力。

     

Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial

BackgroundSarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcomes (PROs) in this RCT.MethodsPatients (n = 1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously + MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ≥20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24.ResultsBoth doses of sarilumab + MTX vs placebo + MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p < 0.0001) that was clinically meaningful, and persisted until week 52. In post hoc analyses, the percentages of patients with improvement equal to or greater than the MCID across all PROs were greater with sarilumab than placebo (p < 0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting equal to or greater than normative scores.ConclusionsIn this RCT in patients with MTX-IR RA, sarilumab + MTX resulted in sustained improvement in PROs that were clinically meaningful, greater than placebo + MTX, and complement the previously reported clinical efficacy and safety of sarilumab.

Trial registration

ClinicalTrials.gov. NCT01061736. February 2, 2010     

Contribution of P2X4 receptor in pain associated with rheumatoid arthritis: a review

Purinergic Signalling - Pain is the most common symptom reported by patients with rheumatoid arthritis (RA) even after the resolution of chronic joint inflammation. It is believed that...     

Relative sialylation and fucosylation of synovial and plasma fibronectins in relation to the progression and activity of rheumatoid arthritis

The expressions of terminal sugars in synovial and plasma fibronectins were studied in relation to rheumatoid arthritis (RA) progression defined according to the early, established and late radiological changes in the patients’ hands. The relative amounts of sialic acid and fucose were analyzed by lectin-ELISA using appropriate sialic acid-linked α2-3 (Maackia amurensis) and α2-6 (Sambucus nigra) lectins as well as fucose-linked α1-6 (Aleuria aurantia), α1-2 (Ulex europaeus), and α1-3 (Tetragonolobus purpureus). In the early RA group, the synovial fibronectin reactivities were the lowest with the all lectins used. In the established and late groups, relative sialylation and fucosylation significantly increased. However, sialylation negligibly decreased, whereas fucosylation remained at nearly the same level in the late group. Moreover, the expression of α1-6-linked fucose was found to be related to disease activity. In contrast, plasma fibronectin reactivity with lectins showed different dynamic alterations. In the early RA group, the reactivity of fibronectin with the lectins used was similar to that of healthy individuals, whereas it increased significantly in the established RA group compared with the early and normal plasma groups. In the late RA group it decreased to a level similar to that of the normal group. The lower expressions of terminal sugars in synovial fibronectin were mainly associated with the early degenerative processes of RA. In conclusion, such alterations may be applicable as a stage-specific marker for diagnosis and therapy of RA patients. The higher expression of terminal sugars in fibronectin could be associated with repair and adaptation processes in longstanding disease.     

Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, but its autoimmune mechanisms are not clearly understood. Recently, anti-citrullinated peptide antibodies have been specifically observed in sera of RA patients. Furthermore, we identified RA-susceptible variant in a gene encoding citrullinating enzyme, peptidylarginine deiminase type 4 (PADI4). Therefore, we hypothesized that proteins which are modified in RA synovium by PADI4 act as autoantigens. Subsequently, we obtained human collagen type I (huCI) as one of the autoantigens using a RA synoviocyte cDNA library by immunoscreening. We also investigated that the levels of anti-citrullinated huCI were significantly higher in RA patient sera than in normal control sera with high specificity (99%) and positively correlated with the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies. We concluded that huCI is a novel substrate protein of PADIs and that citrullinated huCI is a candidate autoantigen of RA.     

Catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis: a computed tomography study on the role of age,disease duration and bone markers

Introduction

The aim of this study was to determine the factors, including markers of bone resorption and bone formation, which determine catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis (RA).

Methods

Forty RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) analysis of the metacarpophalangeal joints II and III of the dominantly affected hand at two sequential time points (baseline, one year follow-up). Erosion counts and scores as well as osteophyte counts and scores were recorded. Simultaneously, serum markers of bone resorption (C-terminal telopeptide of type I collagen (CTX I), tartrate-resistant acid phosphatase 5b (TRAP5b)), bone formation (bone alkaline phosphatase (BAP), osteocalcin (OC)) and calcium homeostasis (parathyroid hormone (PTH), 25-hydroxyvitamin D3 (Vit D)) were assessed. Bone biomarkers were correlated to imaging data by partial correlation adjusting for various demographic and disease-specific parameters. Additionally, imaging data were analyzed by mixed linear model regression.

Results

Partial correlation analysis showed that TRAP5b levels correlate significantly with bone erosions, whereas BAP levels correlate with osteophytes at both time points. In the mixed linear model with erosions as the dependent variable, disease duration (P <0.001) was the key determinant for these catabolic bone changes. In contrast, BAP (P = 0.001) as well as age (P = 0.018), but not disease duration (P = 0.762), were the main determinants for the anabolic changes (osteophytes) of the periarticular bone in patients with RA.

Conclusions

This study shows that structural bone changes assessed with HR-pQCT are accompanied by alterations in systemic markers of bone resorption and bone formation. Besides, it can be shown that bone erosions in RA patients depend on disease duration, whereas osteophytes are associated with age as well as serum level of BAP. Therefore, these data not only suggest that different variables are involved in formation of bone erosions and osteophytes in RA patients, but also that periarticular bone changes correlate with alterations in systemic markers of bone metabolism, pointing out BAP as an important parameter.