Oxidative stress as a potential biomarker for determining disease activity in patients with Rheumatoid Arthritis

Rheumatoid arthritis is an inflammatory, autoimmune disease where oxidative stress has been proposed to contribute to the joint tissue damage. To establish whether measurement of the redox status in blood mirrors the oxidant status at sites of inflammation in patients with rheumatoid arthritis, we concomitantly examined their oxidant status by spectrophotometry and/or flow cytometry. The basal levels of total reactive oxygen species (ROS), superoxide and hydroxyl radicals were significantly raised in neutrophils sourced from peripheral blood and synovial infiltrate, as also showed a strong positive correlation; however, there was no major increase in the reactive nitrogen species RNS generated in monocytes from both sources. Furthermore, raised levels of superoxide in neutrophils of synovial infiltrate showed a positive correlation with NADPH oxidase activity in synovial fluid. Additionally, as ROS generated in both peripheral blood and synovial infiltrate correlated positively with both DAS 28 and CRP/anti-CCP levels, its measurement can serve as an indirect measure of the degree of inflammation in patients with RA.     

Anti-citrullinated antibodies, radiological joint damages and their correlations with disease activity score (DAS28)

Determination of anti-citrullinated peptides (anti-CCP) specificity as a predictor of joint erosive changes, correlation between their serum level and radiological damages as well as disease activity score (DAS28). A trial has been conducted on a 211 patient sample fulfilling ACR criteria for rheumatoid arthritis (RA). There was assigned anti-CCP serum level, disease activity score by the formula for DAS28(3)-CRP and assessed radiological changes degree after Steinbrocker score. In 132 patient (62.559%) the serum anti-CCP concentration was positive for RA. Specificity of the test was 100% and sensitivity 65% (Z = 0.731, p = 0.465). There is a medium intensity correlation between variables representing anti-CCP and Steinbrocker score. Pearson's coefficient was 0.479 and Spearman's rank correlation coefficient was 0.614, i.e. statistically significant (p = 0.000). There is no statistically significant correlation between variables representing anti-CCP and DAS28(3)-CRP Anti-CCP are good RA predictor and their concentration correlate with radiological damages degree.     

(Auto)immunity to cartilage matrix proteins - a time bomb?

Geng and colleagues consolidate and detail the role of cartilage oligomeric matrix protein (COMP) as a (potential) autoantigen in experimental and human arthritis, a finding also supported by the detection of COMP fragments and anti-COMP antibodies in rheumatoid arthritis serum and/or synovial fluid and by synovial B-cell responses against COMP. The reactivity to COMP is yet another example of how, in addition to collagen II and the large aggregating proteoglycan, cartilage-specific proteins can induce arthritis and contribute to autoimmunity. Progression of cartilage damage and degradation in disease is believed to promote the autoimmune reaction to cartilage components. However, Geng and colleagues show that anti-COMP mAbs bind in vivo to undamaged cartilage, as previously also observed for anti-collagen II antibodies. Whether this autoimmunity also involves modifications of cartilage matrix proteins, such as citrullination, remains to be further investigated. Latent, subpathogenic (auto)immune reactions directed against cartilage matrix proteins may thus eventually contribute to the outbreak of human arthritis.     

Role of redox imbalance and cytokines in mediating oxidative damage and disease progression of patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disorder wherein the contributory role of oxidative stress has been established in the synovial fluid. As availability of synovial fluid is limited, this study aimed to evaluate in the peripheral blood of patients with RA, the relationship if any, between the extent of oxidative stress in terms of generation of reactive oxygen species (ROS) in neutrophils, plasma NADPH oxidase and myeloperoxidase activity with markers of oxidative damage, circulating cytokines and disease activity score (DAS28). In patients with RA, neutrophils in peripheral blood demonstrated an enhanced generation of ROS, coupled with depletion of free radical scavenging activity. Furthermore, the NADPH oxidase and myeloperoxidase activity was enhanced as were markers of damage. There was a positive correlation between the DAS 28 and generation of ROS, NADPH oxidase and myeloperoxidase activity as also with oxidative stress mediated protein carbonylation. Patients with RA demonstrated an increase in proinflammatory (IL-17, IL-23, and IFN-γ) and some anti-inflammatory (IL-4, IL-5, and TGF-β) cytokines. Although the levels of IL-17 correlated positively with generation of ROS, myeloperoxidase, markers of protein damage and DAS28, IL-23 correlated positively only with protein damage, and negatively with free radical scavenging activity. Importantly, incubation of neutrophils from healthy donors with plasma or SF from patients with RA translated into an enhanced generation of ROS, along with an elevation of intracellular proinflammatory cytokines. Taken together, in patients with RA, circulating neutrophils mediated a shift in the oxidant/antioxidant balance favouring the former, which translated into protein damage and contributed towards disease progression.     

类风湿性关节炎活动性病变MRI征象及其与FIB、FDP、D-D的相关性研究

摘要 目的：探讨类风湿性关节炎（RA）活动性病变磁共振成像（MRI）征象及其与纤维蛋白原（FIB）、纤维蛋白(原)降解产物（FDP）、D-二聚体（D-D）的相关性研究。方法：选取2020年1月-2021年2月期间我院诊治的61例RA患者,根据28个关节疾病活动指数（DAS28）评分将其分为活动组（35例）和稳定组（26例）。对比两组MRI征象,血清FIB、FDP、D-D水平。采用Spearman相关性分析RA活动期患者MRI各征象间的相关性及MRI各征象与血清FIB、FDP、D-D水平间的相关性。结果：活动组滑膜增厚或滑膜炎、骨髓水肿、软骨及骨侵蚀、腱鞘炎或周围软组织受累、关节腔积液征象人数占比均高于稳定组（P＜0.05）。活动组患者血清FIB、FDP、D-D水平均高于稳定组（P＜0.05）。Spearman相关性分析结果显示,RA活动期患者滑膜增厚或滑膜炎征象与骨髓水肿、软骨及骨侵蚀、关节腔积液征象均呈正相关（P＜0.05）,骨髓水肿征象与软骨及骨侵蚀征象呈正相关（P＜0.05）;RA活动期患者滑膜增厚或滑膜炎、骨髓水肿、关节腔积液征象与血清FIB、FDP、D-D水平均呈正相关（P＜0.05）,软骨及骨侵蚀征象与FIB呈正相关（P＜0.05）。结论：MRI征象可清晰显示RA患者的滑膜、骨质、关节腔及周围肌腱、软组织等异常改变,且MRI征象之间具有相关性,可在一定程度上反映RA的病理改变;血清FIB、FDP、D-D的检测有助于反映RA活动情况;MRI征象与血清FIB、FDP、D-D水平间具有相关性,二者联合应用有助于进一步评估RA活动情况。     

Diagnostic utility of anti-cyclic citrullinated peptide and anti-modified citrullinated vimentin antibodies in rheumatoid arthritis

Several autoantibodies found in RA are directed to epitopes in citrullinated proteins. One of them is anti modified citrullinated vimentin (Anti-MCV). We tested the value a newly developed ELISA for the detection of antibodies against a genetically modified citrullinated vimentin (anti-MCV) in comparison with an anti-CCP based ELISA system for the diagnosis of RA. Thirty-five patients with RA (mean age; 42.6 +/- 10.87 years, mean disease duration; 9.37 +/- 3.98 years) were enrolled in this study. Twenty -five ankylosing spondylitis (mean age; 35.88 +/- 6.64 years, mean disease duration; 10.25 +/- 4.61 years), and 19 healthy subjects (mean age; 40.26 +/- 5.11 years) served as controls. Anti-CCP antibodies and Anti-MCV antibodies were measured using ELISA. In all RA patients, mean anti- CCP level was 69.07 +/- 90.43 U/ml and anti-MCV level was 665.77 +/- 1040.19 U/ml. In patients with AS, the mean anti-CCP level was 10.7 +/- 5.22 U/ml and anti-MCV level was 40.54 +/- 20.15 U/ml. In healthy controls, the mean anti-CCP level was 11.11 +/- 7.65 U/ml, anti-MCV level was 23.12 +/- 12.04 U/ml. In patients with active RA, the mean serum anti-CCP level was 100.54 +/- 98.07 U/ml and anti-MCV level was 998.74 +/- 1154.93 U/ml. In patients with inactive RA, the mean serum anti-CCP level was 8.77 +/- 1.55 U/ml and anti-MCV level was 27.59 +/- 23.10 U/ml. According to these results; In patients with RA, the mean serum anti-MCV and anti-CCP levels were significantly high compared to patients with AS and healthy controls (p=0.002, p=0.001, p=0.002, p=0.001 respectively). The mean serum anti-MCV and anti- CCP levels were significantly higher in active patients with RA than in inactive patients with RA patients (p=0.001 and p=0.001 respectively). In inactive patients with RA, the mean serum anti-MCV and anti-CCP levels were similar in patients with AS and patients (p=0.484, p=0.308, p=0.09 and p=0.222 respectively). The mean serum anti-MCV levels were correlated with DAS 28 (r=0.531, p=0.001), VAS score (r=0.332, p=0.01), ESR (r=0.458, p=0.001), serum CRP levels (r=0.568, p=0.01), serum RF levels (r=0.529, p=0.001), swollen joints number (r=0.525, p=0.001) and tender joints number (r=0.638, p=0.001). As a result; measurement of serum anti-MCV levels is useful for diagnosis of RA and combined use of anti-MCV and RF may be more useful prognostic factor than either method alone, RF and anti-CCP.     

A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis

Introduction

Interleukin (IL)-21 is a member of type I cytokine family. Recent studies indicate that IL-21 can promote T follicular helper (Tfh) cell differentiation and survival, a specialized T cell subset which provides help for B cell. It can also regulate the activation, proliferation and differentiation of human B cell and immunoglobulin (Ig) production as well as isotype switching of plasma cell. Rheumatoid arthritis (RA) is characterized by auto-antibodies overproduction such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, suggesting a pivotal role of Tfh cell and B cell in the pathogenesis of RA. This study aimed to investigate whether IL-21 had a regulatory effect on Tfh cell and B cell in RA.

Methods

Serum IL-21 concentrations were measured by ELISA. The correlations between serum IL-21 levels and clinical features of RA patients were analyzed by Spearman''s rank test. The percentages of Tfh-like cells, IL-21 receptor (R) expression on Tfh-like cells and B cells in peripheral blood (PB) were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) were stimulated by rIL-21 (100 ng/ml) in the presence or absence of anti-CD40 and/or anti-IgM, and changes of IL-21R, activation-associated surface markers (CD25, CD69 and CD40), the proliferation, apoptosis and differentiation of B cells were analyzed by flow cytometry. Production of IgG and IgM in the culture supernatants was determined by ELISA.

Results

The results showed that the serum IL-21 levels in RA patients were significantly higher than that of healthy controls (HC). IL-21 concentrations were positively correlated with 28-joint count disease activity score (DAS28) and anti-CCP antibody in RA patients with high IL-21 levels. Furthermore, the frequencies of peripheral CXCR5⁺PD-1⁺CD4⁺ Tfh-like cells markedly increased in RA patients and the percentages of Tfh-like cells were positively correlated with DAS28 and anti-CCP antibody levels. Moreover, elevated IL-21 levels were also correlated with the frequencies of Tfh-like cells. IL-21R expression on both Tfh-like cells and B cells were significantly enhanced in RA patients. In cultures vitro, exogenous IL-21 upregulated IL-21R expression and activation-associated surface markers on B cells and promoted more B cell proliferation in RA than in HC. This IL-21-mediated effect could be reversed by IL-21R-specific neutralizing antibody. Importantly, IL-21 promoted more differentiation of B cell into plasmablast and higher levels of IgG and IgM production in RA than in HC.

Conclusions

Increased serum IL-21 levels in RA patients correlate with DAS28, anti-CCP antibody and frequencies of Tfh-like cells. IL-21 supports B cell activation, proliferation and antibody secretion via IL-21R pathway. Thus, IL-21 may be involved in the pathogenesis of RA and antagonizing IL-21 could be a novel strategy for the therapy of RA.     

Smoking in combination with antibodies to cyclic citrullinated peptides is associated with persistently high levels of survivin in early rheumatoid arthritis: a prospective cohort study

Introduction

High levels of the oncoprotein survivin may be detected in the majority of patients with early rheumatoid arthritis (RA). Survivin is a sensitive predictor of joint damage and persistent disease activity. Survivin-positive patients are often poor responders to antirheumatic and biological treatment. The aim of this study was to investigate the reproducibility of survivin status and its significance for clinical and immunological assessment of RA patients.

Methods

Survivin levels were measured in 339 patients from the Better Anti-Rheumatic FarmacOTherapy (BARFOT) cohort of early RA at baseline and after 24 months. The association of survivin status with joint damage (total Sharp-van der Heijde score), disease activity (Disease Activity Score based on evaluation of 28 joints (DAS28)), functional disability (Health Assessment Questionnaire (HAQ)), and pain perception (Visual Analogue Scale (VAS)) was calculated in the groups positive and negative for survivin on both occasions, and for the positive-negative and negative-positive groups.

Results

In 268 patients (79%) the levels of survivin were similar at baseline and after 24 months, 15% converted from survivin-positive to survivin-negative, and 5% from survivin-negative to survivin-positive. A combination of smoking and antibodies against cyclic citrullinated peptides (aCCP) predicted persistently (baseline and 24 months) high levels of survivin (odds ratio 4.36 (95% CI: 2.64 to 7.20), P < 0.001), positive predictive value 0.66 and specificity 0.83). The independent nature of survivin and aCCP was demonstrated by statistical and laboratory analysis. Survivin positivity on both test occasions was associated with the progression of joint damage, significantly higher DAS28 and lower rate of remission at 24 and 60 months compared to negative-negative patients. Survivin status was less associated with changes in HAQ and VAS.

Conclusions

Survivin is a relevant and reproducible marker of severe RA. Persistently high levels of survivin were associated with smoking and the presence of aCCP and/or RF antibodies and predicted persistent disease activity and joint damage.     

Pathogenic antibody recognition of cartilage

Antibodies against cartilage proteins are highly prevalent in the sera and synovial fluids of rheumatoid arthritis (RA) patients and also precede disease induction in various spontaneous and induced animal models of arthritis. These antibodies play an important role in the induction and perpetuation of the clinical disease. Antibodies binding to cartilage protein(s), especially the major articular cartilage protein, collagen type II (CII) can induce, in naive mice, an acute form of arthritis that can substantially destroy the cartilage and bone architecture. More importantly, these anti-CII antibodies can also directly cause the destruction of the target tissue preceding and independently of disease development and in the absence of any other pathogenic inflammatory factors or the action of immune cells. Alternatively, antibodies to citrullinated protein antigens and rheumatoid factor are well-validated prognostic and diagnostic markers of severe erosive RA, although their arthritogenic potential is questioned. Recently, we have found that the monoclonal antibodies to citrulline-modified cartilage protein can bind cartilage and synovial tissue and mediate arthritis in mice. Similarly, one of the pathogenic anti-CII monoclonal antibodies has rheumatoid-factor-like activity, suggesting a disease-inducing role for these commonly prevalent antibodies in RA patients. Interestingly, recent findings have also shown that the enzymatic cleavage or modification of pathogenic IgG antibodies protects the cartilage surface, thereby opening up new therapeutic possibilities for protecting the cartilage from inflammatory damage.     

Assessment of Activity Limitations with the Health Assessment Questionnaire Predicts the Need for Support Measures in Patients with Rheumatoid Arthritis: A Multicenter Observational Study

Objective

This study investigated whether the Health Assessment Questionnaire (HAQ) can be used as an instrument to assess the need for social support measures that address activity limitations and participation issues in patients with rheumatoid arthritis (RA).

Methods

This multicenter observational study included patients with RA and disease duration of at least one year, consulting their rheumatologist for routine evaluation of disease activity. In the single study visit data on demographics, disease history and current treatment were collected. DAS28 values were collected to evaluate current RA disease activity. Patients were asked to fill out the HAQ and SF-36 questionnaires. Receiver Operator Characteristics (ROC) curves were constructed to evaluate the performance of the HAQ, SF-36 and DAS28 in predicting the need for nine supporting measures available for chronically ill patients in the Belgian social security system. The expert opinion of the treating rheumatologist was used as a reference.

Results

The study included 316 patients with a mean age of 59.8±12.6 years, disease duration of 11.4±9.3 years, mean DAS28 values of 2.83±1.17. Mean HAQ score was 0.95±0.73, mean SF-36 score 56.5±21.3. HAQ scores >1 were observed in 39.4% of patients. The area under the HAQ ROC curve was consistently >0.7 and higher for the HAQ than for SF-36 or DAS28 for all support measures. Rheumatologists on average recommended 3.67 support measures.

Conclusion

The HAQ score was found to be a good predictor of the need for social support measures in patients with RA.     

类风湿关节炎患者血清维生素D水平与疾病活动度相关

目的:探讨类风湿关节炎(Rheumatoid arthritis,RA)患者血清维生素D(25(OH)D)水平与疾病活动度的关系。方法:总共纳入180例RA患者,同时纳入60例年龄、性别相匹配的健康对照。检测所有参与者的血清25(OH)D水平及所有RA患者C反应蛋白和血沉。同时获取RA患者晨僵时间、疼痛视觉模拟表评分、乏力视觉模拟表评分、压痛关节数、肿胀关节数、健康评估量表得分、情绪变化量表得分等。利用RA患者28个关节疾病活动评分(Disease activity score in 28 joints,DAS28)评估RA疾病活动度。结果:相对于健康对照组(43.89±16.28 ng/m L),RA患者的血清25(OH)D明显降低(28.52±8.95 ng/m L)(P=0.000)。RA患者的血清25(OH)D水平越低,压痛关节数、肿胀关节数越多(P=0.043,r=-0.132;P=0.017,r=-0.177),血沉、C反应蛋白越高(P=0.018,r=-0.177;P=0.007,r=-0.200),同时DAS28评分越高(P=0.007,r=-0.201);患者的晨僵时间、疼痛评分、乏力评分、健康评估量表得分及情绪量表得分与血清维生素D水平负相关(P=0.043,r=-0.151;P=0.019,r=-0.175;P=0.006,r=-0.205;P=0.048,r=-0.147;P=0.017,r=-0.178)。结论:RA患者血清维生素D普遍缺乏,并且与RA患者疾病活动度负相关。     

Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins

Introduction  

Rheumatoid arthritis (RA) is an inflammatory disease, which results in destruction of the joint. The presence of immune complexes (IC) in serum and synovial fluid of RA patients might contribute to this articular damage through different mechanisms, such as complement activation. Therefore, identification of the antigens from these IC is important to gain more insight into the pathogenesis of RA. Since RA patients have antibodies against citrullinated proteins (ACPA) in their serum and synovial fluid (SF) and since elevated levels of citrullinated proteins are detected in the joints of RA patients, citrullinated antigens are possibly present in IC from RA patients.     

Human monoclonal rheumatoid synovial B lymphocyte hybridoma with a new disease-related specificity for cartilage oligomeric matrix protein

Joint-specific self-Ags are considered to play an important role in the induction of synovial T and B cell expansion in human rheumatoid arthritis (RA). However, the nature of these autoantigens is still enigmatic. In this study a somatically mutated IgG2 lambda B cell hybridoma was established from the synovial membrane of an RA patient and analyzed for its Ag specificity. A heptameric peptide of cartilage oligomeric matrix protein (COMP) could be characterized as the target structure recognized by the human synovial B cell hybridoma. The clonotypic V(H) sequences of the COMP-specific hybridoma could also be detected in synovectomy material derived from five different RA patients but in none of the investigated osteoarthritis cases (n = 5), indicating a preferential usage of V(H) genes closely related to those coding for a COMP-specific Ag receptor in RA synovial B cells. Moreover, the COMP heptamer was preferentially recognized by circulating IgG in RA (n = 22) compared with osteoarthritis patients (n = 24) or age-matched healthy controls (n = 20; both p < 0.0001). Hence, the COMP-specific serum IgG is likely to reflect local immune responses toward a cartilage- and tendon-restricted Ag that might be crucial to the induction of tissue damage in RA.     

Association of single nucleotide polymorphisms (SNPs) of PADI4 gene with rheumatoid arthritis (RA) in Indian population

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting ~ 1% of the population worldwide. The genome wide association studies on RA patients revealed linkage with 1p36 locus containing peptidyl arginine deiminase 4 (PADI4) genes. Case-control association studies and mRNA stability assays reported the association of PADI4 gene with RA in Korean and Japanese populations. However, such association was not found in Spanish population. Differences in the association of PADI4 with RA in different populations prompted the present study in Indian population. Anti-CCP antibodies, RF antibody, disease activity scores at 28 joints (DAS28) and mutations in three exons of PADI4 were investigated in RA patients and control group. Among the patients anti-CCP antibody levels were found to be associated with high DAS28 values (r = 0.4526, P < 0.0001). Polymorphism in exon-4 (padi4_104, [rs1748033]) of PADI4 showed significant association of 'C' allele with RA in the study population (P = 0.0008). Polymorphism in exon-3 (padi4_92, [rs874881]) also exhibited moderate association with the disease (P = 0.075). However, no association of the disease was found with the SNPs padi4_89 [rs11203366] and padi4_90 [rs11203367] in exon-2 of PADI4.     

Increased adiponectin is negatively linked to the local inflammatory process in patients with rheumatoid arthritis

Adiponectin has been shown to exert insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties in metabolic diseases. It has been suggested that adiponectin may play a role in rheumatoid arthritis (RA). To assess adiponectin in serum and synovial fluid from patients with RA and osteoarthritis (OA), and in serum from healthy controls. Adiponectin and CRP levels were analyzed by ELISA. The clinical activity of RA patients was assessed according to the 28 joint count Disease Activity Score. Synovial fluid adiponectin was significantly higher in RA than in OA patients (p<0.001). Adiponectin was negatively associated with the leukocyte count in RA synovial fluid (r=-0.45, p<0.05). Serum adiponectin was higher in RA compared to healthy controls (p<0.02), however comparable to OA patients. Serum adiponectin was higher than in synovial fluid in both diseases (p<0.001). In general, women had higher adiponectin levels than men. Adiponectin was not related to age, disease duration, body mass index, or disease activity of RA patients. Adiponectin is decreased in synovial fluid compared to serum indicating that peripheral fat stores are major producers of adiponectin into the blood stream. However, increased synovial fluid adiponectin in RA patients may counterpart the local inflammatory process.     

Cleavage of cartilage oligomeric matrix protein (thrombospondin-5) by matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs.

Cartilage oligomeric matrix protein (COMP) is a pentameric glycoprotein present in cartilage, tendon and ligament. Fragments of the molecule are present in the diseased cartilage, synovial fluid and serum of patients with knee injuries, osteoarthritis and rheumatoid arthritis. Although COMP is a substrate for several matrix metalloproteinases (MMPs), the enzymes responsible for COMP degradation in vivo have yet to be identified. In this study we utilised well-established bovine cartilage culture models to examine IL-1alpha-stimulated COMP proteolysis in the presence and absence of MMP inhibitors. COMP was released from bovine nasal cartilage, in response to IL-1alpha, at an intermediate time between proteoglycans and type II collagen, when soluble MMP levels in the culture medium were undetectable. The major fragment of COMP released following IL-1alpha-stimulation migrated with an apparent molecular mass of approximately 110 kDa (Fragment-110) and co-migrated with both the major fragment present in human arthritic synovial fluid samples and the product of COMP cleavage by purified MMP-9. However, the broad-spectrum MMP and ADAM inhibitor BB94 only partially inhibited the formation of Fragment-110 and failed to inhibit COMP release significantly. Therefore the results of these studies indicate a role for proteinases other than MMPs in the degradation of COMP in bovine cartilage. It was further demonstrated that purified COMP was cleaved by ADAMTS-4, but not ADAMTS-1 or -5, to yield a fragment which co-migrated with Fragment-110. Therefore this is the first demonstration of COMP as a substrate for ADAMTS-4, although it remains to be determined whether this enzyme plays a role in COMP degradation in vivo.     

Physical function continues to improve when clinical remission is sustained in rheumatoid arthritis patients

IntroductionTo investigate the course of functional status assessed by health assessment questionnaire (HAQ) in rheumatoid arthritis (RA) patients with sustained clinical remission (REM).MethodsIn recent RA clinical trials, we identified patients with subsequent visits of ≥24 weeks in clinical REM according to the disease activity score using 28-joint counts including C-reactive protein (DAS28) (≤2.6), or simplified disease activity index (SDAI) (≤3.3). Area under the curve (AUC) and mean HAQ scores throughout the time in sustained REM were compared using t test, analyses of variance (ANOVA) and adjusted general linear modeling (GLM) with repeated measures. In Cox regression analyses, the time to regain full physical function was modeled. Sensitivity analyses were performed in patients of sustained SDAI low disease activity (LDA; SDAI ≤11).ResultsA total of 610 out of 4364 patients achieved sustained DAS28 REM (14 %) and 252 SDAI REM (5.8 %). ANOVA testing for linear trend showed significant decrease of mean HAQ from week 0 (start of REM) to week 24, regardless of REM criteria used. AUC of HAQ throughout 24 weeks of REM was higher in DAS28 compared to SDAI REM (p ≤0.01). GLM adjusting for covariates showed significant decrease of monthly HAQ scores from week 0 to 24 (DAS28: 0.276, 0.243, 0.229, 0.222, 0.219, 0.209 to 0.199; p = 0.0001; SDAI: 0.147, 0.142, 0.149, 0.129, 0.123, 0.117 to 0.114; p = 0.029). Similarly, a decrease of HAQ over time was found in patients of sustained SDAI LDA. In DAS28 REM, the chance of regaining full physical function was higher for female (hazard ratio HR [95 % confidence interval]: 1.41 [1.13–1.76]) and early RA patients (disease duration ≤2 years: HR 1.29 [1.01–1.65]); in SDAI REM no significant differences were found.ConclusionsPhysical function continues to improve if the target of REM or LDA is sustained. The stringency of the remission criteria determines achievement of the best possible functional improvement.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0719-x) contains supplementary material, which is available to authorized users.     

抗CCP 抗体对老年起病类风湿关节炎诊断及预后评估的临床价值

目的：探讨抗环瓜氨酸肽(CCP)抗体对老年起病类风湿关节炎(EORA)诊断和预后评估的临床应用价值。方法：收集2010 年 3 月至2011 年3 月在上海市第一人民医院分院风湿科门诊及住院治疗的EORA 患者98 例,骨性关节炎(OA)患者30 例,风湿性 多肌痛(PMA)患者10 例,其他结缔组织病30 例,正常老年健康对照48 例,应用酶联免疫吸附法检测所有患者血清抗CCP 抗体 水平,并检测其IgM型类风湿因子(IgM-RF)。计算抗CCP抗体、IgM-RF及联合检测两者诊断EORA 的特异度、敏感度、阳性预测 值、阴性预测值。同时记录EORA 患者的临床资料,分析抗CCP 抗体阴性和阳性患者中年龄、性别、疾病活动指数28(DAS28)、 ESR、CRP、骨损害的变化,对其预后进行预测。结果：EORA 患者抗CCP 抗体和IgM-RF的阳性率均明显高于其他结缔组织病患 者和健康对照人群,差异均有统计学意义(P<0.05)。抗CCP 抗体对EORA 诊断的敏感性略低于IgM-RF,但特异性明显提高,差异 均有统计学意义(P<0.05)。抗CCP 抗体及IgM-RF对EORA 诊断的敏感性和特异性分别为：61.2%、75.5%和97.1%、62.9%,两者联 合检测的敏感性及特异性为：49%和98.5%。差异均有统计学意义(P<0.05)。抗CCP 抗体阳性患者和阴性患者比较,年龄、性别、病 程、ESR、CRP水平的差异均无统计学意义(P>0.05),但抗CCP 抗体水平与DAS28 评分呈正相关(P<0.05),与关节x 线分期无明显 相关性(P>0.05)。但抗CCP 抗体阳性患者,更易出现骨损害,预后较差。结论：抗CCP抗体对诊断EORA 具有较高的临床价值,且 可以作为辅助预测和评价预后的指标。     

Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis

Destruction of cartilage and bone are hallmarks of human rheumatoid arthritis (RA), and controlling these erosive processes is the most challenging objective in the treatment of RA. Systemic interleukin-4 treatment of established murine collagen-induced arthritis suppressed disease activity and protected against cartilage and bone destruction. Reduced cartilage pathology was confirmed by both decreased serum cartilage oligomeric matrix protein (COMP) and histological examination. In addition, radiological analysis revealed that bone destruction was also partially prevented. Improved suppression of joint swelling was achieved when interleukin-4 treatment was combined with low-dose prednisolone treatment. Interestingly, synergistic reduction of both serum COMP and inflammatory parameters was noted when low-dose interleukin-4 was combined with prednisolone. Systemic treatment with interleukin-4 appeared to be a protective therapy for cartilage and bone in arthritis, and in combination with prednisolone at low dosages may offer an alternative therapy in RA.     

Novel Cartilage Oligomeric Matrix Protein (COMP) Neoepitopes Identified in Synovial Fluids from Patients with Joint Diseases Using Affinity Chromatography and Mass Spectrometry

To identify patients at risk for progressive joint damage, there is a need for early diagnostic tools to detect molecular events leading to cartilage destruction. Isolation and characterization of distinct cartilage oligomeric matrix protein (COMP) fragments derived from cartilage and released into synovial fluid will allow discrimination between different pathological conditions and monitoring of disease progression. Early detection of disease and processes in the tissue as well as an understanding of the pathologic mechanisms will also open the way for novel treatment strategies. Disease-specific COMP fragments were isolated by affinity chromatography of synovial fluids from patients with rheumatoid arthritis, osteoarthritis, or acute trauma. Enriched COMP fragments were separated by SDS-PAGE followed by in-gel digestion and mass spectrometric identification and characterization. Using the enzymes trypsin, chymotrypsin, and Asp-N for the digestions, an extensive analysis of the enriched fragments could be accomplished. Twelve different neoepitopes were identified and characterized within the enriched COMP fragments. For one of the neoepitopes, Ser⁷⁷, an inhibition ELISA was developed. This ELISA quantifies COMP fragments clearly distinguishable from total COMP. Furthermore, fragments containing the neoepitope Ser⁷⁷ were released into the culture medium of cytokine (TNF-α and IL-6/soluble IL-6 receptor)-stimulated human cartilage explants. The identified neoepitopes provide a complement to the currently available commercial assays for cartilage markers. Through neoepitope assays, tools to pinpoint disease progression, evaluation methods for therapy, and means to elucidate disease mechanisms will be provided.