Soluble HLA-DR antigen levels in serum correlate with rheumatoid arthritis disease activity and the presence of disease-associated epitopes

We investigated correlations between soluble HLA-DR (sHLA-DR) molecules and several clinical, biological and genetic parameters associated with rheumatoid arthritis (RA) disease activity. Serum sHLA-DR concentrations were determined in 146 samples from 89 RA patients by an ELISA format, using an antibody combination of mouse and rat monoclonal anti-human HLA-DR antibodies. The mean sHLA-DR serum level in RA patients was significantly increased with 277+/-19 ng/ml compared to 142+/-13 ng/ml of 80 healthy controls (P<0.001). In ascending order of significance, correlations were found between serum sHLA-DR and EULAR swelling and pain scores, Waaler-Rose, RA factor, ESR and CRP (P=0.025 to P<0.001). High sHLA-DR levels were defined above 374 ng/ml that was the 95% confidence interval of the controls. Thirty-seven blood samples (25%) in 31 RA patients were above this level. The EULAR pain and swelling scores, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and RA factor were higher (P=0.044 to P<0.001) at the moment of high sHLA-DR concentrations, compared to the lower concentrations. Higher disease activity was further found in groups of RA patients respectively heterozygous or homozygous for the disease-associated epitope (Q)R/KRAA within the HLA-DRB1 chain, compared to the group without this epitope (P<0.017 for part of the results). Likewise, sHLA-DR was respectively 169+/-17 (no disease associated epitope), 324+/-34 (heterozygous) and 442+/-69 ng/ml (homozygous for the disease-associated epitope on HLA-DRB1 alleles) (P<0.017). In conclusion, this study shows significant correlations between serum sHLA-DR levels and RA disease activity parameters, as well as increased sHLA-DR in patients with disease-associated epitope on HLA-DRB1 alleles.     

Elevated serum levels of Interleukin‐37 are associated with inflammatory cytokines and disease activity in rheumatoid arthritis

Interleukin‐37 (IL‐37) is closely associated with several inflammatory diseases. However, the role of IL‐37 in the pathogenesis of rheumatoid arthritis (RA) remains unclear. The aim of this study was to assess the associations between serum levels of IL‐37 and disease activity, inflammatory cytokines, and bone loss in patients with RA. Serum cytokines levels were examined by Enzyme‐linked immunosorbent assay (ELISA). Radiographic bone erosion was assessed using the van der Heijde‐modified Sharp score and bone mineral density (BMD) was measured using DXA. Serum IL‐37 levels in RA patients were significantly higher than those in HCs (p < 0.001), and were significantly positively correlated with clinical parameters of disease activity and serum levels of IL‐17 and IL‐23. In addition, serum IL‐37 levels were significantly higher in patients with stage IV of radiographic bone erosion than those with stage III and stage I–II, and they were significantly higher in those with osteopenia and osteoporosis than in those with normal BMD. Our results suggest that serum IL‐37 levels were increased in patients with RA and were positively associated with disease activity, IL‐17/IL‐23 and bone loss in RA, suggesting that IL‐37 may play a critical role in the pathogenesis of RA.     

基质金属蛋白酶MMP-2、MMP-9与类风湿性关节炎关节破坏的关系

目的：观察血清基质金属蛋白酶MMP-2、MMP-9与类风湿性关节炎患者（Rheumatoid arthritis，RA）关节破坏的关系。方法：用双抗体夹心ELISA法测定90例未经治疗的早期RA患者及20例健康人血清中MMP-2、MMP-9，并分析其与RA患者X线表现积分（△Larsen）及健康评分（△HAQ）、CRP的关系。结果：血清MMP-2、MMP-9水平与C反应蛋白（CRP）、△Larsen、△HAQ显著相关，其相关系数及P值分别为r=0．40和0．46，P〈0．01；r=0．28和0．31，P〈0．05；r=0．30和0．34，P〈0．01。18例最初CRP正常的患者，MMP-2及MMP-9水平与观察12个月后出现关节侵蚀改变相关（r=0．59和0．48，P〈0．05）。回归分析发现，最初无骨侵蚀改变的患者，Larsen积分显示的骨侵蚀进展与MMP-2含量密切相关（r=0．32，P〈0．01）。结论：血清MMP-2、MMP-9水平与RA患者的病情活动及早期关节的骨侵蚀显著相关，可以作为无骨破坏的早期RA患者出现骨侵蚀的有益预测指标。     

TWEAK诱导类风湿关节炎成纤维样滑膜细胞合成MMP-3的实验研究

目的:通过观察TWEAK在不同浓度下对RA FLS诱导合成MMP-3的影响,探讨TWEAK参与类风湿关节炎(RA)关节骨及软骨破坏的相关机制,进而寻求治疗RA的新途径.方法:将rhTWEAK与成纤维样滑膜细胞(FLS)共培养,应用ELISA法检测细胞培养液中MMP-3水平;用反转录-聚合酶反应(RT-PCR)检测FLS中MMP-3 mRNA的表达水平.结果:TWEAK终浓度为50、100μg/L组诱导RA FLS合成MMP-3的水平明显高于对照组,具有显著的统计学意义(P＜0.05);TWEAK终浓度为100μg/L诱导RA FLS的MMP-3 mRNA表达水平为对照组的1.26倍,具有显著的统计学意义(P＜0.05);TNF-α和IL-1β对TWEAK诱导RA FLS合成MMP-3及MMP-3 mRNA表达具有协同作用,协同作用组MMP-3的水平及MMP-3mRNA表达水平明显高于单纯TWEAK组,具有显著的统计学意义(P＜0.05).结论:TWEAK通过诱导RA FLS合成MMP-3,直接参与RA的关节损伤,TNF-α和IL-1β在此过程中发挥协同作用.     

Skin manifestations and serum IgE levels in levamisole-treated rheumatoid arthritis patients.

Skin manifestations may occur as adverse effects of immunostimulant therapy with Levamisole. They are generally regarded as drug-induced hypersensitivity reactions. Our observations revealed that, in Levamisole-treated rheumatoid arthritis patients, urticaria was accompanied by an elevation of serum IgE, but other types of skin reactions were not. Moreover, elevation of IgE occurred without any skin reactions in some cases. It is suggested that Levamisole - stimulating T lymphocytes - may also stimulate IgE-mediated atopic responses.     

类风湿关节炎血清中CCL19和CCL21的表达水平与肺间质病变的关系

目的：探讨趋化因子CCL19和CCL21在类风湿关节炎（RA）患者血清中的表达水平与肺间质病变之间的关系,以及与临床指标间的相关性。方法：收集2016年5月至2017年3月于中国医科大学附属第一医院住院的RA患者62例,其中肺间质未受累的34例,合并肺间质改变的28例,特发性间质性肺炎（IIP）患者18例,以健康正常人20例为对照组。ELISA测定血清中的CCL21和CCL19水平。采用单因素方差分析,LSD-t检验,Kruskal-Wallis检验,Pearson和Spearman相关分析等进行统计分析。结果：RA患者血清中的CCL21和CCL19水平均高于正常人（P<0.05;P<0.01）,合并间质性肺炎（ILD）的RA患者血清中CCL21浓度高于无ILD的RA,高于正常人（P<0.05;P<0.01）;IIP患者血清中的CCL21水平比正常人高（P<0.01）;男性血清中的CCL21水平高于女性（P<0.05）;RA患者血清中CCL21水平与白蛋白和BMI负相关（r=-0.280,P<0.05;r=-0.605,P<0.05）;CCL19水平与C4水平负相关（r=-0.326,P<0.05）,与D-二聚体水平正相关（r=0.592,P<0.05）。 结论：趋化因子CCL21和CCL19在RA患者血清中高表达,可能参与了RA的发病过程,其中CCL21可能还参与了RA的肺间质受累过程。     

Measuring disease activity and response to treatment in rheumatoid arthritis

Introduction: Effective treatment of rheumatoid arthritis (RA) requires suppression of the underlying inflammation. Measurement of such inflammation, the disease activity, is mandatory to target treatment and maximize outcomes. However, this is not as straightforward as it may seem.

Areas covered: The many tools developed to measure disease activity in RA, from composite scores and patient-reported outcomes, to laboratory markers and imaging are discussed, with a focus on their utility in guiding therapy and assessing response. The complex issues in measuring disease activity in RA, whether in clinical trials or normal clinical practice, and in the context of national guidelines and recommendations, available time, and resources are considered.

Expert commentary: The key to effective management of RA is the rapid suppression of inflammation, ideally to remission, with maintenance of such remission. The aim is to prevent disability and maximize quality of life. Central to this is the ability to determine disease activity (potentially open to suppression) as opposed to damage (irreversible). A variety of measures are currently available, allowing better assessment of response to treatment. In the future, the development of predictive biomarkers allowing targeting of drugs may revolutionize this field and render the tools of today redundant.     

The relation between stress and disease activity in rheumatoid arthritis

This study investigated the relation between stress and current disease activity in rheumatoid arthritis (RA). During a routine clinic appointment, subjects were given ratings of global disease status by their physicians and completed self-report measures of major stress and minor stress. In addition, each subject's erythrocyte sedimentation rate was taken. After controlling for disease severity and major stress, minor stress accounted for a significant amount of the variance in inflammation level. These results suggest that minor stress is associated with current disease activity in RA.     

The correlation between increased serum concentrations of interleukin-6 family cytokines and disease activity in rheumatoid arthritis patients

Purpose

This study was performed to determine whether the serum concentrations of interleukin (IL)-6 family cytokines are elevated in patients with rheumatoid arthritis (RA) and to investigate the relationship between IL-6 family cytokine levels and disease activity in RA patients.

Materials and Methods

We obtained serum samples from 40 patients with RA and 40 age- and sex-matched healthy controls, and we assessed the clinical parameters of disease activity, including the 28-joint disease activity score (DAS28) and C-reactive protein (CRP) levels. Serum samples from five patients with high disease activity (DAS28 > 5.1) were also collected at the eighth week of treatment. Serum concentrations of IL-6, IL-11, and leukemia inhibitory factor (LIF) were measured using an enzyme-linked immunosorbent assay (ELISA).

Results

Serum concentrations of IL-6 family cytokines, including IL-6, IL-11, and LIF, were significantly elevated in patients with RA compared to those of healthy controls. Although there was no significant relationship between IL-6 family cytokine levels and DAS28, the IL-6 levels of patients with RA showed a significant correlation with CRP levels. After eight weeks of medical treatment in patients with high disease activity, a decrease in DAS28 was associated with a significant decrease in the serum concentrations of IL-6 and IL-11.

Conclusion

The serum concentrations of IL-6 family cytokines were significantly elevated in patients with RA, and they decreased with medical treatment. These findings suggest a possible role for IL-6 family cytokines in the pathogenesis of RA.     

类风湿性关节炎滑膜组织中PTTG1和MMP—2的表达及意义

目的 检测类风湿性关节炎(rheumatoid arthritis,RA)患者滑膜被覆细胞及滑膜下组织中垂体肿瘤转化基因1(pituitary tumor transforming gene 1,PTTG1)及MMP-2的表达及分布状况,探讨其在RA发病中的作用.方法 采用免疫组化SP法检测68例RA患者,14例骨性关节炎(osteoarthritis,OA)患者滑膜被覆细胞及滑膜下组织中PTTG1及MMP-2的表达状况.结果 PTTG1在RA组、OA组阳性率分别为64.7%和21.4%;MMP-2在RA组、OA组阳性率分别为73.5%和28.6%,差异具有统计学意义(P<0.05),且PTTG1和MMP-2之间表达具有相关性(rs=0.776,P<0.05).结论 PTTG1和MMP-2在RA组滑膜组织的表达均明显升高,且二者之间的表达具有相关性,从而证实其在RA的发病机制中可能具有一定的作用.     

Variation in the matrix metalloproteinase-3, -7, -12 and -13 genes is associated with functional status in rheumatoid arthritis

As matrix metalloproteinases (MMPs) play an important role in rheumatoid arthritis, we investigated whether variation in MMP genes was associated with functional disability in rheumatoid arthritis patients. A cohort of patients with seropositive rheumatoid arthritis were recruited and genotyped for the MMP1-1607 1G > 2G, MMP3-1612 5A > 6A, MMP7-153C > T, MMP7-181G > A, MMP12-82A > G and MMP13-77A > G polymorphisms. Genotypes were then analysed in relation to functional disability assessed by Steinbrocker index and Health Assessment Questionnaire (HAQ) score. We detected an association between the MMP13-77 A > G polymorphism and Steinbrocker index, with patients of the A/A genotype having higher score than patients of the A/G or G/G genotype (P = 0.005), and the association remained significant after adjusting for age, sex, erythrocyte sedimentation rate, presence of erosive disease, Ritchie score, prednisolone therapy and years of diagnosis (P = 0.003). We also observed a relationship of Steinbrocker index with the MMP3-1612 5A > 6A, MMP7-181 A > G and MMP12-82A > G polymorphisms (P = 0.082, P = 0.037 and P = 0.045). No association was detected between the MMP1-1607 1G > 2G and MMP7-153C > T polymorphisms and either Steinbrocker index or HAQ score. These results suggest that MMP3, MMP7, MMP12 and MMP13 genotypes may play a role in determining functional status of rheumatoid arthritis.     

Correlation of antibody to rheumatoid arthritis associated nuclear antigen and immune complexes to disease activity in patients with rheumatoid arthritis

Twenty-seven patients with rheumatoid arthritis (RA) maintained on drug regimens were studied monthly for 6-10 months. Disease activity was assessed and levels of anti-RA associated nuclear antigen (RANA) and immune complexes were determined. Anti-RANA generally paralleled disease activity in 64% of cases. Immune complex levels paralleled disease activity in 56% of cases and paralleled anti-RANA in 52% of patients. Immune complexes paralleled anti-RANA together with disease activity in only 33% of patients. Anti-RANA and/or immune complex levels paralleled disease activity indices in 82% of cases. Significant fluctuations (greater than or equal to four-fold) in anti-RANA were frequently found (65%) and were associated with concordant changes in immune complex levels 50% of the time and with changes in disease activity indices 59% of the time. The data suggest that levels of anti-RANA and immune complexes may be important in RA and warrant further investigation.     

Association between polymorphisms in the human chemokine receptor genes CCR2 and CX3CR1 and rheumatoid arthritis

Cell trafficking into the rheumatoid synovium is thought to play an important role in the inflammation seen in rheumatoid arthritis. Chemokine receptors play a central role in this process, and several common variants are known, including the CCR2 variant, CCR2-64I, and two variants of the CX3CR1 gene, V249I and T280M. All three variants result in functional amino acid substitutions. We studied the association of these chemokine receptor variants with susceptibility to and severity of rheumatoid arthritis in two Dutch patient populations; 282 consecutive rheumatoid arthritis patients from a rheumatology outpatient clinic, and a cohort of 101 female rheumatoid arthritis patients, followed closely for a 12-year period, from whom hand and feet X-rays taken at three year intervals were scored and analyzed in this study. Although there was a trend towards increased severity of disease in patients carrying CX3CR1 variants, this was not independent of known risk factors. We found no evidence for a significant independent role for the CCR2 and CX3CR1 variants in the susceptibility to or severity of rheumatoid arthritis.     

Expression of cyclooxygenase-1 and -2 in rheumatoid arthritis synovium

The aim of this study was to investigate the expression and localization of cyclooxygenase-1 and -2 (COX-1 and COX-2) in synovial tissues from patients with rheumatoid arthritis (RA). Synovial tissues from 9 patients with RA and 5 patients with osteoarthritis (OA) were examined for COX-1 and COX-2 expressions by immunohistochemical staining using 2 polydonal COX-1 and COX-2 antibodies. In RA synovia, synovial lining cells showed intense immunostaining for COX-1, whereas slight to moderate staining was observed in inflammatory cells, stromal fibroblast-like cells and vascular endothelial cells. There was no significant difference in COX-1 expression between RA and OA synovia. The localization of COX-2 expression dearly differed from that of COX-1 expression, being most intense in inflammatory cells. However, there was no difference in COX-1 and COX-2 expressions between RA and OA synovial tissues. Our observations support that inflammatory mechanisms modulated by COX-1 and COX-2 in chronic RA synovium might be similar to those in chronic OA synovium.