Evidence for activation of platelets in the synovial fluid from patients with rheumatoid arthritis

Summary Platelets were isolated by gel filtration from paired samples of peripheral blood and synovial fluid (SF) aspirated from inflamed knee joints from 20 adult patients with rheumatoid arthritis (RA) as well as from peripheral blood obtained from 20 healthy subjects. The platelets from the three different sources were investigated for quantitative differences in the number of two distinct types of intracellular storage organelles using immunofluorescence staining for platelet factor 4 (PF4) and labelling with the fluorescent substance mepacrine (MC). The number of PF4-stained organelles per cell was the same in the peripheral normal and RA platelets. This number was distinctly lower in the SF platelets. The peripheral and SF platelets from the RA patients had the same number of MC-labelled organelles. This number was distinctly lower than in the normal cells. The results suggest that the peripheral RA platelets had been activated to liberate serotonin and other substances from one type of organelles, and that the SF platelets had been activated to an additional liberation of PF4 from another such type. Liberated PF4, serotonin, and other substances from SF platelets may, in several ways, contribute to the inflammatory responses of RA.     

The significance of platelet activation in ankylosing spondylitis

The objective of this study was to explore the significance of platelet activation in patients with ankylosing spondylitis (AS). Thirty-five AS patients and 15 normal controls were selected from November 2005 to October 2006. The number of CD62P- and CD63-positive cells were detected by flow cytometry. At the same time, the erythrocyte sedimentation rate (ESR), platelet count (PLT) and C-reactive protein (CRP) were determined in both groups. The percentage of CD62P-positive cell in AS patients (13.60 ± 7.64%) was significantly higher than that in control group (2.78 ± 1.04%; P < 0.01). The percentage of CD63-positive cell in AS patients (6.92 ± 4.16%) was significantly higher than that in control group (4.13 ± 1.85%; P < 0.05). The levels of CRP (20.18 ± 23.17 mg/l), PLT (259.54 ± 102.59 × 10⁹/l) and ESR (36.86 ± 31.23 mm/h) in AS patients were higher than those in normal controls, respectively (3.21 ± 2.18 mg/l, P < 0.01; 197.00 ± 55.70 × 10⁹/l, P < 0.01; 12.25 ± 5.05 mm/h, P < 0.05). Platelet activation may be a sign of AS exacerbation.     

抗Sa抗体在类风湿关节炎中的意义

目的测定自身免疫性结缔组织病中抗Ｓａ抗体的阳性率，着重分析抗Ｓａ抗体在类风湿关节炎（ＲＡ）中的意义。方法从人胎盘中提取Ｓａ抗原，采用免疫印迹法，测定了４０例健康人及４７８例各种自身免疫性结缔组织病患者血清中的抗Ｓａ抗体，并分析了该抗体与ＲＡ的某些临床及实验室指标的相关性。结果抗Ｓａ抗体在各组患者中的阳性率分别为：ＲＡ为３１．９％（６１／１９１），干燥综合征为３．０％（２／６７），系统性红斑狼疮为４．３％（２／４６），白塞病、肌炎／皮肌炎、其他自身免疫性结缔组织病及正常人中均为０。研究分析表明，抗Ｓａ抗体对ＲＡ的诊断敏感性为３１．９％，特异性为９８７％，阳性预报率为９３．８％，阴性预报率为７１．３％。与抗Ｓａ抗体阴性的ＲＡ患者相比，抗Ｓａ抗体阳性的患者在关节受累、晨僵、血沉、抗核抗体、Ｘ线分期和二线药物的使用方面有显著差异。结论我们在国内首次制备了Ｓａ抗原，并建立了Ｓａ抗体的检测方法，它是一种不同于类风湿因子、对ＲＡ诊断较为特异的新型自身抗体。该抗体与疾病的严重程度相关，能否有助于ＲＡ的早期诊断和分型尚需更多病例的积累和观察。     

Platelets as target cells in rheumatoid arthritis and systemic lupus erythematosus: A platelet specific immunoglobulin inducing the release reaction

Summary Sera from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were assessed for in vitro platelet activation as measured by serotonin release; 24% (30) of 124 tested RA sera and 51% (35) of 69 SLE sera induced a significant 3H serotonin release. Investigation of 17 synovial fluid samples from RA patients revealed significant release in 82%. Concomitant testing for lymphocytotoxic antibodies and immune complexes did not show any correlation to platelet activation. Upon gel filtration the release-inducing activity of positive sera was localized in the region of 160 000 Daltons. Further characterization by ion exchange chromatography, immune electrophoresis, chromatographic and SDS PAGE molecular weight determinations, as well as analytical ultracentrifugation all confirmed the IgG nature of the release-inducing protein. Negative blocking experiments performed by preincubation of platelets with Fc-IgG fragments prior to challenge with a release-inducing serum excluded the participation of Fc receptors in the reaction. It was concluded that the release was caused by a platelet reactive IgG antibody. This antibody may also cause release of platelet mediators in vivo and may thus contribute to the pathogenesis of the generalized vasculopathy in both diseases.     

Associations with subregional BMD-measurements in patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) have bone loss to various degrees at different skeletal sites. The subregional bone mineral density (BMD) of the hand and the correlation of BMD to other regional bone losses, parameters of inflammation or bone resorption was evaluated in 421 patients with RA and controls. RA patients had significantly (P < 0.01) lower BMD values in the carpus (0.405 ± 0.004 g/cm²), metacarpal joint II (0.318 ± 0.036 g/cm²) and metacarpal joint III (0.326 ± 0.022 g/cm²) compared to controls. There was no difference in bone density at the lumbar spine or hip. Significant (P < 0.001) correlations were found between BMD total of the hand, its subregions, the forearm and hip. Parameters of inflammation correlated significantly (P < 0.001) with pyridinolines (r = 0.378), desoxypyridinolines (r = 0.183), forearm (r = −10, P < 0.05), MCP II (r = −0.190, P < 0.001), MCP III (r = 0.204, P < 0.001) and carpus (r = 0.191, P < 0.001).     

Clinical significance of rheumatoid factor isotypes in seropositive arthritis

Summary In this cross-sectional study a comparison was made of rheumatoid factor (RF) isotypes in 203 RF positive patients with arthritis. Of these, 129 had rheumatoid arthritis (RA) and 74 a milder disease that would formerly have been classified as probable RA. The majority (74%) of the RA patients had elevations of two or three RF isotypes compared with only 34% of the patients with the milder form of arthritis. A striking feature was that combined elevation of IgM RF and IgA RF was found in 67% of the RA patients compared to only 20% of the patients with milder arthritis who most frequently had an isolated elevation of IgM RF (41%). RA patients with an isolated elevation of IgA RF were younger and had a shorter disease history than RA patients with an isolated elevation in IgM RF or a combined elevation of IgA RF and IgM RF. The prevalence of raised IgM RF was, furthermore, found to increase with age and disease duration. We concluded that a raised level of IgA RF is an adverse phenomenon in patients with seropositive arthritis while patients with an isolated increase in IgM RF may be expected to experience a relatively mild disease course.     

D-二聚体在类风湿关节炎中的临床意义

目的探讨D-二聚体在类风湿关节炎(RA)中的临床意义。方法纳入RA患者134例(RA组),同时纳入健康体检者(健康对照组)、系统性红斑狼疮(SLE,SLE组)及原发性干燥综合征(PSS,PSS组)患者各30例。依据28个关节的疾病活动度评分(DAS28),将RA患者分为缓解组(DAS28<2.6)、低疾病活动组(2.6≤DAS28<3.2)、中疾病活动组(3.2≤DAS28≤5.1)及高疾病活动组(DAS28>5.1)。检测各组受试者血浆D-二聚体水平并进行比较,采用Pearson相关分析和多因素logistic回归分析评估RA患者D-二聚体与其他指标之间的相关性。结果RA组受试者D-二聚体水平明显高于健康对照组、SLE组、PSS组(P<0.01)。不同疾病活动组RA患者D-二聚体水平比较差异有统计学意义(P<0.01),其中缓解组低于3个疾病活动组,低疾病活动组和中疾病活动组均低于高疾病活动组(P<0.01)。Pearson相关分析结果显示,RA患者D-二聚体与年龄、PLT计数、红细胞沉降率、C反应蛋白、DAS28、凝血酶原时间、纤维蛋白降解产物、纤维蛋白原水平均呈正相关,与血红蛋白呈负相关(P<0.01)。多因素logistic回归分析,结果显示,DAS28、纤维蛋白降解产物水平升高是RA患者D-二聚体水平升高的危险因素(P<0.01)。结论RA患者D-二聚体水平可较好地反映疾病活动度,对判断预后具有意义,可作为评价RA病情活动性的参考指标之一。     

Statin treatment for rheumatoid arthritis: a promising novel indication

The results of several cross-sectional trials suggest that patients with rheumatoid arthritis (RA) have increased vascular risk and cardiovascular mortality. It was demonstrated that inflammation plays a pivotal role in the pathogenesis of both RA and atherosclerosis. This association may explain the high incidence of cardiovascular disease in RA patients. A number of recent studies show that routine statin use in patients with RA offers considerable advantages. Statin treatment has been supported to exert a beneficial effect on disease activity, swollen joint count, endothelial dysfunction, and arterial stiffness in RA patients. These improvements are coupled with a mild to moderate improvement in plasma markers of inflammation, such as C-reactive protein and erythrocyte sedimentation rate. Statins have a satisfactory safety profile with relatively few adverse effects. In the absence of side effects and contraindications, it may be reasonable to consider statin use in selected cases, particularly in patients with a long history of active RA who are at increased cardiovascular risk.     

Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis

Objectives

The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks.

Methods

One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels.

Results

Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks.

Conclusions

Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.     

Remarkable efficacy of tocilizumab for treating rheumatoid arthritis in patients with high platelet counts

Objectives. To optimize the efficacy of treatment with tocilizumab for rheumatoid arthritis (RA), we comparatively analyzed the outcome of tocilizumab treatment in patients with normal background changes associated closely with IL-6.

Patients and Methods. The study involved 87 patients with RA satisfying the diagnostic criteria of the American College of Rheumatology (ACR) and receiving continuous tocilizumab treatment for 24 weeks or longer. The outcome of tocilizumab treatment in these patients was comparatively analyzed in relation to the baseline platelet count (the high platelet count group and the normal group), pretreatment hemoglobin levels (the low group and the normal platelet count group), and speed of bone destruction (the rapid progression group and slow progression group).

Results. Treatment with tocilizumab significantly improved the 28-joint disease activity score using the erythrocyte sedimentation rate (DAS28-ESR) and Clinical Disease Activity Index (CDAI), regardless of baseline platelet count, hemoglobin level, or annual speed of bone destruction (ΔTSS). The margins of improvement in DAS28-ESR and CDAI did not differ depending on baseline hemoglobin level or ΔTSS, but the improvement was significantly greater in the high platelet count group than in the normal platelet count group.

Conclusions. These results suggest that in patients with high platelet count, IL-6 is a more important factor involved in RA pathogenesis and that tocilizumab is suitable as a first-line biologic for the treatment of RA patients with high platelet count.     

Raised C-reactive protein response in rheumatoid arthritis patients with secondary Sjögren's syndrome

Summary The levels of serum C-reactive protein (CRP) were found to be significantly higher in the presence than in the absence of secondary Sjögren's syndrome in patients with rheumatoid arthritis, while the values of erythrocyte sedimentation rate and serum fibrinogen were not significantly different. The levels of CRP were found to be normal in 22 out of 24 patients with primary Sjögren's syndrome.     

Pericarditis in rheumatoid arthritis

Summary The annual incidence of clinically manifest pericarditis was found to be 0.34% in 157 females and 0.44% in 77 males with rheumatoid arthritis, observed for a mean time of 5.7 years. The development of pericarditis was independent of disease duration, but was related to extensive joint involvement, subcutaneous nodules, and a high Waaler Rose titre. Concomitant pleural effusion was present in four of five patients. Pericarditis in rheumatoid arthritis may indicate a serious prognosis quo ad vitam. Four of the five patients died within eight years, but their age at death was relatively high (62–73 years).     

Anti-CCP antibodies in rheumatoid arthritis and psoriatic arthritis

Our aim is to assess the prevalence and associated clinical features of anti-CCP (cyclic citrullinated peptide) antibodies for RF (rheumatoid factor)-positive and RF-negative rheumatoid arthritis (RA) and psoriatic arthritis (PsA). In a prospective, cross-sectional, multi-centre study, we determined the titres of anti-CCP antibodies in 208 RA patients (129 RF-positive, 79 RF-negative), 56 PsA patients and 39 healthy controls (HC). Clinical parameters including disease activity (disease activity score 28-DAS28), physical disability (health assessment questionnaire-HAQ), functional capacity (functional class) and radiological erosions were investigated in patients with RA. In PsA patients, clinical and radiological features were determined. Anti-CCP2 antibodies were measured using a second-generation anti-CCP enzyme-linked immunosorbent assay (Euro-Diagnostica, Netherlands). One-hundred four of 129 RF-positive RA (81%), 16 of 79 RF-negative RA (20%), seven of 56 PsA patients (12.5%) and none of the HC had anti-CCP antibodies. RA patients with anti-CCP antibodies had significantly higher disease activity, greater loss of function and more frequent erosive disease than anti-CCP antibody-negative group. In subgroup analysis, anti-CCP antibodies in RF-negative patients were also associated with erosive disease. All PsA patients with anti-CCP antibodies had symmetric arthritis with higher number of swollen joints. The prevalence of anti-CCP antibodies in RF-positive RA patients was significantly higher than in RF-negative RA and PsA patients. Anti-CCP antibodies were also associated with erosive disease in RF-negative RA patients. Both anti-CCP and RF tests were negative in 30% of the patients. Anti-CCP positivity was a frequent finding in PsA and associated with symmetrical polyarthritis.     

Clinical significance of anti-Ro antibodies in rheumatoid arthritis

The objective of our study was to determine the frequency of anti-Ro antibodies in patients with rheumatoid arthritis (RA), their clinical significance and possible serologic and genetic associations. Consecutive patients with RA (ACR ’87) were studied. Other connective tissues diseases were excluded. Demographic characteristics, extra articular manifestations, and treatment were reviewed. Presence of leukopenia, thrombocytopenia, hypergammaglobulinemia, hypocomplementemia, and cryoglobulinemia were consigned. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anti-Ro, and anti-La were determined by ELISA in all patients; and HLA-DR was determined by PCR and oligotyping. X-rays of the hands and feet were evaluated by Larsen’s score. The study included 106 patients, 94 women and 12 men; mean age was 50.3 ± 11.4 years, mean disease duration was 11.2 ± 6.8 years. Main extra articular manifestations were subcutaneous nodules, xerophthalmia, and xerostomia; 75.5% of the patients were RF+. Anti-Ro antibodies were detected in 12.2% of the patients. When positive and negative anti-Ro patients were compared, no significant difference in any studied variable was observed. According to our results, anti-Ro antibodies lack clinical relevance in patients with RA.     

男性类风湿关节炎患者的血清性激素水平测定及其临床意义

采用放射免疫法检测34例男性类风湿关节炎（RA）患者（RA组）的血清雌二醇（E2），睾酮（T），硫酸脱氢表雄酮（DHEAS）水平，并与30例健康男性（对照组）作对照。结果发现患者血清T，DHEAS水平明显低于正常对照组（P＜0．05，P＜0．001），而E2水平虽低于对照组，但无显著差异（P＞0．05），提示雄激素减低在男性RA的发病中起一定的作用。     

Evidence-based review of biologic markers as indicators of disease progression and remission in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease characterised by inflammation resulting in structural joint damage and functional disability. Tumour necrosis factor-alpha (TNFα) is a pivotal mediator and driver of inflammation in RA. Inflammation is closely related to the production of C-reactive protein (CRP), and a close correlation exists between serum CRP and TNFα levels. CRP levels are therefore a convenient, objective biomarker of disease activity. CRP correlates closely with changes in inflammation/disease activity, radiological damage and progression and functional disability. Identification of TNFα as a driver of RA progression has led to the introduction of TNFα-blocking agents and, subsequently, improvement of disease management. TNFα-blocking agents provide rapid, profound and sustained suppression of disease activity in correspondence with a marked reduction in CRP levels. A reduction in CRP level correlates closely with the positive clinical response to TNFα-blocking therapy. Thus, CRP levels can be used to predict, assess and monitor response to treatment with TNFα-blocking agents, and may be helpful in determining the optimal TNFα-blocker dosage. Given the close correlation between inflammation and disease progression and the relation between inflammation and CRP, the latter, if used effectively in clinical practice, may be means to identify patients likely to progress rapidly and who require intensive anti-TNFα therapy. The purpose of this review is to identify how CRP levels may be useful for monitoring the effect of therapy on halting disease progression and why monitoring CRP levels at baseline and after treatment should become a routine part of clinical practice.     

Neutrophil-to-lymphocyte ratio is a reliable marker of treatment response in rheumatoid arthritis patients during tocilizumab therapy

Objective: To investigate the reliable markers reflecting treatment response better than the traditional inflammatory indices in patients with rheumatoid arthritis (RA) receiving tocilizumab therapy.

Methods: A total of 58 RA patients treated with tocilizumab for more than six months from January 2013 to December 2014 were initially included. Flares were defined as events that required steroid dose escalation, intra-articular steroid injections, or switching tocilizumab to other biologic agents. The clinical and laboratory data were retrospectively collected from electronic medical records.

Results: Of the 52 patients except for six patients who were excluded, 16 experienced flares, and 36 were stable during tocilizumab therapy. The C-reactive protein (CRP) level did not significantly differ between a stable state before flares and at flares. Compared with those at the preflare time point, erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR) were significantly higher at flares; however, ESR levels (n?=?9) were within the normal limit or decreased (n?=?4) at flares. Interestingly, NLR increased at flares in all but one patient in the flare group.

Conclusion: NLR is a more reliable marker than ESR or CRP for evaluating the disease activity in patients with RA during tocilizumab therapy.     

Corticosteroid prescribing in rheumatoid arthritis and psoriatic arthritis

Corticosteroid usage was assessed in rheumatoid arthritis (RA) and psoriatic arthritis (PA) patients in Italy. A multicentre, observational study was undertaken in 10 Italian rheumatological centres from 1990 to 1992 using a computerised clinical data bank. Nine hundred and seven RA patients and 180 PA patients were studied; 510 (56.2%) RA patients and 44 (24.4%) PA patients were using corticosteroids. The percentage of patients taking corticosteroids ranged from 20.5 to 85.4% for RA patients and from 0 to 55% for PA patients for the different centres. Methylprednisolone was the most prescribed corticosteroid, both in RA patients (63.2%) and in PA patients (65.9%). The average methylprednisolone daily dose was 5.7±3.6 mg in RA patients and 4.5±1.4 mg in PA patients. The data provide evidence that corticosteroids are taken in an unexpectedly high percentage of patients with RA and PA in Italy.     

类风湿关节炎动脉粥样硬化的研究进展

类风湿关节炎是一种慢性自身免疫性疾病,主要损害外周关节滑膜,类风湿关节炎的致残率较高.近年来,心血管疾病作为其主要的死亡原因之一,引起人们越来越多的关注.绝大部分患者在心血管方面的改变以动脉粥样硬化为主,本文就与类风湿关节炎有关的动脉粥样硬化发病机制的研究进展作一综述.     

Synovial membrane enhancement and bone erosion by magnetic resonance imaging for prediction of radiologic progression in patients with early rheumatoid arthritis

Objective The aim of this study was to determine the prognostic factors related to radiographic progression in patients with early rheumatoid arthritis (RA) (less than 1 year after onset) undergoing enhanced MRI at entry.Methods Demographic characteristics, disease duration, and enhanced MRI of the dominant wrists were recorded at entry. Duration of morning stiffness, number of swollen joints, serum rheumatoid factor (RF), erythrocyte sedimentation rate, C-reactive protein (CRP) level, and radiographs of hands and feet (Sharp/van der Heijde score) were assessed at each follow-up. Outcome was defined as damage seen on radiography.Results One hundred fourteen patients were followed up for 10 years. Logistic regression analysis showed that high MRI score, CRP, and RF positivity were associated with radiologic progression. The MRI score at baseline was a better predictor than CRP level and RF positivity at entry.Conclusion The assessment of synovial membrane enhancement and bone erosion by MRI of the wrist in early RA is very helpful to predict erosive outcome.