Activated lymphocytes in the peripheral blood of patients with rheumatoid arthritis.

The peripheral blood and synovial fluid of patients with rheumatoid arthritis (RA), when compared to controls, has a higher proportion of mononuclear cells actively synthesizing DNA (S-phase cells). Such cells can be marked by radioautography after incubation with tritiated thymidine and can also be quantitated by the 4-h spontaneous in vitro uptake of tritiated thymidine. As our previous studies showed a marked and rapid decrease in this latter measure, in response to in vivo methotrexate, we suggested that the responsible cells may have a direct role in pathogenesis rather than merely reflecting the inflammation that is present. We have therefore tried to characterize them further. A mean of 46% of these autoradiography positive cells from the peripheral blood of patients with active RA bear CD3 markers and 61% Ia. On some occasions up to 25% stain for Leu M3 and 25% for Leu 7. None were esterase positive. Cell separation studies confirm that such cells were found in both T cell and non-T cell enriched populations. These cells, therefore, appear to be heterogeneous. A decreased number was seen in peripheral blood lymphocytes from patients who had received remittive therapy for over 4 months when compared to other patients with RA and this was associated with a lower 4-h spontaneous uptake of labelled thymidine.     

Morphological evidence that activated polymorphs circulate in the peripheral blood of patients with rheumatoid arthritis.

Purified peripheral blood polymorphonuclear leucocytes (PMNs) from patients with rheumatoid arthritis (RA) have been found to differ from purified PMNs from normal subjects in ways that are consistent with their prior activation. However, it is currently contentious whether activated PMNs really circulate in patients with RA, or whether they are produced as an in vitro artefact of purification. Recently developed rapid leucocyte fixation and preparation technique showed that the proportion of polarised (activated) PMNs (36.9 (24.7)%, mean (SD); n = 31) was increased relative to that in control subjects (8.1 (5.6)%; n = 12). Serum cytidine deaminase levels, a biochemical marker of PMN lysis, were also increased in patients with RA (11.59 (7.26) U/ml) compared with those in controls (6.82 (3.78) U/ml), but the proportion of polarised PMNs and the levels of cytidine deaminase activity were unrelated to clinical assessments of inflammatory disease activity. Twelve patients who were not receiving drugs or who were receiving only non-steroidal anti-inflammatory drugs (NSAIDs) had more polarised PMNs than 19 patients receiving second line treatment in addition to NSAIDs (patients receiving NSAIDs, 49.6 (25.9)%; patients receiving second line treatment, 27.5 (21.1)%). Fluorescence activated cytometric analysis of CR1 and CR3 expression on PMNs from a randomly selected subgroup of patients with RA showed that the serum level of cytidine deaminase activity was correlated positively with the expression of CR1 (the C3b receptor) on the cell surface and that the proportion of polarised PMNs was positively correlated with the expression of CR3 (or CD11b/CD18), the iC3b receptor that is upregulated on activation. It is suggested that the polarised PMNs which circulate in blood samples from patients with RA represent cells which have been activated but not yet marginated, or activated cells which have marginated but subsequently returned to the circulating pool.     

Reduction of peripheral blood lymphocytes in patients receiving gold therapy for rheumatoid arthritis.

Peripheral blood lymphocytes were monitored prospectively in 10 patients with rheumatoid arthritis (RA) receiving up to 1 g of sodium aurothiomalate. There was a significant fall in the absolute lymphocyte count from a mean +/- SEM of 1956 +/- 190/mm3 (1.956 +/- 0.19 X 10(9)/l) to 1232 +/- 210/mm3 (1.232 +/- 0.21 X 10(9)/l) (p less than 0.01). The number of of circulating lymphocytes fell in all patients by an amount which ranged between 108/mm3 (0.108 X 10(9)/l) and 1394/mm3 (1.394 X 10(9)/l), with a mean fall of 727/mm3 (0.727 X 10(9)/l). No significant change was noted in the total white cell count or total polymorphonuclear cell count over the same period. In contrast there was no change in the total lymphocyte count in an age and sex matched group of RA patients treated with penicillamine. This previously unreported observation may give new insight into the mechanism of action of gold salts in RA.     

Phenotypes of peripheral blood T lymphocytes in rheumatoid arthritis and juvenile rheumatoid arthritis. Findings in patients with varying disease activity and clinical subgroups

Summary The percentage of T4 and T8 positive cells in peripheral blood of 78 patients with rhematoid arthritis (RA) and 26 patients with juvenile rheumatoid arthritis (JRA) was determined using a rosette technique. The T4/T8 ratio ± SEM (standard error of the mean) in the RA patients was increased, 2.02±0.09, as compared with normal blood donors, 1.71±0.06 (p<0.02). The subgroups of RA patients who had a significantly increased T4/T8 ratio were ANA positive patients (p<0.02) and patients on no medication (p<0.05). In the total group of JRA patients the T4/T8 ratio was 2.01±0.12 versus 1.75±0.08 in controls (p=0.061). Polyarticular JRA patients had an increased T4/T8 ratio as compared with controls (p<0.05) while patients with the pauciarticular form had a normal ratio (p>0.10). No correlation between the T4/T8 ratio and a disease outcome index, a laboratory activity index, ESR, WBC, platelet count, hemoglobin, serum albumin, age and disease duration was found (K< ±0.20, p>0.10).     

Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis

Cytofluorometric analysis was performed to characterize the surface phenotype and activation status of freshly isolated synovial tissue lymphocytes (STL) and peripheral blood lymphocytes (PBL) from 7 patients with rheumatoid arthritis (RA). Proliferative synovium was enzymatically digested to obtain tissue-derived lymphocytes. Indirect immunofluorescent staining of patient PBL and STL with a variety of monoclonal antibodies failed to reveal a consistent alteration in the number of CD4+ (helper/inducer) PBL or STL. However, there was a significant decrease in the number of CD8+ (suppressor/cytotoxic) cells in rheumatoid STL (P less than 0.05). A significant reduction in the density of the T cell differentiation antigens CD3 and CD4 was observed in RA PBL and STL, compared with control PBL. These differences in antigen density were not seen when normal PBL were subjected to the same enzymatic digestion. Both RA PBL and STL manifested increased expression of HLA-DR antigens, without augmentation of interleukin-2 receptor expression. Alterations in the expression of the T cell differentiation antigens and activation antigens by patient PBL closely paralleled the abnormalities observed in STL. In contrast, STL of patients with RA exhibited an increase in the expression of the adhesion-related glycoproteins (leukocyte function-associated 1 [LFA-1] and very late activation 1 [VLA-1] antigens), not observed with autologous PBL. These studies demonstrate that lymphocytes isolated from the synovial tissues of RA patients bear an activated phenotype, exemplified by the modulation of CD3 and CD4 and the expression of HLA-DR.(ABSTRACT TRUNCATED AT 250 WORDS)     

淋巴细胞激活诱导的受体4-1BB在类风湿关节炎T淋巴细胞亚群上的表达

目的探讨类风湿关节炎(RA)T淋巴细胞上淋巴细胞激活诱导的受体4-1BB的表达及其作用机制。方法应用流式细胞术检测30例RA患者和20名正常对照者外周血T细胞活化前后4-1BB的表达。结果RA患者CD4~ T和CD8~ T细胞表达的4-1BB明显高于正常对照组[表达百分率分别为(18．56±4．08)％,(10．33±2．13)％,(1．24±0．12)％,(0．87±0．09)％,P＜0．01],经抗CD3单抗体外刺激后CD4~ T和CD8~ T细胞表达的4-1BB均显著高于活化前[表达百分率为(33±4)％和(21±8)％,P＜0．01]。RA患者CD4~ T/CD8~ T比值明显升高,而且与4-1BB~ CD4~ T细胞数呈正相关关系(r=0．84,P＜0.01),另外4-1BB~ CD4~ T细胞数与血沉、IgA呈正相关关系(r=0．476,P＜0．05；r=0．659,P＜0．05)。结论RA患者T细胞表达的4-IBB在RA的发生发展中具有重要意义,4-1BB可能通过对CD4~ T活化与增殖参与关节炎症和免疫反应。     

Phenotypes of T lymphocytes from peripheral blood and synovial fluid of patients with rheumatoid arthritis and juvenile rheumatoid arthritis. Evidence in favour of normal helper and suppressor functions of T lymphocytes from patients with juvenile rheumatoid arthritis

Lymphocytes from peripheral blood (PB) and synovial fluid (SF) from 21 patients with rheumatoid arthritis (RA) and 18 patients with juvenile rheumatoid arthritis (JRA) were studied with respect to T cell phenotypes using monoclonal antibodies in a rosette assay. The percentage of HLA-DR positive T cells was counted in PB and SF using indirect immunofluorescence. Suppressor cell activity of T cells from PB and SF was investigated by measuring the immunoglobulin production by pokeweed mitogen (PWM) stimulated B cells mixed with T cells at various ratios. The mean T4/T8 ratio was significantly lower in SF than in PB of both RA and JRA patients (p = 0.0062 and p less than 0.0001 respectively). The mean percentages of HLA-DR positive T cells were elevated in SF compared with PB in both patients groups (p less than 0.03 and p less than 0.04 in RA and JRA patients respectively). Mean suppressor cell activity and helper cell activity of T cells from SF and PB of JRA patients was normal. Thus there seems to be a dichotomy between the number of T8+ cells and suppressor cell function in mononuclear cells from SF of patients with JRA. This indicates that a considerable proportion of the T8+ cells in the SF do not have suppressor functions.     

Phenotypically activated gammadelta T lymphocytes in the peripheral blood of patients with tuberculosis.

Surface molecules with the potential relevance for resistance against Mycobacterium tuberculosis were investigated. The expression of lymphocyte function antigen-1, very late antigen (VLA)-4, l-selectin, intercellular adhesion molecule (ICAM)-1, major histocompatibility complex class II, Fas, and CD40 on alphabeta T cells, gammadelta T cells, NK cells, and monocytes of healthy donors and patients with tuberculosis were analyzed. A high activation status of gammadelta T cells and increased levels of soluble ICAM-1 in plasma of patients with tuberculosis versus healthy individuals was detected. Tuberculosis patients with and without an underlying systemic disease could be segregated by differential expression of VLA-4 and ICAM-1 on gammadelta T cells and on monocytes. The composition of peripheral blood mononuclear cells varied slightly, whereas the proportion of monocytes decreased significantly in patients with tuberculosis, compared with healthy controls. The activation phenotype of peripheral gammadelta T cells in patients with tuberculosis emphasizes the role of these T cells in controlling the inflammatory process during tuberculosis and perhaps other microbial infections.     

Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate

Because of a previously observed plateau of clinical response after long-term methotrexate (MTX) therapy for rheumatoid arthritis (RA), we investigated whether such treatment might lead to acquired resistance to the drug. We studied the activity of dihydrofolate reductase (DHFR) (the target enzyme of MTX) in peripheral blood mononuclear cells of 11 RA patients who had been treated with MTX for a median of 43 months. The enzyme levels were markedly increased compared with levels found in the cells of 6 RA patients treated with other slow-acting drugs. Quantitative dot-blot analysis of DNA from 7 of these patients showed no evidence of DHFR gene amplification. No correlation was observed between increased levels of DHFR and either response to therapy or to the weekly MTX dosage. Phytohemagglutinin-stimulated peripheral blood lymphocytes from 6 patients with increased levels of DHFR showed no evidence of MTX resistance in vitro. The increased DHFR levels may result from binding of MTX to the enzyme, which may block the normal degradation pathways; they do not appear to be a marker of impending drug resistance.     

Apoptosis of peripheral blood lymphocytes in patients with juvenile idiopathic arthritis

BACKGROUND: Recent data suggested that abnormalities in mechanisms regulating apoptosis may have a role in the development of the rheumatoid process. OBJECTIVE: To evaluate different aspects of apoptosis in children with juvenile idiopathic arthritis (JIA). METHODS: The frequency of TUNEL positive peripheral blood (PB) lymphocytes (apoptotic index (AI)), as well as serum CD95 (APO1/Fas) antigen expression and serum levels of sFas and interleukin 15 (IL15), were examined in 44 cases of JIA. Results were correlated with type of onset, activity of JIA, and acute phase indicators. RESULTS: The AI of lymphocytes was significantly higher in patients with JIA than in controls (p=0.020). The mean AI of lymphocytes was increased in JIA with systemic type of onset and high activity (p=0.001). Moreover, IL15 levels in systemic disease were higher than in controls (p=0.012). An increased AI correlated with raised IL15 (p=0.046), erythrocyte sedimentation rate (p=0.005) and C reactive protein (CRP; p=0.017). Additionally, correlation was found between IL15 and CRP levels (p=0.039). CD95 and sFas levels were unchanged compared with controls. CONCLUSION: PB lymphocytes of children with JIA have an increased tendency to undergo apoptosis. The degree of apoptosis depends on the type of onset and activity of JIA and correlates with serum levels of IL15. Further studies are needed to explain whether this is an epiphenomenon of the disease activity or is related to the pathogenesis of JIA.     

类风湿关节炎外周血单个核细胞磷酸二酯酶活性的变化及与间质性肺疾病的关系

目的 观察类风湿关节炎(RA)外周血单个核细胞(PBMC)磷酸二酯酶(PDEs)活性的变化及与间质性肺疾病(ILD)的关系,探讨PDEs在RA及RA-ILD发病机制中的作用.方法 67例初治活动期RA患者分为RA-ILD组30例和单纯RA组37例,同时设健康对照组20名,高效液相色谱法测定PBMCs中环磷酸腺苷(cAMP) PDEs的活性变化,并与患者的临床、实验室及肺损伤指标进行相关性分析.采用单因素方差分析、Student-Newman-Keuls检验、t检验、Spearman相关分析进行统计学分析.结果 ①RA患者PBMC-cAMP-PDEs活性(51±11)高于对照组(34±8,P＜0.01),其中RA-ILD组PBMC-cAMP-PDEs活性(58±10)高于单纯RA组(46±7,P＜0.0l).②RA患者PBMC-cAMP-PDEs水平与晨僵时间、关节压痛数、关节肿胀数、X线分期、红细胞沉降率(ESR)、C反应蛋白(CRP)、类风湿因子(RF)以及28个关节疾病活动指数(DAS28)评分呈正相关(r值分别为0.432、0.441、0.527、0.430、0.466、0.616、0.662、0.519,P均＜0.01).③RA-ILD患者PBMC-cAMP-PDEs水平与ERS、CRP、RF、CT评分呈正相关(r值分别为0.466、0.616、0.662、0.488,P均＜0.01),与动脉血氧分压(PaO2)呈负相关(r=--0.563,P＜0.01),与肺活量(VC)及一氧化碳弥散吸收率(DLCO)无明显相关性(r值分别为0.118、-0.259,P＞0.05).结论 RA及RA-ILD患者免疫细胞内PDEs活性增高,并与RA疾病活动性及RA-ILD肺损伤严重程度有关,提示PDEs可能参与了RA及RA-ILD的发病过程.     

Phenotypic analysis of peripheral blood monocytes isolated from patients with rheumatoid arthritis.

The expression of CD14, Fc gamma receptor I (Fc gamma RI), Fc gamma RII, and HLA-DR on peripheral blood monocytes from patients with rheumatoid arthritis (RA) was studied to investigate their nature and their role in the pathogenesis of rheumatoid synovitis. Peripheral blood mononuclear cells obtained from 9 patients with active RA, 8 patients with RA in complete remission, and 14 healthy individuals, were stained with various monoclonal antibodies and analyzed on a fluorescence activated cell sorter. The expression of CD14 as well as Fc gamma RI and Fc gamma RII was upregulated on peripheral blood monocytes from patients with active RA, although the expression of HLA-DR was not increased. In addition, the expression of Fc gamma RI and Fc gamma RII on monocytes was still upregulated in patients with RA in complete remission, whereas the expression of CD14 on monocytes was normalized in these patients. These results indicate that peripheral blood monocytes in patients with active RA are already activated to express higher densities of CD14. In addition, our observation that CD14 density was increased on a subset of circulating blood monocytes in active RA, that HLA-DR was not significantly altered and that Fc gamma RI and Fc gamma RII were increased in both active and inactive RA is not compatible with the expected actions of interferon gamma. Finally, it is suggested that peripheral blood monocytes in patients with RA may have intrinsic abnormalities as evidenced by the enhanced expression of Fc gamma R, which is repeatedly observed regardless of the disease activity of RA.     

类风湿关节炎患者外周血中B细胞凋亡的研究

目的 探讨类风湿关节炎(RA)患者外周血中B细胞的凋亡变化及临床意义.方法 流式细胞术检测81例RA患者(其中活动期51例,缓解期30例)及80名健康对照者外周血B细胞表达比例.免疫磁珠法分选出10例活动期RA患者、10例缓解期RA患者和10名健康对照者外周血中B细胞,进行体外培养;分别在24、48、72、96 h收集细胞,流式细胞术检测B细胞的凋亡率.采用单因素方差分析,t检验和Spearman相关分析进行统计分析.结果 以CD19、CD22为标记的B细胞在活动期、缓解期RA患者及健康对照者外周血中比例分别为:(26±11)％、(12±8)％、(10±6),(26±10)％、(12±8)％、(11±5)％;活动期RA患者外周血B细胞比例显著高于缓解期和健康对照组(P＜0.01).活动期RA患者外周血B细胞表达比例与疾病活动指数(DAS)28、血清IgG含量呈正相关(r=0.380,P=0.006;r=0.320,P=0.023),与其他临床参数无相关性.体外培养的活动期RA患者外周血B细胞凋亡率显著低于缓解期RA患者和健康对照组.结论 活动期RA外周血中B细胞凋亡途径受到抑制,可能导致其外周血B细胞比例显著增高,且B细胞增高比例与疾病活动度密切相关.     

Quantitative absorption of interleukin-2 by peripheral blood and synovial fluid lymphocytes from patients with rheumatoid arthritis

Summary Peripheral blood (PBL) and synovial fluid lymphocytes (SFL) from 18 patients with definite rheumatoid arthritis (RA) and from one patient with Reiter's disease (RD) were examined for their capacity to absorb quantitatively interleukin-2 (IL-2) from a standardized, lectin-free IL-2 source. For comparison normal ConA blasts and PBL from various inflammatory and noninflammatory diseases as well as from healthy control persons were studied. IL-2 activity was quantitated by measuring ³H-thymidine-2-deoxyriboside uptake in the IL-2 dependent murine T cell line CTL6. ConA blasts exhibited a high IL-2 absorption capacity and served as a positive control for calibrating the absorption assay. In a population of normal PBL at least 5–10% of ConA blasts were required to detect IL-2 absorption. Significant absorption was assumed if more than 50% of IL-2 activity was removed from 200 l of a lectin-free IL-2 standard following incubation with 5 × 10₆ lymphoid cells for 2 h at 4°C; this criterion was fulfilled with 8 out of 20 SFL and 4 out of 14 PBL preparations from RA patients. As a rule SFL absorbed more IL-2 than PBL. Control PBL did not absorb significant quantities of IL-2. PBL from the RD patient apparently produced an IL-2 inhibitor during incubation with the IL-2 standard. IL-2 absorption by ConA blasts and SFL was fully inhibited by preincubation of the absorbing cells with monoclonal anti-TAC antibody, a reagent known to react with the human IL-2 receptor. The results are discussed in view of current concepts of antigen/mitogen induced T cell activation.     

类风湿关节炎并发骨质疏松患者外周血淋巴细胞亚群的表达水平

目的检测类风湿关节炎(rheumatoid arthritis,RA)并发骨质疏松(osteoporosis,OP)患者外周血淋巴细胞亚群的表达水平并探讨其临床意义。方法收集山西医科大学第二医院住院诊治的734例RA患者的基本临床资料、外周血淋巴细胞亚群及骨密度(bone mineral density,BMD)检查结果,根据BMD结果以及是否曾有脆性骨折史将以上患者分为RA未并发OP组551例和并发OP组183例,比较两组临床资料的不同,同时选取81例健康人群作为健康对照组,分析3组外周血淋巴细胞亚群的差异,并对RA并发OP患者行BMD与外周血淋巴细胞亚群间的相关性分析。结果 RA患者OP发生率为24. 93%,其中12. 57%有骨折史。RA并发OP组女性患者比例明显高于未并发OP组(P=0. 021),且年龄较大(61. 85±10. 36 vs. 56. 63±12. 01,P<0. 001),病程更长(7. 17±5. 82 vs. 5. 28±6. 33,P=0. 001),疾病活动相关指标更高(P<0. 05)。相较于健康对照组,RA未并发OP组B细胞水平下降,Th17细胞水平升高,但差异均无统计学意义,Th2细胞及Th17/Treg比值明显升高(P<0. 01),Treg细胞及Th1/Th2比值降低(P<0. 05); RA并发OP组B细胞绝对计数下降(P<0. 05),Th17细胞水平及Th17/Treg比值明显升高(P<0. 01),Treg细胞水平显著下降(P<0. 001)。相较于RA未并发OP组,并发OP组B细胞及Treg细胞水平均明显下降(P<0. 01),Th17细胞水平及Th17/Treg比值升高(P<0. 05)。RA并发OP患者的腰椎BMD与B淋巴细胞和Treg细胞绝对计数及百分计数呈正相关(B淋巴细胞r=0. 290、0. 315; Treg细胞r=0. 318、0. 248,P<0. 05),与Th17细胞绝对计数和百分计数及Th17/Treg比值呈负相关(Th17细胞r=-0. 254、-0. 265; Th17/Treg r=-0. 242,P<0. 05);同样股骨BMD与B淋巴细胞和Treg细胞绝对计数及百分计数也呈正相关(B淋巴细胞r=0. 238、0. 256; Treg细胞r=0. 259、0. 255,P<0. 05),与Th17细胞绝对计数和百分计数及Th17/Treg比值也呈负相关(Th17细胞r=-0. 248、-0. 283; Th17/Treg r=-0. 216,P<0. 05)。结论 RA并发OP患者存在B细胞显著下降和Th17/Treg比例失衡,此与RA患者本身的免疫紊乱密切相关,在RA疾病早期关注免疫微环境并调节其平衡对预防骨质疏松的发生至关重要。     

类风湿关节炎并发骨质疏松患者外周血淋巴细胞亚群的表达水平

目的检测类风湿关节炎(rheumatoid arthritis,RA)并发骨质疏松(osteoporosis,OP)患者外周血淋巴细胞亚群的表达水平并探讨其临床意义.方法收集山西医科大学第二医院住院诊治的734例RA患者的基本临床资料、外周血淋巴细胞亚群及骨密度(bone mineral density,BMD)检查结果,根据BMD结果以及是否曾有脆性骨折史将以上患者分为RA未并发OP组551例和并发OP组183例,比较两组临床资料的不同,同时选取81例健康人群作为健康对照组,分析3组外周血淋巴细胞亚群的差异,并对RA并发OP患者行BMD与外周血淋巴细胞亚群间的相关性分析.结果RA患者OP发生率为24.93%,其中12.57%有骨折史.RA并发OP组女性患者比例明显高于未并发OP组(P=0.021),且年龄较大(61.85±10.36 vs.56.63±12.01,P<0.001),病程更长(7.17±5.82 vs.5.28±6.33,P=0.001),疾病活动相关指标更高(P<0.05).相较于健康对照组,RA未并发OP组B细胞水平下降,Th17细胞水平升高,但差异均无统计学意义,Th2细胞及Th17/Treg比值明显升高(P<0.01),Treg细胞及Th1/Th2比值降低(P<0.05);RA并发OP组B细胞绝对计数下降(P<0.05),Th17细胞水平及Th17/Treg比值明显升高(P<0.01),Treg细胞水平显著下降(P<0.001).相较于RA未并发OP组,并发OP组B细胞及Treg细胞水平均明显下降(P<0.01),Th17细胞水平及Th17/Treg比值升高(P<0.05).RA并发OP患者的腰椎BMD与B淋巴细胞和Treg细胞绝对计数及百分计数呈正相关(B淋巴细胞r=0.290、0.315;Treg细胞r=0.318、0.248,P<0.05),与Th17细胞绝对计数和百分计数及Th17/Treg比值呈负相关(Th17细胞r=-0.254、-0.265;Th17/Treg r=-0.242,P<0.05);同样股骨BMD与B淋巴细胞和Treg细胞绝对计数及百分计数也呈正相关(B淋巴细胞r=0.238、0.256;Treg细胞r=0.259、0.255,P<0.05),与Th17细胞绝对计数和百分计数及Th17/Treg比值也呈负相关(Th17细胞r=-0.248、-0.283;Th17/Treg r=-0.216,P<0.05).结论RA并发OP患者存在B细胞显著下降和Th17/Treg比例失衡,此与RA患者本身的免疫紊乱密切相关,在RA疾病早期关注免疫微环境并调节其平衡对预防骨质疏松的发生至关重要.