IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4(+)CD45RB(hi)CD25(-) cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell-dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis.     

Biological therapies for psoriasis

Introduction: Biological therapies have revolutionized moderate-to-severe psoriasis treatment. Increased understanding of disease pathogenesis has yielded multiple therapeutic targets involving the IL-23/Th17 pathway, while current therapies continue to be monitored for long-term efficacy and safety.

Areas covered: This review details current understanding of psoriasis immunopathogenesis specifically related to therapeutic targets. Approved and emerging biological psoriasis therapies targeting TNF-α, IL-12/23p40, IL-17 and IL-23p19 are covered. Biological agent uses in special circumstances are reviewed together with the emerging debate on biosimilar therapies and their potential future role in psoriasis and other inflammatory diseases.

Expert opinion: Psoriasis treatment has expanded and has become more effective due to increased understanding of disease pathogenesis. However, lack of efficacy in select psoriasis patients, safety concerns and limited treatment efficacy in psoriasis variants (e.g., pustular) are areas which still need improvement. As such, pharmacogenomics will be of vital importance in future for individualized psoriasis care. Further, a better understanding of the multiple psoriasis comorbidities, especially cardiovascular disease, continues to be of significant interest in the psoriasis community. Last, the emergence of biosimilar agents has the potential to change psoriasis treatment, especially as it relates to better access for the psoriasis community worldwide.     

Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells

IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro. The aim of this study was to assess the impact of TNF inhibition on IL-17 production in collagen-induced arthritis, a model of RA. TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic. Th1 and Th17 cell populations were also expanded in collagen-immunized TNFR p55^−/− but not p75^−/− mice. The expression of IL-12/IL-23 p40 was up-regulated in lymph nodes (LN) from p55^−/− mice, and the expansion of Th1/Th17 cells was abrogated by blockade of p40. Treatment of macrophages with rTNF also inhibited p40 production in vitro. These findings indicate that at least one of the ways in which TNF regulates Th1/Th17 responses in arthritis is by down-regulating the expression of p40. Finally, although TNF blockade increased numbers of Th1 and Th17 cells in LN, it inhibited their accumulation in the joint, thereby providing an explanation for the paradox that anti-TNF therapy ameliorates arthritis despite increasing numbers of pathogenic T cells.     

Foxp3磷酸化通过调控调节性T细胞功能对类风湿关节炎大鼠TNF-α抑制状态影响的分子机制

目的探究Foxp3磷酸化通过调节性T细胞功能改善类风湿关节炎大鼠肿瘤坏死因子-α(TNF-α)抑制状态的分子机制。方法建立类风湿关节炎大鼠模型,分组为正常组(无特殊处理)、模型组(类风湿关节炎模型)和实验组(类风湿关节炎模型+尾静脉注射TNF-α阻滞剂进行治疗)。酶联免疫吸附(ELISA)检测炎症因子白介素10(IL-10)、白介素17(IL-17)和转化生长因子-β(TGF-β)水平;流式细胞术检测T细胞阳性率;Western Blot检测TNF-α表达以及试剂盒检测Foxp3磷酸酶活性。结果与正常组相比,模型组IL-10、TGF-β水平显著降低,IL-17水平显著升高(P<0.05);与模型组相比,实验组IL-10、TGF-β的水平显著升高,IL-17的水平显著降低(P<0.05)。与正常组相比,模型组CD4^+CD25^+T细胞和CD4^+CD25^+Foxp3^+T细胞检测阳性率均显著降低(P<0.05);与模型组相比,实验组以上指标检测比率均显著增加(P<0.05);与正常组相比,模型组的TNF-α蛋白相对表达量显著增加(P<0.05);与模型组相比,实验组TNF-α蛋白的相对表达量显著降低(P<0.05)。与正常组相比,模型组的Foxp3磷酸酶活性显著降低(P<0.05);与模型组相比,实验组Foxp3磷酸酶活性显著升高(P<0.05)。结论通过尾静脉注射TNF-α阻滞剂治疗后,大鼠炎症反应水平、TNF-α蛋白表达及FOXP^3磷酸酶活性均降低,机制可能是Foxp3磷酸化通过调控调节性T细胞数量及炎症因子的变化参与对类风湿关节炎大鼠抑制状态,从而一定程度缓解类风湿关节炎不良症状。     

Role of interleukin-17 in cartilage and bone destruction in rheumatoid arthritis

Interleukin 17 is a newly discovered inflammatory cytokine produced by T cells. Although pathogenesis of rheumatoid arthritis is still unknown more and more data show that IL-17 has an influence in this process. The concentration of this interleukin is very high locally in the joint fluid and synovium of the patients with rheumatoid arthritis. The most recent studies show, that IL-17 is situated at the top of inflammatory cascade and stimulates fibroblasts, synovial cells and macrophages to higher production of proinflammatory cytokines. Moreover IL-17 initiates the loss of proteoglycans and stimulates increased production of enzymes in chondrocytes causing degradation of collagen. Rheumatoidal synovial fibroblasts produce metalloproteinases, which can be regulated by IL-17 in the presence of proinflammatory cytokines. It is suggested, that IL-17 stimulates osteoblasts to synthesis of prostaglandin E2 (PGE2) and expression of receptor gene NF - kappa ss (RANK), which induces osteclastogenesis. Probably IL-17 is responsible for intensive resorption of bone tissue in rheumatoid arthritis. It seems, that IL-17 plays an important role in the immunological response and in the destruction of cartilage and bone tissue in rheumatoid arthritis. The deeper understanding of the mechanism of IL-17 action on the cartilage and bone cells may help to introduce the new methods of treatment in rheumatoid arthritis.     

Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation

Interleukin (IL) 23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 affects memory T cell and inflammatory macrophage function through engagement of a novel receptor (IL-23R) on these cells. Recent analysis of the contribution of IL-12 and IL-23 to central nervous system autoimmune inflammation demonstrated that IL-23 rather than IL-12 was the essential cytokine. Using gene-targeted mice lacking only IL-12 (p35-/-) or IL-23 (p19-/-), we show that the specific absence of IL-23 is protective, whereas loss of IL-12 exacerbates collagen-induced arthritis. IL-23 gene-targeted mice did not develop clinical signs of disease and were completely resistant to the development of joint and bone pathology. Resistance correlated with an absence of IL-17-producing CD4+ T cells despite normal induction of collagen-specific, interferon-gamma-producing T helper 1 cells. In contrast, IL-12-deficient p35-/- mice developed more IL-17-producing CD4+ T cells, as well as elevated mRNA expression of proinflammatory tumor necrosis factor, IL-1beta, IL-6, and IL-17 in affected tissues of diseased mice. The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.     

全身麻醉复合神经阻滞对行全膝关节置换术患者外周血T淋巴细胞亚群细胞因子的影响

目的探讨全身麻醉复合神经阻滞对行全膝关节置换术患者外周血T淋巴亚群细胞因子的影响.方法选取骨关节炎择期行全膝关节置换术患者60例,美国麻醉医师协会（ASA）n级,年龄65-80岁,体质量45-80kg.采用随机数字表法将其分为2组（n=30）：G组为全身麻醉组;N组为全身麻醉复合超声定位下以0.5%罗哌卡因行转子下坐骨神经和股神经阻滞组.两组患者术后均行患者自控静脉镇痛（PCIA）.观察术中心电图（ECG）、脉搏氧饱和度（SPO2）、呼气末二氧化碳分压（PETCO2）,两组患者麻醉诱导前（T0）、术毕（T1）、术后24h（T2）、72h（T3）各个时点抽取外周静脉血,ELISA测量1型辅助性T细胞（Th1）、Th2、Th17、调节性T细胞（Treg）肿瘤坏死因子（TNF-α、白细胞介素4（IL-4）、白细胞介素17（IL-17）、转化生长因子β（TGF-β）的浓度.记录术后T2、T3时疼痛VAS评分.结果与G组比较,T1-3时N组血浆中促炎因子TNF-α、IL-17浓度明显降低（P〈0.05）,抑炎因子IL-4、TGF-β显著升高（P〈0.05）.T2时N组疼痛VAS评分明显降低（P〈0.05）.无神经阻滞并发症发生.结论全膝关节置换手术应用全身麻醉复合超声引导转子下坐骨神经及股神经阻滞能平衡T淋巴亚群细胞因子浓度,减轻炎症损伤.     

The IL-23/IL-17 axis in inflammation

IL-23 induces the differentiation of naive CD4(+) T cells into highly pathogenic helper T cells (Th17/Th(IL-17)) that produce IL-17, IL-17F, IL-6, and TNF-alpha, but not IFN-gamma and IL-4. Two studies in this issue of the JCI demonstrate that blocking IL-23 or its downstream factors IL-17 and IL-6, but not the IL-12/IFN-gamma pathways, can significantly suppress disease development in animal models of inflammatory bowel disease and MS (see the related articles beginning on pages 1310 and 1317). These studies suggest that the IL-23/IL-17 pathway may be a novel therapeutic target for the treatment of chronic inflammatory diseases.     

Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders

Introduction: Advances in the understanding of TNF-α and IL-17 synergistic functions have recently led to the concept that patients who do not respond or who respond inadequately to TNF-α inhibitors may have IL-17-driven diseases, opening up the way for a new class of therapeutic development: Th17-inhibitors.

Areas covered: In this review, the authors discuss the central role that the IL-23/Th17 axis plays in the pathogenesis of several inflammatory diseases, such as psoriasis, highlighting its position as a relevant therapeutic target. In particular, the authors start by giving a brief historical excursus on biologic agent development up until the success of TNF-α inhibitors, and continue with an overview of IL12/23 pathway inhibition. Next, they describe Th17 cell biology, focusing on the role of IL-17 in host defense and in human immune-inflammatory diseases, discussing the use and side effects of IL-17 inhibitors.

Expert opinion: The IL-23/Th17 signaling pathway plays a central role in the pathogenesis of several inflammatory diseases, such as psoriasis. Recent data has demonstrated that biologics neutralizing IL-17 (ixekizumab, secukinumab) or its receptor (brodalumab) are highly effective with a positive safety profile in treating moderate to severe psoriasis, offering new treatment possibilities, especially for patients who do not respond adequately to anti-TNF-α therapies.     

IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6

Uncontrolled mucosal immunity in the gastrointestinal tract of humans results in chronic inflammatory bowel disease (IBD), such as Crohn disease and ulcerative colitis. In early clinical trials as well as in animal models, IL-12 has been implicated as a major mediator of these diseases based on the ability of anti-p40 mAb treatment to reverse intestinal inflammation. The cytokine IL-23 shares the same p40 subunit with IL-12, and the anti-p40 mAbs used in human and mouse IBD studies neutralized the activities of both IL-12 and IL-23. IL-10-deficient mice spontaneously develop enterocolitis. To determine how IL-23 contributes to intestinal inflammation, we studied the disease susceptibility in the absence of either IL-23 or IL-12 in this model, as well as the ability of recombinant IL-23 to exacerbate IBD induced by T cell transfer. Our study shows that in these models, IL-23 is essential for manifestation of chronic intestinal inflammation, whereas IL-12 is not. A critical target of IL-23 is a unique subset of tissue-homing memory T cells, which are specifically activated by IL-23 to produce the proinflammatory mediators IL-17 and IL-6. This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases.     

Zalutumumab in head and neck cancer

Introduction: Plaque psoriasis is a chronic inflammatory disease that can result in significant physical, psychological and quality of life impairments. Until recently, biologic treatment for psoriasis was limited to tumor necrosis factor-α inhibitors and an interleukin (IL)-12/23 p40 subunit inhibitor. Newly developed biologics targeting the pro-inflammatory IL-17A cytokine have shown success in providing higher levels of clinical efficacy in patients with psoriasis. Secukinumab, a member of this novel class of IL-17 inhibitors, is the latest biologic to receive US FDA approval for the treatment of moderate-to-severe plaque psoriasis.

Areas covered: This comprehensive review will cover the pharmacology, efficacy, safety and future role of secukinumab and other IL-17 blockers in the treatment of plaque psoriasis.

Expert opinion: While biologics have revolutionized patient care for chronic plaque psoriasis, they are associated with loss of response over time. When treatment failure occurs with existing biologics, physicians are left with few alternative treatment options to offer patients. The introduction of secukinumab has provided an additional therapeutic agent that offers improved skin clearance, better health related quality of life and a favorable side-effect profile.     

Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

Prostaglandins, particularly prostaglandin E2 (PGE2), play an important role during inflammation. This is exemplified by the clinical use of cyclooxygenase 2 inhibitors, which interfere with PGE2 synthesis, as effective antiinflammatory drugs. Here, we show that PGE2 directly promotes differentiation and proinflammatory functions of human and murine IL-17–producing T helper (Th17) cells. In human purified naive T cells, PGE2 acts via prostaglandin receptor EP2- and EP4-mediated signaling and cyclic AMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1β and IL-23 to drive retinoic acid receptor–related orphan receptor (ROR)-γt, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the reported Th17 phenotype. While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates interferon (IFN)-γ production and inhibits production of the antiinflammatory cytokine IL-10 in Th17 cells predominantly through EP4. Furthermore, PGE2 is required for IL-17 production in the presence of antigen-presenting cells. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.Prostaglandins, prostaglandin E2 (PGE2) in particular, play an important role in the regulation of inflammatory responses. PGE2 is a key mediator of pyrexia, hyperalgesia, and arterial dilation, which increases blood flow to inflamed tissues and, in combination with enhanced microvascular permeability, results in edema. The relevance of this pathway in promoting inflammation is supported by the clinical use of cyclooxygenase inhibitors, which interfere with prostaglandin synthesis and are used as effective antiinflammatory agents (1). However, PGE2 can also exert antiinflammatory properties and is a negative regulator of neutrophil, monocyte, and lymphocyte function, particularly of Th1 cells that produce IFN-γ (2). This apparent paradox has puzzled many investigators for decades. The interplay among PGE2, IL-23, and IL-1β biology may now provide an explanation of this paradox.Th17 cells have been recognized as a unique subset of effector T cells that are distinct from the Th1 and Th2 subsets (3–6), and they have been implicated as potent effectors of autoimmune disorders, such as multiple sclerosis, psoriasis, arthritis, and inflammatory bowel disease (IBD) (7–10). We and others have previously reported that IL-23 and IL-1β are crucial factors during development of human Th17 cells (9, 11, 12). In addition, IL-23 and the IL-23–dependent Th17 cell population play essential roles in chronic inflammation and autoimmunity (13).PGE2 has been shown to exacerbate inflammation and disease severity in murine models of IBD and collagen-induced arthritis through the IL-23–IL-17 pathway (14, 15). These effects have been attributed to actions of PGE2 on innate cells, as PGE2 enhances the production of IL-23 and IL-1β in macrophages and DCs, while down-regulating IL-12 production (16). A recent report has shown that PGE2, together with IL-23, favors the expansion of human Th17 cells from PBMCs, and that PGE2 enhances IL-17 production induced by IL-23 from memory CD4⁺ cells (17). However, the molecular mechanism of PGE2-mediated signaling during human Th17 cell development has not yet been examined.In this study, we show that PGE2 acts directly on both human and murine T cells to enhance Th17 development and effector cytokine production. In human T cells, PGE2 acts via the prostaglandin receptor EP2- and EP4-mediated signaling and cAMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1β and IL-23 to drive retinoic acid receptor–related orphan receptor (ROR)-γt, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the previously reported Th17 phenotype (8, 18). While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates IFN-γ production and inhibits production of the antiinflammatory cytokine IL-10 in both naive and memory Th17 cells predominantly through EP4. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.     

IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential

IL-17 (interleukin-17), a hallmark cytokine of Th17 (T-helper 17) cells, plays critical roles in host defence against bacterial and fungal infections, as well as in the pathogenesis of autoimmune diseases. The present review focuses on current knowledge of the regulation, functional mechanisms and targeting strategies of IL-17 in the context of inflammatory autoimmune diseases. Evidence shows that IL-17 is highly up-regulated at sites of inflammatory tissues of autoimmune diseases and amplifies the inflammation through synergy with other cytokines, such as TNF (tumour necrosis factor) α. Although IL-17 was originally thought to be produced mainly by Th17 cells, a newly defined T-cell subset with a specific differentiation programme and tight regulation, several other cell types (especially innate immune cells) are also found as important sources for IL-17 production. Although IL-17 activates common downstream signalling, including NF-κB (nuclear factor κB), MAPKs (mitogen-activated protein kinases), C/EBPs (CCAAT/enhancer-binding proteins) and mRNA stability, the immediate receptor signalling has been shown to be quite unique and tightly regulated. Mouse genetic studies have demonstrated a critical role for IL-17 in the pathogenesis of variety of inflammatory autoimmune diseases, such as RA (rheumatoid arthritis) and MS (multiple sclerosis). Importantly, promising results have been shown in initial clinical trials of monoclonal antibodies against IL-17 or its receptor (IL-17R) to block IL-17-mediated function in treating autoimmune patients with psoriasis, RA and MS. Therefore targeting IL-17/IL-17R, IL-17-producing pathways or IL-17-mediated signalling pathways can be considered for future therapy in autoimmune diseases.     

Briakinumab

Background: Psoriasis is a chronic, autoimmune, T-cell mediated, inflammatory disease. An improved understanding of the pathogenesis of the autoimmune response has led to the development of targeted biologic therapies. Briakinumab is a human monocolonal antibody that blocks the activity of the cytokines IL-12 and IL-23. Immune dysregulation has been implicated in multiple inflammatory disorders and briakinumab has been investigated for the treatment of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. Objectives: This review focuses on briakinumab and its use in chronic plaque-type psoriasis. Methods: A literature review was performed, searching Medline and the clinicaltrials.gov database for all articles with the keywords ABT-874, IL-12/IL-23 and psoriasis. Conclusions: Although limited by small sample sizes, length of follow-up, and a lack of direct comparisons with other psoriasis treatments, initial data regarding the safety and efficacy of briakinumab for the treatment of psoriasis is promising. Ongoing Phase III trials may provide additional information regarding the relative efficacy and safety of briakinumab.     

Measurement of synovial tumor necrosis factor-alpha in diagnosing emergency patients with bacterial arthritis

Because of the high morbidity and mortality in patients with bacterial arthritis, rapidly and correctly diagnosing this critical condition is a challenge to emergency clinicians. Synovial fluid samples were obtained from 75 patients with arthritis disorders who presented to an emergency service, and levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were measured. Twenty patients with culture-proven bacterial arthritis had higher levels of synovial TNF-α than patients with osteoarthritis or with inflammatory arthritis, including gouty arthritis, rheumatoid arthritis, reactive arthritis, and lupus arthritis. There was a good sensitivity for synovial TNF-α level in diagnosing patients with bacterial arthritis. Nearly 100% of patients with bacterial arthritis had elevated synovial TNF-α levels. However, synovial IL-1β and IL-6 levels failed to discriminate bacterial arthritis from other inflammatory arthritis. Measurement of synovial TNF-α level may be useful as a diagnostic aid in emergency patients with bacterial arthritis disorders.     

IL-17 mediates articular hypernociception in antigen-induced arthritis in mice

IL-17 is an important cytokine in the physiopathology of rheumatoid arthritis (RA). However, its participation in the genesis of nociception during RA remains undetermined. In this study, we evaluated the role of IL-17 in the genesis of articular nociception in a model of antigen (mBSA)-induced arthritis. We found that mBSA challenge in the femur–tibial joint of immunized mice induced a dose- and time-dependent mechanical hypernociception. The local IL-17 concentration within the mBSA-injected joints increased significantly over time. Moreover, co-treatment of mBSA challenged mice with an antibody against IL-17 inhibited hypernociception and neutrophil recruitment. In agreement, intraarticular injection of IL-17 induced hypernociception and neutrophil migration, which were reduced by the pre-treatment with fucoidin, a leukocyte adhesion inhibitor. The hypernociceptive effect of IL-17 was also reduced in TNFR1^−/− mice and by pre-treatment with infliximab (anti-TNF antibody), a CXCR1/2 antagonist or by an IL-1 receptor antagonist. Consistent with these findings, we found that IL-17 injection into joints increased the production of TNF-α, IL-1β and CXCL1/KC. Treatment with doxycycline (non-specific MMPs inhibitor), bosentan (ET_A/ET_B antagonist), indomethacin (COX inhibitor) or guanethidine (sympathetic blocker) inhibited IL-17-induced hypernociception. IL-17 injection also increased PGE₂ production, MMP-9 activity and COX-2, MMP-9 and PPET-1 mRNA expression in synovial membrane. These results suggest that IL-17 is a novel pro-nociceptive cytokine in mBSA-induced arthritis, whose effect depends on both neutrophil migration and various pro-inflammatory mediators, as TNF-α, IL-1β, CXCR1/2 chemokines ligands, MMPs, endothelins, prostaglandins and sympathetic amines. Therefore, it is reasonable to propose IL-17 targeting therapies to control this important RA symptom.     

辛伐他汀对类风湿关节炎的治疗作用研究

目的探讨辛伐他汀治疗类风湿关节炎（RA）的免疫学机制，为辛伐他汀治疗活动期类风湿关节炎以及改善其预后提供实验依据。方法70例活动期RA患者随机分为两组，治疗组：辛伐他汀40mg／d＋甲氨蝶呤10mg／周＋来氟米特20mg／d；对照组：甲氨蝶呤10mg／周＋来氟米特20mg／d。分别于治疗前、治疗后12周、24周用放射免疫法测白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α），酶联免疫法测基质金属蛋白酶3（MMP-3）的浓度，观察辛伐他汀对RA患者炎性因子的影响。结果（1）治疗前两组各项指标差异无统计学意义（P均〉0．05）；（2）RA患者血清中致炎因子IL-6、TNF-α、MMP-3水平与CRP的水平相关；（3）治疗12周时治疗组和对照组相比炎性凶子IL-6、TNF-α、MMP-3及临床指标的下降无统计学意义（P均〉0．05）；（4）治疗24周时治疗组和对照组相比炎性因子IL-6、TNF-α、MMP-3及临床指标的下降有统计学意义（P均〈0．05）；（5）两组的不良反应差异无统计学意义（P均〉0．05）。结论辛伐他汀可以降低RA致炎因子的水平；辛伐他汀不但可以配合免疫调节剂治疗活动期RA，而且对预防和治疗RA引起的早期动脉粥样硬化起着非常重要的作用，从而改善了RA的病情和预后。