Artemether: A New Therapeutic Strategy in Experimental Rheumatoid Arthritis

The current research was designed to determine the effect of artemether in treatment of experimental rheumatoid arthritis. Collagen-induced arthritis was induced in Lewis rats. The intramusculary administration of artemether (ART) and intraperitoneally injection of methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was taken intermittently. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay.The biocompatibility of ART and MTX were assessed using fibrosarcoma cell line. Data showed that i.m. injection of ART to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed a reduced inflammatory cell infiltrate in joints of treated rats; tissue edema, and bone erosion in the paws were markedly reduced following ART therapy. Furthermore, our radiography results paralleled our histological findings. Cytotoxicity analysis of ART showed greater tolerability compared with MTX. Treatment with ART significantly diminished NO formation in treated rats compared with nontreated controls. Our data shed light on the therapeutic efficacy of artemether in experimental rheumatoid arthritis compared with a choice drug (methotrexate), and it may be offered as a second-line drug in treatment of rheumatoid arthritis.     

Design of a New Line in Treatment of Experimental Rheumatoid Arthritis by Artesunate

This study was aimed to evaluate the therapeutic potency of a new antimalarial drug, artesunate, in an experimental model of rheumatoid arthritis. Collagen-induced arthritis (CIA) was induced in Lewis rats.The intraperitoneally administration of artesunate (ARS) and methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was intermittent. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay. The biocompatibility of ARS and MTX were assessed using fibrosarcoma cell line. Our results showed that i.p. injection of artesunate to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed reduced inflammatory cells infiltrate in joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following ARS therapy. Moreover, our radiographic results paralleled histological findings. Cytotoxicity analysis of ARS showed greater tolerability compared with MTX. Treatment with ARS significantly diminished nitric oxide formation in treated rats compared with untreated controls. Our findings revealed the therapeutic efficacy of artesunate in experimental rheumatoid arthritis compared with a choice drug (methotrexate). This result may recommend it as a second-line drug in the treatment of rheumatoid arthritis.     

Design of a new line in treatment of experimental rheumatoid arthritis by artesunate

This study was aimed to evaluate the therapeutic potency of a new antimalarial drug, artesunate, in an experimental model of rheumatoid arthritis. Collagen-induced arthritis (CIA) was induced in Lewis rats.The intraperitoneally administration of artesunate (ARS) and methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was intermittent. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay. The biocompatibility of ARS and MTX were assessed using fibrosarcoma cell line. Our results showed that i.p. injection of artesunate to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed reduced inflammatory cells infiltrate in joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following ARS therapy. Moreover, our radiographic results paralleled histological findings. Cytotoxicity analysis of ARS showed greater tolerability compared with MTX. Treatment with ARS significantly diminished nitric oxide formation in treated rats compared with untreated controls. Our findings revealed the therapeutic efficacy of artesunate in experimental rheumatoid arthritis compared with a choice drug (methotrexate). This result may recommend it as a second-line drug in the treatment of rheumatoid arthritis.     

大鼠佐剂性关节炎模型表现特征及评价指标

目的:描述大鼠佐剂性关节炎(Adjuvant-induced arthritis,AA)临床表现主要指标的评价方法。方法:完全弗氏佐剂免疫SD大鼠诱导AA模型,进行全身及关节炎指数评分、计算关节肿胀数、测定足爪肿胀度、进行足爪X线摄片、踝关节病理检查及评分。结果:大鼠免疫后11天(d11)出现足爪红肿,全身及关节炎指数评分和关节肿胀数增加。炎症高峰期在免疫后d19～d28。大鼠出现活动障碍,可见耳朵、鼻和尾根部"关节炎"结节。X线可见关节软组织肿胀、骨密度降低、骨侵蚀病灶以及关节间隙狭窄甚至消失。踝关节病理见滑膜组织增生,炎细胞浸润,血管翳出现等。结论:大鼠AA是兼有局部关节炎症和全身表现的类风湿性关节炎动物模型。关节炎指数、关节肿胀数、足爪肿胀度、足爪X线摄片、踝关节病理等是评价AA模型临床表现的主要指标。     

Anti-inflammatory effects of methotrexate on reversed passive Arthus reactions in rats

The anti-inflammatory effects of methotrexate (MTX), an anti-rheumatic drug for treating rheumatoid arthritis, on acute inflammation were studied by using Arthus reactions induced in the pleural cavity and dorsal skin of rats. The effects were compared with those of dexamethasone (DEX), a synthetic analog of adrenocortical steroid, and of ketoprofen (KET), a nonsteroidal anti-inflammatory agent. In reversed passive Arthus (RPA) reactions induced in the pleural cavity by an anti-bovine-albumin serum, DEX significantly suppressed both neutrophil accumulation and plasma exudation at the sites of injection of an antibody, whereas MTX and KET had no effect. In the RPA reaction induced in the dorsal skin by an anti-ovalbumin serum, all three drugs inhibited exudation to the same level. However, DEX and MTX suppressed neutrophil accumulation, whereas KET did not. We found that the oral administration of MTX for 3 days significantly inhibited both neutrophil accumulation and exudation in the RPA reaction in the dorsal skin, suggesting that MTX is an effective anti-inflammatory agent. However, the manifestation of these anti-inflammatory effects might be restricted by differences in the inflammation models in rats.     

FK506 is superior to methotrexate in therapeutic effects on advanced stage of rat adjuvant-induced arthritis

OBJECTIVE AND DESIGN: The anti-arthritic properties of FK506 were compared with methotrexate (MTX) in established adjuvant-induced arthritis (AIA) in rats. MATERIAL: Female Lewis rats. TREATMENT: Arthritic rats were orally administered with FK506 (1-5.6 mg/kg) and MTX (0.1-1 mg/kg) from days 15-24. METHODS: Arthritis was induced by injection of Mycobacterium tuberculosis into the right hind footpad on day 0. Efficacy was determined on the basis of paw inflammation measured by paw volume and histological change, hyperalgesia and grip strength. Grip strength measurement was employed as an indication of function of paws in arthritic rats. Peripheral white blood cell (WBC) counts and thymus weights were measured, mainly as indicators of toxic side effects. RESULTS: FK506 suppressed paw inflammation and hyperalgesia without toxic effects on WBC and thymus in established AIA. MTX slightly suppressed paw inflammation and hyperalgesia at the highest dose (1 mg/kg). Toxic effects were observed at lower doses than the effective treatment dose with MTX. Grip strength was found to decrease during development of AIA. FK506, but not MTX, treated rats recovered grip strength loss. CONCLUSIONS: The results show that FK506 is more effective and less toxic than MTX in treating established AIA in rats.     

Effect of FTY720, a novel immunosuppressant,on adjuvant-induced arthritis in rats

OBJECTIVE AND DESIGN: Anti-arthritic effect of FTY720, a novel immunosuppressant, was compared with those of immunosuppressants cyclosporin A and tacrolimus in adjuvant-induced arthritis in rats. MATERIAL: Male LEW rats. TREATMENT: FTY720 (0.03-0.3 mg/kg), cyclosporin A (1-10 mg/kg) or tacrolimus (0.3-3 mg/kg) were orally administered to rats for 21 days beginning on the day (day 0) of adjuvant inoculation. In addition, the anti-arthritic effect of FTY720 (0.3 mg/kg) and cyclosporin A (10 mg/kg) were evaluated by administration to animals for 5 consecutive days (days 2-6, 6-10, and 10-14). METHODS: Adjuvant-induced arthritis was produced by intradermal injection of 0.5 mg heat-killed Mycobacterium tuberculosis. Hindpaw edema was measured plethysmographically. The day of arthritis onset was determined macroscopically. Bone degradation was determined by radiography. Peripheral blood leukocytes were classified microscopically. RESULTS: All test compounds inhibited the incidence of arthritis, hindpaw edema and bone destruction. In addition, FTY720 but not cyclosporin A or tacrolimus markedly decreased the number of peripheral blood lymphocytes. FTY720 treatment on days 6 to 10 inhibited the bone destruction and hindpaw edema. CONCLUSION: These results suggest that the anti-arthritic effect of FTY720 in this adjuvant-induced arthritic model was more potent than those of cyclosporin A and tacrolimus. FTY720 administered on days 6 to 10 showed the inhibitory effect on the bone destruction and hindpaw edema. FTY720 may be effective in the treatment of rheumatoid arthritis.     

Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis

Eotaxin‐2 is a potent chemoattractant for eosinophils, basophils and T helper type 2 (Th2) lymphocytes. The eotaxin‐2/CCL24 receptor CCR3 is expressed in human brain, skin, endothelium and macrophages. The aim of the current study was to evaluate the protective effect of a monoclonal anti‐eotaxin‐2 antibody on the development of adjuvant‐induced arthritis in rats (AIA). Adjuvant arthritis was induced in Lewis rats by intradermal injection of incomplete Freund's adjuvant +Mycobacterium tuberculosis. Rats were treated by intraperitoneal (i.p.) injection with three monoclonal antibodies against eotaxin‐2 (G7, G8, D8) three times per week. Controls were treated with total mouse immunoglobulin G (IgG), methotrexate (MTX) or phosphate‐buffered saline (PBS). Arthritis severity was evaluated by measuring ankle swelling, arthritic score, whole animal mobility and body weight. Sample joints were obtained for pathological evaluation and postmortem X‐ray of ankle joints was performed to document erosions. Significant inhibition of arthritis was observed in rats treated with anti‐eotaxin‐2 antibodies compared to those treated with immunoglobulin or PBS. Inhibition was manifest in ankle diameter, arthritic score and mobility score. The antibody marked D8 showed the greatest efficacy. The effect was observed both in animals treated before the appearance of arthritis and in those where treatment was begun after development of joint inflammation. Combined treatment with D8 and MTX caused additional protection. Significant reduction of inflammation in D8‐treated animals was also demonstrated in pathological and X‐ray examinations. Inhibition of eotaxin‐2 by monoclonal antibodies has a significant protective effect in adjuvant arthritis. These results may introduce a novel therapeutic target in rheumatoid arthritis and additional inflammatory joint disorders.     

Differential effects of methotrexate and liposomally conjugated methotrexate in rat adjuvant-induced arthritis.

In this study we evaluated the comparative efficacy of free and liposomally conjugated methotrexate on both disease induction and suppression of acute inflammation in rat adjuvant-induced arthritis. Rats were given either empty liposomes (E-LIPO), free methotrexate (MTX) or the liposomally conjugated methotrexate (MTX-LIPO) at a dose of 100 micrograms/day for 7 consecutive days by the intravenous route. When MTX treatment was initiated on the day of arthritis induction the drug suppressed but did not abolish the development of joint inflammation. Free MTX had no significant anti-inflammatory effect upon an established arthritis when dosing was commenced on day 11 post-adjuvant induction. Conversely, MTX-LIPO did not affect the progression of the arthritis when dosing was started on day 0, but exerted a significant anti-inflammatory effect on an established arthritis. MTX-LIPO treatment was significantly less haematotoxic than free MTX.     

Treatment of experimental arthritis with M2000, a novel designed non-steroidal anti-inflammatory drug

The current study was planned to explore the therapeutic potency of M2000 (beta-D-mannuronic acid), a novel designed non-steroidal anti-inflammatory drug (NSAID) in adjuvant-induced arthritis model. Arthritis was induced in Lewis rats by a single intradermal injection (0.1 ml) of heat-killed Mycobacterium tuberculosis (0.3 mg) in Freund's incomplete adjuvant into the right footpad. Fourteen days after injection of adjuvant, the contralateral left footpad volume was measured. The animals with paw volumes 0.37 ml greater than normal paws were then randomized into treatment groups. Orally and intraperitoneally administrations of test drugs (M2000, 40/mg/kg/day and indomethacin, 2/mg/kg/day) were started on day 15 post-adjuvant injection and continued until final assessment on day 25. The left hind limb was removed for histological evaluation. The WEHI-164 cell line was used for assaying tolerability and matrix metalloproteinase type 2 (MMP-2) activity. MMP-2 activity was assessed using zymography. Pharmacotoxicology study was carried out on animal models based on the evaluation of serum and urine determinants, histology of kidney, gastrointestinal tolerability and body temperature. Results showed that the orally administration as well as intraperitoneally injection of M2000 to arthritic rats induced a significant reduction in paw oedema. Histopathological assessment showed a reduced inflammatory cells infiltrate in joints of treated rats, as well as the number of osteoclasts present in the subchondral bone, tissue oedema and bone erosion in the paws were markedly reduced following M2000 therapy. Cytotoxicity analysis of M2000 showed a much higher tolerability compared with other tested drugs (diclofenac, piroxicam and dexamethasone). The inhibitory effect of M2000 in MMP-2 activity was significantly greater than that of dexamethasone and of piroxicam at a concentration of 200 microg/ml. Moreover, the toxicological study revealed that M2000 had no influence on serum (blood urea nitrogen, creatinine, triglyceride and cholesterol) and urine (urea and urinary protein excretion) determinants, glomerular histology and body temperature in normothermic rats and had no ulcerogenic effects on rats' stomach. Our data show that M2000, as a novel NSAID, could be strongly suggested as the safest anti-inflammatory drug for long-term administration.     

关节腔注射用甲氨蝶呤温敏性缓释凝胶的制备及性能考察

目的利用聚己内酯-聚乙二醇-聚己内酯（PCL-PEG-PCL）两亲性聚合物温敏凝胶作为载体材料,构建抗类风湿性关节炎药物甲氨蝶呤关节腔注射用给药体系。方法采用开环聚合法,以辛酸亚锡为催化剂、PEG1500为引发剂,与己内酯单体开环聚合得到PCL-PEG-PCL两亲性嵌段共聚物;对得到的PCL-PEG-PCL嵌段共聚物的组成结构及相对分子质量进行表征;采用翻转试管法测定PCL-PEG-PCL聚合物的溶胶-凝胶相转变温度,绘制溶胶-凝胶相转变曲线;评价甲氨蝶呤PCL-PEG-PCL温敏凝胶载药体系的缓释性能;考察PCL-PEG-PCL温敏凝胶关节腔注射后在大鼠体内的生物相容性。结果 PCL-PEG-PCL两亲性嵌段共聚物水溶液具有温敏性溶胶-凝胶相转变能力,其溶胶-凝胶相转变温度介于室温与体温之间。甲氨蝶呤PCL-PEG-PCL温敏凝胶的体外释放研究表明PCL-PEG-PCL温敏凝胶对甲氨蝶呤具有较好的缓释能力,提高载药量和温敏凝胶浓度将减缓甲氨蝶呤从PCL-PEG-PCL温敏凝胶的释放。大鼠滑膜苏木精-伊红染色结果显示,关节腔注射PCL-PEG-PCL温敏凝胶未引起炎症反应发生。结论 PCL-PEG-PCL温敏凝胶作为关节腔局部注射用载药体系具有较好的药物缓释性能和生物相容性。     

Cell-type specific response of peripheral blood lymphocytes to methotrexate in the treatment of rheumatoid arthritis

The mode of action of methotrexate in the treatment of rheumatoid arthritis is still questionable. Although in vitro results suggest an immunosuppressive effect of methotrexate, several clinical studies have failed to confirm these effects in patients treated with oral low-dose methotrexate. With respect to the highly variable bioavailability of methotrexate, we investigated the effects of an intravenous administration of 15 mg methotrexate per week on peripheral blood lymphocyte subsets in eight patients with rheumatoid arthritis. Methotrexate after 12 weeks significantly (P<0.01) reduced total peripheral blood lymphocytes and led to a pronounced redistribution of lymphocyte subsets with a preferred reductive effect on B-lymphocytes (P<0.005) and T-lymphocytes (P<0.05). Natural killer cells and killer cell-like T cells, on the other hand, were unaffected by the treatment. Our results suggest a cell-type specific effect of intravenously administered low-dose methotrexate on peripheral blood lymphocytes. This effect, in our opinion, may contribute to the mode of action of methotrexate as an immunosuppressive drug in the treatment of rheumatoid arthritis.Abbreviations NSAID nonsteroidal anti-inflammatory drug - DMARD disease-modifying antirheumatic drug - MTX methotrexate - RF rheumatoid factor - CRP C-reactive protein - BSR blood sedimentation rate - NK cells natural killer cells - VAS visual analog scale Correspondence to: T.C. Wascher     

类风湿性关节炎滑膜成纤维细胞骨保护素和骨形态发生蛋白-2的表达及干预

目的 探讨甲氨蝶呤（MTX）及白细胞介素-6受体（IL-6R）抗体对类风湿关节炎（RA）滑膜成纤维细胞增殖的干预及对骨保护素（OPG）、骨形态发生蛋白-2（BMP-2）的影响.方法 获取RA患者滑膜组织,消化并传代培养成纤维细胞.CCK-8法检测IL-6R抗体、甲氨蝶呤（MTX）对RA滑膜成纤维细胞活性影响;荧光定量（qRT）-PCR检测OPG和BMP-2表达.结果 与空白组相比,MTX组、IL-6R抗体组成纤维细胞的活性受到抑制（F=29.30,34.22,P＜0.05）,MTX联合IL-6R抗体组成纤维细胞的活性显著受到抑制（F=52.04,P ＜0.01）.qRT-PCR显示与空白组相比,IL-6R抗体组、MTX联合IL-6R抗体组OPG、BMP-2的表达均上升（P＜0.05）.与MTK组相比,IL-6R抗体组OPG、BMP-2的表达增加（P＜0.05）.结论 IL-6R抗体单独或联合MTK使用均能明显抑制RA滑膜成纤维细胞的活性,与MTX相比,IL-6R抗体能升高OPG、BMP-2的表达.本研究为应用IL-6R抗体预防和治疗RA关节破坏提供实验依据.     

Suppression and augmentation of rat adjuvant arthritis with monoclonal anti-interferon-gamma antibody

The effects of a monoclonal antibody (MoAb DB-1), which neutralized rat interferon-gamma (IFN-gamma), on the induction and progression of adjuvant arthritis in Lewis rats induced by intraplantar injection of Freund's complete adjuvant was studied. The animals were treated intraperitoneally with MoAb DB-1 (0.3-5 mg) for various times. Prophylactic treatment with MoAb DB-1, starting 2 days prior to arthritis induction, inhibited oedema in both the injected and non-injected hind paws and delayed joint destruction as shown by radiography. However, despite continued MoAb treatment, the disease progressed. High doses of MoAb DB-1 exacerbated the disease. A control MoAb of the same isotype did not have significant effects on adjuvant arthritis. Therapeutic treatment with the MoAb DB-1 starting 8 days after arthritis induction caused only slight and short-lived inhibitory effects. IFN-gamma appears to be a critical lymphokine for the development of adjuvant arthritis.     

非T 细胞结合肽( FNS007) 对胶原诱导型大鼠关节炎的影响

目的：探讨非T细胞结合肽（FNS007）对大鼠Ⅱ型胶原（Collagen typeⅡ,CⅡ）诱导的关节炎（Collagen-induced arthritis,CIA）的影响及可能机制。方法：以牛CⅡ免疫Lewis大鼠诱发CIA模型后,随机分为模型组、FNS007低（0.25 mg/kg）、中（0.5 mg/kg）、高（1.0 mg/kg）剂量组及阳性药(甲氨蝶呤)组,另设空白对照组,尾静脉注射相应药物,隔天一次,空白对照组及模型组大鼠给予溶媒磷酸盐缓冲液(Phosphate buffered solution,PBS)。实验期间观察踝关节宽度以及爪厚度,关节炎评分。给药后第22天处死大鼠,ELISA法测定血清中TNF-α、IFN-γ和IL-6的水平及抗CⅡ抗体水平;X光分析FNS007对CIA大鼠后爪骨损伤的疗效,并对大鼠踝关节进行组织病理学检查。 结果：FNS007 高剂量明显抑制CIA大鼠足爪肿胀程度,爪厚度和踝关节宽度明显降低;炎症评分明显降低; 血清促炎性细胞因子TNF-α、IFN-γ、IL-6的含量和抗CⅡ抗体的水平明显降低; X光评分和组织病理评分明显降低。FNS007 中剂量和低剂量组的以上指标也有不同程度的改善。 结论：FNS007对大鼠CIA具有治疗作用,其机制与其抑制T细胞活化,抑制CIA大鼠体内抗CⅡ 的产生,并降低促炎性细胞因子TNF-α、IFN-γ、IL-6的含量,从而抑制异常免疫反应有关。     

A Novel Combination of Methotrexate and Epigallocatechin Attenuates the Overexpression of Pro-inflammatory Cartilage Cytokines and Modulates Antioxidant Status in Adjuvant Arthritic Rats

The present study was designed to evaluate the combinatory effect of methotrexate (MTX) and epigallocatechin (EGCG) on the progression of adjuvant-induced arthritis in rats. Adjuvant arthritis (AA) was induced by a single intradermal injection of Freund's complete adjuvant. AA rats were treated with methotrexate (0.3 mg/kg) thrice a week, EGCG (100 mg/kg) daily, and combination of MTX and EGCG thrice a week for a period of 28 days. Paw swelling changes and histopathological and radiographic analysis was assessed to evaluate the antiarthritic effect. Lipid peroxidation and antioxidant enzyme activities in joint tissue homogenate were performed to observe the modulation of antioxidant status along the expression of different pro-inflammatory cartilage cytokines like TNF-α and IL-6. MTX and EGCG combination potentiated both the antiarthritic (decrease of hind paw volume) and the antioxidant effect (SOD, GSH, and catalase) as well as suppression of lipid peroxidation. Combination therapy of MTX and EGCG significantly inhibited the development phase of arthritis, which is supported by histopathological, radiographical, and attenuation of overexpression of cartilage cytokines. EGCG act as potent antioxidant and immunomodulator, suggesting that combined administration of MTX along with EGCG suppressed the development phase of arthritic progression in rats.     

Characteristic features of actinomycin D-induced paw inflammation of the rat.

Features of paw edema induced by subplantar injection of actinomycin D (act D) were investigated in rats. The paw edema was produced as early as the 1st day and reached a maximal level on the 3rd or the 4th day. Thereafter, it began to subside progressively and was considerably reduced by the 16th day following act D (20 μgm) injection. A direct dose response relationship between the amount of act D injected and the intensity of the paw edema was obtained. No difference in β-glucuronidase and acid phosphatase activity was found between saline and act D-injected paws on the 2nd day. This was followed by an increase in the activity of both enzymes on the 4th, 8th, and 16th days after injection. The histamine content of the saline and act D-injected paws remained unchanged during the early phase of inflammation. A marked increase in the histamine content was noted during the late phase in the drug-injected paw. The effects of act D treatment on capillary permeability to Evans blue dye (EBD) and the edema formation of the paw revealed that a maximal increase in vascular permeability to EBD occurred on the 1st day and was maintained until the 8th day. In contrast to permeability, the paw edema on the 1st day was minimal and increased progressively until the 3rd or 4th day. Thereafter, both the permeability and the paw edema began to diminish and were considerably reduced on the 16th day. Aspirin and hydrocortisone treatment were ineffective in suppressing the act D-induced paw inflammation. Indomethacin produced a somewhat dose-related anti-inflammatory effect against the inflammation caused by this drug.     

Methotrexate in the treatment of steroid-dependent asthma

A 63-year-old woman with refractory psoriatic arthritis and asthma, requiring intermittent steroid therapy, was treated with methotrexate (MTX). Her arthritis responded rapidly and it was noted that her asthma required no further steroid therapy. Six patients with established steroid-dependent asthma were then treated with 7.5 to 15.0 mg of MTX per week, after protocols used to treat psoriasis and rheumatoid arthritis. Five patients reduced their steroid usage while on MTX. Side effects were minimal while taking MTX. It was concluded that MTX may have a role in reducing cortisone requirements in steroid-dependent asthma.     

Sjogren's syndrome presenting as remitting seronegative symmetric synovitis with pitting edema (RS3PE)

Remitting seronegative symmetric synovitis with pitting edema (RS3PE) syndrome is characterized by symmetrical and acute synovitis, pitting edema, the absence of rheumatoid factor, increased acute phase reactants, lack of bony erosions on radiography, and benign and short clinical course. Half of all patients with Sjogren's syndrome experience arthritis during the disease course. We here describe the first case of Sjogren's syndrome presenting as RS3PE. She had swelling in knees, ankles, and wrists. After then the swelling spread to her lower legs, feet, face, and both hands. She was admitted to another hospital and was suspected of lupus or rheumatoid arthritis. Three months later, she had dry mouth and had lower lip biopsy. She was admitted to this hospital due to development of swelling in face and lower legs for 3 days. On physical examination, she had pitting edema in both hands and feet dorsum. Laboratory test showed elevated erythrocyte sedimentation rate, positivity of rheumatoid factor, anti-nuclear antibody, and anti-Ro antibody. There was no erosion in the hands radiography. Schirmer's test and lip biopsy was compatible with Sjogren's syndrome. She was diagnosed RS3PE and Sjogren's syndrome. She was begun with prednisolone and her symptoms improved gradually.     

Inhalation of Carbon Monoxide Ameliorates Collagen-induced Arthritis in Mice and Regulates the Articular Expression of IL-1β and MCP-1

Carbon monoxide (CO), long considered a toxic gas, has recently been shown to mediate anti-inflammatory effects in various animal models. The aim of this study was to investigate whether the inhalation of CO ameliorated collagen-induced arthritis (CIA) in mice. CIA was induced in female DBA/1 mice by the injection of an anti-type II collagen antibody and lipopolysaccharide. The CO treatment group was exposed to CO gas at a concentration of 200 ppm in a closed cage starting on the day of the injection with an anti-type II collagen antibody and throughout the remaining study period. The clinical arthritis scores was examined daily for swelling of the paws as a sign of arthritis. For histopathology, the sections of the hind legs were evaluated by hematoxylin-eosin staining. Moreover, we evaluated the expression of interleukin (IL)-1β and monocyte chemoattractant protein-1 (MCP-1) mRNA in the hind paws. Both clinical arthritis scores as well as histological findings of joint inflammation were significantly reduced in mice treated with CO gas inhalation compared to untreated mice. Further, CO significantly inhibited the increased expression of IL-1β and MCP-1 mRNA in paws at day 3 after the induction of arthritis. In conclusion, the inhalation of CO protected mice from the synovial inflammation of CIA. Based on these data, the beneficial effects of CO in murine RA model may be attributed to its anti-inflammatory properties.