Methotrexate for Rheumatoid Arthritis

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4–8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number of patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.     

Mechanisms of Methotrexate Action in Rheumatoid Arthritis

Objective. To measure the effect of methotrexate (MTX) treatment in rheumatoid arthritis (RA) on the expression of synovial collagenase, stromelysin, and tissue inhibitor of metalloproteinase 1 (TIMP-1) gene expression in a prospective study. Methods. Serial percutaneous synovial biopsies (pretreatment and after 3–4 months) were performed on the knees of 8 patients (7 with RA, 1 with seronegative arthritis) who were beginning oral MTX therapy. Synovial gene expression was determined by quantitative in situ hybridization using computer-assisted image analysis. Results. After therapy, patients had decreased joint counts, morning stiffness, and erythrocyte sedimentation rates. Synovial inflammation in the biopsy tissues was slightly decreased after therapy. In situ hybridization on pretreatment and posttreatment frozen sections was performed to quantify synovial messenger RNA (mRNA) levels. Collagenase gene expression significantly decreased after MTX therapy (P = 0.006) even though cell density in the region was unchanged. TIMP-1 and stromelysin mRNA levels were not changed by MTX therapy. To study the mechanism of MTX action in vitro, MTX-treated and control fibroblast-like synoviocytes were stimulated with interleukin-1β (IL-1β). MTX did not alter collagenase or TIMP-1 mRNA levels after IL-1 exposure. Conclusion. MTX therapy decreases collagenase gene expression but not TIMP-1 or stromelysin gene expression in the synovium. This action is probably an indirect effect due to an alteration in the synovial cytokine milieu, rather than a direct effect on gene expression.     

Pancytopenia and Colitis with Clostridium difficile in a Rheumatoid Arthritis Patient Taking Methotrexate, Antibiotics and Non-steroidal Anti-inflammatory Drugs

Methotrexate (MTX) is widely used despite its side-effects. We describe a rheumatoid arthritis (RA) patient taking low-dose MTX who developed severe pancytopenia and colitis with Clostridium difficile after the administration of antibiotics for acute pyelonephritis. Our case suggests that low-dose MTX may seriously interact with antibiotics and that these side-effects should always be considered when RA patients are treated with MTX and antibiotics. Received: 13 January 2000 / Accepted: 25 July 2000     

Induction Therapy with Combination TNF Inhibitor and Methotrexate in Early Rheumatoid Arthritis

With the introduction of more objective disease activity measures and the development of biological therapies, there were dramatic changes in the treatment of rheumatoid arthritis (RA). The combination therapy with tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) has unprecedentedly improved prognosis and outcomes, and very low disease activity or remission has been achievable goal in RA. Although the concept of remission induction and maintenance was first discussed in longstanding RA patients, several clinical trials have demonstrated that there is a therapeutic window of opportunity, and early effective control of inflammation in early RA could lead to less joint damage and better long-term outcomes. Emerging evidence suggests that early combination therapy with TNF inhibitor and MTX leads to rapid clinical remission and thereby improved quality of life. Furthermore, remission status may be sustained in some patients even if a TNF inhibitor is discontinued after sustained remission in early RA patients. While there are many potential benefits of early remission induction therapy with the combination of a TNF inhibitor and MTX, the best therapeutic regimen and strategy for remission induction and maintenance in early RA remain controversial. There are no data to decide a priori when and in whom TNF blocker drugs are indicated in early disease-modifying anti-rheumatic drug (DMARD)-naïve RA.     

Development of Intravascular Large B-cell Lymphoma during Methotrexate Treatment for Rheumatoid Arthritis

A 56-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for six years visited our hospital with dyspnea and dizziness. Abdominal ultrasonography revealed mild splenomegaly. Laboratory examinations showed a marked elevation in soluble interleukin-2 receptor and lactate dehydrogenase levels. These abnormalities revealed a spontaneous regression after MTX discontinuation, however, they worsened again four months later. Skin biopsies revealed a diagnosis of intravascular large B-cell lymphoma (IVLBCL), and we diagnosed MTX-associated IVLBCL (MTX-IVLBCL) based on its characteristic course. Despite the recurrence of IVLBCL, it showed a good response to chemotherapy. MTX-IVLBCL should therefore be treated with consideration since it has different characteristics from that of de novo IVLBCL.     

Long-Term Prospective Study of Methotrexate in the Treatment of Rheumatoid Arthritis

Objective. To determine the long-term efficacy and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA). Methods. Eighty-four—month open prospective trial at a single academic rheumatology center. Results. Twenty-six patients were enrolled in a prospective study of the long-term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84-month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity. Conclusion. The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.     

Interleukin-2 Receptor Levels in the Sera of Rheumatoid Arthritis Patients Treated with Methotrexate

Objective. To evaluate the association of the level of soluble serum interleukin-2 receptor (sIL-2R) with disease activity and response to therapy in patients with rheumatoid arthritis (RA). Methods. The sIL-2R levels of 148 patients with refractory RA were determined by enzyme-linked immunosorbent assay. This parameter was correlated with other clinical observations obtained during a prospective, randomized, placebo-controlled trial of methotrexate, sponsored by the Cooperative Systematic Studies of Rheumatic Diseases consortium. Using statistical modeling, the usefulness of sIL-2R as a measure of disease activity and a predictor of outcome was evaluated. Results. The mean sIL-2R level in all RA patients was markedly elevated compared with that in normal control subjects, and decreased significantly during the trial. There was no correlation of the sIL-2R level and the joint pain/tenderness count either at study entry or study end. There was a significant correlation of the sIL-2R level and the erythrocyte sedimentation rate, both at study entry and study end. A multiple linear regression model showed that treatment with methotrexate, but not the sIL-2R level or the change in sIL-2R level, predicted a change in joint count. A stepwise multiple logistic regression model defined no significant predictive information for outcome for the level of sIL-2R at study entry. Conclusion. After controlling for the simultaneous effects of other important clinical variables, the level of sIL-2R does not appear to predict the response to methotrexate in patients with refractory RA. Further analysis of cohorts of patients with earlier RA needs to be performed.     

甲氨蝶呤及环磷酰胺联合用药对类风湿关节炎患者外周血淋巴细胞凋亡的影响

目的 探讨甲氨蝶呤（MTX）和环磷酰胺（CTX）及两者联合治疗对类风湿关节炎（RA）患者外周血淋巴细胞凋亡的影响。方法 入选活动期RA患者30例，随机分为3组（单用MTX组、单用CTX组及联合用药组），Annexin V-FITC及碘化丙锭（PI）双标记RA患者外周血淋巴细胞，应用流式细胞术检测MTX、CTX及联合组治疗前后外周血淋巴细胞凋亡的变化；同时以10例健康志愿者外周血淋巴细胞凋亡情况为正常对照。结果 活动期RA患者外周血淋巴细胞早期凋亡率与正常人比较差异无统计学意义（P〉0．05）。单用MTX及单用CTX组患者用药后较用药前外周血淋巴细胞早期凋亡率均明显增加，差异均有统计学意义（P〈0．05）；联合用药后外周血淋巴细胞早期凋亡率较单用MTX、CTX组明显增加，差异有统计学意义（P〈0．05）。RA患者基线外周血淋巴细胞早期凋亡率与疾病活动指数（DAS）28、血沉（ESR）、C反应蛋白（CRP）疾病活动指标间无相关性。结论 MTX联合CTX治疗能更加有效地诱导RA患者外周血淋巴细胞凋亡。