A case of rheumatoid arthritis exhibiting accelerating rheumatoid pleurisy during low-dose weekly methotrexate therapy

Abstract

A 75-year-old Japanese man suffering from rheumatoid arthritis (RA) had received methotrexate (MTX) treatment for 9 years and developed bilateral pleural thickening with exudative pleural effusions despite remission of the polyarthritis. A diagnosis of rheumatoid pleurisy, made by exclusion, was supported by the elevated rheumatoid factor level of the pleural fluid. The pleurisy developed concomitantly with MTX-induced leukocytopenia, and discontinuation of the MTX treatment partially improved the CRP level. These findings indicate a causal relation between the rheumatoid pleurisy and MTX and suggest that MTX therapy may be ineffective in the treatment of rheumatoid pleurisy. Treatment with 10?mg of prednisolone and 100?mg of cyclosporine A daily resulted in rapid resolution of the pleurisy. Although MTX-induced rheumatoid pleurisy is a rare condition, MTX therapy should be considered carefully in RA patients with concomitant rheumatoid pleurisy.     

Gynecomastia associated with low-dose methotrexate therapy for rheumatoid arthritis

A 68-year-old man with a 3-year history of rheumatoid arthritis (RA) developed gynecomastia 3 months after beginning oral low-dose methotrexate (MTX) therapy. Four months after MTX therapy was discontinued, the gynecomastia symptoms improved. Only eight cases of gynecomastia resulting from low-dose MTX administration have been reported worldwide, and no cases have previously been reported in Japan. Although it occurs infrequently, gynecomastia resulting from low-dose MTX therapy should be considered in male patients with RA.     

Gynecomastia associated with low-dose methotrexate therapy for rheumatoid arthritis

Abstract

A 68-year-old man with a 3-year history of rheumatoid arthritis (RA) developed gynecomastia 3 months after beginning oral low-dose methotrexate (MTX) therapy. Four months after MTX therapy was discontinued, the gynecomastia symptoms improved. Only eight cases of gynecomastia resulting from low-dose MTX administration have been reported worldwide, and no cases have previously been reported in Japan. Although it occurs infrequently, gynecomastia resulting from low-dose MTX therapy should be considered in male patients with RA.     

Pharmacokinetics and efficacy of low-dose methotrexate in patients with rheumatoid arthritis

This article evaluates the relationship between the pharmacokinetics of methotrexate (MTX), its efficacy in the treatment of rheumatoid arthritis (RA), and serum folic acid (FA) levels. The pharmacokinetics of MTX was studied in 29 patients with RA treated with low-dose MTX. The weekly dose of MTX was given orally at 2–4mg every 12h over a period of 24–36h. Blood samples were taken 4h after the first administration in any given week. A Bayesian method was used to estimate individual MTX pharmacokinetic variables. We then investigated the efficacy of MTX and the serum FA levels in these patients. We examined C-reactive protein levels (CRP) and the erythrocyte sedimentation rate (ESR), and analyzed the values obtained before and after MTX treatment in order to evaluate the efficacy of the MTX treatment. The degree of improvement in CRP and ESR was significantly correlated with the length of time the MTX concentration–time curve remained above 0.02µM in one week. Furthermore, the degree of improvement in CRP was also significantly correlated with the area under the concentration–time curve (AUC) for MTX. These results suggest that serum MTX measurements could be useful in determining individual patient regimens.     

Rheumatoid nodulosis during methotrexate therapy in a patient with rheumatoid arthritis

We report a 62-year-old man with rheumatoid arthritis (RA) who developed nodulosis after methotrexate (MTX) treatment. The epithelioid cells of nodules were positive for matrix metalloproteinases (MMP)-2, MMP-3, MMP-9, and Ki67. The synovial tissues obtained from the same patient were negative for MMP-3, MMP-9, and Ki67. This study demonstrated that MTX-induced nodules are different from synovial tissues in terms of MMP expression, suggesting the presence of different pathologic mechanisms and differential MTX susceptibility.     

Rheumatoid nodulosis during methotrexate therapy in a patient with rheumatoid arthritis

Abstract

We report a 62-year-old man with rheumatoid arthritis (RA) who developed nodulosis after methotrexate (MTX) treatment. The epithelioid cells of nodules were positive for matrix metalloproteinases (MMP)-2, MMP-3, MMP-9, and Ki67. The synovial tissues obtained from the same patient were negative for MMP-3, MMP-9, and Ki67. This study demonstrated that MTX-induced nodules are different from synovial tissues in terms of MMP expression, suggesting the presence of different pathologic mechanisms and differential MTX susceptibility.     

Lack of increase in postoperative complications with low-dose methotrexate therapy in patients with rheumatoid arthritis undergoing elective orthopedic surgery

To determine the potential contribution of intermittent low-dose methotrexate (MTX) treatment (2–8 mg/week) to postoperative complications, we studied 122 patients with rheumatoid arthritis (RA) who had 201 surgical procedures. The patients with treatment with MTX were allocated to two groups: those who continued MTX (group A, 77 procedures) and those who discontinued MTX more than 1 week (group B, 21 procedures). The patients who had no treatment with MTX were allocated to group C (103 procedures). The incidence of postoperative infection, poor wound healing, and flare-up of RA was compared between the three groups. Postoperative infection occurred in 3.9%, 4.8%, and 3.9% in groups A, B, and C, respectively. Poor wound healing was experienced in 1.3%, 9.5%, and 7.8% in groups A, B, and C, respectively. At 4 weeks postoperatively, 3.9%, 14.3%, and 6.8% of flares were seen in groups A, B, and C, respectively. No significant difference was found in the patients with or without perioperative use of MTX. From these results, it is unlikely that continuation of intermittent low-dose MTX treatment increases the risk of postoperative complications in patients with RA. Continued treatment with MTX during perioperative period could suppress disease flares, especially in severe RA patients.     

Lack of increase in postoperative complications with low-dose methotrexate therapy in patients with rheumatoid arthritis undergoing elective orthopedic surgery

Abstract

To determine the potential contribution of intermittent low-dose methotrexate (MTX) treatment (2–8mg/week) to postoperative complications, we studied 122 patients with rheumatoid arthritis (RA) who had 201 surgical procedures. The patients with treatment with MTX were allocated to two groups: those who continued MTX (group A, 77 procedures) and those who discontinued MTX more than 1 week (group B, 21 procedures). The patients who had no treatment with MTX were allocated to group C (103 procedures). The incidence of postoperative infection, poor wound healing, and flare-up of RA was compared between the three groups. Postoperative infection occurred in 3.9%, 4.8%, and 3.9% in groups A, B, and C, respectively. Poor wound healing was experienced in 1.3%, 9.5%, and 7.8% in groups A, B, and C, respectively. At 4 weeks postoperatively, 3.9%, 14.3%, and 6.8% of flares were seen in groups A, B, and C, respectively. No significant difference was found in the patients with or without perioperative use of MTX. From these results, it is unlikely that continuation of intermittent low-dose MTX treatment increases the risk of postoperative complications in patients with RA. Continued treatment with MTX during perioperative period could suppress disease flares, especially in severe RA patients.     

Serum levels and pharmacodynamics of methotrexate and its metabolite 7-hydroxy methotrexate in Japanese patients with rheumatoid arthritis treated with 2-mg capsule of methotrexate three times per week

Methotrexate (MTX) is the first-choice drug for rheumatoid arthritis (RA); however, the pharmacodynamics of MTX in Japanese patients with RA treated legitimately according to the government recommended dosage, 6 mg per week, are unknown. Methotrexate and its metabolite, 7-hydroxy MTX (7-OH MTX), were measured in sera of 16 outpatients with active RA in the first week of MTX treatment and 4–12 weeks after the introduction at 0, 1, 2, 4, and 8 h after administration of the first and the third 2-mg capsule, followed by sampling at 48, 96, and 168 h. The mean maximal serum drug concentration (mean C_max) of MTX attained at 1–2 h after ingestion of the first capsule was 0.215 and 0.252 μM, respectively, in the first and the follow-up week. The mean C_max after ingestion of the third capsule was 0.223 μM and 0.357 μM. The mean C_max of 7-OH MTX was 0.0334 and 0.0289 μM for the first capsule, and 0.0495 and 0.0672 μM for the third capsule. The results indicate that MTX does not accumulate or deposit in the body of Japanese patients with RA when treated with 6 mg per week, and pharmacodynamics of MTX are comparable to those in overseas patients treated with 7.5 mg per week.     

Serum levels and pharmacodynamics of methotrexate and its metabolite 7-hydroxy methotrexate in Japanese patients with rheumatoid arthritis treated with 2-mg capsule of methotrexate three times per week

Abstract

Methotrexate (MTX) is the first-choice drug for rheumatoid arthritis (RA); however, the pharmacodynamics of MTX in Japanese patients with RA treated legitimately according to the government recommended dosage, 6?mg per week, are unknown. Methotrexate and its metabolite, 7-hydroxy MTX (7-OH MTX), were measured in sera of 16 outpatients with active RA in the first week of MTX treatment and 4–12 weeks after the introduction at 0, 1, 2, 4, and 8?h after administration of the first and the third 2-mg capsule, followed by sampling at 48, 96, and 168?h. The mean maximal serum drug concentration (mean C_max) of MTX attained at 1–2?h after ingestion of the first capsule was 0.215 and 0.252?µM, respectively, in the first and the follow-up week. The mean C_max after ingestion of the third capsule was 0.223?µM and 0.357?µM. The mean C_max of 7-OH MTX was 0.0334 and 0.0289?µM for the first capsule, and 0.0495 and 0.0672?µM for the third capsule. The results indicate that MTX does not accumulate or deposit in the body of Japanese patients with RA when treated with 6?mg per week, and pharmacodynamics of MTX are comparable to those in overseas patients treated with 7.5?mg per week.     

The effect of methotrexate on bone metabolism markers in patients with rheumatoid arthritis

The aim of the present study was to evaluate the influence on urinary excretion levels of N-telopeptide of type I collagen (NTX) and deoxypyridinoline (DPD) as a useful marker for bone resorption, and on serum-bone alkaline phosphate (BAP) levels as a useful marker for bone formation and an early marker of osteoblast differentiation in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). Thirty patients with RA, diagnosed according to the criteria of the American College of Rheumatology, were involved in this study between March 2003 and January 2005. None of the patients had a history of hormone (estrogen) replacement therapy. All patients were treated with MTX. Methotrexate was administered perorally at a dosage of 4–10 mg/week. All patients underwent general and physical examinations and routine blood and urinary analysis at the baseline, 3 months and 6 months after the initial treatment. Then the levels of NTX and DPD in urine and BAP in serum were measured in all patients. For comparison with the effect of other DMARDs on bone metabolism markers in RA patients, we measured the levels of NTX and DPD in urine and BAP in serum of RA patients, 13 patients treated with salazosulfapyridine (SASP), and 14 patients treated with actarit (ACT). In patients treated with MTX, NTX levels decreased significantly at 3 months after the initial treatment and remained low at 6 months after the initial treatment, and DPD levels significantly decreased at 6 months after the initial treatment. The mean serum BAP levels changed without significant differences from the baseline at 3 months and 6 months. In patients treated with SASP and ACT, all bone metabolism markers had not changed significantly at the three time points. On disease activity erythrocyte sedimentation rate, C-reactive protein, the number of swollen joints and tender joints, and mHAQ score decreased significantly at 3 months after the initial treatment, and remained at low levels at 6 months after the initial treatment with MTX. Methotrexate therapy looks promising in inhibiting generalized bone loss in patients with RA. In addition, NTX is a more sensitive marker than DPD.     

The effect of methotrexate on bone metabolism markers in patients with rheumatoid arthritis

Abstract

The aim of the present study was to evaluate the influence on urinary excretion levels of N-telopeptide of type I collagen (NTX) and deoxypyridinoline (DPD) as a useful marker for bone resorption, and on serum-bone alkaline phosphate (BAP) levels as a useful marker for bone formation and an early marker of osteoblast differentiation in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). Thirty patients with RA, diagnosed according to the criteria of the American College of Rheumatology, were involved in this study between March 2003 and January 2005. None of the patients had a history of hormone (estrogen) replacement therapy. All patients were treated with MTX. Methotrexate was administered perorally at a dosage of 4–10?mg/week. All patients underwent general and physical examinations and routine blood and urinary analysis at the baseline, 3 months and 6 months after the initial treatment. Then the levels of NTX and DPD in urine and BAP in serum were measured in all patients. For comparison with the effect of other DMARDs on bone metabolism markers in RA patients, we measured the levels of NTX and DPD in urine and BAP in serum of RA patients, 13 patients treated with salazosulfapyridine (SASP), and 14 patients treated with actarit (ACT). In patients treated with MTX, NTX levels decreased significantly at 3 months after the initial treatment and remained low at 6 months after the initial treatment, and DPD levels significantly decreased at 6 months after the initial treatment. The mean serum BAP levels changed without significant differences from the baseline at 3 months and 6 months. In patients treated with SASP and ACT, all bone metabolism markers had not changed significantly at the three time points. On disease activity erythrocyte sedimentation rate, C-reactive protein, the number of swollen joints and tender joints, and mHAQ score decreased significantly at 3 months after the initial treatment, and remained at low levels at 6 months after the initial treatment with MTX. Methotrexate therapy looks promising in inhibiting generalized bone loss in patients with RA. In addition, NTX is a more sensitive marker than DPD.     

Pneumocystis jiroveci pneumonia associated with low-dose methotrexate treatment for rheumatoid arthritis: report of two cases and review of the literature

Low-dose methotrexate (MTX) therapy is widely used for rheumatoid arthritis (RA) because of its favorable efficacy and toxicity profile. Although Pneumocystis jiroveci pneumonia (PCP) is most often seen in severely immunosuppressed patients, PCP complicating low-dose MTX therapy for RA has been reported to sometimes occur. We herein report two cases of patients who developed PCP during treatment with low-dose MTX, and discuss the importance of prophylaxis for this opportunistic infection.     

Musculoskeletal ultrasonography assists the diagnostic performance of the 2010 classification criteria for rheumatoid arthritis

Objective

We investigated whether musculoskeletal ultrasonography (MSKUS) assists the diagnostic performance of the 2010 rheumatoid arthritis (RA) classification criteria.

Methods

Sixty-nine early arthritis patients were consecutively enrolled. None of the patients had been treated. In MSKUS of bilateral wrist and finger joints from 22 sites, the findings obtained by gray-scale and power Doppler (PD) assessment were graded on a semiquantitative scale from 0 to 3. Plain magnetic resonance imaging (MRI) of both wrist and finger joints was also examined. Diagnosis of RA was defined by the initiation of disease-modifying antirheumatic drugs within the first 3 months. The diagnostic performance of the patients was evaluated at entry using 2010 RA classification criteria in conjunction with MSKUS.

Results

The indispensable MSKUS finding for differentiating RA was the presence of a PD grade 2 or 3 that was superior to 2010 RA classification criteria or MRI-proven bone edema. We propose that the decision tree algorithm of 2010 RA classification criteria with PD grade 2 or 3 reveals the best discriminative ability.

Conclusion

MSKUS, especially with a strong PD signal, is very useful to assist the diagnostic performance of the 2010 RA classification criteria in the early recognition of RA.     

Acute erythroleukemia in a rheumatoid arthritis patient during low-dose methotrexate therapy

Acute leukemia is uncommonly seen with rheumatoid arthritis during or following treatment with low-dose methotrexate, a safe and effective treatment for the arthritic condition. We describe here a 68-year-old woman with rheumatoid arthritis who developed acute erythroleukemia during low-dose methotrexate therapy (total dose 1702.5 mg). This may be the first such case reported in the literature.     

亚甲基四氢叶酸还原酶基因多态性对小剂量甲氨喋呤治疗类风湿关节炎不良反应的影响

目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因C677T多态性对小剂量甲氨喋呤（MTX）治疗类风湿关节炎的影响。方法收集类风湿关节炎患者治疗前及治疗后0,12,24及48 w的临床表现及实验室指标和不良反应信息,评估疗效。采用实时荧光定量聚合酶链反应（FQ-PCR）方法测定类风湿关节炎患者183例（RA组）及健康对照组100例的MTHFR基因C677T多态性,比较两组间基因型分布及等位基因频率。结果 C677T基因型分布在RA组与健康对照组间差异无统计学意义（P〉0.05）;C677T各基因型在MTX治疗有效率差异无统计学意义（P〉0.05）。TT基因型组肝毒性及血液系统不良反应的发生率明显高于CC基因型组,差异均有统计学意义（P〈0.05）。结论 MTHFR基因C677T多态性与RA发病和MTX疗效无关,但与MTX治疗后血液系统不良反应、肝毒性有关联。     

A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy

Summary Baseline and sequential liver biopsies were performed in ten patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) for more than 4 years. Liver biopsies were performed in all patients before the initiation of MTX therapy and were repeated after reaching a cumulative dose of 1500 mg or more. In four patients a third biopsy was performed 3 years after the first one. No significant worsening of hepatic architecture was found in any of our patients after 4 to 71/2 years of MTX therapy. No correlations between histologic findings and various clinical or pharmacological variables could be found. Our results suggested that prolonged MTX administration in RA patients did not cause severe hepatic abnormalities.     

Effects of low-dose mizoribine pulse therapy in combination with methotrexate in rheumatoid arthritis patients with an insufficient response to methotrexate

Abstract

The aim was to determine the efficacy of low-dose intermittent pulse administration of mizoribine (MZR), a purine synthesis inhibitor, in combination with methotrexate (MTX) to control the symptoms of rheumatoid arthritis (RA) in patients with an insufficient clinical response to MTX alone. Twenty-seven patients with active RA, despite treatment with MTX, were enrolled and given MZR in combination with MTX and continued for 24 weeks. The primary endpoint was assessment of clinical improvements using the European League against Rheumatism (EULAR) criteria. Administering MZR to RA patients with an insufficient response to MTX produced significant improvements in the Disease Activity Score 28 (DAS28) after 8–24 weeks. In addition, after 24 weeks, 60.0% and 8.0% of patients had achieved moderate and good responses, respectively, and there were significant reductions in Modified Health Assessment Questionnaire and serum matrix metalloproteinase-3 levels. The present preliminary study suggests that low-dose MZR in combination with MTX is well tolerated and provides both clinical and economic benefits.     

Effects of low-dose mizoribine pulse therapy in combination with methotrexate in rheumatoid arthritis patients with an insufficient response to methotrexate

The aim was to determine the efficacy of low-dose intermittent pulse administration of mizoribine (MZR), a purine synthesis inhibitor, in combination with methotrexate (MTX) to control the symptoms of rheumatoid arthritis (RA) in patients with an insufficient clinical response to MTX alone. Twenty-seven patients with active RA, despite treatment with MTX, were enrolled and given MZR in combination with MTX and continued for 24 weeks. The primary endpoint was assessment of clinical improvements using the European League against Rheumatism (EULAR) criteria. Administering MZR to RA patients with an insufficient response to MTX produced significant improvements in the Disease Activity Score 28 (DAS28) after 8–24 weeks. In addition, after 24 weeks, 60.0% and 8.0% of patients had achieved moderate and good responses, respectively, and there were significant reductions in Modified Health Assessment Questionnaire and serum matrix metalloproteinase-3 levels. The present preliminary study suggests that low-dose MZR in combination with MTX is well tolerated and provides both clinical and economic benefits.     

Concurrent acute megaloblastic anaemia and pneumonitis : A severe side-effect of low-dose methotrexate therapy during rheumatoid arthritis

Summary In a patient suffering from rheumatoid arthritis, we report the first simultaneous occurrence of two side effects of low-dose methotrexate : an acute megaloblastic anaemia and a pneumonitis. A combination of methotrexate suspension, folinic acid and corticosteroids led to recovery. The correlation between the haematologic and pneumologic toxicity is discussed.