Current and Future Role of Methotrexate in RA Therapy
The profile of side effects of MTX has been studied over 25 years, with very few clinically important adverse effects in the weekly low doses used for RA therapy. Indeed, MTX courses show some of the longest continuation rates reported in clinical medicine, obviously as a result of both its efficacy and safety. The safety profile of MTX indicates that it is among the safest of all drugs used for the treatment of chronic inflammatory arthritis.
The incidence of cancer and the mortality due to cancer have been studied in a group of 789 randomly selected RA patients between 1999 and 2005, and compared with the general population. The standardized incidence ratio of cancer in RA was 1.23 (95% CI: 0.78–1.85). An increased risk of leukemia, non-Hodgkin's lymphoma and lung cancer was found in patients with RA, but the overall standardized mortality ratio of cancer was not higher than expected. RA patients, however, with kidney or lung cancer had a higher mortality than expected. Male gender, elderly age, longstanding disease and having used cytotoxic drugs other than MTX were identified as predictive factors for cancer. The authors concluded that the overall incidence and mortality of cancer in RA was not greater than expected, although an increased risk of hematopoietic and lung cancer in RA was found.
In another study of 23,810 patients with RA from Quebec (Canada) over the period 1980–2003, hematologic malignant neoplasms developed in 619 patients, including lymphoma in 346 patients, leukemia in 178 patients and multiple myeloma in 95 patients. The unadjusted rate ratios for hematologic malignancies after drug exposure were: MTX 1.18 (95% CI: 0.99–1.40); azathioprine 1.44 (95% CI: 1.01–2.03); and cyclophosphamide 2.21 (95% CI: 1.52–3.20). Apart from cyclophosphamide, which is clearly associated with an increased risk of neoplasia, such an association was less convincing for azathioprine and even less for MTX.
There is no evidence that MTX worsens interstitial lung disease in RA patients.
A review of RA patients followed-up over 14 years at the hospital for Special Surgery in New York (NY, USA) indicated that 3.4% of 182 patients with RA who had ever been treated with MTX had abnormal liver function tests. One hundred and fifty two patients (83.5%) with 2007 evaluations had no abnormal results, compared with 30 patients (16.5%) who had at least one abnormal liver function result over 784 tests. Twenty-two out of the 30 patients with at least one abnormal test (73.3%), however, continued treatment without biopsy or other further evaluation or change in treatment, while subsequent liver function assessments were within normal limits. Only three patients had leucopenia, the lowest 2300/µl, while MTX was discontinued in only one case. Twenty two patients had mild hypoalbuminemia, which resulted in no change of the MTX dose. The most common cause for discontinuation was inadequate response, not adverse events.
Long-term Safety of MTX
The profile of side effects of MTX has been studied over 25 years, with very few clinically important adverse effects in the weekly low doses used for RA therapy. Indeed, MTX courses show some of the longest continuation rates reported in clinical medicine, obviously as a result of both its efficacy and safety. The safety profile of MTX indicates that it is among the safest of all drugs used for the treatment of chronic inflammatory arthritis.
The incidence of cancer and the mortality due to cancer have been studied in a group of 789 randomly selected RA patients between 1999 and 2005, and compared with the general population. The standardized incidence ratio of cancer in RA was 1.23 (95% CI: 0.78–1.85). An increased risk of leukemia, non-Hodgkin's lymphoma and lung cancer was found in patients with RA, but the overall standardized mortality ratio of cancer was not higher than expected. RA patients, however, with kidney or lung cancer had a higher mortality than expected. Male gender, elderly age, longstanding disease and having used cytotoxic drugs other than MTX were identified as predictive factors for cancer. The authors concluded that the overall incidence and mortality of cancer in RA was not greater than expected, although an increased risk of hematopoietic and lung cancer in RA was found.
In another study of 23,810 patients with RA from Quebec (Canada) over the period 1980–2003, hematologic malignant neoplasms developed in 619 patients, including lymphoma in 346 patients, leukemia in 178 patients and multiple myeloma in 95 patients. The unadjusted rate ratios for hematologic malignancies after drug exposure were: MTX 1.18 (95% CI: 0.99–1.40); azathioprine 1.44 (95% CI: 1.01–2.03); and cyclophosphamide 2.21 (95% CI: 1.52–3.20). Apart from cyclophosphamide, which is clearly associated with an increased risk of neoplasia, such an association was less convincing for azathioprine and even less for MTX.
There is no evidence that MTX worsens interstitial lung disease in RA patients.
A review of RA patients followed-up over 14 years at the hospital for Special Surgery in New York (NY, USA) indicated that 3.4% of 182 patients with RA who had ever been treated with MTX had abnormal liver function tests. One hundred and fifty two patients (83.5%) with 2007 evaluations had no abnormal results, compared with 30 patients (16.5%) who had at least one abnormal liver function result over 784 tests. Twenty-two out of the 30 patients with at least one abnormal test (73.3%), however, continued treatment without biopsy or other further evaluation or change in treatment, while subsequent liver function assessments were within normal limits. Only three patients had leucopenia, the lowest 2300/µl, while MTX was discontinued in only one case. Twenty two patients had mild hypoalbuminemia, which resulted in no change of the MTX dose. The most common cause for discontinuation was inadequate response, not adverse events.