Folate supplementation during Methotrexate therapy for rheumatoid arthritis
Methotrexate (MTX), an antifolate, is an anchor drug for the treatment of rheumatoid arthritis (RA). Both folic acid (FA) and folinic acid (FLN) supplements have been shown to reduce the toxicity of MTX when used in RA therapy. The effect of folate supplementation on MTX efficacy still needs to be studied. FA supplementation has been found to have a beneficial effect on homocysteine (hcy) metabolism and may prevent the formation of the less effective metabolite 7-hydroxy-MTX. The cost of FA supplements is substantially less than the cost of FLN supplements. This article reviews clinical trials related to folate supplementation during MTX therapy for RA.
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ABSTRACT: Methotrexate is widely used in the management of rheumatoid arthritis patients and is considered a first line drug. This study was conducted on 245 patients suffering from rheumatoid arthritis to study the adverse effects of low-dose methotrexate in adult patients of Kashmir valley fulfilling the revised American College of Rheumatology criteria. Adverse effects of the drug were seen in 96 (32.2%) patients but most of these were mild in nature. GI side effects were the most common adverse effects requiring treatment. Hepatic, haematological and muco-cutaneous effects were also seen. Considering the beneficial effects of the drug and the mild nature of the adverse effects, we recommend methotrexate in all patients of rheumatoid arthritis. Further, we also recommend regular use of folic acid in all patients on methotrexate and a follow-up of all patients to diagnose and manage any adverse effect of the drug. in patients of rheumatoid arthritis treated by intramuscular methotrexate. Methotrexate is a quick acting disease modifying agent and halts the progression of bony erosions, thereby preventing joint deformity and morbidity. Methotrexate (N-10 methyl aminopterin) is a folate analogue and an ideal agent for rheumatoid arthritis. It is cheap and has a convenient weekly dosage 5,6.7,8,9 . It can be given orally, intramuscularly or by subcutaneous injection, with similar rates of absorption, regardless of the route of administration. Serum levels peak after 1-2 hours. Absorption is delayed by intestinal pathology such as inflammatory bowel disease, shortened bowel or malabsorption syndrome, but not by food. Methotrexate enters the cells where it is polyglutamated and the latter form may be responsible for the therapeutic effects of Methotrexate. Toxicity is the main reason for discontinuation of the drug 10 . The most common side effects are those involving GIT (nausea, vomiting), hepatic, CNS (headache, dizziness), haematological and rarely respiratory. Most of these can be reduced by supplemented folic acid / folinic acid without interfering with the efficacy of the drug. Methotrexate is teratogenic and thus its use is contraindicated during pregnancy and lactation. Non-Hodgkin's (B-Cell) lymphoma which reversed with discontinuation of methotrexate has also been reported in patients with rheumatoid arthritis 11 .
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ABSTRACT: Despite limited understanding of therapeutic aetiopathogenesis of ulcerative colitis and Crohn’s disease, there is a strong evidence base for the efficacy of pharmacological and biological therapies. It is equally important to recognise toxicity of the medical armamentarium for inflammatory bowel disease (IBD).
Sulfasalazine consists of sulfapyridine linked to 5-aminosalicylic acid (5-ASA) via an azo bond. Common adverse effects related to sulfapyridine ‘intolerance’ include headache, nausea, anorexia, and malaise. Other allergic or toxic adverse effects include fever, rash, haemolytic anaemia, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible sperm abnormalities.
The newer 5-ASA agents were developed to deliver the active ingredient of sulfasalazine while minimising adverse effects. Adverse effects are infrequent but may include nausea, dyspepsia and headache. Olsalazine may cause a secretory diarrhoea. Uncommon hypersensitivity reactions, including worsening of colitis, pancreatitis, pericarditis and nephritis, have also been reported.
Corticosteroids are commonly prescribed for treatment of moderate to severe IBD. Despite short term efficacy, corticosteroids have numerous adverse effects that preclude their long term use. Adverse effects include acne, fluid retention, fat redistribution, hypertension, hyperglycaemia, psycho-neurological disturbances, cataracts, adrenal suppression, growth failure in children, and osteonecrosis. Newer corticosteroid preparations offer potential for targeted therapy and less corticosteroid-related adverse effects.
Azathioprine and mercaptopurine are associated with pancreatitis in 3 to 15% of patients that resolves upon drug cessation. Bone marrow suppression is dose related and may be delayed.
The adverse effects of methotrexate include nausea, leucopenia and, rarely, hypersensitivity pneumonia or hepatic fibrosis. Common adverse effects of cyclosporin include nephrotoxicity, hypertension, headache, gingival hyperplasia, hyperkalaemia, paresthesias, and tremors. These adverse effects usually abate with dose reduction or cessation of therapy. Seizures and opportunistic infections have also been reported.
Antibacterials are commonly employed as primary therapy for Crohn’s disease. Common adverse effects of metronidazole include nausea and a metallic taste. Peripheral neuropathy can occur with prolonged administration. Ciprofloxacin and other antibacterials may be beneficial in those intolerant to metronidazole.
Newer immunosuppressive agents previously reserved for transplant recipients are under investigation for IBD. Tacrolimus has an adverse effect profile similar to cyclosporin, and may cause renal insufficiency. Mycophenolate mofetil, a purine synthesis inhibitor, has primarily gastrointestinal adverse effects.
Biological agents targeting specific sites in the immunoinflammatory cascade are now available to treat IBD. Infliximab, a chimeric antibody targeting tumour necrosis factor-α has been well tolerated in clinical trials and early postmarketing experience. Additional trials are needed to assess long term adverse effects.
Available from: Daniel Kurnik
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ABSTRACT: Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter.
: To determine the relative bioavailability of oral low-dose methotrexate administered with and without concomitant folic acid vs. subcutaneous administration in patients with stable Crohn's disease.
Ten patients were randomized to receive their regular maintenance dose of methotrexate (15-25 mg) for three consecutive weeks: orally, orally with 5 mg folic acid or subcutaneously. Blood samples were drawn at specified intervals during 24 h, and methotrexate levels were determined by fluorescence immunoassay. Areas under the curve extrapolated to infinity (AUC infinity ) were compared between the three routes.
The geometric mean AUC infinity values (95% confidence intervals) were 360 nmol x h/L (301-430 nmol x h/L), 261 nmol x h/L (214-318 nmol x h/L) and 281 nmol x h/L (209-377 nmol x h/L) per milligram of methotrexate administered for subcutaneous, oral and oral with folic acid administration, respectively (P < 0.05 and P < 0.01 for oral with folic acid and oral vs. subcutaneous administration, respectively). The geometric mean relative bioavailabilities (95% confidence intervals) were 0.73 (0.62-0.86) and 0.77 (0.60-0.99) for oral and oral with folic acid administration, respectively (difference not significant).
In patients with stable Crohn's disease, the oral bioavailability of methotrexate is highly variable and averages 73% of that of subcutaneous administration. Concomitant folic acid has no significant effect on the bioavailability. Dose adjustments based on individual pharmacokinetic assessment should be considered when switching patients from parenteral to oral therapy.
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