History of methotrexate
Methotrexate (MTX) was originally developed in the 1940s by researchers at Lederle Laboratories (now part of Pfizer). The chemist Yellapragada Zubbarov and his team were instrumental in its development. The discovery of methotrexate as an effective agent in chemotherapy was a major breakthrough in medicine. It was recognized that methotrexate acts as an antimetabolite by inhibiting folic acid biosynthesis, which is necessary for cell growth and replication. This discovery led to further research into its use in other diseases characterized by rapidly proliferating cells, such as autoimmune diseases and rheumatoid arthritis in particular.
Mechanism of action of methotrexate
- Antimetabolic effect: Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase (DHFR). DHFR is a crucial enzyme in folic acid metabolism, which is necessary for the synthesis of tetrahydrofolate (THF). THF is an essential cofactor for the synthesis of purine nucleotides and thymidylate, which in turn are required for DNA and RNA synthesis. By inhibiting DHFR, methotrexate interrupts cell division, which is particularly effective in rapidly dividing cells such as inflammatory cells and cancer cells.
- Immunomodulatory effects: At lower doses, as used in rheumatology, methotrexate has anti-inflammatory and immunomodulatory effects. It affects various pathways of the immune system, including inhibition of lymphocyte proliferation, reduction of cytokine production (e.g. interleukin-1 and -6, tumor necrosis factor-alpha) and modulation of immune cell function. These effects contribute to the reduction of pathological immune reactions that lead to joint inflammation and damage in autoimmune diseases such as rheumatoid arthritis.
- Anti-inflammatory effect: Methotrexate promotes the release of adenosine, a molecule that has anti-inflammatory properties. Adenosine can dampen inflammatory reactions by modulating the function of neutrophils, the release of cytokines and other inflammatory processes.
MTX in the treatment of rheumatoid arthritis (RA)
Mode of action
Methotrexate is used in RA because of its anti-inflammatory and immunomodulating properties. It inhibits the enzyme dihydrofolate reductase, which leads to reduced production of DNA and RNA and thus suppresses the rapid division of pro-inflammatory cells. This reduces inflammation, swelling and pain in RA patients.
- Immune system: By modulating the immune system, methotrexate reduces the pathological immune response that leads to joint damage in RA.
- Anti-inflammatory: It reduces the production of pro-inflammatory cytokines and inhibits the proliferation of immune cells that contribute to joint inflammation.
MTX in the treatment of other rheumatologic diseases
Methotrexate is not only used for rheumatoid arthritis (RA), but also for a number of other rheumatologic diseases. Here are some of the most important areas of application:
- Psoriatic arthritis: In this disease, which is associated with psoriatic skin symptoms and arthritic joint complaints, methotrexate can improve both the skin lesions and the joint inflammation.
- Juvenile idiopathic arthritis (JIA): Used in children and adolescents, methotrexate can help control joint inflammation and promote physical development and growth.
- Ankylosing spondylitis (AS) with peripheral joint involvement: Also known as ankylosing spondylitis, is an inflammatory disease that primarily affects the spine. Methotrexate is sometimes used to relieve symptoms, although its efficacy in this indication is less well established than in RA or psoriatic arthritis.
- For collagenosis such as
- Systemic lupus erythematosus (SLE): In this systemic autoimmune disease, methotrexate can be used in certain cases, especially if there is joint involvement. It is often used as part of a treatment regimen that also includes other medications.
- Dermatomyositis and polymyositis: These inflammatory muscle diseases, which are often accompanied by skin rashes, can in some cases be treated with methotrexate to reduce muscle inflammation and weakness.
- Sjögren's syndrome: In this condition, which is characterized by dry eyes and a dry mouth, methotrexate can be used to treat joint symptoms or other systemic manifestations.
- Systemic sclerosis: Systemic sclerosis is a rare, chronic disease characterized by an overproduction of collagen, resulting in thickening and hardening of the skin and sometimes damage to internal organs. The role of methotrexate in systemic sclerosis is primarily due to its immunomodulatory and anti-inflammatory properties. Although methotrexate is not the primary standard treatment for systemic sclerosis, it is used in patients with skin involvement and milder disease severity. Studies have shown that in some cases, methotrexate can help reduce skin thickening and improve mobility, leading to a better quality of life.
- Vasculitides: Methotrexate is used for vasculitides that affect large, medium-sized or small vessels. These include granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), panarteritis nodosa, giant cell arteritis.
Advantages of MTX therapy
- High efficacy and effectiveness: Methotrexate is particularly effective in reducing disease activity and slowing joint damage associated with RA and other inflammatory diseases.
- Well-established safety profile, long-term data: It has been used for decades, providing a comprehensive understanding of its safety, efficacy and long-term effects.
- Improved quality of life: Patients often report a significant improvement in their quality of life due to reduced pain, stiffness and fatigue as well as improved joint function.
- Flexible dosing and routes of administration: Methotrexate can be administered orally, subcutaneously or intramuscularly, which allows treatment to be customized.
- Flexibility: It can be used alone or in combination with other medications, making it a versatile option in treatment strategy.
- Cost-effectiveness: Compared to biologics, methotrexate is a more cost-effective option, making it an accessible choice for a broad patient population.
Necessity of folic acid substitution during MTX therapy
The role of folic acid in combination with methotrexate is also important. Methotrexate acts as a folic acid antagonist by inhibiting the enzyme dihydrofolate reductase, which is necessary for the conversion of dihydrofolate into tetrahydrofolate. This reaction is crucial for the synthesis of nucleotides needed for DNA synthesis. Inhibition of this pathway can lead to a deficiency of folic acid, which in turn can impair cell division and repair and can lead to side effects such as mouth ulcers, gastrointestinal disorders, hair loss and blood count changes.
To minimize the side effects of methotrexate, additional folic acid supplementation is recommended. Folic acid supplementation can help to compensate for the inhibition of folic acid metabolism caused by methotrexate, thereby reducing the risk of side effects and improving the tolerability of the drug. Supplementation helps to meet the body's need for folic acid without interfering with the therapeutic effect of methotrexate on the underlying disease.
As a rule, folic acid is taken once a week on the day after the methotrexate dose.
Combination with other basic therapeutics
Methotrexate is often used in combination with other basic therapeutic agents such as hydroxychloroquine and sulfasalazine, especially in a therapeutic strategy known as triple therapy. MTX can also be combined very well with leflunomide. This combination can further reduce disease activity and provide better control of symptoms, especially in patients who do not respond adequately to monotherapy.
Combination with biologics
- Synergistic effect: The combination of methotrexate with biologics, such as TNF inhibitors, IL-6 receptor antagonists and B-cell depleting therapies, has proven to be more effective than the respective monotherapy. Combination therapy can promote disease remission and slow down the progression of joint damage.
- Increased effectiveness of biologics: Methotrexate can increase the effectiveness of biologics by reducing the formation of antibodies against the biologics and slowing their clearance from the body.
- Expansion of treatment options: For patients who do not respond to methotrexate monotherapy, the combination with biologics offers a valuable expansion of treatment options.
- Optimization of therapy: Combination therapy allows for customized treatment where dosages can be adjusted and side effects minimized while maintaining optimal disease control.
Dosage and administration
The dosage of methotrexate must be adjusted individually, usually starting with a low dose that is gradually increased. It can be administered orally or as a subcutaneous injection, with subcutaneous administration often offering better absorption and efficacy. The dose is based on weight, namely 0.3 mg per kilogram of body weight.
Monitoring and side effects
As with any long-term therapy, regular monitoring is required to detect potential side effects at an early stage. Regular monitoring of blood values and lung function tests is crucial.
Side effects
Methotrexate can very rarely cause side effects, including
- Nausea, vomiting and diarrhea
- Mouth ulcers
- Elevated liver values
- Bone marrow suppression
- Lung involvement such as pneumonitis
- Increased risk of infection
Conclusion
In summary, methotrexate is a cornerstone in the treatment of rheumatoid arthritis and other inflammatory diseases due to its efficacy, safety and cost-effectiveness. Combining methotrexate with other basic therapeutics or biologics can improve treatment outcomes, provide more options for personalized therapy approaches and may help improve patients' long-term disease control and quality of life.
