Methotrexate Accord: Uses, Dosage & Side Effects
A disease-modifying antirheumatic drug (DMARD) used as a subcutaneous injection for rheumatoid arthritis, psoriasis, and other autoimmune conditions
Methotrexate Accord is a prescription medication containing methotrexate, one of the most widely used and well-studied disease-modifying antirheumatic drugs (DMARDs) in medicine. Available as a solution for injection in a pre-filled injector (7.5 mg), it is primarily used to treat active rheumatoid arthritis, severe psoriasis that has not responded to other therapies, and certain forms of juvenile idiopathic arthritis. Methotrexate works by modifying the immune system response and reducing inflammation. It is administered once weekly — a critical dosing principle, as daily use can be fatal. The subcutaneous injection route offers improved bioavailability compared to oral tablets. Regular blood monitoring is essential throughout treatment, and folic acid supplementation is recommended to reduce side effects.
Quick Facts: Methotrexate Accord
Key Takeaways
- Methotrexate Accord is a subcutaneous injection formulation of methotrexate, the first-line DMARD recommended by EULAR, ACR, and WHO for the treatment of rheumatoid arthritis, offering better bioavailability than oral tablets.
- The medication is administered once weekly — never daily. Accidental daily dosing has caused fatal toxicity and is a well-documented medication safety concern that requires careful patient education.
- Folic acid supplementation (typically 5 mg once weekly on a different day) is recommended alongside methotrexate to reduce common side effects such as nausea, mouth ulcers, and liver enzyme elevations without compromising efficacy.
- Regular blood monitoring (full blood count, liver function tests, renal function) is mandatory before starting treatment, frequently during dose adjustment, and at regular intervals throughout therapy to detect potential toxicity early.
- Methotrexate is strictly contraindicated in pregnancy due to teratogenicity and embryotoxicity. Effective contraception is required for both women (during treatment and 6 months after) and men (during treatment and 3 months after).
What Is Methotrexate Accord and What Is It Used For?
Methotrexate Accord contains the active substance methotrexate, a folic acid antagonist that has been used in medicine for over six decades. Originally developed in the 1940s as an antineoplastic (anticancer) agent, methotrexate was later found to have potent immunomodulatory and anti-inflammatory properties at lower doses. Today, low-dose methotrexate is the cornerstone of treatment for rheumatoid arthritis and one of the most extensively studied medications in the field of autoimmune disease. The World Health Organization (WHO) includes methotrexate on its Model List of Essential Medicines, recognizing it as one of the most efficacious, safe, and cost-effective medications available for priority health conditions.
At the molecular level, methotrexate exerts its effects through several interconnected mechanisms. Its primary mechanism involves inhibition of dihydrofolate reductase (DHFR), an enzyme essential for the conversion of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is a cofactor required for the synthesis of purine and pyrimidine nucleotides, which are the building blocks of DNA and RNA. By blocking this pathway, methotrexate reduces the proliferation of rapidly dividing cells, including activated lymphocytes (immune cells) that drive the inflammatory process in autoimmune diseases. However, at the low doses used in rheumatology and dermatology (typically 7.5–25 mg per week), methotrexate also acts through additional anti-inflammatory mechanisms, most notably by increasing extracellular concentrations of adenosine. Adenosine is a powerful endogenous anti-inflammatory molecule that suppresses the production of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), while also inhibiting neutrophil chemotaxis and adhesion to endothelial cells.
The Methotrexate Accord formulation is specifically designed for subcutaneous injection and is available as a pre-filled injector. This delivery method offers several clinical advantages over oral methotrexate tablets. Subcutaneous administration provides significantly higher and more consistent bioavailability, particularly at doses above 15 mg per week. Studies have shown that oral methotrexate bioavailability plateaus at approximately 15 mg due to a saturable absorption mechanism in the gastrointestinal tract, whereas subcutaneous injection achieves near-complete absorption regardless of dose. This means that patients who have had an inadequate response to oral methotrexate may benefit from switching to the subcutaneous route before escalating to biologic therapies, a strategy endorsed by the European Alliance of Associations for Rheumatology (EULAR) guidelines.
Methotrexate Accord is indicated for the following conditions:
- Active rheumatoid arthritis (RA) in adults: Methotrexate is the first-line DMARD for RA, as recommended by EULAR, the American College of Rheumatology (ACR), and the British Society for Rheumatology (BSR). It reduces joint inflammation, slows radiographic progression of joint damage, and improves physical function and quality of life. Clinical response is typically observed within 4–8 weeks, with maximum benefit achieved after 3–6 months of treatment.
- Severe psoriasis (psoriasis vulgaris) in adults: When psoriasis is extensive, disabling, or has failed to respond adequately to other systemic treatments such as phototherapy, retinoids, or ciclosporin, methotrexate is an effective treatment option. It reduces the rate of skin cell proliferation and the associated inflammatory process, leading to clearing or significant improvement of psoriatic plaques.
- Polyarthritic forms of severe, active juvenile idiopathic arthritis (JIA): In children and adolescents who have not responded adequately to nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate is the first-line DMARD for polyarticular JIA, with evidence supporting its efficacy from multiple randomized controlled trials.
The clinical evidence supporting methotrexate in rheumatoid arthritis is extensive and robust. A landmark Cochrane systematic review (Lopez-Olivo et al., 2014) analyzing data from over 70 randomized controlled trials confirmed that methotrexate significantly improves clinical outcomes in RA, including reductions in swollen and tender joint counts, inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), patient and physician global assessments, and functional disability scores. Furthermore, long-term observational studies spanning decades of clinical use have demonstrated that methotrexate is associated with sustained clinical benefits, reduced cardiovascular mortality, and improved long-term outcomes compared with patients not receiving DMARD therapy.
Research published in the Annals of the Rheumatic Diseases has shown that switching from oral to subcutaneous methotrexate can improve clinical response in up to 30% of patients who had inadequate response to oral therapy. The subcutaneous route also tends to produce fewer gastrointestinal side effects such as nausea and vomiting. EULAR guidelines now recommend considering subcutaneous administration before concluding that methotrexate has failed and escalating to biologic DMARDs.
What Should You Know Before Taking Methotrexate Accord?
Contraindications
Methotrexate Accord must not be used in the following circumstances. These are absolute contraindications, meaning the medication should never be given to patients with these conditions regardless of the potential benefits:
- Hypersensitivity: Known allergy to methotrexate or any of the excipients (inactive ingredients) in the formulation.
- Pregnancy and breastfeeding: Methotrexate is teratogenic (causes birth defects) and embryotoxic (can cause miscarriage). It is classified as pregnancy category X by the FDA and is absolutely contraindicated during pregnancy and breastfeeding.
- Severe hepatic impairment: Patients with significant liver disease, including alcoholic liver disease, chronic hepatitis B or C, or pre-existing hepatic fibrosis or cirrhosis, should not receive methotrexate due to the risk of further hepatotoxicity.
- Severe renal impairment: Since methotrexate is primarily excreted by the kidneys (80–90% unchanged), significant renal impairment (creatinine clearance below 20 mL/min) leads to dangerous accumulation and increased toxicity risk.
- Pre-existing blood dyscrasias: Patients with clinically significant bone marrow suppression (leukopenia, thrombocytopenia, or anemia) should not start methotrexate, as it further suppresses bone marrow function.
- Active serious infections: Including tuberculosis, HIV, and hepatitis B or C. Methotrexate suppresses the immune system and can worsen infections.
- Severe immunodeficiency syndromes: Patients with existing severe immune system compromise are at heightened risk of opportunistic infections.
- Mouth ulcers or active gastrointestinal ulcer disease: Pre-existing mucosal damage is worsened by methotrexate.
- Excessive alcohol consumption: Due to synergistic hepatotoxicity.
Warnings and Precautions
Methotrexate for rheumatoid arthritis and psoriasis is taken ONCE WEEKLY, not daily. Accidental daily dosing of methotrexate has resulted in fatal toxicity due to severe bone marrow suppression, sepsis, and multi-organ failure. This remains one of the most common and serious medication errors worldwide. Always confirm your dosing schedule with your doctor or pharmacist, and choose a specific day of the week as your “methotrexate day.”
Before starting methotrexate and regularly during treatment, your doctor will perform the following monitoring tests:
- Full blood count (FBC): To check white blood cells, red blood cells, and platelets. Methotrexate can suppress bone marrow production of all blood cell types (pancytopenia).
- Liver function tests (LFTs): Including ALT, AST, albumin, and bilirubin. Methotrexate can cause liver inflammation and, rarely, liver fibrosis with long-term use.
- Renal function: Including serum creatinine and estimated glomerular filtration rate (eGFR). Impaired kidney function increases the risk of methotrexate accumulation and toxicity.
- Chest X-ray: Baseline assessment, particularly if there is a history of lung disease. Methotrexate can rarely cause pneumonitis (lung inflammation).
- Hepatitis B and C serology: To rule out active viral hepatitis before immunosuppressive therapy.
Monitoring frequency varies by guideline but typically follows this pattern: full blood count, liver enzymes, and renal function are checked every 1–2 weeks during dose initiation and for the first 6 weeks, then monthly until the dose is stabilized, and every 2–3 months thereafter for the duration of treatment. Any dose increase should be followed by more frequent monitoring. The British Society for Rheumatology (BSR) DMARD monitoring guidelines provide detailed protocols that are widely adopted internationally.
Methotrexate pneumonitis is a rare but potentially serious adverse reaction that can occur at any time during treatment. Symptoms include dry cough, progressive shortness of breath, fever, and malaise. If you develop any unexplained respiratory symptoms while taking methotrexate, stop taking the medication and seek urgent medical attention. Early recognition and discontinuation of methotrexate, combined with corticosteroid treatment, typically leads to resolution.
Pregnancy and Breastfeeding
Methotrexate is strictly contraindicated during pregnancy. It is classified as a known human teratogen based on extensive evidence from clinical case reports and animal studies. Methotrexate exposure during pregnancy, particularly during the first trimester, can cause a pattern of birth defects known as “fetal methotrexate syndrome,” which includes craniofacial abnormalities, limb defects, growth restriction, and central nervous system abnormalities. Methotrexate is also embryotoxic and can cause spontaneous abortion at therapeutic doses — indeed, it is used clinically to manage ectopic pregnancy for this reason.
Women of childbearing potential must use reliable contraception during methotrexate treatment and for at least 6 months after the last dose. A pregnancy test should be performed before starting treatment. Men should also use contraception during methotrexate therapy and for at least 3 months after the last dose, although the evidence regarding male-mediated teratogenicity is less definitive. Recent systematic reviews suggest the risk of birth defects from paternal methotrexate use is likely very low, but a washout period remains the standard recommendation as a precautionary measure.
Methotrexate is excreted in breast milk and is contraindicated during breastfeeding. If methotrexate therapy is essential, breastfeeding must be discontinued.
Fertility
Methotrexate can impair fertility in both men and women. In women, it may cause menstrual irregularities and, at higher doses, ovarian suppression. In men, methotrexate may temporarily reduce sperm count and quality (oligospermia). These effects are generally reversible after discontinuation of the drug. Patients who wish to conceive should discuss timing of discontinuation with their rheumatologist, as the recommended washout period is 6 months for women and 3 months for men after the last dose.
How Does Methotrexate Accord Interact with Other Drugs?
Drug interactions with methotrexate are clinically important because many of the interacting medications are commonly used. Unlike monoclonal antibodies, methotrexate is a small molecule that is subject to traditional pharmacokinetic interactions affecting absorption, distribution, protein binding, metabolism, and renal excretion. The primary concern with most interactions is increased methotrexate exposure leading to enhanced toxicity, particularly bone marrow suppression and mucosal damage.
Major Interactions
| Drug/Class | Mechanism | Clinical Effect | Recommendation |
|---|---|---|---|
| NSAIDs (ibuprofen, naproxen, diclofenac) | Reduced renal excretion of methotrexate; displacement from protein binding | Increased methotrexate toxicity, particularly at higher doses | Use with caution; monitor blood counts and renal function closely. Low-dose NSAIDs with low-dose MTX is generally safe with monitoring |
| Trimethoprim / Sulfamethoxazole | Additive antifolate effect; reduced renal tubular secretion of methotrexate | Severe pancytopenia (potentially fatal) | Avoid combination. Use alternative antibiotics (e.g., amoxicillin for UTI) |
| Proton pump inhibitors (omeprazole, lansoprazole) | Inhibition of renal tubular secretion via H+/K+-ATPase | Delayed methotrexate elimination; increased toxicity risk | Consider H2 blockers (ranitidine) as alternative; monitor if PPI is essential |
| Penicillins (amoxicillin, piperacillin) | Reduced renal tubular secretion of methotrexate | Delayed methotrexate excretion; increased toxicity | Monitor blood counts if co-administered; consider alternative antibiotics |
| Leflunomide | Additive hepatotoxicity; additive immunosuppression | Increased risk of liver damage and pancytopenia | Combination sometimes used under specialist supervision with enhanced monitoring |
| Live vaccines (MMR, varicella, BCG, yellow fever) | Immunosuppression reduces immune response and may allow vaccine virus replication | Risk of disseminated vaccine infection; reduced vaccine efficacy | Contraindicated during treatment. Inactivated vaccines can be given but may have reduced efficacy |
| Phenytoin | Methotrexate displaces phenytoin from protein binding | Increased free phenytoin levels; risk of toxicity | Monitor phenytoin levels and adjust dose if needed |
Minor Interactions and Considerations
Several additional drug interactions warrant awareness, although they are generally manageable with appropriate monitoring:
- Folic acid: High-dose folic acid supplementation may theoretically reduce methotrexate efficacy by competing for the same metabolic pathways. However, at the standard supplemental doses used in clinical practice (5 mg weekly), folic acid does not appear to diminish the therapeutic effects of methotrexate in RA or psoriasis, as demonstrated in the landmark FOLVARI trial and multiple systematic reviews.
- Alcohol: Although not a traditional drug interaction, alcohol significantly increases the risk of methotrexate hepatotoxicity. The ACR guidelines recommend limiting alcohol intake, and many rheumatologists advise abstinence or minimal consumption.
- Theophylline: Methotrexate may increase serum theophylline levels by reducing renal clearance. Theophylline levels should be monitored if the combination is necessary.
- Ciclosporin: Concurrent use increases the risk of nephrotoxicity and methotrexate toxicity. Monitoring of both drug levels and renal function is essential if the combination is used.
- Hepatotoxic drugs: Other medications that can cause liver damage (e.g., azathioprine, retinoids, sulfasalazine) should be used cautiously with methotrexate, and liver function should be monitored more frequently.
Always carry an up-to-date medication list and inform any new healthcare providers (including dentists and pharmacists) that you are taking methotrexate. Some commonly purchased over-the-counter medications, such as ibuprofen, can affect methotrexate levels. If you need pain relief, paracetamol (acetaminophen) is generally considered the safest option in standard doses for patients on low-dose methotrexate, although your doctor should be consulted for personalized advice.
What Is the Correct Dosage of Methotrexate Accord?
Methotrexate Accord should always be used exactly as prescribed by your doctor. The dosing regimen is individualized based on the condition being treated, your body weight, kidney function, disease severity, and how you respond to the medication. The pre-filled injector is designed for subcutaneous (under the skin) self-injection after appropriate training from a healthcare professional.
Adults — Rheumatoid Arthritis
| Phase | Dose | Frequency | Notes |
|---|---|---|---|
| Starting dose | 7.5–10 mg | Once weekly | Some guidelines recommend starting at 15 mg/week for faster onset |
| Dose escalation | Increase by 2.5–5 mg | Every 2–4 weeks | Based on disease response and tolerability |
| Usual maintenance | 15–25 mg | Once weekly | Most patients achieve optimal response at 15–20 mg/week |
| Maximum dose | 25–30 mg | Once weekly | Doses above 25 mg do not provide additional efficacy (ceiling effect) |
The EULAR 2022 updated recommendations for RA management emphasize that methotrexate should be rapidly escalated to 25 mg weekly (preferably subcutaneously) within the first 4–8 weeks if the initial dose does not provide adequate disease control. This “treat-to-target” strategy aims to achieve remission or low disease activity as rapidly as possible to prevent irreversible joint damage. Clinical response is typically assessed at 3 months using validated composite measures such as DAS28, CDAI, or SDAI, and again at 6 months to determine whether treatment modification is needed.
Adults — Psoriasis
For severe psoriasis, methotrexate is usually started at a dose of 7.5–10 mg once weekly, with gradual dose escalation based on clinical response. The usual maintenance dose is 7.5–22.5 mg once weekly. A test dose of 2.5–5 mg may be given initially to assess for adverse reactions before proceeding to the full starting dose. Clinical improvement in psoriasis may take 4–8 weeks to become apparent, with full benefit typically achieved after 3–4 months of therapy.
Children — Juvenile Idiopathic Arthritis
In children with polyarticular juvenile idiopathic arthritis, the recommended dose is 10–15 mg per square meter of body surface area (mg/m²) once weekly. Your child’s rheumatologist will calculate the exact dose based on the child’s weight and height. The subcutaneous route is often preferred in children due to improved bioavailability and reduced gastrointestinal side effects compared with oral administration. Folic acid supplementation is also recommended for children on methotrexate.
Elderly Patients
Older adults may be more susceptible to methotrexate toxicity due to age-related decline in renal function, reduced folate stores, and more frequent polypharmacy. The BSR guidelines recommend starting at a lower dose (e.g., 7.5 mg weekly) and escalating cautiously, with renal function closely monitored. Elderly patients should have their creatinine clearance calculated before starting methotrexate and at regular intervals, as serum creatinine alone may not accurately reflect kidney function in this population.
Missed Dose
If you miss your weekly dose, take it as soon as you remember, provided it is within 2 days of the scheduled dose. If more than 2 days have passed, skip the missed dose and take the next dose on your usual day. Never take a double dose to make up for a forgotten injection. Using a weekly reminder (phone alarm, calendar mark, or medication diary) is strongly recommended to help maintain consistent dosing.
Overdose
Methotrexate overdose, whether accidental (e.g., daily instead of weekly dosing) or intentional, is a medical emergency requiring immediate hospital treatment. The specific antidote is calcium folinate (folinic acid, leucovorin), which must be given as soon as possible. Folinic acid rescues normal cells from the toxic effects of methotrexate by providing an alternative source of reduced folate. If you suspect an overdose, call your local emergency number or poison control center immediately.
Symptoms of methotrexate toxicity include severe mouth ulcers, vomiting, diarrhea, black or bloody stools, fever, signs of infection (due to low white blood cells), unusual bruising or bleeding (due to low platelets), extreme fatigue, jaundice (yellowing of skin or eyes), and dark urine. In severe cases, methotrexate toxicity can lead to fulminant bone marrow failure, sepsis, renal failure, and death. The risk is highest in the first days to weeks of accidental daily dosing, in patients with impaired renal function, and in patients concurrently taking drugs that increase methotrexate levels.
What Are the Side Effects of Methotrexate Accord?
Like all medicines, methotrexate can cause side effects, although not everybody gets them. The side effect profile of methotrexate is well characterized from decades of clinical use in millions of patients worldwide. Most side effects are mild and manageable, particularly with appropriate monitoring and folic acid supplementation. However, some potentially serious adverse effects require prompt medical attention. The frequency classifications below follow the standard European Medicines Agency (EMA) convention.
Very Common
Affects more than 1 in 10 people
- Nausea (up to 30% of patients; often worst in the first 24–48 hours after dosing)
- Elevated liver enzymes (transaminases ALT/AST) — usually mild and transient
- Loss of appetite (anorexia)
- Stomatitis (mouth ulcers/inflammation)
- Fatigue and malaise
Common
Affects 1 in 10 to 1 in 100 people
- Diarrhea
- Headache
- Leukopenia (low white blood cells)
- Thrombocytopenia (low platelets)
- Anemia
- Injection site reactions (redness, swelling, itching)
- Dizziness
- Hair thinning (alopecia) — usually mild and reversible
- Skin rash
- Abdominal pain
Uncommon
Affects 1 in 100 to 1 in 1,000 people
- Pneumonitis (lung inflammation) — dry cough, breathlessness, fever
- Liver fibrosis or cirrhosis (with long-term use)
- Pancytopenia (suppression of all blood cell types)
- Photosensitivity (increased skin sensitivity to sunlight)
- Increased susceptibility to infections (due to immunosuppression)
- Renal impairment
- Mood changes, depression
Rare
Affects fewer than 1 in 1,000 people
- Severe bone marrow failure (aplastic anemia)
- Opportunistic infections (Pneumocystis jirovecii pneumonia, herpes zoster dissemination)
- Lymphoproliferative disorders (methotrexate-associated lymphoma — often reversible upon discontinuation)
- Stevens-Johnson syndrome or toxic epidermal necrolysis
- Severe hepatotoxicity or acute liver failure
- Anaphylactic reaction
- Osteoporosis (with long-term use)
- Impaired fertility (oligospermia in men)
The risk of many side effects can be significantly reduced through appropriate folic acid supplementation, regular blood monitoring, and dose adjustment. A Cochrane systematic review by Shea et al. confirmed that folic acid supplementation reduces the incidence of gastrointestinal side effects (nausea, vomiting, abdominal pain), liver enzyme elevations, and stomatitis by approximately 30–80%, depending on the specific side effect. Despite this substantial evidence, folic acid remains underprescribed in some settings.
Nausea is the most commonly reported side effect and the most frequent reason patients discontinue methotrexate. Strategies to manage methotrexate-related nausea include: taking the injection in the evening before bed, taking anti-nausea medication (ondansetron or prochlorperazine) on the day of injection, ensuring adequate hydration, splitting folic acid supplementation across multiple days of the week, and switching from oral to subcutaneous administration (which typically reduces gastrointestinal side effects).
Contact your doctor or seek emergency care immediately if you experience: unexplained fever or signs of infection (sore throat, chills); unusual bruising or bleeding; severe mouth ulcers; persistent dry cough or shortness of breath; yellowing of the skin or eyes (jaundice); black or bloody stools; or severe skin rash. These may indicate serious methotrexate toxicity requiring immediate medical intervention.
How Should You Store Methotrexate Accord?
Proper storage of Methotrexate Accord is important to ensure the medication remains effective and safe for use. As a cytotoxic (cell-damaging) medication, methotrexate requires careful handling in addition to appropriate storage conditions.
- Temperature: Store below 25°C (77°F). Do not refrigerate or freeze. Freezing can damage the pre-filled injector mechanism and alter the solution.
- Light protection: Keep the pre-filled injector in its original carton to protect from light. Methotrexate is sensitive to light and can degrade if exposed to prolonged direct sunlight or strong artificial light.
- Keep out of reach of children: Methotrexate is a cytotoxic medication and is particularly dangerous if accidentally ingested by children. Store in a secure location.
- Expiry date: Do not use Methotrexate Accord after the expiry date printed on the carton and pre-filled injector label. The expiry date refers to the last day of that month.
- Visual inspection: Before each use, inspect the solution through the viewing window of the pre-filled injector. The solution should be clear and yellow. Do not use if the solution is cloudy, discolored, or contains visible particles.
Disposal of used pre-filled injectors should follow local cytotoxic waste disposal guidelines. Do not throw used injectors in household waste or recycling. In most healthcare systems, your pharmacy or doctor can provide a sharps disposal container. If methotrexate solution comes into contact with the skin, wash the affected area immediately with soap and water. If it contacts the eyes, rinse thoroughly with water and seek medical advice.
What Does Methotrexate Accord Contain?
Understanding the composition of your medication helps ensure safe use, particularly if you have known allergies or sensitivities to specific ingredients.
- Active ingredient: Methotrexate 7.5 mg per pre-filled injector
- Excipients (inactive ingredients):
- Sodium chloride — used to adjust the osmolality (salt concentration) of the solution to make it compatible with body tissues
- Sodium hydroxide — used to adjust the pH (acidity) of the solution
- Water for injections — the solvent for the solution
Methotrexate Accord contains sodium. Each pre-filled injector contains less than 1 mmol (23 mg) of sodium per dose, meaning it is essentially “sodium-free.” This is relevant for patients on a sodium-restricted diet due to conditions such as heart failure or hypertension.
The pre-filled injector is a single-use medical device designed for subcutaneous self-injection. It contains a pre-set dose of methotrexate solution and is equipped with a spring-loaded mechanism that automatically delivers the injection when activated. The needle is concealed before and after injection to reduce needle-stick injuries and needle phobia. Each injector is for single use only and should be disposed of immediately after use in an appropriate sharps container.
Frequently Asked Questions About Methotrexate Accord
Methotrexate Accord is a disease-modifying antirheumatic drug (DMARD) used to treat active rheumatoid arthritis in adults, severe psoriasis that has not responded to other treatments, and polyarthritic forms of severe juvenile idiopathic arthritis. It works by modifying the immune system to reduce inflammation and slow disease progression. Methotrexate is considered the first-line DMARD for rheumatoid arthritis by all major international rheumatology guidelines, including EULAR, ACR, and BSR.
Methotrexate Accord is injected once a week, always on the same day of the week. This is critical to understand — methotrexate must never be taken daily, as this can cause fatal toxicity. Choose a day that works best for your schedule (many patients choose a Friday or Saturday evening so they can rest during any post-injection nausea), and set a weekly reminder on your phone or calendar.
Alcohol should be avoided or significantly reduced while taking methotrexate. Both substances are processed by the liver, and combining them increases the risk of liver damage (hepatotoxicity). Most rheumatologists advise either complete abstinence or very limited, occasional consumption (e.g., no more than 1–2 units per week). Your doctor will monitor your liver function through regular blood tests and can give you personalized advice based on your liver health.
Folic acid is prescribed alongside methotrexate because methotrexate works by interfering with folic acid metabolism. Supplementing with folic acid (typically 5 mg once a week on a different day from your methotrexate injection) helps protect your normal cells and significantly reduces common side effects including nausea, mouth ulcers, and liver enzyme elevations. Multiple clinical studies have confirmed that folic acid supplementation does not reduce the effectiveness of methotrexate for treating arthritis or psoriasis.
Methotrexate is a slow-acting medication. You may start to notice some improvement in symptoms within 4–6 weeks, but the full therapeutic effect typically takes 3–6 months. It is important to continue taking methotrexate as prescribed even if you do not notice immediate improvement. Your rheumatologist will assess your response at 3 months and may adjust the dose or add additional medications if needed. Many patients continue methotrexate for years once a good response is achieved.
Subcutaneous methotrexate offers several advantages over oral tablets. It provides higher and more consistent bioavailability (especially at doses above 15 mg), causes fewer gastrointestinal side effects (nausea and vomiting), and may produce a better clinical response. Research published in the Annals of the Rheumatic Diseases showed that up to 30% of patients who had an inadequate response to oral methotrexate improved after switching to the subcutaneous route. The main disadvantage is that it requires injection, although the pre-filled injector device makes self-administration straightforward.
References
- European Medicines Agency (EMA). Methotrexate Accord – Summary of Product Characteristics. Updated 2025. Available at: www.ema.europa.eu
- Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18. doi:10.1136/ard-2022-223356
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res. 2021;73(7):924-939. doi:10.1002/acr.24596
- Ledingham J, Gullick N, Irving K, et al. BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs. Rheumatology. 2017;56(6):865-868. doi:10.1093/rheumatology/kew479
- Lopez-Olivo MA, Siddhanamatha HR, Shea B, et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;(6):CD000957. doi:10.1002/14651858.CD000957.pub2
- Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;(5):CD000951. doi:10.1002/14651858.CD000951.pub2
- Braun J, Kästner P, Flaxenberg P, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis. Arthritis Rheum. 2008;58(1):73-81. doi:10.1002/art.23144
- World Health Organization (WHO). Model List of Essential Medicines – 23rd edition. Geneva: WHO; 2023.
- Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68(7):1094-1099. doi:10.1136/ard.2008.092668
- British National Formulary (BNF). Methotrexate. National Institute for Health and Care Excellence (NICE). Updated 2025. Available at: bnf.nice.org.uk
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