What is the difference between osteoarthritis and rheumatoid arthritis?
To understand why a medication like methotrexate may or may not be effective for osteoarthritis (OA), it is crucial to first distinguish it from rheumatoid arthritis (RA). While both conditions cause joint pain, their underlying causes and biological mechanisms are fundamentally different:
- Osteoarthritis (OA): This is a degenerative joint disease, often referred to as "wear-and-tear" arthritis. It occurs when the cartilage that cushions the ends of bones wears down over time, leading to bone-on-bone friction, pain, and stiffness. While some inflammation can be present, it is not the primary driver of the disease process.
- Rheumatoid Arthritis (RA): This is an autoimmune disease in which the body's immune system mistakenly attacks the lining of the joints (the synovium), causing painful inflammation. Methotrexate, a disease-modifying anti-rheumatic drug (DMARD), works by suppressing the overactive immune response that causes this inflammation.
Shifting perspectives: Research on methotrexate for osteoarthritis
Given methotrexate's success in treating RA, researchers have long explored its potential for managing OA, especially in patients with signs of inflammation like synovitis (inflamed joint lining). The evidence, however, has been mixed and has prompted differing guideline recommendations.
Promising findings for hand and knee OA
Several recent studies suggest a potential benefit, particularly for subsets of OA patients:
- Hand Osteoarthritis: A 2023 study published in The Lancet found that methotrexate (20mg weekly) moderately reduced pain and stiffness over six months in patients with symptomatic hand OA and synovitis. This was seen as a proof-of-concept that targeting inflammation could work for some hand OA patients.
- Knee Osteoarthritis: A 2024 randomized controlled trial suggested that oral methotrexate could reduce knee pain, stiffness, and improve function at six months for patients with knee OA. Another meta-analysis also concluded that methotrexate could help alleviate pain in OA patients (both hand and knee) and improve knee function.
Contradictory and discouraging results
Not all research supports the use of methotrexate for OA. The MESKO trial, published in June 2025, studied patients with inflammatory knee OA. It found no significant difference between the methotrexate group and the placebo group in reducing pain or effusion-synovitis over 52 weeks. This contradicts the earlier promising findings and highlights the inconsistency in the evidence.
Methotrexate for osteoarthritis vs. rheumatoid arthritis: A comparison
| Feature | Osteoarthritis (OA) | Rheumatoid Arthritis (RA) |
|---|---|---|
| Underlying Cause | Degenerative joint disease from cartilage breakdown. | Autoimmune disorder where the immune system attacks joint linings. |
| Medication Classification | Methotrexate is an off-label use for a select subgroup with inflammatory features. | Methotrexate is a standard, first-line, and FDA-approved DMARD. |
| Efficacy Profile | Mixed results, with some studies showing modest benefits for specific subgroups (e.g., hand OA with synovitis), but not universally effective. | Well-established and effective at reducing inflammation, joint damage, and symptoms. |
| Mechanism of Action | Thought to target the inflammatory component of OA, likely mediated by adenosine. | Suppresses the overactive immune system to reduce systemic inflammation. |
| Standard Treatment | Lifestyle modifications (weight loss, exercise), NSAIDs (oral or topical), and injections. | Methotrexate is a primary treatment, often combined with other DMARDs or biologics. |
| Clinical Guidelines | Major organizations like the American College of Rheumatology have historically recommended against methotrexate for OA. | Strongly recommended as a cornerstone of treatment by major rheumatology bodies. |
Understanding the risks and side effects of methotrexate
Even at the lower doses used for rheumatic diseases, methotrexate comes with significant risks and requires careful monitoring. Key side effects include:
- Gastrointestinal Issues: Nausea, vomiting, diarrhea, and mouth sores are common, though often manageable with a folic acid supplement.
- Liver Toxicity: Long-term use can lead to liver damage. Regular blood tests are required to monitor liver function.
- Increased Infection Risk: As an immunosuppressant, methotrexate can weaken the immune system, making individuals more susceptible to infections.
- Lung and Kidney Issues: Rare but serious side effects can include lung and kidney problems.
- Pregnancy Concerns: Methotrexate is contraindicated in pregnancy due to the risk of severe birth defects.
Alternative and guideline-recommended treatments for osteoarthritis
Before considering an off-label drug like methotrexate, patients should explore standard, evidence-based treatments for OA. The American College of Rheumatology (ACR) and other bodies recommend a range of effective therapies:
- Nonpharmacologic interventions:
- Weight loss: Losing even a small amount of weight can significantly reduce stress on weight-bearing joints like the knees and hips.
- Exercise: Strength training and low-impact aerobic exercises, such as swimming or cycling, can improve pain and function.
- Physical therapy: A physical therapist can provide tailored exercises and techniques to improve joint function.
- Pharmacologic therapies:
- Topical NSAIDs: Gels and creams containing nonsteroidal anti-inflammatory drugs (NSAIDs) can be applied directly to the affected joint, offering pain relief with fewer systemic side effects than oral NSAIDs.
- Oral NSAIDs: Pills like ibuprofen and naproxen are effective for pain and inflammation but carry a higher risk of gastrointestinal and cardiovascular side effects, particularly with long-term use.
- Intra-articular Corticosteroid Injections: Injections into the joint can provide temporary but potent pain relief, especially during flare-ups.
- Supplements:
- Glucosamine and Chondroitin: Guidelines have provided inconsistent recommendations for these supplements, with some recommending against them due to insufficient evidence of effectiveness in studies without industry funding.
Conclusion: Weighing the evidence on methotrexate for osteoarthritis
For the vast majority of individuals with osteoarthritis, methotrexate is not a standard treatment and is not recommended by major rheumatology guidelines like those from the ACR. Its role, if any, is limited to a small, select subset of patients with specific inflammatory features who have not responded to conventional therapies. Furthermore, its off-label use must be weighed against its significant side effect profile and the requirement for consistent medical monitoring.
The ongoing research into its potential benefits, particularly in inflammatory hand OA, highlights a shifting understanding of OA as a purely degenerative disease. However, the conflicting results from trials like MESKO, which showed no benefit for knee OA, emphasize that there is no universal answer. Patients should prioritize established and safer treatment options and discuss all possibilities, risks, and benefits with a rheumatology specialist.
For more information on recommended treatments for arthritis, please consult the resources from the Arthritis Foundation.
