Methotrexate for Joint Pain

Overseen By Michael Kolinsky

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must be taking: Hydroxychloroquine, Prednisone

Must not be taking: Immunosuppressives, Corticosteroids

Disqualifiers: Rheumatoid arthritis, Lupus, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate methotrexate's effectiveness in treating joint pain, stiffness, and swelling caused by cancer treatments that affect the immune system. Current treatments often involve stopping cancer therapy and using prednisone, a steroid with potential side effects. Methotrexate may offer a better alternative. The trial seeks individuals who have developed significant joint pain during cancer treatments and did not respond well to hydroxychloroquine, another treatment for this condition. Participants should have cancer, be receiving specific cancer therapies, and struggle with treatment-related joint issues. As a Phase 2 trial, this research focuses on assessing methotrexate's effectiveness in an initial, smaller group, offering participants a chance to potentially benefit from a promising treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it allows the use of prednisone and hydroxychloroquine as part of the study or standard care. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that methotrexate is likely to be safe for humans?

Research shows that methotrexate is generally well-tolerated by people with joint problems. Studies have found it to be a reliable option for reducing pain and improving joint function, especially for conditions like rheumatoid arthritis and osteoarthritis. The most common side effects involve the stomach, but these are usually manageable.

Using methotrexate at low doses over a long period has proven safe, with serious side effects being rare when used correctly. Its long history of use for other conditions suggests safety for many people.

While methotrexate is not perfect, it offers a possible alternative to steroids like prednisone, which can have more serious side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Methotrexate is unique because, unlike other treatments for joint pain that primarily focus on symptom relief, it targets the underlying inflammation process directly. Most treatments for joint pain, such as NSAIDs or corticosteroids, provide temporary relief by reducing inflammation symptoms, but methotrexate works by altering immune system activity to prevent inflammation from occurring in the first place. Researchers are excited about methotrexate because it has the potential to provide more long-lasting relief and improve joint health over time. Additionally, it's paired with folic acid to minimize side effects and prednisone to offer immediate relief, making this combination both comprehensive and strategic.

What evidence suggests that methotrexate might be an effective treatment for inflammatory joint pain?

Research has shown that methotrexate can greatly reduce pain and improve joint function. In one study, patients experienced significantly less pain, leading to a better quality of life. Another study found that methotrexate helped reduce pain and improve joint function over time. This treatment effectively eases joint pain, making it a promising option for those who don't find relief from other treatments like hydroxychloroquine. Overall, methotrexate appears to be an effective treatment for joint pain caused by cancer treatments. ^{3 6 7 8 9}

Who Is on the Research Team?

Michael Kolinsky

Principal Investigator

AHS-CCI

Are You a Good Fit for This Trial?

This trial is for adults with cancer who developed arthritis or joint pain from immune-targeting cancer treatments. They must have tried hydroxychloroquine without success, or still need steroids after 3 months. Participants should be over 18, able to consent, and have a decent performance status (ECOG 0-2). Their kidneys must function well, blood counts within normal ranges, and liver tests normal.

Inclusion Criteria

I am able to understand and agree to the study's requirements.

My kidney function, measured by creatinine levels or clearance, is within normal range.

I was on hydroxychloroquine for my condition or in the IMPACT 2.0 trial and had a significant reaction or still need steroids after 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Methotrexate 20 mg PO weekly for 12 weeks, with folic acid 1mg PO daily and prednisone starting at 20 mg PO daily for 8 weeks tapering dose

12 weeks

Weekly visits for methotrexate administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of cytokine profiles, immunophenotyping, and musculoskeletal ultrasound

4 weeks

2 visits (in-person)

Long-term follow-up

Participants are monitored for progression-free survival and other long-term outcomes

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Methotrexate

Trial Overview The IMPACT 2.1 study is testing methotrexate as a treatment for inflammatory joint pain in patients who didn't respond well to hydroxychloroquine or are on long-term steroids due to side effects from certain cancer immunotherapies.

How Is the Trial Designed?

Group I: Single Arm Experimental Treatment 1 Intervention

Methotrexate 20 mg PO weekly for 12 weeks. Folic acid 1mg PO daily for as long as Methotrexate is given. Prednisone starting at 20 mg PO daily for 8 weeks tapering dose.

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Published Research Related to This Trial

The PROMOTE trial is a phase III study involving 160 participants with symptomatic knee osteoarthritis, testing the efficacy of methotrexate (MTX) to reduce pain and synovitis over 12 months.

The trial aims to determine if MTX can effectively alleviate knee pain by targeting synovitis, with MRI assessments planned to explore the relationship between synovitis reduction and symptom improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial. Kingsbury, SR., Tharmanathan, P., Arden, NK., et al.[2022]

Methotrexate is the most well-studied and effective first-line treatment for rheumatoid arthritis, providing pain relief and functional improvement at doses of 7.5 mg to 25 mg per week, with infrequent treatment withdrawals due to side effects.

Combining methotrexate with TNF-alpha antagonists like etanercept or adalimumab can enhance treatment effectiveness in severe cases, although this combination may carry a higher risk of severe adverse effects and requires more complex administration compared to methotrexate alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rheumatoid arthritis: choice of antirheumatic treatment. Methotrexate first. [2015]

Methotrexate shows a success rate of 39% to 88% in treating rheumatoid arthritis patients who do not respond to other treatments, indicating its potential efficacy as a second-line therapy.

While methotrexate can cause mild side effects that often resolve with dose adjustments, it carries a risk of serious reactions like pneumonitis and should be used cautiously in fertile individuals due to possible teratogenic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Methotrexate in rheumatoid arthritis]. Alamo, M., Grisanti, M.[2013]

Methotrexate is an effective treatment for severe rheumatoid arthritis and is often used as a first-line therapy due to its good tolerance and patient compliance, even when used alone or in combination with other drugs.

While methotrexate shows promise for treating severe corticosteroid-dependent asthma and other autoimmune diseases, its efficacy in these areas still needs further confirmation, but it generally has a good safety profile with reversible side effects upon discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Non-cancer uses of methotrexate]. Brion, N., Paule, B.[2017]

In a study of 110 patients with undifferentiated arthritis, those treated with methotrexate (MTX) showed a lower progression to rheumatoid arthritis (RA) compared to those on placebo, with 40% versus 53% progression rates, respectively.

MTX not only delayed the diagnosis of RA in patients but also resulted in less radiographic joint damage over 18 months, indicating its efficacy in managing undifferentiated arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. van Dongen, H., van Aken, J., Lard, LR., et al.[2022]

Methotrexate is an effective treatment for psoriatic arthritis, supported by a substantial body of evidence demonstrating its benefits in managing the condition.

The review highlights both the advantages and limitations of methotrexate, whether used alone or in combination with other disease-modifying antirheumatic drugs (DMARDs) and biological therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of methotrexate in psoriatic arthritis: what is the evidence? Ianculescu, I., Weisman, MH.[2017]

Methotrexate (MTX) is a safe and well-tolerated treatment for rheumatic diseases, showing no confirmed severe pulmonary or liver side effects even under strict safety standards.

The risk of infection with MTX is comparable to other disease-modifying antirheumatic drugs, and long-term use has not shown any mutagenic potential, ensuring its continued importance in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Methotrexate toxicity. Myths and facts]. Keysser, G.[2021]

Low doses of methotrexate do not lead to more adverse effects compared to conventional anti-rheumatic drugs, indicating its safety profile in this context.

However, serious complications like pancytopenia can occur, often triggered by interactions with other medications or conditions that increase cell formation, highlighting the need for careful monitoring and the use of leukovorin when bone marrow suppression is suspected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pancytopenia during low-dosage methotrexate treatment in patients with rheumatoid arthritis]. Nygaard, H.[2013]

A 76-year-old female patient experienced acute liver failure and bone marrow damage while being treated with methotrexate for vertebral joint disease, highlighting the serious risks associated with this medication.

The patient's treatment was not in accordance with medical recommendations, which may have contributed to the adverse effects and ultimately led to her death, emphasizing the importance of adhering to prescribed treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pancytopenia after methotrexate treatment]. Zak, K., Prystupa, A., Dybała, A., et al.[2013]

In a 16-week study involving 315 patients with rheumatoid arthritis who had an unsatisfactory response to methotrexate (MTX), both etanercept (ETN) monotherapy and etanercept combined with methotrexate (ETN+MTX) were found to be effective in improving patient-reported outcomes such as function, pain, and disease activity.

There were no significant differences in the effectiveness of ETN alone versus ETN+MTX, indicating that both treatment strategies can effectively reduce symptoms and improve overall health in patients with active rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. van Riel, PL., Freundlich, B., MacPeek, D., et al.[2022]

In a study of 10 patients with rheumatoid arthritis who had been on methotrexate for an average of 40 months, stopping the medication led to a significant worsening of their condition within just one month.

The results indicate that long-term benefits from methotrexate are not sustained after discontinuation, highlighting the necessity for ongoing treatment to maintain clinical improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study. Kremer, JM., Rynes, RI., Bartholomew, LE.[2022]

In a 24-week randomized trial with 28 patients suffering from refractory rheumatoid arthritis, oral methotrexate significantly reduced joint pain, morning stiffness, and overall disease activity compared to placebo, indicating its short-term efficacy.

While methotrexate showed beneficial effects, it also had side effects such as transaminase elevation and nausea in some patients, highlighting the need for longer studies to fully assess its safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of low-dose methotrexate in rheumatoid arthritis. Weinblatt, ME., Coblyn, JS., Fox, DA., et al.[2022]

Methotrexate has been shown to provide significant short-term benefits for rheumatoid arthritis patients, with a 26% greater improvement in joint inflammation and a 39% greater reduction in pain compared to controls.

While methotrexate can be effective, about one third of patients may need to stop treatment due to adverse effects, although serious side effects are rare, highlighting the importance of careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Tugwell, P., Bennett, K., Gent, M.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40455462/

Low-Dose Methotrexate for the Treatment of Inflammatory ... The results of this randomized clinical trial show that, compared to placebo, low-dose methotrexate did not reduce pain or effusion-synovitis over 52 weeks.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6712359/

Efficacy of Methotrexate on Pain Severity Reduction and ... The results of this study showed a significant reduction in pain intensity in patients based on NRS and pain subscales of WOMAC, along with improved QOL ...

3. journals.lww.com journals.lww.com/md-journal/fulltext/2025/10100/the_effectiveness_and_safety_of_methotrexate_in.11.aspx

The effectiveness and safety of methotrexate ... Results showed MTX reduced pain and improved joint function compared ... results showed that methotrexate can significantly reduce pain.

4. bmcrheumatol.biomedcentral.com bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-024-00412-8

Predictive factors of methotrexate monotherapy success in ... The rate of MTX monotherapy success in our study was 59.4%. Lower disease activity, normal ESR, normoweight, and fewer tender joints at baseline ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0140673623015726

Methotrexate to treat hand osteoarthritis with synovitis ... In a Cochrane review of seven randomised controlled trials, methotrexate monotherapy (5–25 mg weekly) clinically improved symptoms at 52 weeks and significantly ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9389345/

Safety Profile of Methotrexate Therapy in Patients With ... The purpose of this study is to determine the frequency of different adverse effects of methotrexate therapy in patients with rheumatoid arthritis.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12517922/

The effectiveness and safety of methotrexate in the ... MTX demonstrates potential in effectively alleviating pain, improving joint function, and slowing disease progression in patients with OA. Its safety profile is ...

8. ard.bmj.com ard.bmj.com/content/68/7/1100

Long-term safety of methotrexate monotherapy in patients ... This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.

9. bmcrheumatol.biomedcentral.com bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-024-00381-y

Methotrexate treatment strategies for rheumatoid arthritis In terms of safety, although there was a trend towards increased gastrointestinal toxicity in the higher-dosed group, the percentage of patients ...