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

Trial Summary

What is the purpose of this trial?

Many people develop joint pain, stiffness and swelling due to their cancer treatment that targets the immune system. The severity of symptoms ranges from mild to debilitating and sometimes requires delaying or stopping cancer treatment. The usual plan is to discontinue cancer treatment and give relatively high doses of a medication called prednisone (a steroid, which is an anti-inflammatory medication which may suppress the immune system), with a gradual lowering of the dose over several weeks. While this can be effective, prednisone can cause several side effects, and it is not known if this is the best or safest treatment. Hydroxychloroquine is a medication being studied on IMPACT 2.0 on participants who develop inflammatory joint pain while taking cancer treatments that affect their immune system. It is possible that the hydroxychloroquine treatment may not work well on some participants on IMPACT 2.0. Hydroxychloroquine is also given as standard of care to participants with this type of inflammatory joint pain. The goal of this study is to learn how well methotrexate is at treating inflammatory joint pain in participants from IMPACT 2.0 that don't do well on treatment with hydroxychloroquine and in patients given hydroxychloroquine as standard of care to treat this type of inflammatory joint pain caused by taking cancer treatments which target their immune system.

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.

What data supports the effectiveness of the drug methotrexate for joint pain?

Methotrexate has been shown to help reduce joint pain and inflammation in people with rheumatoid arthritis, with studies indicating improvements in pain and joint swelling compared to those not taking the drug. However, the benefits may decrease over time, and some people may experience side effects. ^{1 2 3 4 5}

Is methotrexate generally safe for humans?

Methotrexate is generally considered safe and well-tolerated for treating rheumatic diseases, but it can have side effects like mild liver issues and rare serious conditions like pancytopenia (a drop in blood cells). It should be used with caution, especially in people taking other medications, and requires regular monitoring. ^{1 6 7 8 9}

How does the drug methotrexate differ from other treatments for joint pain?

Methotrexate is unique for joint pain treatment because it targets synovitis (inflammation of the joint lining), which is common in osteoarthritis and associated with pain. Unlike other treatments, it has a well-established safety profile and is already a gold standard for inflammatory conditions like rheumatoid arthritis, making it a promising option for reducing pain in osteoarthritis. ^{8 10 11 12 13}

Research Team

Michael Kolinsky

Principal Investigator

AHS-CCI

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 (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]

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]

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]

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 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]

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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. [2022]

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy of low-dose methotrexate in rheumatoid arthritis. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

[Methotrexate toxicity. Myths and facts]. [2021]

7. Norway pubmed.ncbi.nlm.nih.gov

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

8. Chile pubmed.ncbi.nlm.nih.gov

[Methotrexate in rheumatoid arthritis]. [2013]

9. Poland pubmed.ncbi.nlm.nih.gov

[Pancytopenia after methotrexate treatment]. [2013]

10. England 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. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[Non-cancer uses of methotrexate]. [2017]

12. France pubmed.ncbi.nlm.nih.gov

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

13. Italy pubmed.ncbi.nlm.nih.gov

The role of methotrexate in psoriatic arthritis: what is the evidence? [2017]