Image shows the word Methotrexate written on a clipboard with pills and a stethoscope

Methotrexate is a disease-modifying drug that is commonly used to tamp down inflammation in people who are newly diagnosed with rheumatoid arthritis or psoriatic arthritis. But could it also be an effective intervention for knee osteoarthritis, which is not a disease driven by systemic inflammation?

New research presented at ACR Convergence 2020, the annual meeting of the American College of Rheumatology, found that adults with primary knee osteoarthritis with some inflammation had significant improvements in levels of inflammation, as well as physical function of the knee, after three months of treatment with oral methotrexate.

Although the latest American College of Rheumatology treatment guidelines for osteoarthritis does not favor methotrexate, this seems to be largely based on evidence related to its use in hand osteoarthritis rather than knee osteoarthritis.

Many people with knee osteoarthritis have clinical signs of inflammation in the knee join, like swelling, warmth, and pain. This inflammation can lead to more pain, loss of function, and progressive damage in joints with osteoarthritis.

However, there are currently no approved drug therapies to address the progressive aspects of the condition. Pain relievers, steroid injections, and other treatments can address OA symptoms like pain, but do not change the course of disease.

This can eventually lead to the need for total knee replacement surgery.

Decreasing knee inflammation in these patients could help rescue the joint and perhaps prevent or delay the need for surgery.

Researchers at SSKM Hospital in Kolkata, India, compared oral methotrexate to a placebo treatment with glucosamine (a common supplement for pain relief in arthritis patients) in adults with primary knee osteoarthritis.

The male and female patients recruited for the study had primary knee osteoarthritis with swelling and pain in both knee joints for at least six months. They also had X-ray evidence of osteoarthritis. Researchers excluded those with advanced or secondary osteoarthritis, those who had undergone arthroscopy (a procedure for diagnosing and treating joint problems), those who had intra-articular steroid injection in the previous three months, and patients with renal or hepatic disease, uncontrolled diabetes, or gout.

The researchers checked patients with signs of local inflammation, like pain and swelling of the whole knee with warmth, for erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) blood levels. Elevated levels are signs of increased inflammation. Patients who had increases in both inflammatory markers on one exam — or either marker on two exams — held one month apart were placed in an “inflammatory group.” Other patients were put in a “non-inflammatory group.”

Blood samples from all patients and healthy controls were tested for selected osteoarthritis biomarkers, and patients in the inflammatory group of primary knee osteoarthritis were screened for other inflammatory arthritis with blood tests, a clinical exam, musculoskeletal ultrasound and X-ray, and MRI scans of their knees.

Inflammatory group patients were randomly selected to take either 15 to 20 mg per week of oral methotrexate or 1,500 mg per day of glucosamine as a placebo, then were checked monthly for three months. The patients were allowed to take tramadol or acetaminophen for pain if necessary and were given non-steroidal anti-inflammatory drugs, or NSAIDs (a class of drugs that includes aspirin and ibuprofen) for seven to 10 days at the start of the study to improve compliance.

From July 2016 to June 2019, a total of 344 people with primary knee osteoarthritis were examined. The researchers found that 249 patients had local inflammation (or swelling with pain and warmth in both knees), and 172 of those 249 patients showed elevated erythrocyte sedimentation rate and/or C-reactive protein.

Patients with primary knee osteoarthritis with evidence of inflammation showed significant improvements on WOMAC scores (a commonly used measurement of physical function) and decreases in levels of erythrocyte sedimentation rate and C-reactive protein after three months of taking oral methotrexate.

Meanwhile, patients who took glucosamine showed no significant improvement in these measures of inflammation and function. The results of this study suggest that methotrexate can be an effective intervention for people with knee osteoarthritis who experience pain and inflammation.

Treatments offered to patients with primary knee osteoarthritis are usually physical support and knee replacement, which are basically directed to manage the effect of the disease,” the study’s coauthor, Biswadip Ghosh, MD, an Associate Professor in the Department of Rheumatology at the Institute of Post Graduate Medical Education and Research in Kolkata, India, said in a press release.

“Our study provides hope to patients not only from this inexpensive molecule, methotrexate, but other therapies directed towards one cause of the disease: inflammation. We should think of using methotrexate if we find signs of both local and systemic inflammation in patients with primary knee osteoarthritis when conventional therapies are not helpful.”

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Ghosh B, et al. Comparison of Methotrexate and Glucosamine in Primary Knee Osteoarthritis with Inflammation [abstract]. Arthritis & Rheumatology. November 2020.