New hope for people with hand osteoarthritis

Clinicians are often challenged with limited effective treatment options for hand osteoarthritis, which is a major cause of pain and disability, affecting 44% of women and 38% of men. With better understanding of the causes of osteoarthritis, there is new hope on the horizon for patients. For those with hand osteoarthritis, this hope comes in the form of methotrexate, an old, well established, inexpensive medication.

Hand osteoarthritis - degenerative or inflammatory?

Osteoarthritis is a heterogenous condition with the drivers of disease varying across different joints and individuals. In the past, osteoarthritis was believed to be a degenerative condition. However, research over the last 2-3 decades has shown that osteoarthritis is a complex condition with inflammation playing an important role in the disease process in joints such as the hands and knees. Local inflammation (synovitis) is common in those with hand osteoarthritis and is associated with pain and joint damage even though blood tests reflecting systemic inflammation such as erythrocyte sediment rate (ESR) and C-reactive protein (CRP) are normal. The huge unmet need for treatments for hand osteoarthritis, coupled with this knowledge, underpinned a number of studies funded by the pharmaceutical industry that have tested biological drugs, such as adalimumab, an anti-tumour necrosis factor drug effective in rheumatoid arthritis. However, such drugs have not worked for hand osteoarthritis.

Repurposing an old drug for hand osteoarthritis

Given these findings, we examined methotrexate, a medication that has been in widespread use for rheumatoid arthritis and other inflammatory forms of arthritis since the 1980s. Methotrexate has a broader action than the more selective biological agents. In a randomised control trial, we selected people with hand osteoarthritis, moderate pain and synovitis as seen on hand magnetic resonance imaging. We found that pain reduced in both the placebo and methotrexate groups over the first month, as is commonly seen in studies of osteoarthritis, but continued to reduce at three months and six months in the methotrexate but not the placebo group. The effect was assessed as moderate, and the timing of the improvement is consistent with the known action of methotrexate.

The results of our study are supported by findings that a daily dose of 10 mg of prednisolone also improves symptoms in hand osteoarthritis, suggesting that targeting inflammation will improve patient outcomes. Treatment of hand osteoarthritis with prednisolone is not recommended due to the significant morbidity associated with prednisolone use, especially in older individuals. As such, there has been off-label prescription of prednisolone in the community, reflecting the desperation for a drug that is effective for hand osteoarthritis.

Further trials are needed to establish if the effect of methotrexate extends beyond the six months seen in our study as there was still improvement occurring at six months. There is also the need to better identify those most likely to benefit and to determine whether the reduction in pain is also associated with less joint damage. Preliminary analyses of our data suggest that the benefits of methotrexate are greater in women than men. This will need to be clarified in larger studies and may be important given that a very inflammatory form of hand osteoarthritis is seen in women around menopause.

Knee osteoarthritis

Knee osteoarthritis is also associated with inflammation, including metabolically driven inflammation due to obesity. Although one open label trial suggested methotrexate may be effective in knee osteoarthritis, this has not been confirmed in subsequent studies presented in abstract form, so methotrexate is not currently recommended for knee osteoarthritis. Methotrexate has not been examined in other osteoarthritic joints. However, it is unlikely to have much benefit at other sites as there is little evidence for inflammation in other joints. For example, unlike knee osteoarthritis, hip osteoarthritis is predominantly affected by the shape of the joint rather than obesity, or metabolic or inflammatory factors.

Conclusion

Our study has provided data that doctors can use to inform a discussion with their patients about the potential use of methotrexate for their hand osteoarthritis. However, several issues remain. These include a better understanding of who is most likely to benefit, the optimal duration of therapy, and whether symptomatic improvement is also paralleled by less joint damage. We are addressing these questions in a follow-up, open label pragmatic trial METHODS-Extend study.

Professor Flavia Cicuttini is Head of Rheumatology at Alfred Health and runs a research program aimed at developing new approaches to managing musculoskeletal conditions such as osteoarthritis.

Dr Yuan Lim is a rheumatologist at Alfred Health with post-graduate research interest in improving outcomes in musculoskeletal disease, particularly in osteoarthritis.

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