Pre-arthritis methotrexate use improves RA course, fails to prevent clinical arthritis
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Methotrexate use at the pre-arthritis stage of symptoms and subclinical inflammation fails to prevent clinical arthritis, but does improve symptoms and MRI-detected inflammation vs. placebo, according to data published in The Lancet.
“To date, no evidence exists that treatment initiated in the pre-arthritis phase is effective in preventing the development of clinical arthritis or reducing the disease burden of patients with rheumatoid arthritis,” Doortje I. Krijbolder, MD, of the department of rheumatology at Leiden University Medical Center, in the Netherlands, and co-authors wrote. “We hypothesized that this phase of symptoms and subclinical joint inflammation is a therapeutic window to permanently modify the disease course.”
To investigate the impact of methotrexate in patients in the pre-arthritis phase of arthralgia, Krijbolder and colleagues conducted a randomized, double-blind, placebo-controlled, proof-of-concept trial at a single center in the Netherlands. To be eligible for enrollment, patients needed to be aged 18 years or older, have arthralgia and be at risk for developing RA. Eligibility criteria also included recent-onset arthralgia with a high suspicion of progression and an MRI scan demonstrating confirmed subclinical joint inflammation of the hands or forefeet.
Patients were excluded from if they had a history of clinical arthritis or any previous or current use of disease-modifying antirheumatic drugs or glucocorticoids. Additionally, patients were excluded if they could not get an MRI, if they were pregnant or breastfeeding, had bone marrow hypoplasia or had elevated hepatic enzyme concentrations.
A total of 236 included patients were randomized 1:1 into either the active therapy or placebo group. Upon enrollment, patients received a 120 mg glucocorticoid injection, or a placebo injection, followed by a 52-week course of methotrexate or placebo. Concomitant therapy using analgesics or NSAIDs was permitted during follow-up.
The primary endpoint was the development of clinical arthritis that persisted for at least 2 weeks and met the 2010 criteria for RA, or involved two or more joints. A coprimary endpoint was the withdrawal of DMARDs after 2 years. Secondary endpoints included assessments of physical function, patient-reported symptoms and work productivity. In all, 119 patients received methotrexate therapy and 117 received placebo.
According to the researchers, the primary endpoint was met in similar numbers in both groups after 2 years. A total of 23 (19%) patients in the methotrexate group developed clinical arthritis, compared with 21 (18%) patients who received placebo (HR = 0.81; 95% CI, 0.45-1.48).
However, physical function improved more in the methotrexate group, with sustained the improvement over the placebo group, according to the researchers. In addition, patients who received methotrexate reported lower levels of pain, less morning joint stiffness and less MRI-detectable inflammation. Serious adverse events were consistent across both groups, the authors wrote.
“This trial showed that a single intramuscular glucocorticoid injection and a 1-year course of methotrexate did not prevent the development of detectable clinical arthritis, but could offer new perspectives on lowering the burden of disease,” Krijbolder and colleagues wrote. “A strength of this study is the additional 12-month follow-up after treatment stop, which ensured that a potential delay in clinical arthritis development was not falsely interpreted as a preventive effect.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
The prevention of rheumatoid arthritis seems like science fiction even though, with the continued development of pharmaceuticals targeted at the immune system, it seems closer than in the days when we routinely used gold injections. In this present trial, the researchers attempted to treat at the first appearance of arthralgia in patients at risk for RA to reduce the development of persistent arthritis. Their literature search revealed articles using intramuscular dexamethasone, rituximab (Rituxan, Genentech), statins, abatacept (Orencia, Bristol Myers Squibb), or hydroxychloroquine that failed to show prevention of RA, although the studies with the last two agents have yet to be published.
Their screening of “clinically suspect arthralgia” eliminated patients with osteoarthritis, gout, psoriatic arthritis and fibromyalgia. They did not require any positive blood work. Besides arthralgia, the participants had to have subclinical inflammation on an MRI scan of the hands or feet. Patients who had taken or were taking corticosteroids or disease modifying anti-rheumatic drugs (DMARDs) were excluded.
Although their placebo-controlled study did not show prevention of RA using a single 120 mg injection of methylprednisolone and up to 25 mg of methotrexate per week for 52 weeks, they did see a delay in the development of clinical arthritis in the treatment group in the following year.
The treatment of early RA is much more aggressive now than it was in the past. In the 1980s, treatment of RA was based on a “pyramid approach,” with non-steroidal anti-inflammatory drugs (NSAIDs) being used as initial therapy, and DMARDs being added later, usually after the development of erosive disease. Then “inverting the pyramid” became the mantra in the early 1990s, led by the late Ken Wilske, MD, of Seattle, with earlier use of methotrexate and the use of combination therapy until control was established. We have seen a great improvement in our treatment of RA in the past 10 years, but prevention of RA continues to be elusive.
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