Groundbreaking Study Shows 30% Reduction in Knee and Hip Operations with Colchicine

These are encouraging results: 30% fewer hip and knee operations when using colchicine, a simple, cheap medicine with a lot of experience in primary care. This was evident from a study into cardiovascular events that also looked at patients with osteoarthritis.1,2 Calin Popa, rheumatologist and researcher at the Sint Maartenskliniek, is enthusiastic about these results. This fall he will start a large study in which colchicine will be examined in 1,400 patients with osteoarthritis in the hip or knee. A subsidy of €800,000 has been awarded for this from the ZonMw Good Use of Medicines programme.

It has been hypothesized for years that inflammation plays a role in cardiovascular disease. Despite the use of lipid-lowering medication, blood pressure lowering drugs and blood thinners, people still relatively often develop a new myocardial infarction or new stroke, Popa explains. About 6 years ago, the results of the first studies with anti-inflammatory medication for cardiovascular disease became known. In the CANTOS study, it appeared to have a positive effect as an addition to standard medication.3 A link was also shown between cardiovascular diseases and osteoarthritis: osteoarthritis decreased by inhibiting the inflammatory mechanism. Popa: “The results were positive, but the drug used was too expensive to be used for a large patient population. It did give us reason to investigate further.”

Significantly fewer cardiovascular events

Jan Hein Cornel, cardiologist at Radboud university medical center, looked at the effect of colchicine in 5,522 patients with chronic coronary disease in the LoDoCo2 study.1 Colchicine is a well-known drug against gout that is prescribed in primary care, is cheap and is well used. treaties. The risk of cardiovascular events was found to be significantly lower (30%) in those receiving 0.5 mg colchicine once daily than in patients on placebo. This study was used to specifically look at the effects on osteoarthritis. Popa: “We analyzed in the LoDoCo2 study population which patients had to undergo knee or hip surgery due to osteoarthritis. Colchicine showed that 30% fewer joint replacement operations were needed compared to the group that received placebo. However, not everyone who participated in the LoDoCo2 study had osteoarthritis, which means that these results are less generalizable to the entire group of osteoarthritis patients. In order to be able to make further statements, the findings must be further confirmed in that group.”

Unique study design

What is special is that colchicine had previously been written off as an osteoarthritis agent. Popa explains that various studies and a meta-analysis have been conducted with colchicine for osteoarthritis. A Danish study into hand osteoarthritis was recently discussed during the EULAR 2023.4 Popa: “It was said that we had to definitively close the chapter on colchicine in osteoarthritis. However, all these studies have a different primary endpoint, namely reduction of pain. They also have a short follow-up of up to 5-6 months and a smaller patient population with 36-150 patients per study. Changes in the osteoarthritis itself have not yet been examined, so not at structural outcomes! More time is often required to properly investigate the latter. The study that we hope to start this fall – called the ECHO trial – differs from previous studies with colchicine in osteoarthritis and perhaps from other studies on osteoarthritis in general that have been done so far. We hope to study 1,400 patients, spread throughout the Netherlands, with a follow-up of 3 years and joint replacement surgery as the primary outcome measure. That makes this study unique. This is therefore not the first study with colchicine in osteoarthritis, but it is the first to investigate the potential DMOAD property (disease-modifying osteoarthritis drug) of colchicine.”

Side effects

Previous studies have been done on osteoarthritis with other anti-inflammatory drugs including methotrexate, hydroxychloroquine and prednisone. Methotrexate seems to help in pre-selected patients with a lot of inflammation. In patients with inflammatory erosive hand osteoarthritis, treatment with bisphosphonates appears to inhibit joint damage, but not the symptoms. Moreover, these drugs have more side effects, according to Popa. Like almost all medications, colchicine also has side effects. These are mainly dose-dependent gastrointestinal side effects that are in most cases transient. Muscle pain and, to a lesser extent, disturbed kidney function also occur.5 Popa calls it positive that in the LoDoCo2 study everyone received colchicine in a run-in phase of one month. Of these, only 10% could not tolerate the drug and had to stop taking it, after which 90% were randomized and participated in the study. “This means that the vast majority of people could tolerate the drug well and there was little chance that they would stop participating because of the side effects. Similar rates of around 10% were found in both groups – placebo and colchicine – dropping out of the study during the 3.5 year follow-up period. The conclusion seems to be that there are fewer side effects with colchicine than with other anti-inflammatory drugs, the effect is more effective and the drug is suitable for a larger patient population.”

“An additional advantage is that the research did not reveal any additional muscle complaints and damage,” Popa continues. “You are always warned about this when you want to prescribe colchicine in combination with a statin.” In Cornel’s cardiovascular study, more than 95% of participants received this combination and this did not lead to more muscle complaints in colchicine users compared to placebo. However, according to Popa, it is still wise to remain cautious, especially when combining statins with more than 1 tablet (0.5 mg) of colchicine per day.

Clinical practice

What do the results so far mean for rheumatology? “My message is that an anti-inflammatory drug can also be effective for osteoarthritis. In osteoarthritis there is a low-grade inflammation, but it is definitely present. It is very important that we are aware of this. There is sufficient evidence to suggest that it is useful to treat osteoarthritis with systemic anti-inflammatory drugs. Look at our study, the CANTOS study (interleukin 1 inhibition) or the HOPE trial with prednisone for hand osteoarthritis.6 I would like to emphasize that colchicine could be a very attractive means for treating knee and hip osteoarthritis in the future. treatment: it is (still) cheap, is provided by the GP and in some cases can postpone or even prevent major surgery.” If there is sufficient evidence that colchicine is effective against osteoarthritis, the drug could become available to osteoarthritis patients fairly quickly, according to Popa. “The drug is already on the market and the Medicines Evaluation Board (CBG) and the Dutch Healthcare Institute (ZIN) are already aware of the research and support it. However, we have not gotten that far yet and so we have to wait a few more years for the results of this study before we can hopefully prescribe colchicine for osteoarthritis.”

References

1 Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med 2020;383:1838-47.
2 Low-dose colchicine for secondary prevention of cardiovascular disease – LoDoCo2 trial
3 Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-31.
4 Døssing A, Henriksen M, Ellegaard K, et al. Colchicine twice a day for hand osteoarthritis (COLOR): a double-blind, randomised, placebo-controlled trial. Lancet 2023;5:E254-62.
5 Leaflet | Medicines Evaluation Board
6 Kloppenburg M. Inflammation is a relevant treatment target in osteoarthritis. Lancet 2023;402:1725-26.

2024-02-26 08:09:42
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