Negative studies of colchicine and a herbal-supplement cocktail have dashed hopes of non-surgical treatments – with fewer side effects than ordinary painkillers – for osteoarthritis, according to results of two randomised trials.
In one, colchicine proved to be no better than placebo for pain relief or patient-reported functional improvement in OA of the knee. The other, testing a mix of herbal supplements that other studies had suggested are beneficial, likewise found no advantage over placebo in hand OA.
Both studies were presented at the American College of Rheumatology (ACR) annual meeting, reports Medpage Today.
No medications now available for OA do more than relieve pain and other symptoms. Medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids come with significant side effects with chronic use, and injectables such as steroids and hyaluronic acid must be repeated periodically with diminishing effectiveness.
In no case do they stop the underlying disease process.
Colchicine Trial
Understanding of that process has evolved over time, said Jonathan Samuels, MD, of NYU Langone Health in New York City, in an ACR presentation.
Until recently, it was believed to be simply a degenerative process in which joint components break down with age. But it now appears to be “a disease of low-grade chronic inflammation”, he said.
Progression comes with effusions and synovitis, and various immune system components such as leukocytes show activation and cytokine release increases – as seen in rheumatic joint diseases. Thus, agents that block these processes ought to prove helpful in OA.
With this picture in mind, his group believed that colchicine would be worth a trial. The drug had been in use for a long time, and has a variety of immunomodulatory effects.
Samuels listed inhibition of macrophages and neutrophils and of leukocyte-endothelium adhesion, as well as reduced expression of key interleukin species. “Colchicine has many potential targets in knee OA,” he said.
He noted that the current CLOAK trial was not the first to test the drug in OA: the 2018 OLKOA study also failed to show a benefit. But patients in that study were allowed to use NSAIDs, thus becoming a potential confounding influence, Samuels said.
CLOAK enrolled 120 patients, randomising them in equal numbers to daily colchicine or placebo for 12 weeks. Patients needed to be older than age 40, not severely obese, with knee OA rated as grade two or three on the Kellgren-Lawrence scale. They also had to promise not to use NSAIDs, intra-articular injections, supplements, acupuncture, or any other new pain medications.
Patients also diagnosed with other rheumatic diseases were excluded, as were those with diabetes or renal or hepatic impairment.
Mean patient age was 67 and about one-third were men. Patient-reported average knee pain stood at about six on a 10-point scale at baseline. A fluke of the randomisation was that nearly half of the placebo group had effusions, versus just 32% of those assigned to colchicine, but otherwise the groups were well-matched, Samuels said.
That probably made no difference. Every outcome measure showed that both groups improved nearly equally – indeed, the placebo group enjoyed numerical advantages for most.
The analysis focused on change from baseline in Knee Injury and OA Outcome Score. The placebo group showed a decrease of about 1.4 points, compared with 1.0 in the colchicine group. Mean effusion size also shrank to nearly the same degree in both groups.
Subgroup analyses examining only patients completing the full 12 weeks or those with more severe baseline disease by various measures (C-reactive protein level, Kellgren-Lawrence grade, baseline pain, etc.) also failed to identify a group benefitting more from colchicine than placebo.
Even within the colchicine group, patients with more severe disease showed no greater improvement than those with milder symptoms.
Supplement trial
Similar disappointment beset the herbal supplement study reported by Xiaoqian Liu, MD, of the University of Sydney, in patients with OA of the hand.
A wide range of herbal products have been touted over time as effective in hand OA, but studies, albeit of low quality, Liu emphasised, had suggested that four particular ones were better than the rest. These are:
• Curcumin (a component of the spice turmeric)
• Pine bark extract
• Methylsulfonylmethane (MSM), a sulphur compound included in many over-the-counter nutritional supplements
• Boswellia serrata extract, also known as Indian frankincense
For the trial, these four substances were formulated into two separate capsules that patients took multiple times daily. Daily doses were 168mg for curcumin, 100mg for pine bark extract, 1 500mg for MSM, and 250mg for B. serrata extract.
The primary outcome was change from baseline in a 100-point, patient-reported hand pain scale. Some functional assessments were conducted as well.
Much of the study was conducted online, with only occasional in-person contact (such as when otherwise eligible patients had no recent hand x-ray, and thus had one performed in the clinic). Capsules were sent by mail and patients reported their pain and functional capabilities through their devices.
This was among the limitations Liu cited, in that “a good level of technology literacy and skill was required”.
The study enrolled 106 patients in Australia aged at least 40, and who rated their baseline pain at ≥40 and ≤90 on a visual analogue (VAS) scale, and with Kellgren-Lawrence grade of at least 2.
Mean age was 66 and a large majority were women. Overweight was common but obesity was not. Baseline hand pain averaged 60 on the 100-point VAS scale.
As in the colchicine trial, both the active-treatment and placebo group showed similar degrees of improvement in pain after 12 weeks, with a numerical advantage for placebo (-8.6 points for the supplement cocktail and -14.6 points with placebo) that fell short of statistical significance.
Scores on other measures including the Functional Index of Hand OA, the Patient’s Global Assessment, and a quality-of-life scale, all improved to similar degrees in the two study arms.
No major safety issues were seen in either study, but the supplement capsules weren’t tolerated by all patients – four assigned to the active treatment quit prematurely because of gastrointestinal symptoms.
Diarrhoea-like symptoms were also slightly more common with colchicine than placebo in that trial.
Limitations
Both studies also had to overcome hurdles related to the Covid-19 pandemic that might have influenced the results. In the colchicine trial, Samuels said, the drug supplier lost access to the original 0.8mg dose and had to substitute a dose of 0.6mg partway through.
Liu mentioned that the pandemic had interfered to some degree, but there had also been a major wildfire affecting many participants; these events in tandem might have had both mental and physical consequences for patients, she said.
As well, both studies faced the same major limitation: they only ran for 12 weeks. It’s possible that longer treatment and follow-up periods would show a true benefit for the respective treatments.
That was particularly true for the colchicine study: Samuels and colleagues hypothesised that the drug would inhibit pathogenic immune processes related to disease progression, but no such effect could be expected in 12 weeks.
Study details
An Online Trial to Assess the Efficacy and Safety of a Supplement Combination in People with Hand Osteoarthritis
Xiaoqian Liu, Sarah Robbins, Jillian Eyles et al.
Presented at ACR Convergence on 16 November 2024
Background/Purpose
Hand osteoarthritis is a debilitating and highly prevalent disease with limited treatment options. The aim of this study was to investigate the efficacy and safety of a newly developed combined supplement in people with hand osteoarthritis (OA).
Methods
This was an internet-based, double-blind, randomised, placebo-controlled trial without face-to-face interaction between investigators and participants. The main eligibility criteria were aged over 40 years with symptomatic hand OA and Kellgren Lawrence grade (KLG) 2 and above. The recruitment was conducted across Australia. Eligible participants were randomly assigned to receive either a combined supplement or placebo (1:1) for 12 weeks. The active ingredients in the combined supplement were Boswellia serrata extract 250 mg/day, pine bark extract 100 mg/day, methylsulfonylmethane 1,500 mg/day and curcumin 168 mg/day. The primary outcome was change in hand pain assessed using a visual analogue scale (VAS, 0-100) from baseline to week 12. Secondary outcomes included change in functional Index of Hand Osteoarthritis, patient global assessment and health-related quality of life. Adverse events were monitored weekly.
Results
We included a total of 106 participants with a mean age of 65.6 years and 81% female. The majority of the participants were moderate to severe on the radiographic assessment, with 40% KLG 3 and 45% KLG 4, and 37% participants had erosive OA. Pain VAS decreased over 12 weeks in both active and placebo groups with mean change (95%CI) -8.64 (-14.35 to -2.92, p=0.004) and -14.63 (-20.94 to -8.32, p < 0.001), respectively. The adjusted between-group difference over 12 weeks was 5.34 (95%CI, -2.39 to 13.07, p=0.17). Five participants (10%) in the supplement combination group discontinued study treatment due to AE vs four participants (7%) in the placebo group.
Conclusion
Treatment with the supplement combination was not superior to treatment with a placebo for improving hand pain over 12 weeks. Results do not support the initiation of supplement combination therapy for people with moderate- to late-stage- hand OA.
Study 2 details
CoLchicine for Treatment of OsteoArthritis of the Knee: Clinical Outcomes from a 90-day Double-Blind, Placebo-Controlled Study
Jonathan Samuels, Katherine Tse, Wei David et al.
Presented at ACR Convergence on 16 November 2024
Background/Purpose
Knee osteoarthritis (OA) leads to progressive disability, but approved pharmacologic treatments target analgesia without affecting disease course. Colchicine is well-tolerated and inhibits inflammation thought to modulate OA, but trials to date have yielded mixed results. We tested whether daily colchicine improves pain, function and synovial effusion size in patients with knee OA.
Methods
A total of 120 participants with painful knee OA and radiographic Kellgren-Lawrence grades 2 or 3 were enrolled, excluding individuals with inflammatory or crystal arthritis. Participants were randomised to receive daily colchicine or placebo (1:1) for 12 weeks, while avoiding other anti-inflammatory agents. The primary outcome was change in visual analogue scale (VAS) for signal knee pain. Secondary outcomes included changes in the Knee Osteoarthritis Outcome Score (KOOS) subscales (pain, other symptoms, activities of daily living, sports and recreation, quality of life) and in the size of sonographically-identified effusions.
Results
The colchicine and placebo groups were similar at baseline in age, race, gender, ethnicity, VAS pain, and mean levels of serum urate, with a slightly higher mean C-reactive protein (CRP) and radiographic severity in the colchicine group. From baseline to end of treatment for the colchicine vs. placebo groups, we observed no significant between-group differences in mean changes of VAS pain ( -1.1±2.3 vs. -1.5±2.6, p=0.40, Fig. 1C), KOOS subscores (for pain: 3.4±18.7 vs. 9.8±19.9, p= 0.09, Fig. 1D with other KOOS subscores in Fig. 2A) or sonographic size of synovial effusions in millimeters (-0.35 ±3.7 vs. -0.26 ±3.2, p= 0.93, Fig. 2B). These findings for the entire cohort remained when analyzing the per-protocol study completer subset (n=100). The subsets of patients with greater baseline inflammation (CRP or serum urate), or more severe VAS pain or radiographic KL severity, also failed to demonstrate a significant benefit from colchicine vs placebo. Acetaminophen use was permitted as needed, but was not taken less often by patients in the colchicine group.
Conclusion
In this largest double-blind controlled study of colchicine for treatment of knee OA, colchicine failed to improve knee pain, function, or size of synovial effusions. Whether longer treatment with colchicine, higher doses, or a larger cohort would improve pain and function or modify radiographic progression remains to be determined. Current analyses of biomarker levels from these patients’ blood and synovial fluid samples at baseline and 12 weeks will help determine if there is a biochemical effect of colchicine on OA, even if it is not manifesting clinically in a short period of time.
Medpage Today article – Two Treatments That Don’t Work for Osteoarthritis (Open access)
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