Richard Robinson

Intra-articular injection of two widely used plant and mineral extract-based formulations provide long-lasting pain relief in patients with moderate to severe pain from knee osteoarthritis, according to the first-ever double-blind trial of the treatments. Results were reported here at the 2014 annual meeting of the American College of Rheumatology.

Pain relief from three injections over two weeks of the two formulations, Tr14 (Traumeel®) and Ze14 (Zeel®), was significantly better than placebo beginning at two weeks after the first injection, and lasting out to the study’s end at 99 weeks.

Both Tr14 and Ze14 are mixtures of 14 different extracts, which include yarrow, belladonna, Echinacea, and sulfur. “These compounds have been available and used intra-articularly for a long time,” according to lead study author Carlos Lozada, MD, a rheumatologist in the University of Miami Health System. The impression among clinicians who have administered the treatment “has been that there was something there, but there were no double-blind data to support that,” he said, which was the rationale for the trial. “The study was undertaken to see if there was a true effect.”

The study enrolled 232 patients at 30 sites in the United States. Eligible patients were men and women ages 45 to 80 years, with moderate-to-severe chronic knee osteoarthritis based on both clinical and radiographic criteria, who were taking either an NSAID or acetaminophen for pain.

Patients were randomized 1:1 to either Tr14 plus Ze14 or matching placebo, injected intra-articularly on days 1, 8, and 15, the standard injection schedule in clinical treatment.Care was taken to maintain the blind through masking of the injected solutions, Lozada said.

Patients were evaluated every 2 weeks. Acetaminophen rescue was allowed, but not in the 24 hours before a study visit. No other pain medications were allowed.

On the primary endpoint, the change from baseline on the knee subscale of the WOMAC A (Pain) Scale, treatment with Tr14/Ze14 was significantly better than placebo beginning at day 15 (at the time of the final injection), and remained significantly better at all study visits except for day 29.

On the 100 mm visual analog scale, patients receiving Tr14/Ze14 had pain reduction at 99 weeks of approximately 33 mm, and those receiving placebo of approximately 26 mm. Superiority to placebo was also seen in the secondary endpoint of pain following a 50 meter unassisted walk.

Adverse events were generally mild and unrelated to treatment, Lozada said, and there were no treatment-related serious adverse events.

“In this trial, the combination of the two treatments was shown to be safe and effective for moderate to severe pain associated with knee osteoarthritis,” he said. “We need to continue to build on this study, to better understand which components may be responsible for this effect.”

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Intra-articular injection of two widely used plant and mineral extract-based formulations provide long-lasting pain relief in patients with moderate to severe pain from knee osteoarthritis, according to the first-ever double-blind trial of the treatments.

Intra-articular Injection of Traumeel and Zeel Reduce Knee Pain in Double-blind Trial

A “biosimilar” form of etanercept is clinically equivalent to the branded form for rheumatoid arthritis, according to data presented here at the meeting of the American College of Rheumatology. The new drug, called HD203, was approved for use in South Korea on November 11, 2014.

In results from a randomized trial presented here, HD203 showed equivalent efficacy and safety to “reference etanercept” (Enbrel), a widely used TNF-alpha inhibitor.

HD203 is manufactured by the same process as reference etanercept, and has the same amino acid sequence and structure, according to lead author Sang-Cheol Bae, MD, of Hanyang University Hospital in Seoul, South Korea.

According to the US Food and Drug Administration, a biological product is bioequivalent to a reference product if “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components and… there are no clinically meaningful differences in terms of safety, purity, and potency.” They are distinguished from generics, which have simpler chemical structures, and are considered identical to their reference compounds.

“Extensive pharmacokinetic studies have been performed, and head-to-head analyses support the bioequivalence of the two molecules,” Bae said, laying the foundation for the clinical trial.

In the trial, 269 RA patients were randomized 1:1 to receive HD203 or the reference etanercept, both at 25 mg SC twice weekly, along with methotrexate, for 24 weeks. The proportion of patients achieving ACR20 at 24 weeks was the primary endpoint.

Two hundred thirty-three patients were treated according to protocol: 115 on HD203 and 118 on reference etanercept. Approximately 82% of patients in both groups achieved ACR20, with no significant difference between the groups. No differences were seen on the set of secondary endpoints, including ACR50 and ACR70 at 24 weeks, or any of the three response measures at week 12 or week 48, during an extension phase.

Additionally, the two treatments were equivalent in their effects on disease activity at 24 weeks, and response rate measured by the EULAR score, a combination of clinical measures.

Adverse events, serious adverse events, and withdrawal due to adverse events were also equivalent between the two treatment arms.

Eight patients taking HD203 and 3 patients taking the reference etanercept developed “mostly transient” anti-drug antibodies, Bae said.

“In addition to the previously generated analytical, non-clinical and clinical data, this study confirms the biosimilarity of HD203 and reference etanercept,” he concluded.

No information was available on whether HD203 will be offered at a lower price than the currently marketed formulation. HD203 is manufactured by Hanwha Chemical Corporation of South Korea.

A "biosimilar" form of etanercept is clinically equivalent to the branded form for rheumatoid arthritis, according to data presented at the 2014 annual meeting of the American College of Rheumatology.

HD203 Biosimilar is Clinically Equivalent to Etanercept

A blood test may offer a reliable way to identify rheumatoid arthritis patients who are unlikely to respond to anti-tumor necrosis factor-alpha inhibitors, speeding treatment with other drugs and lowering costs. The study outlining these findings was presented here at the 2014 annual meeting of the American College of Rheumatology.

The study showed that a pre-treatment serum ratio of interferon-beta to interferon-alpha greater than 1.3 was associated with a lack of response.

“It is clear that different rheumatoid arthritis patients respond to different therapies, and yet we do not understand the biological differences between patients that cause this variable response, or have methods for predicting which treatment will best suit a particular patient,” said lead author Timothy Niewold, MD, of the Mayo Clinic in Rochester, Minnesota.

The need for such a predictor is especially acute with the TNF-alpha inhibitors, he said, since they are widely used and are expensive, but there is a large proportion of patients who don’t respond.

Niewold said he and his colleagues chose to study serum levels of interferon-alpha and —beta, “because there is a lot of variation between people in the levels of these proteins, and they remain relatively stable,” making them potentially valuable discriminators among patients.

The researchers measured levels of both proteins in a study set of 32 RA patients before they began TNF-alpha inhibitors, and then monitored their response to therapy. They found that IFN-beta/IFN-alpha > 1.3 was associated with lack of response at 14 weeks. The same cut-off ratio was a significant predictor of non-response in a validation set of 80 patients, where no patient with a ratio above 1.3 achieved a good response to treatment.

The odds ratio for the cut-off as a predictor of non-response versus good response was 18.0, and for non-response versus moderate or good response it was 4.3, both highly significant.

The predictive value of the cut-off was independent of anti-CCP antibody titer or whether the TNF-alpha inhibitor was a monoclonal antibody or a decoy receptor.

“We want to get disease under control quickly, and it would be very clinically usefulto have predictors of response,” Niewold said. “We are excited that this may be a good predictor.”

He cautioned that the test requires validation in larger group, and that advances are likely to be needed to streamline the interferon assay before it becomes clinically widely available.

A blood test may offer a reliable way to identify rheumatoid arthritis patients who are unlikely to respond to anti-tumor necrosis factor-alpha inhibitors, speeding treatment with other drugs and lowering costs.

Baseline Interferon Ratio Predicts Response to anti-TNF Therapy

Running does not increase the risk for knee osteoarthritis (OA), according to a new study presented here at the meeting of the American College of Rheumatology. No increase in knee OA or knee pain was associated with habitual running in any age group in a study of over 600 individuals who reported running as a regular activity at some point in their lives.

“Controversy exists over whether habitual running is harmful or beneficial,” said lead author Grace Hsiao-Wei Lo, MD, of Baylor College of Medicine in Houston, Texas. Guidelines from the Centers for Disease Control recommend either 150 minutes weekly of moderate aerobic activity, such as brisk walking, or 75 minutes weekly of vigorous aerobic activity, such as running.

Concern over the risks of running have been partially alleviated by studies showing no increase in KO among elite runners, but the small sample sizes and unique populations in those studies have limited their applicability to the millions of recreational runners.

To address these concerns, Lo and colleagues examined subjects enrolled in the Osteoarthritis Initiative, a multicenter longitudinal observational study. They administered the Lifetime Physical Activity Questionnaire, asking about frequently performed leisure activities (defined as having been performed 10 or more times) during 4 epochs in the subject’s past: from 12 to 18 years of age, 19 to 34, 35 to 49, and age 50 or older. Those who identified running as one of their frequent activities were defined as runners during that epoch. As part of the Initiative, subjects also underwent knee radiography and pain assessment at the 48-month visit.

Of the 2,683 participants, 776 (29%) were classified as runners during at least one epoch. Runners were much more likely to be male than non-runners, and had a marginally lower body mass index.

Frequent knee pain was reported at any time in life by 42% of non-runners and 35% of runners, providing an odds ratio 0.89 favoring running (95% CI 0.81-0.98). Knee pain was also less in all individual epochs, again with odds ratios favoring running, though each with 95% confidence intervals that spanned 1.0.

There was no significant difference in the rate of radiographic osteoarthritis among the two groups at any time point. Symptomatic OA (knee pain plus radiographic OA) was significantly less common in runners over the lifespan (30% vs 23%, 95% CI 0.79-0.98), and also less common in 2 of the 4 epochs.

“Non-elite running at any time in life does not appear detrimental,” Lo concluded, and may be protective of knee pain, radiographic osteoarthritis, and symptomatic osteoarthritis.” She noted that the findings are not applicable to those with pre-existing knee OA, who were excluded from the Osteoarthritis Initiative. “However, among those without OA, running should not be discouraged over a concern of an increased risk of developing knee OA.”

Running does not increase the risk for knee osteoarthritis (OA), according to study results presented at the 2014 annual meeting of the American College of Rheumatology. No increase in knee OA or knee pain was associated with habitual running in any age group in a study of over 600 individuals who reported running as a regular activity at some point in their lives. 