Etanercept Showing Promise in Erosive Hand Osteoarthritis

Pam Harrison

June 16, 2016

LONDON — Subcutaneous etanercept (Enbrel, Immunex Corp), a tumor necrosis factor (TNF) inhibitor, improves pain and structural damage in patients with osteoarthritis of the hand, provided they are symptomatic, have clear signs of inflammation, and are in a pre-erosive or erosive state, a proof-of-concept study indicates.

"In the total study population, etanercept was not superior to placebo on VAS [visual analogue scale] pain measures at 24 weeks, our primary outcome measure," said Margreet Kloppenburg, MD, professor of rheumatology at the Leiden University Medical Centre in the Netherlands.

However, "in patients who met our stringent inclusion criteria — who were symptomatic and who had inflammation on study entry — and who finished the year-long trial, etanercept was superior to placebo on measures of both pain and erosive evolution, and it was especially effective in joints with soft tissue swelling," she reported here at the European League Against Rheumatism (EULAR) Congress 2016.

In the multicenter trial, 90 patients were randomly assigned to receive either subcutaneous etanercept, 50 mg a week for 24 weeks followed by 25 mg a week for 1 year, or placebo.

On study entry, patients had to have primary osteoarthritis of the hand and symptoms and signs of inflammation. They also had to be in a pre-erosive or erosive state in order that progression would be evident over time.

Pain After 24 Weeks of Treatment

The primary outcome measure was pain after 24 weeks of treatment, measured on a 100-mm VAS.

Dr Kloppenburg and her colleagues assessed changes in structural outcome at 1 year with the Ghent University Scoring System (GUSS), which measures joint space, subchondral bone plate, and subchondral bone architecture.

The mean age at study entry was 60 years. Although most of the participants met the stringent inclusion criteria, not all did.

In the intent-to-treat analysis at 24 weeks, there was a decrease in pain of about 25 mm on the VAS in the etanercept group, which was 5.7 mm greater than the decrease in the placebo group, but the difference was not significant.

The between-group difference in pain increased to a mean of 8.5 mm after 1 year, but again, this was not significant.

The per protocol analysis involved 61 patients. At 1 year, there was significantly less pain in the etanercept group than in the placebo group (mean difference, 11.8 mm; P = .04).

In terms of structural damage, measured with the GUSS score, there was significantly more remodeling at 1 year in the etanercept group than in the placebo group (P < .05).

And at 1 year, there was more radiographic progression in patients who had soft tissue swelling or erythema at baseline than in those who did not.

In the etanercept group, the change in GUSS score at 1 year from baseline was greater in this subset of patients than in those without soft tissue swelling or erythema at baseline (6.9 vs 0.9).

In the placebo group, the change in GUSS score at 1 year from baseline was also greater in patients with soft tissue swelling or erythema at baseline than in those without (-9.3 vs 0.6).

In this subset of patients, the mean difference in GUSS score between the etanercept group and the placebo group was 15.8 (P = .008).

Table. Change in Outcomes With Subcutaneous Etanercept

  Baseline Mean Difference  
Measure Etanercept Group Placebo Group At 24 Weeks At 1 Year P Value
Intent-to-treat analysis          
   VAS pain (mm) 71.1 68.5 5.7 8.5 .10
Per protocol analysis          
   VAS pain (mm) 68.9 65.9 11.8 .04
   Joint pain on GUSS 286 288 3.1 <.05

 

Inflammation and Synovitis

"We know from magnetic resonance imaging studies and ultrasound that you can see inflammation and synovitis in a subset of patients with hand osteoarthritis," Dr Kloppenburg told Medscape Medical News.

This subset of patients with erosive symptoms makes up only about 10% of patients with symptomatic radiographic hand osteoarthritis, she added.

Nevertheless, the use of TNF inhibitors in patients with hand osteoarthritis has shown signs of early promise in small open-label trials.

Unfortunately, a previous randomized controlled trial did not support the efficacy of adalimumab (Humira, AbbVie Inc), another TNF inhibitor, in severe hand osteoarthritis, as reported by Medscape Medical News.

"When we looked into these trials, we saw that they involved patients with hand osteoarthritis, but inflammation or synovitis was not an inclusion criterion," Dr Kloppenburg explained. "That's why we thought it would be good to set up this new study and make inflammation and synovitis exclusivity inclusion criteria."

This is still only a proof-of-concept trial. More evidence is needed to support the use of etanercept in clinical practice and to determine which patients will benefit as well as the appropriate doses and duration of therapy.

"We simply don't know the answers to these questions yet," she stressed. "We really need something to help these patients, because erosive hand osteoarthritis results in a high disease burden in this subset of patients. It would be great to find something to help them."

Better Treatment Options

Physicians do need better options for the treatment of hand osteoarthritis, said EULAR President Gerd Burmester, MD, from Charité Universitätsmediz in Berlin.

"We are currently doing a study evaluating hydroxychloroquine in erosive OA of the hands," he told Medscape Medical News.

Although nonsteroidal anti-inflammatory drugs can provide some symptomatic relief, patients with osteoarthritis of the hand often experience significant pain despite treatment, and standard options are unlikely to stop radiographic progression of the disease, he added.

"There are a lot of aspects of the disease, including cosmetic concerns, that patients often have that are not discussed at all in the literature but that, nevertheless, are a major problem," Dr Burmester pointed out.

"Any attempt to look into this disease is extremely important, and this study raises the hypothesis that a cytokine-directed approach might be of help in the erosive form of the disease," he said.

Osteoarthritis is a very heterogeneous disease, with multiple causal pathways that lead to a final common end that includes pain, joint destruction, and physical destruction, said Gillian Hawker, MD, from the University of Toronto.

"The two pathways that seem most important are biomechanical factors that affect loading on the joints and systemic factors like aging, inflammation, and genetics," she told Medscape Medical News.

Erosive hand osteoarthritis seems to be related predominantly to the systemic pathway, with genetics and inflammation playing a major role.

Therefore, a number of drugs that target different elements of the systemic inflammatory immune pathways are being investigated as potential treatments for patients with erosive hand osteoarthritis, including the biologic agents.

In their secondary analyses, Dr Kloppenburg's team found that "those who received the biologic agent had a slow resolution of their synovitis, which is interesting and warrants further study," Dr Hawker said. However, because this was not the primary goal of the study, the "findings are more hypothesis-generating," she added.

But biologic therapies are expensive and carry real potential risks, she cautioned. "As such, we would not use them in osteoarthritis unless the benefits clearly outweigh these risks."

This study was funded by Pfizer. Dr Kloppenburg reports relationships with Pfizer, AbbVie, APPROACH, Levicept, GlaxoSmithKline, Servier, and UCB. Dr Burmester and Dr Hawker have disclosed no relevant financial relationships.

European League Against Rheumatism (EULAR) Congress 2016: Abstract OP0095. Presented June 9, 2016.

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