OKINADA: TNF inhibition disappoints in knee osteoarthritis

Short-term tumour necrosis factor (TNF) inhibition with adalimumab falls short of producing improvements in patients with radiographic knee osteoarthritis (OA), according to the proof-of-concept OKINADA trial presented at this year’s European Alliance of Associations for Rheumatology (EULAR) Congress.

In an analysis of 59 knee OA patients treated across 11 sites in Canada, “TNF inhibition was not effective in ameliorating symptoms of OA of the knee … in a time frame of 16 weeks, although treatment was safe,” said lead investigator Dr Walter Maksymowych of the University of Alberta in Edmonton, Canada.

The primary endpoint of the combined Outcome Measures in Rheumatology and Osteoarthritis Research Society International (OMERACT-OARSI) responder criteria at week 16 was not met, Maksymowych added.

He pointed out the two pathways to attaining the OMERACT-OARSI response. One was an improvement in pain or function of ≥50 percent and an absolute change of ≥20 mm. The other was an improvement of ≥20 percent with an absolute change of ≥10 mm in at least two of the following three categories: pain, function, and patient’s global assessment.

At week 16, the number of patients who achieved response via either pathway was not significantly different in the adalimumab and placebo arms (9 out of 30, 30.0 percent vs 7 out of 29, 24.1 percent, respectively; p=0.62). [EULAR 2022, abstract OP0229]

Likewise, adalimumab did not outperform placebo in terms of the following secondary endpoints: ≥20-percent improvement Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain (p=0.30), ≥50 percent-improvement in KOOS for pain (p=0.69), KOOS for activities of daily living (p=0.71), KOOS for knee-related quality of life (p=0.66), KOOS for symptoms (p=0.42), KOOS for sport and recreation function (p=0.76), patient’s global assessment of disease status (p=0.10), investigator global assessment of disease status (p=0.30), and expanded Target Joint Assessment score (p=0.87).

Laboratory markers such as C-reactive protein and erythrocyte sedimentation rate were also comparable between the two treatment groups.

“There was little to say about safety,” Maksymowych said, adding that there were no serious adverse events and new safety signals that emerged during treatment.

Four patients on adalimumab and seven on placebo discontinued treatment due to adverse events or increasing knee pain.

At baseline, all 59 patients in OKINADA had a diagnosis of OA of the index knee and classified according to American College of Rheumatology criteria, including radiological evidence of OA (Kellgren-Lawrence grades 2 or 3) with clinical signs of knee effusion. They had persistent knee pain of ≥1 month duration with a pain score of ≥4 (0-10 NRS) in the index knee at screening and baseline despite conventional treatment with maximum tolerated acetaminophen and/or nonsteroidal anti-inflammatory drug.

Patients in the active treatment group (mean age 63.5 years, 56.7 percent female) received adalimumab 40 mg subcutaneously every 2 weeks, while those in the control group (mean age 60.9 years, 62.1 percent female) received placebo on the same schedule.

The findings from OKINADA are in line with data from recent trials demonstrating that TNF inhibition has a null effect on pain and MRI-detected synovitis or bone marrow lesions in patients with erosive hand OA. [Ann Rheum Dis 2012;71:891-898; Ann Rheum Dis 2015;74:1697-1705; Osteoarthritis Cartilage 2018;26:880-887]

“However, the progression of bone erosions was reduced in a subgroup of patients with more clinically swollen distal interphalangeal joints in one trial. Consequently, it remains possible that TNFα inhibition may have beneficial effects in specific subgroups of patients with a high inflammatory component,” Maksymowych noted.

He also acknowledged that OKINADA might be limited by the short-term design of the placebo-controlled period, which “does not permit an assessment of the structure-modifying effect” of adalimumab.

Furthermore, the recruited patients had established disease, and the selection for inflammatory phenotype was based only on the clinical evidence of effusion, Maksymowych said.

The magnetic resonance imaging findings of OKINADA, according to Maksymowych, will be analysed separately and reported once the results are available.