No Pain Relief With IL-6 Blockade in Hand OA

The interleukin (IL)-6 receptor blocker tocilizumab (Actemra) was not effective in alleviating pain from hand osteoarthritis (OA), a French randomized multicenter study found.

After two intravenous infusions of tocilizumab or placebo, the mean change from baseline on a 100-point visual analog scale of pain at 6 weeks was -7.9 in the active treatment group and -9.9 in the placebo group, which was not a significant difference (P=0.7), according to Pascal Richette, MD, PhD, of Hôpital Lariboisière in Paris, and colleagues.

There also were no differences between tocilizumab and placebo on multiple secondary endpoints such as stiffness and swollen joints, the researchers reported online in Annals of the Rheumatic Diseases.

Hand OA is a common ailment, affecting an estimated one in 10 adults with pain, stiffness, and impairments in physical function, and despite recommendations for pharmacologic and nonpharmalogic treatments, many patients fail to achieve relief.

In recent years, imaging and clinical studies have implicated synovitis, bone marrow lesions, and local inflammation as contributory mechanisms in hand OA, but earlier studies on IL-1 and tumor necrosis factor (TNF) inhibitors have found no benefits in terms of pain relief, suggesting little influence for the inflammatory cytokines IL-1 or TNF on hand OA.

“IL-6 is a pleiotreopic inflammatory cytokine involved in many diseases and particularly OA, where it acts as a mediator of hypoxia-inducible factor 2α to upregulate matrix metalloproteinase 3 and 13 levels,” Richette and colleagues explained.

High levels of IL-6 in the serum have been linked with knee OA, and the cytokine has also been detected in the joint synovium of OA patients. In addition, targeting IL-6 in a murine model inhibited the progression of OA.

Therefore, to explore the possibility of blocking IL-6 for hand OA pain relief, the investigators enrolled 91 patients from 11 centers during the years 2015 to 2018, randomizing them to two infusions of 8 mg/kg tocilizumab or placebo at 4-week intervals. A total of 79 patients completed the 12-week study.

Participants’ mean age was 64.4, and 82% were women. Disease duration was approximately 10 years, mean baseline pain score was 58.6, and the number of painful and swollen joints was 5.7 and 2.9, respectively.

Change in pain scores remained similar in the tocilizumab and placebo groups through weeks 8 and 12, with no significant differences seen at any time point.

Moreover, no differences were seen at week 12 on various secondary endpoints for tocilizumab versus placebo:

• Morning stiffness (minutes), -8.5 vs -19.6, for a difference of 11.1 (95% CI -19.3 to 41.6, P=0.4)

• Swollen joints, -1.4 vs -1.2, for a difference of -0.1 (95% CI -1.1 to 0.8, P=0.7)

• Patient global assessment, -13.4 vs -12.9, for a difference of -0.5 (95% CI -9.3 to 8.2, P=0.9)

• Physician global assessment, -14.2 vs -12.1, for a difference of -2.1 (95% CI -11.1 to 6.8, P=0.6)

• Functional index for hand OA, -1.0 vs -0.1, for a difference of -0.9 (95% CI -2.7 to 0.8, P=0.2)

Overall, the rate of any adverse events was higher in the tocilizumab group (69% vs 53.7%). Serious adverse events in the tocilizumab group included one each of neutropenia (<1,000/mm³), fracture, and suicide attempt, while in the placebo group there was one case of road traffic injury.

Nonserious adverse events included infections in 12 patients in the tocilizumab group and six patients in the placebo group. No deaths occurred.

“Our study failed to demonstrate the efficacy of IL-6 blockade over placebo to alleviate pain and improve function in patients with hand OA,” the researchers observed.

They also noted that previous trials of cytokine-targeting therapies in hand OA had also failed to demonstrate benefits. These included the TNF inhibitors etanercept (Enbrel) and adalimumab (Humira), and the dual variable-domain immunoglobulin that inhibits IL-1α and 1β, lutikizumab.

These negative outcomes suggest that pain in hand OA is a complex process that may extend beyond inflammation, subchondral bone, structural damage, and nociception.

“A growing body of evidence supports a role for the innate immune pathways in OA pain, with the involvement of proteins such as C-C motif chemokine ligand 2 and nerve growth factor or aggrecan fragment that activates toll-like receptor 2 on joint nociceptors,” the researchers wrote.

“Targeting IL-6 signaling may be ineffective to improve symptoms in hand OA,” Richette and co-authors concluded, cautioning, however, that the study was powered to detect a large analgesic effect (0.6), and may have been underpowered to identify a lesser effect.