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Lutikizumab Ineffective for Erosive Hand Osteoarthritis (CME/CE)

Action Points

  • Treatment with lutikizumab, an anti-interleukin-1α and anti-interleukin-β dual variable immunoglobulin in a phase IIa double-blind study in patients with erosive hand osteoarthritis did not produce significant improvements in hand joint pain, despite adequate neutralization of these two cytokines.
  • Note that lutikizumab also produced no improvements in other symptomatic, functional, and structural endpoints in erosive hand osteoarthritis compared with placebo, but injection site reactions, neutropenia, and discontinuations because of adverse effects occurred more frequently with the drug compared with placebo.

CME Author: Vicki Brower

Study Authors: Margreet Kloppenburg, Charles Peterfy, et al.

Target Audience and Goal Statement:

Rheumatologists, internists, and family medicine specialists

The goals were to measure the efficacy and safety of lutikizumab, an anti-interleukin-1α (IL-1α) and anti-interleukin 1β (IL-1β) dual variable domain immunoglobulin in patients with erosive hand osteoarthritis (OA).

Questions Addressed:

  • Did this drug relieve pain in patients with erosive hand OA?
  • What are the safety, pharmacokinetics, and pharmacodynamics of lutikizumab in these patients?
  • Did this treatment improve other symptomatic, functional, and structural endpoints for this drug compared to placebo?

Study Synopsis and Perspective:

In a phase IIa study in 110 patients with erosive hand OA, lutikizumab, a dual variable-domain immunoglobulin that inhibits IL-1α and IL-1β, was no more effective than placebo in reducing pain and inflammation.

Hand OA is common, particularly among older women, and is associated with substantial disability, including pain and swelling, but available treatments are limited, and no disease-modifying agents have demonstrated efficacy to date.

Preclinical studies and mouse models indicated that IL-α and IL-β were potential mediators of synovitis, cartilage damage, and bone loss in patients with this condition, but this clinical trial did not confirm earlier research regarding pain, nor did it improve other symptomatic, functional, and structural secondary endpoints.

For this randomized placebo-controlled study Kloppenburg and colleagues enrolled 131 adults with active inflammation of the hand joints, with pain ratings of six or higher on an 11-point scale, and at least one erosion of an interphalangeal joint. All underwent radiography and MRI of the hand joints at baseline and week 26. Radiographs were scored according to the Osteoarthritis Research Society International (OARSI) criteria and MRIs according to the Outcome Measures in Rheumatology/Hand Osteoarthritis MRI Scoring system (OMERACT/HOAMRIS).

Participants’ mean age was 66, and most were white women. Mean duration of OA was 11 years, mean Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain score at baseline was 39 (pain score ranges from 0 – 50), and mean tender and swollen joint counts were 12 and 6, respectively.

Patients were randomized to receive subcutaneous lutikizumab, 200 mg every 2 weeks for 24 weeks, or placebo subcutaneous injection. They were permitted rescue medication for pain with acetaminophen or ibuprofen.

At week 16, change from baseline in pain as measured on the AUSCAN was similar for patients who had been randomized to lutikizumab (−9.2, 95% CI −13.8 to −4.6) or placebo (−10.7, 95% CI −15.4 to −6), according to Margreet Kloppenburg, MD, PhD, of Leiden University Medical Center in the Netherlands, and colleagues.

At week 16, least squares mean difference between lutikizumab and placebo in change of pain was a nonsignificant 1.5 (95% CI −1.9 to 5), the researchers reported online in Annals of the Rheumatic Diseases.

As with the pain endpoint, no significant differences were seen between the two groups in change from baseline in AUSCAN function at week 16, which was −14.6 (95% CI −22.1 to −7.1) for lutikizumab, and −17.2 (95% CI −24.9 to −9.4) for placebo, for a mean difference of 2.5 (95% CI −3.2 to 8.3).

Other secondary endpoints also had similar results for lutikizumab and placebo at week 26, respectively:

  • Tender joints, −5.8 vs −4.7, P=0.32
  • Swollen joints, −2.2 vs −1.8, P=0.64
  • OARSI joint space narrowing, 0.03 vs 0.14, P=0.51
  • HOAMRIS synovitis, 0.85 vs 0.92, P=0.89
  • Joints with synovitis on MRI, 0.54 vs 0.46, P=0.79

Source Reference: Annals of the Rheumatic Diseases, Dec. 14, 2018 DOI: 10.1136/annrheumdis-2018-213336

Study Highlights: Explanation of Findings

Erosive hand OA is an unmet medical need: there are no treatments currently which prevent structural damage, although non-steroidal anti-inflammatories (NSAIDs), topical and oral, may relieve pain. In a previous study with an inhibitor of another pro-inflammatory cytokine, antitumor necrosis factor (anti-TNF), demonstrated that this approach prevented structural damage though it did not produce pain relief. An antimalarial drug, hydroxychloroquine, was also tested in a randomized placebo-controlled study known as HERO (Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis), but also produced no significant symptomatic, or radiographic, efficacy in patients with severe hand OA.

Preclinical studies with IL-1α and IL-1 β blockade, however, indicated that inflammatory cytokines IL-1α and IL-1β are involved in the pathogenesis of OA. “IL-1α and IL-1β bind to the IL-1 type 1 receptor, leading to the production of proinflammatory molecules, proteases and other mediators, which result in joint pain, inflammation and cartilage destruction,” the researchers said.

In a mouse model of human OA, inhibiting or blocking the two interleukins resulted in a decline in OA progression, and in a phase I trial of knee OA the treatment it was associated with decreases in neutrophils, C-reactive protein (CRP) and biomarkers of synovitis, such as matrix metalloproteinase-degraded collagen types I and III.

Although the drug treatment did lead to significant declines in serum levels of IL-1α and IL-1β and in levels of neutrophils, CRP levels, and matrix metalloproteinase-degraded collagen type 1, it did not resolve clinical signs and symptoms of erosive hand OA in this study. The pharmacokinetics of preclinical and phase 1 studies were replicated and confirmed in this trial, but that did not affect symptoms.

Adverse events and serious adverse events were similar in the two groups, but more patients in the lutikizumab group reported injection site reactions. Study withdrawals, because of adverse events, occurred in five patients receiving lutikizumab and two given placebo, and two patients receiving the active treatment withdrew from the study because of neutropenia. Low-density lipoprotein cholesterol levels increased more in the active treatment group.

One strength of the study was its stringent enrollment of only those with moderate to severe inflammation.

An important limitation of the study is the possibility that 26 weeks was not long enough to detect changes in pain, function, and structure, researchers noted. In addition, researchers did not measure hand joint synovial fluid levels of the drug or the target cytokines, which leaves open the question of whether the inflammatory cytokines had been reduced locally in the joint, which could impact pain and function. They also noted that they had no adequate explanation for the low use of non-steroidal anti-inflammatories (NSAIDS) or other pain relievers, given the high average level of pain patients had at baseline.

“In conclusion, despite adequate systemic lutikizumab pharmacodynamic effects, lutikizumab did not significantly improve clinical outcomes or imaging outcomes in patients with erosive hand OA compared with placebo, suggesting that targeting IL-1 may be ineffective for the treatment of erosive hand OA,” the authors wrote.

Nancy Walsh wrote the original study for MedPage Today

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