Can Targeting RANKL in RA Heal Erosions? Save

Treatment with denosumab (Prolia) helped heal bone erosions over 2 years among patients with rheumatoid arthritis whose disease activity was well controlled, researchers reported.

In a double-blind study that enrolled 110 patients, the number of patients who showed healing of erosions at 12 months was similar among those randomized to denosumab and those receiving placebo (18% vs 13%, P=0.45), but significantly more patients given denosumab experienced healing by 24 months (20% vs 6%, P=0.045), according to Lai-Shan Tam, MD, of the Chinese University of Hong Kong, and colleagues.

Treatment with denosumab (Prolia) helped heal bone erosions over 2 years among patients with rheumatoid arthritis whose disease activity was well controlled, researchers reported.

In a double-blind study that enrolled 110 patients, the number of patients who showed healing of erosions at 12 months was similar among those randomized to denosumab and those receiving placebo (18% vs 13%, P=0.45), but significantly more patients given denosumab experienced healing by 24 months (20% vs 6%, P=0.045), according to Lai-Shan Tam, MD, of the Chinese University of Hong Kong, and colleagues.

"[Denosumab] could be considered a treatment option for retarding bone damage progression independent of the disease activity control," the researchers wrote online in Annals of the Rheumatic Diseases.

Bone erosions in rheumatoid arthritis reflect disease progression and are associated with functional disability. The development of erosions is regulated through the receptor activator of nuclear factor kappa B ligand (RANKL) pathway, which influences osteoclast function and survival.

Denosumab is a monoclonal antibody that inhibits the RANKL pathway and has been shown to block the progression of erosions in patients with rheumatoid arthritis, but whether actual repair of these lesions could occur has been unclear. In a small pilot study, Tam's group found that the width, depth, and volume of erosions measured by high-resolution peripheral quantitative CT were reduced over 6 months in patients given denosumab.

Among patients who have achieved sustained low disease activity or remission, symptoms may be few but there can be ongoing erosion progression resulting from low-grade inflammation and persistent activation of the RANKL pathway.

To explore the possibility that denosumab might induce long-term erosion healing in rheumatoid arthritis, the researchers assigned patients to receive subcutaneous injections of denosumab 60 mg or placebo at baseline, 6 months, 12 months, and 18 months.

They also received standard treatment with conventional disease-modifying antirheumatic drugs (DMARDs) according to a treat-to-target protocol, with dose and drug adjustments of DMARDs, nonsteroidal anti-inflammatory drugs, and glucocorticoids as needed to control disease activity.

Erosions were measured on high-resolution peripheral quantitative CT at 2-4 metacarpophalangeal head among patients who achieved low disease activity or remission and had at least one erosion at baseline.

"Erosions were defined as sharply marginated bone lesions with juxta-articular localization with a cortical break seen in at least two adjacent slices, which were often accompanied by loss of the adjacent trabecular bone," the investigators wrote.

Erosion healing was defined as a decrease in the volume of the erosion greater than the smallest detectable change of 0.2 mm3 plus an increase in the marginal bone mineral density above the smallest detectable change of 6.3 mmHA/cm3, or full disappearance of the lesion.

Of the 110 patients enrolled from 2017 to 2018, 80% were women and mean age was 57. Mean disease duration was almost 8 years and mean Disease Activity Score in 28 joints (DAS28) was 2.51 (remission is a DAS28 below 2.6). Baseline score on the Health Assessment Questionnaire Disability Index (HAQ-DI) was 0.25. The 2-year study period was completed by 102 patients.

At baseline, 137 and 114 erosions were detected in the denosumab and placebo groups, respectively.

Among six of the patients in the placebo group who showed erosion healing at 1 year, three experienced progression during the second year. "Even if erosion healing occurred in a small proportion of patients in the placebo group in the first year, the effect was not sustainable," Tam and colleagues wrote.

In contrast, in the denosumab group, six out of nine patients had sustained healing over the 2 years and four additional patients showed healing during the second year.

Logistic regression analysis was then performed after adjustment for multiple covariates including age, sex, disease duration and activity, erosion volume, HAQ-DI, and maintenance of remission, revealing that denosumab use was associated with healing of erosions (OR 3.39, 95% CI 1.08-10.63, P=0.036). Additional predictors of erosion healing were younger age (OR 0.93, 95% CI 0.87-1.0, P=0.039) and greater erosion width at baseline (OR 3.25, 95% CI 1.30-8.12, P=0.012).

Comparison of individual erosions found that denosumab treatment was associated at 24 months with the following:

• Fewer new erosions (9% vs 19%, P=0.009)
• Less progression of erosions (8% vs 18%, P=0.019)
• More regression of erosions (18% vs 9%, P=0.046)

Other differences between the groups included a marginally greater proportion of radiographic progression observed in the placebo group (27.3% vs 12.7%, P=0.057) and greater increases in bone mineral density at the total hip and femoral neck in the denosumab group, but no significant difference was seen on the HAQ-DI.

In discussing their findings, the investigators noted that their study was not powered to detect significant radiographic changes, and they specifically enrolled patients with low to moderate disease activity "in order to study the more focused effect on erosion healing by targeting the RANKL pathway." Also, they explained that longer follow-up may be needed to detect differences in functional disability on the HAQ-DI.

A limitation of the study was the lack of information about bone metabolism and markers of cartilage turnover.

Source Reference: So H, et al "Effects of RANKL inhibition on promoting healing of bone erosion in rheumatoid arthritis using HR-pQCT: a 2-year, randomized, double-blind, placebo-controlled trial" Ann Rheum Dis 2021; DOI: 10.1136/annrheumdis-2021-219846.