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We read with deep interest the article by Kloppenburg et al,1 which was aimed at assessing the efficacy, safety, pharmacokinetics and pharmacodynamics of anti-interleukin (IL)-1α/β dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA). The results indicated that administration of 200 mg lutikizumab subcutaneously every 2 weeks for 24 weeks did not improve pain or imaging outcomes in erosive HOA compared with a placebo. This conclusion might be disappointing for doctors and even patients who desire a wider choice in drugs.
In this study, the authors administered lutikizumab to neutralise the expression of IL-1α and IL-1β; however, to the best of our knowledge, until recently, the source of IL-1 was unclear and whether active IL-1b is produced in osteoarthritic cartilage remains highly controversial,2 although it is well known that IL-1 is one of the two prototypical proinflammatory cytokines that participate in the pathogenesis of degradation of extracellular matrix and joint inflammation in OA.3 IL-1 was first identified in the late 1970s as an inflammatory mediator capable of tissue damage and was widely added to cultured chondrocytes or synovial cells to mimic the osteoarthritic condition in vitro.4 Previous studies confirmed that in cartilaginous specimens, IL-1β, but not IL-1α, was detected as diffuse staining of the extracellular matrix, especially surrounding superficial zone chondrocytes.5 However, not every osteoarthritic cartilage could express IL-1α and IL-1β; the mild-to-moderate osteoarthritic cartilage had a higher proportion of IL-1α and IL-1β positive cells than more severely degenerated cartilage. Moreover, IL-1α and IL-1β expression in patients with severely degenerated cartilage was even lower than that in asymptomatic people.5 The production of IL-1 requires caspase 1 to activate its precursor, pro-IL-1β. Caspase 1 itself must be converted from procaspase 1 to active caspase 1 via the molecular scaffold, ‘inflammasome’; however, the inflammasome constituents, the nucleotide-binding domain leucine-rich repeats family protein 3, apoptotic speck-containing protein and caspase 1, were not strongly expressed in osteoarthritic cartilage; therefore, IL-1β may not be produced by the cartilage.5 6 Therefore, in erosive HOA, the expression levels of IL-1α and IL-1β might not be originally elevated or changed with the progression of OA; in this study, IL-1α and IL-1β serum levels were measured at baseline and weeks 2 and 4, and it was difficult to determine the changes in IL-1α and IL-1β serum levels afterwards.
According to the recommendations of Osteoarthritis Research Society International regarding the design and conduct of clinical trials for HOA,7 it is best to evaluate parameters, including pain, physical function, patient global assessment, health-related quality of life, joint activity and hand strength in the clinical trials. To the best of our knowledge, the authors did not report the results of the patient global assessment, health-related quality of life, joint activity and hand strength in this paper. It is necessary to determine whether there was any difference in the improvement of hand symptoms after treatment with the drug when both hands of the patient were involved.
We respect the significant contributions of the authors, and look forward to the follow-up results of this study.
Contributors CC: concept and writing; JT: concept; FZ: concept and revising.
Funding This work was supported by the Natural Science Foundation of China (grant number 81501923).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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