Hayer Silvia, Niederreiter Birgit, Kalkgruber Marlene, Wanic Konrad, Maißner Julia, Smolen Josef S, Aletaha Daniel, Blüml Stephan, Redlich Kurt
Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria.
Hietzing Hospital, 2nd Department of Medicine, Vienna, Austria.
Bone Joint Res. 2022 Jul;11(7):484-493. doi: 10.1302/2046-3758.117.BJR-2021-0481.R1.
Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficiency of two major cytokines, namely interleukin (IL)-1 and IL-6, in this study double deficient mice for IL-1αβ and IL-6 were investigated in different tumour necrosis factor (TNF)-driven inflammatory bone disorders, namely peripheral arthritis and sacroiliitis, as well as systemic bone loss.
Disease course, histopathological features of arthritis, and micro-CT (µCT) bone analysis of local and systemic bone loss were assessed in 15-week-old hTNFtg in comparison to hTNFtg, hTNFtg, and hTNFtg mice. µCT bone analysis of single deficient and wild-type mice was also performed.
Combined deficiency of IL-1/IL-6 markedly ameliorated TNF-mediated arthritis and bilateral sacroiliitis, but without additive benefits compared to single IL-1 deficiency. This finding confirms the important role of IL-1 and the marginal role of IL-6 in TNF-driven pathways of local joint damage, but questions the efficacy of potential combinatorial therapies of IL-1 and IL-6 in treatment of RA. In contrast, combined deficiency of IL-1/IL-6 led to an additive protective effect on TNF-driven systemic bone loss compared to single IL-1 and IL-6 deficiency. This finding clearly indicates a common contribution of both IL-1 and IL-6 in TNF-driven systemic bone loss, and points to a discrepancy of cytokine dependency in local and systemic TNF-driven mechanisms of inflammatory arthritis.
Combinatorial treatments in RA might provide different benefits to inflammatory local arthritis and systemic comorbidities. Cite this article: 2022;11(7):484-493.
类风湿关节炎（RA）患者治疗反应不足需要新的治疗策略来阻止疾病进展。细胞因子抑制剂联合使用在RA中的潜在益处仍不明确，需要进一步研究。为了探究两种主要细胞因子，即白细胞介素（IL）-1和IL-6联合缺乏的影响，在本研究中，对IL-1αβ和IL-6双缺陷小鼠在不同肿瘤坏死因子（TNF）驱动的炎性骨疾病中进行了研究，这些疾病包括外周关节炎、骶髂关节炎以及全身性骨质流失。
与hTNFtg、hTNFtg和hTNFtg小鼠相比，对15周龄的hTNFtg小鼠的病程、关节炎的组织病理学特征以及局部和全身性骨质流失的显微CT（µCT）骨分析进行了评估。还对单缺陷和野生型小鼠进行了µCT骨分析。
IL-1/IL-6联合缺乏显著改善了TNF介导的关节炎和双侧骶髂关节炎，但与单IL-1缺乏相比没有额外益处。这一发现证实了IL-1在TNF驱动的局部关节损伤途径中的重要作用以及IL-6的边缘作用，但对IL-1和IL-6联合治疗RA的疗效提出了质疑。相比之下，与单IL-1和IL-6缺乏相比，IL-1/IL-6联合缺乏对TNF驱动的全身性骨质流失产生了额外的保护作用。这一发现清楚地表明IL-1和IL-6在TNF驱动的全身性骨质流失中都有共同作用，并指出了在局部和全身性TNF驱动的炎性关节炎机制中细胞因子依赖性的差异。
RA中的联合治疗可能对炎性局部关节炎和全身性合并症提供不同的益处。引用本文：2022；11(7):484-493。
