Efficacy of tocilizumab in patients with hand osteoarthritis: double blind, randomised, placebo-controlled, multicentre trial

Richette, Pascal; Latourte, Augustin; Sellam, Jérémie; Wendling, Daniel; Piperno, M.; Goupille, Philippe; Pers, Yves-Marie; Eymard, Florent; Ottaviani, Sébastien; Ornetti, Paul; Flipo, René‐Marc; Fautrel, Bruno; Peyr, Olivier; Bertola, Jean Pierre; Vicaut, Éric; Chevalier, Xavier

doi:10.1136/annrheumdis-2020-218547

Cited by 62 publications

(51 citation statements)

References 59 publications

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“…Failed in relieving pain in hand OA patient Richette et al (2020). Etanercept TNF-α Decreased some SASP expression in human OA chondrocytes in vitro Žigon-Branc et al (2017).…”

Section: Discussionmentioning

confidence: 99%

Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

Zhang

Liang

et al. 2021

Front. Pharmacol.

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Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. For a long time, OA has been considered as a degenerative disease, while recent observations indicate the mechanisms responsible for the pathogenesis of OA are multifaceted. Aging is a key factor in its development. Current treatments are palliative and no disease modifying anti-osteoarthritis drugs (DMOADs) are available. In addition to articular cartilage degradation, cellular senescence, synovial inflammation, and epigenetic alterations may all have a role in its formation. Accumulating data demonstrate a clear relationship between the senescence of articular chondrocytes and OA formation and progression. Inhibition of cell senescence may help identify new agents with the properties of DMOADs. Several anti-cellular senescence strategies have been proposed and these include sirtuin-activating compounds (STACs), senolytics, and senomorphics drugs. These agents may selectively remove senescent cells or ameliorate their harmful effects. The results from preclinical experiments and clinical trials are inspiring. However, more studies are warranted to confirm their efficacy, safety profiles and adverse effects of these agents.

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“…Failed in relieving pain in hand OA patient Richette et al (2020). Etanercept TNF-α Decreased some SASP expression in human OA chondrocytes in vitro Žigon-Branc et al (2017).…”

Section: Discussionmentioning

confidence: 99%

Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

Zhang

Liang

et al. 2021

Front. Pharmacol.

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“…As there are significant differences in the pathological mechanisms between RA and OA, the clinical results for their use in RA do not directly transfer to their use in OA conditions. A recent double-blinded, randomized controlled trial (NCT02477059) demonstrated that tocilizumab did not significantly reduce pain or improve function in patients with hand OA, and subsequently generated more adverse events such as infections and neutropenia within the treatment group 46 . This result is somewhat surprising in lieu of our findings, however hand OA is likely under the control of different signaling mechanisms as compared to PTOA of the knee.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis

Liao

Ren

Luo

et al. 2021

Preprint

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Osteoarthritis (OA) and post-traumatic OA (PTOA) are prevalent joint disorders and leading causes of chronic pain. The disease pathology of OA/PTOA is caused by imbalanced catabolic and anabolic responses and pro-inflammatory changes; however, their connection to pain is not well studied. Since IL-6 is involved in cartilage degradation and conditions of inflammatory pain, we set out to identify whether IL-6 and IL-6 signaling mechanisms contribute to both PTOA-associated cartilage degradation and pain. We performed a modified destabilization of the medial meniscus (DMM) surgery, a model of PTOA, on conventional IL-6 KO and control mice and assessed both cartilage degradation and pain-associated phenotypes. Genetic removal of Il6 in males attenuates PTOA-associated cartilage catabolism, decreases innervation of soft tissues associated with the knee joint, and reduces nociceptive pain signaling, without improving subchondral bone sclerosis or chondrocyte apoptosis. We further demonstrate that specific downstream mediators of IL-6 signaling, the Janus kinases (JAKs), are critical in regulating both cartilage catabolism and pain signaling. We identified STAT3 as a key regulator of cartilage catabolism downstream of JAK; however, inhibition of STAT3 decreases cartilage anabolism while enhancing pain signals. ERK was found to be important for neurite outgrowth and pain signaling; however, inhibition of ERK was less effective in reducing cartilage catabolism. Therefore, our data demonstrate that IL-6 mediates both PTOA-associated cartilage degradation and pain, and provides critical details regarding the downstream mediators of IL-6 signaling as therapeutic targets for disease-modifying osteoarthritis drugs.

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“… 153 Recently, in a phase-3 trial evaluating the efficacy of tocilizumab in hand OA for 12 weeks (n=104), it revealed no more effectiveness than placebo for pain relief (−7.9 vs −9.9 on VAS score in the tocilizumab and placebo groups). 154 …”

Section: Synovitis-driven Endotypementioning

confidence: 99%

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

Oo¹,

Little²,

Duong³

et al. 2021

DDDT

156

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Osteoarthritis (OA) is a complex heterogeneous articular disease with multiple joint tissue involvement of varying severity and no regulatory-agency-approved diseasemodifying drugs (DMOADs). In this review, we discuss the reasons necessitating the development of DMOADs for OA management, the classifications of clinical phenotypes or molecular/mechanistic endotypes from the viewpoint of targeted drug discovery, and then summarize the efficacy and safety profile of a range of targeted drugs in Phase 2 and 3 clinical trials directed to cartilage-driven, bone-driven, and inflammation-driven endotypes. Finally, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers.

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Efficacy of tocilizumab in patients with hand osteoarthritis: double blind, randomised, placebo-controlled, multicentre trial

Cited by 62 publications

References 59 publications

Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

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