Elsevier

The Lancet

Volume 368, Issue 9538, 2–8 September 2006, Pages 855-863
The Lancet

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Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomised trial

https://doi.org/10.1016/S0140-6736(06)69210-6Get rights and content

Summary

Background

Chaperonin 10 (heat shock protein 10, XToll™) has anti-inflammatory properties related to the inhibition of Toll-like receptor signalling pathways. Our aim was to establish whether chaperonin 10 is safe and effective in the treatment of rheumatoid arthritis.

Methods

In this randomised, double-blind, multicentre study, 23 patients with moderate to severe active rheumatoid arthritis receiving disease-modifying antirheumatic drugs were randomly allocated to three treatment groups receiving intravenous chaperonin 10 twice weekly for 12 weeks at doses of 5 mg (n=8), 7·5 mg (8), or 10 mg (7). The primary outcomes were change in disease activity score (DAS28) and improvement of core disease measures (American College of Rheumatology response score) from baseline to week 12. All analyses were done by intention to treat. This study is registered with the Australian Clinical Trials Registry, number ACTRNO12606000041550.

Findings

Primary endpoint measures improved from day 14 in all groups and continued to improve to day 84. By end of study, a 20% improvement of core disease measures was seen in six (86%, 95% CI 43–100), a 50% improvement in four (57%, 14–86), and a 70% improvement in two (29%, 0–57) patients given the highest dose of chaperonin 10. Clinical remission (as defined by a DAS28 <2·6) was achieved in three (13%) of 23 patients. Three individuals dropped out during the study: one in the 5 mg group (rheumatoid arthritis not controlled), one in the 7·5 mg group (adverse event), and one in the 10 mg group (lost to follow-up). The most common adverse events were exacerbation of rheumatoid arthritis (both during and after the study) and upper respiratory tract infection. Only one adverse event was judged to be of severe intensity.

Interpretation

Chaperonin 10 seems to be well tolerated and efficacious in treatment of the symptoms of rheumatoid arthritis, at least in the short term.

Introduction

Chaperonin 10, which is also called heat shock protein 10, is a 70 kDa mitochondrial protein (heptamer) known mainly for its role in intracellular protein folding, in concert with heat shock protein 60.1 Extracellular chaperonin 10 might have a role in the modulation of the innate immune response. The molecule has anti-inflammatory and immunomodulatory properties via inhibition of downstream events in Toll-like receptor (TLR) activated pathways.2 Due to their roles in the regulation and linking of the immune and inflammatory responses, TLRs and their exogenous and endogenous ligands, which propagate inflammation, are the subject of intense research.3, 4, 5 TLRs are highly expressed in synovial tissue3, 6, 7 and their activation contributes to the pathological processes of autoimmune and chronic inflammatory diseases such as rheumatoid arthritis. We have shown that chaperonin 10 inhibits both the TLR4-mediated induction of nuclear factor kappa B (NFκB) activation by lipopolysaccharide and the production of tumour necrosis factor (TNF) α and interleukin 6 in human peripheral blood mononuclear cells (PBMC) from healthy volunteers and patients with multiple sclerosis.2, 8

Although the initial trigger of rheumatoid arthritis is not defined, many cell populations seem to be implicated. Inflammatory cells—including monocytes, macrophages, dendritic cells, T cells, and B cells—infiltrate the synovial membrane, where together with chondrocytes, osteoclasts, and synovial fibroblasts they secrete cytokines, chemokines, and matrix metalloproteinases, inducing osteoclastogenic activity and resulting in the erosion of cartilage and bone.9, 10, 11, 12 Many pro-inflammatory cytokines (including TNFα, interleukin 1, and interleukin 6) and anti-inflammatory cytokines (interleukin 4, interleukin 10, tumour growth factor β) are released. The inflammatory response in rheumatoid arthritis is thought to be a result of the balance of these mediators shifting in favour of the pro-inflammatory cytokines, thus driving the arthritic process. TNFα is a critical mediator in the inflammatory response cascade9, 10, 11, 12 and is the target for several of the latest registered treatments for rheumatoid arthritis, including two monoclonal antibodies (infliximab and adalimumab)11, 13 and a recombinant TNF decoy receptor (etanercept).14, 15 The TNF inhibitors are more specific in their activity than are disease-modifying antirheumatic drugs (DMARDs; eg, methotrexate), which often become ineffective over time and can produce serious adverse events.16

The primary objective of this study was to determine the clinical efficacy and safety of chaperonin 10 in patients with moderate-to-severe active rheumatoid arthritis, even with concurrent treatment with standard DMARDs.

Section snippets

Participants

Otherwise healthy non-pregnant patients aged 18–75 years with disease duration of at least 6 months, onset of rheumatoid arthritis after 18 years of age (with one exception), and classified as American College of Rheumatology (ACR) functional class I–III17, 18 were eligible for enrolment. Enrolment criteria included active disease at screening, which was defined as eight or more tender and swollen joints, and either an ESR of 28 mm/h or more, a C-reactive protein (CRP) concentration of 10 mg/L

Results

Figure 1 shows the trial profile. The baseline characteristics of the three groups are shown in table 1. The ratio of women to men was higher in the 7·5 mg group than the other groups and three patients in the same group were not taking any concurrent DMARDs.

Three patients withdrew early from the study (figure 1). One patient in the 10 mg group reached the end of the study but failed to attend the safety follow-up visit. One patient in the 7·5 mg group withdrew because of an adverse event of

Discussion

Our findings suggest that treatment of individuals with active rheumatoid arthritis with chaperonin 10 results in short-term improvement of disease activity indicators, with improvements in symptoms seen as early as day 14 and sustained to day 84 of treatment. Rapid improvements in physical functioning and quality of life, as well as inhibition of cytokine production in vitro, were also seen.

This protocol was designed without placebo as an exploratory proof-of-principle investigation of the

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