Elsevier

Joint Bone Spine

Volume 80, Issue 2, March 2013, Pages 165-170
Joint Bone Spine

Original article
Blockade of intra-articular TNF in peripheral spondyloarthritis: Its relevance to clinical scores, quantitative imaging and synovial fluid and synovial tissue biomarkers

https://doi.org/10.1016/j.jbspin.2012.06.016Get rights and content

Abstract

Objectives

This open-label study is based on a translational approach with the aim of detecting changes in the clinical condition as well as in imaging and synovial biological markers in both synovial fluid (SF) and synovial tissue (ST) in peripheral spondyloarthritis (SpA) patients following intra-articular (IA) blockade of TNF-α by serial etanercept injections.

Methods

Twenty-seven SpA patients with resistant knee synovitis underwent four biweekly IA injections of etanercept (E) (12.5 mg). The primary outcome of Thompson's Knee Index (THOMP), and secondary outcomes of Knee Joint Articular Index (KJAI), C-reactive protein (CRP), HAQ-Disability Index (HAQ-DI), maximal synovial thickness (MST) according to ultrasonography (US) and contrast-enhanced magnetic resonance (C+MR) imaging, ST-CD45+ mononuclear cells (MNC) and ST-CD31+ vessels, IL-1β, IL-1Ra and IL-6 levels in SF were assessed at baseline and at the end of the study.

Results

At the study end, clinical and imaging outcomes as well as ST and SF biological markers were significantly reduced compared to baseline. There were significant correlations between clinical, imaging and biological markers (CRP with either THOMP, or KJAI, or HAQ-DI or SF-IL-1Ra; US-MST with KJAI, ST-CD45+ with either THOMP, or KJAI, or ST-CD31+, or SF-IL-1β; SF-IL-6 with either THOMP, or KJAI, or SF-IL-1β, or IL-1Ra).

Conclusions

The proof of concept study revealed early improvement either in local and systemic clinical scores, in synovial thickness measures by C+MR and US, or expression of synovial biological markers. CD45+, CD31+ in ST and IL-6 and IL-1β in SF may be considered potential biomarkers of the peripheral SpA response to IA TNF-α blocking.

Introduction

Synovial immunopathology has been well characterized in spondyloarthropathies (SpA) [1], by delineation of disease-specific features, of the similarity between different SpA subtypes, including psoriatic arthritis (PsA), as well by highlighting the histopathological characteristics induced by effective treatment in SpA synovitis, such as down-regulation of leucocyte infiltration and hypervascularity [2]. Nevertheless, only limited data on synovial biomarkers of peripheral joint involvement in SpA are available [3].

Peripheral arthritis in SpA is often resistant to intra-articular (IA) drugs or surgical therapies. Consequently, therapies that specifically target affected joints would constitute a welcome alternative [4], [5]. So far, a few small randomized studies on serial TNF-α-blocking injections in individual joints have been described in the literature [6], [7], [8]. Likewise, very few studies providing “proof of concept” have addressed the issue of the local assessment of inflammation at single joint level [9] to detect early changes resulting from the blockade of intra-articular (IA) TNF-α.

A randomized, blind-controlled, single-centre study on serial low dosage injections of IA etanercept (E) in resistant knee joint synovitis (KJS) has shown early slow down of KJS inflammation, along with the good patient compliance and safety profile. Either the superiority of low-dose of IA etanercept to placebo, or the drug's short term effect after the cross-over, has been reflected in a higher than expected drop-out rate of IA-P treated knees and a lower power of the study (Fig. 1) [10], [11]. The open-label extension of the IA blind study was designed to analyse the response to serial low dosage injections of IA E in resistant SpA KJS (Fig. 1) [10], [11]. A translational approach was used, based on specific tools such as biological synovial markers, composite clinical scores and ultrasound (US) and contrast-enhanced magnetic resonance (C+MR) imaging, and quantitative measures of the synovitis response to IA TNF-α blockade.

Synovial hypervascularity along with leucocyte ST infiltration is a distinctive feature of SpA synovitis. However, only limited data are available as to their association with either clinical disease activity or with the response to systemic TNF-blocking therapy in peripheral SpA [2], [3]. Among the immunocytochemical markers, the synovial tissue expression of CD45+, the leucocyte-common antigen (LCA) by mononuclear cells (MNC), along with that of the CD31+ platelet endothelial cell adhesion molecule (PECAM)-1 by mature synovial vessels, were assessed.

The cytokine (CK) patterns observed so far in synovial fluid (SF) of patients with SpA were disparate [12], [13]. Further, the potential role of synovial fluid inflammatory CK as biomarkers of the response to anti-TNF therapy has recently been suggested [13], [14].

The proof of concept study showed early improvement either in local and systemic clinical scores, synovial thickness measures by C+MR- and US, or in the expression of CD45+-, CD31+-ST and IL-6-SF synovial markers that are significantly interactive and correlate with clinical measures.

Section snippets

Study design

The study represents the prospective open-label extension of a randomized, placebo-controlled, single-centre study protocol on serial IA etanercept (E) injections that was approved by the local ethics committee (Etanercept/TNR-001:n.878P; ClinicalTrials.gov Identifier: NCT00678782).

All patients signed informed consent statements before entering the study. Joints were assessed before each IA injection and 2 weeks after the final one. The blind study protocol consisted of the administration

Results

All 27 SpA KJS completed the IA-E open-label prospective study. At baseline of the blind study, IA-E and IA-P groups showed no statistically significant differences in both the ACR-SJC score (2.353 ± 2.09 vs 3.765 ± 3.666; p:ns) and in the ACR-TJC score (4.765 ± 4.711 vs 3.706 ± 2.932; p:ns).

Neither severe nor moderate adverse effects and no IA drug-related adverse events were reported during the whole study.

Discussion

This open-label extension study, compared to the previous blind study, allows a more accurate longitudinal evaluation of the local effect of the new IA therapeutic procedure, since the definite number of IA drug injections for each knee joint of peripheral SpA affected patients and the single joint translational approach, including a wider range of imaging, clinical, and synovial biological measures.

The early significant improvement in the clinical composite inflammation and functional indexes

Disclosure of interest

Ugo Fiocco has received speaking fees and/or research grants from Wyeth Lederle, Schering Plough and Bristol-Myers Squibb.

Leonardo Punzi has received speaking fees and/or research grants from Wyeth Lederle, Schering Plough, Bristol-Myers Squibb, Abbott International, Rottapharm, Fidia Farmaceutici and Roche.

Funding: This work was in part supported by a joint research grant from the Padova University Hospital and Wyeth Lederle SpA (Wyeth Pharmaceuticals, USA).

The work of Roberto Nardacchione was

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