EXTENDED REPORT

Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF and IL18 but not CXCL12

M van Oosterhout¹, E W N Levarht¹, J K Sont², T W J Huizinga¹, R E M Toes¹, J M van Laar¹

¹ Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands
² Department of Medical Decision Making, Leiden University Medical Centre

Correspondence to:
Correspondence to:
M van Oosterhout
Leiden University Medical Centre, Department of Rheumatology, C4R, PO Box 9600, 2300 RC Leiden, Netherlands; M.van_Oosterhout{at}LUMC.nl

Background: Tumour necrosis (TNF) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNF independent pathways play a role in the disease.

Objectives: To evaluate the immunopathological effects of combination therapy on rheumatoid synovial tissue in order to identify TNF independent mechanisms.

Methods: 12 rheumatoid patients, including four DMARD (disease modifying antirheumatic drug) naive patients with early disease, were studied for the effect of combination therapy with infliximab and methotrexate on the synovial infiltrate. Biopsies and clinical assessments (DAS28) were carried out before the first and after the third infusion of infliximab. Synovial inflammation was scored semiquantitatively. Co-expression of CD38⁺ cells was studied by an immunofluorescent double labelling technique.

Results: Marked clinical responses were associated with a global reduction in the synovial infiltrate and expression of cytokines, notably interleukin 18 and TNF, but low grade disease activity persisted. There was no effect on the expression of CXC chemokine ligand (CXCL12), and germinal centre-like structures were still detectable in synovial tissue in two patients after treatment. CD38⁺ activated T cells were more resistant to treatment than CD38⁺ plasma cells. No differences in clinical response or effects on synovial infiltrate were observed between DMARD refractory and DMARD naive patients.

Conclusions: Persistent expression of CXCL12 and incomplete resolution of lymphocytic infiltrates after infliximab plus methotrexate indicates that TNF independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease.

Abbreviations: ACR, American College of Rheumatology; CXCL, CXC chemokine ligand; CXCR, CXC chemokine ligand receptor; DAS28, 28 joint disease activity score; DMARD, disease modifying antirheumatic drug; EULAR, European League Against Rheumatism; IL, interleukin; TNF, tumour necrosis factor

Keywords: CXCL-12; infliximab; interleukin 18; rheumatoid arthritis; synovitis

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