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Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12.
Ann Rheum Dis 2005; 64(4):537-43AR

Abstract

BACKGROUND

Tumour necrosis alpha (TNF alpha) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNF alpha 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 alpha 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 alpha, 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 alpha independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease.

Authors+Show Affiliations

Leiden University Medical Centre, Department of Rheumatology, PO Box 9600, 2300 RC Leiden, Netherlands. M.van_Oosterhout@LUMC.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

15769913

Citation

van Oosterhout, M, et al. "Clinical Efficacy of Infliximab Plus Methotrexate in DMARD Naive and DMARD Refractory Rheumatoid Arthritis Is Associated With Decreased Synovial Expression of TNF Alpha and IL18 but Not CXCL12." Annals of the Rheumatic Diseases, vol. 64, no. 4, 2005, pp. 537-43.
van Oosterhout M, Levarht EW, Sont JK, et al. Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12. Ann Rheum Dis. 2005;64(4):537-43.
van Oosterhout, M., Levarht, E. W., Sont, J. K., Huizinga, T. W., Toes, R. E., & van Laar, J. M. (2005). Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12. Annals of the Rheumatic Diseases, 64(4), pp. 537-43.
van Oosterhout M, et al. Clinical Efficacy of Infliximab Plus Methotrexate in DMARD Naive and DMARD Refractory Rheumatoid Arthritis Is Associated With Decreased Synovial Expression of TNF Alpha and IL18 but Not CXCL12. Ann Rheum Dis. 2005;64(4):537-43. PubMed PMID: 15769913.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12. AU - van Oosterhout,M, AU - Levarht,E W N, AU - Sont,J K, AU - Huizinga,T W J, AU - Toes,R E M, AU - van Laar,J M, PY - 2005/3/17/pubmed PY - 2005/4/26/medline PY - 2005/3/17/entrez SP - 537 EP - 43 JF - Annals of the rheumatic diseases JO - Ann. Rheum. Dis. VL - 64 IS - 4 N2 - BACKGROUND: Tumour necrosis alpha (TNF alpha) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNF alpha 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 alpha 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 alpha, 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 alpha independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease. SN - 0003-4967 UR - https://www.unboundmedicine.com/medline/citation/15769913/Clinical_efficacy_of_infliximab_plus_methotrexate_in_DMARD_naive_and_DMARD_refractory_rheumatoid_arthritis_is_associated_with_decreased_synovial_expression_of_TNF_alpha_and_IL18_but_not_CXCL12_ L2 - http://ard.bmj.com/cgi/pmidlookup?view=long&pmid=15769913 DB - PRIME DP - Unbound Medicine ER -