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

M van Oosterhout; E W N Levarht; J K Sont; T W J Huizinga; R E M Toes; J M van Laar

doi:10.1136/ard.2004.024927

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

M van Oosterhout, E W N Levarht, J K Sont, T W J Huizinga, R E M Toes, J M van Laar

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	537-43
Number of pages	7
Journal	Annals of the Rheumatic Diseases
Volume	64
Issue number	4
DOIs	https://doi.org/10.1136/ard.2004.024927
Publication status	Published - Apr 2005
Externally published	Yes

Keywords

Adult
Antibodies, Monoclonal
Antirheumatic Agents
Arthritis, Rheumatoid
Arthroscopy
Chemokine CXCL12
Chemokines, CXC
Drug Therapy, Combination
Female
Humans
Immunoenzyme Techniques
Infliximab
Interleukin-18
Ligands
Male
Methotrexate
Middle Aged
Synovial Membrane
Synovitis
Treatment Failure
Treatment Outcome
Tumor Necrosis Factor-alpha
Clinical Trial
Journal Article

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10.1136/ard.2004.024927

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van Oosterhout, M., Levarht, E. W. N., Sont, J. K., Huizinga, T. W. J., Toes, R. E. M., & 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), 537-43. https://doi.org/10.1136/ard.2004.024927

@article{d76dbb815e104987b77ad19547a167e2,

title = "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",

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.",

keywords = "Adult, Antibodies, Monoclonal, Antirheumatic Agents, Arthritis, Rheumatoid, Arthroscopy, Chemokine CXCL12, Chemokines, CXC, Drug Therapy, Combination, Female, Humans, Immunoenzyme Techniques, Infliximab, Interleukin-18, Ligands, Male, Methotrexate, Middle Aged, Synovial Membrane, Synovitis, Treatment Failure, Treatment Outcome, Tumor Necrosis Factor-alpha, Clinical Trial, Journal Article",

author = "{van Oosterhout}, M and Levarht, {E W N} and Sont, {J K} and Huizinga, {T W J} and Toes, {R E M} and {van Laar}, {J M}",

year = "2005",

month = apr,

doi = "10.1136/ard.2004.024927",

language = "English",

volume = "64",

pages = "537--43",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "Elsevier",

number = "4",

}

van Oosterhout, M, Levarht, EWN, Sont, JK, Huizinga, TWJ, Toes, REM & van Laar, JM 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, vol. 64, no. 4, pp. 537-43. https://doi.org/10.1136/ard.2004.024927

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. / van Oosterhout, M; Levarht, E W N; Sont, J K et al.
In: Annals of the Rheumatic Diseases, Vol. 64, No. 4, 04.2005, p. 537-43.

Research output: Contribution to journal › Article › Academic › peer-review

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 - 2005/4

Y1 - 2005/4

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.

AB - 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.

KW - Adult

KW - Antibodies, Monoclonal

KW - Antirheumatic Agents

KW - Arthritis, Rheumatoid

KW - Arthroscopy

KW - Chemokine CXCL12

KW - Chemokines, CXC

KW - Drug Therapy, Combination

KW - Female

KW - Humans

KW - Immunoenzyme Techniques

KW - Infliximab

KW - Interleukin-18

KW - Ligands

KW - Male

KW - Methotrexate

KW - Middle Aged

KW - Synovial Membrane

KW - Synovitis

KW - Treatment Failure

KW - Treatment Outcome

KW - Tumor Necrosis Factor-alpha

KW - Clinical Trial

KW - Journal Article

U2 - 10.1136/ard.2004.024927

DO - 10.1136/ard.2004.024927

M3 - Article

C2 - 15769913

SN - 0003-4967

VL - 64

SP - 537

EP - 543

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 4

ER -

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

Abstract

Keywords

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