Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway.
OBJECTIVES: To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and m...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2012
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| _version_ | 1826297555318734848 |
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| author | Alzabin, S Abraham, S Taher, T Palfreeman, A Hull, D McNamee, K Jawad, A Pathan, E Kinderlerer, A Taylor, P Williams, R Mageed, R |
| author_facet | Alzabin, S Abraham, S Taher, T Palfreeman, A Hull, D McNamee, K Jawad, A Pathan, E Kinderlerer, A Taylor, P Williams, R Mageed, R |
| author_sort | Alzabin, S |
| collection | OXFORD |
| description | OBJECTIVES: To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα and anti-IL-17 in experimental arthritis. METHODS: A longitudinal study of two independent cohorts (cohort 1, n=24; cohort 2, n=19) of patients with RA treated with anti-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFα therapy. IL-12/23p40 production was assessed in plasma Peripheral blood lymphocytes (PBLs) and monocytes. Mice with collagen-induced arthritis (CIA) were treated with anti-TNFα alone, anti-IL17 alone or a combination of the two. Efficacy of treatment and response was assessed from changes in Disease Activity Score 28-erythrocyte sedimentation rate scores in patients, and in clinical scores and histological analysis in CIA. RESULTS: Significant increases in circulating Th17 cells were observed in patients after anti-TNFα therapy and this was accompanied by increased production of IL-12/23p40. There was an inverse relationship between baseline Th17 levels and the subsequent response of patients with RA to anti-TNFα therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNFα-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFα and IL-17 in CIA was more effective than monotherapy, particularly with respect to the duration of the therapeutic effect. CONCLUSIONS: These findings, which need to be confirmed in a larger cohort, suggest that a Th17-targeted therapeutic approach may be useful for anti-TNFα non-responder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed. |
| first_indexed | 2024-03-07T04:33:26Z |
| format | Journal article |
| id | oxford-uuid:cf1cbd57-ba21-4a89-9902-657fc9e52135 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:33:26Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:cf1cbd57-ba21-4a89-9902-657fc9e521352022-03-27T07:40:17ZIncomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cf1cbd57-ba21-4a89-9902-657fc9e52135EnglishSymplectic Elements at Oxford2012Alzabin, SAbraham, STaher, TPalfreeman, AHull, DMcNamee, KJawad, APathan, EKinderlerer, ATaylor, PWilliams, RMageed, ROBJECTIVES: To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα and anti-IL-17 in experimental arthritis. METHODS: A longitudinal study of two independent cohorts (cohort 1, n=24; cohort 2, n=19) of patients with RA treated with anti-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFα therapy. IL-12/23p40 production was assessed in plasma Peripheral blood lymphocytes (PBLs) and monocytes. Mice with collagen-induced arthritis (CIA) were treated with anti-TNFα alone, anti-IL17 alone or a combination of the two. Efficacy of treatment and response was assessed from changes in Disease Activity Score 28-erythrocyte sedimentation rate scores in patients, and in clinical scores and histological analysis in CIA. RESULTS: Significant increases in circulating Th17 cells were observed in patients after anti-TNFα therapy and this was accompanied by increased production of IL-12/23p40. There was an inverse relationship between baseline Th17 levels and the subsequent response of patients with RA to anti-TNFα therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNFα-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFα and IL-17 in CIA was more effective than monotherapy, particularly with respect to the duration of the therapeutic effect. CONCLUSIONS: These findings, which need to be confirmed in a larger cohort, suggest that a Th17-targeted therapeutic approach may be useful for anti-TNFα non-responder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed. |
| spellingShingle | Alzabin, S Abraham, S Taher, T Palfreeman, A Hull, D McNamee, K Jawad, A Pathan, E Kinderlerer, A Taylor, P Williams, R Mageed, R Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. |
| title | Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. |
| title_full | Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. |
| title_fullStr | Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. |
| title_full_unstemmed | Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. |
| title_short | Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. |
| title_sort | incomplete response of inflammatory arthritis to tnfα blockade is associated with the th17 pathway |
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