Abstract
ObjectiveThe immune inflammatory disorders rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps) share common pathologic features and show responsiveness to anti-tumor necrosis factor (TNF) agents yet they are phenotypically distinct. The aim of this study was to examine if anti-TNF therapy is associated with divergent gene expression profiles in circulating cells and target tissues of patients with these diseases.MethodsPeripheral blood CD14+ and CD14− cells were isolated from 9 RA, 12 PsA and 10 Ps patients before and after infliximab (IFX) treatment. Paired synovial (n = 3, RA, PsA) and skin biopsies (n = 5, Ps) were also collected. Gene expression was analyzed by microarrays.Results26 out of 31 subjects responded to IFX. The transcriptional response of CD14+ cells to IFX was unique for the three diseases, with little overlap (<25%) in significantly changed gene lists (with PsA having the largest number of changed genes). In Ps, altered gene expression was more pronounced in lesional skin (relative to paired, healthy skin) compared to blood (relative to healthy controls). Marked suppression of up-regulated genes in affected skin was noted 2 weeks after therapy but the expression patterns differed from uninvolved skin. Divergent patterns of expression were noted between the blood cells and skin or synovial tissues in individual patients. Functions that promote cell differentiation, proliferation and apoptosis in all three diseases were enriched. RA was enriched in functions in CD14− cells, PsA in CD14+ cells and Ps in both CD14+ and CD14− cells, however, the specific functions showed little overlap in the 3 disorders.ConclusionDivergent patterns of altered gene expression are observed in RA, PsA and Ps patients in blood cells and target organs in IFX responders. Differential gene expression profiles in the blood do not correlate with those in target organs.
Highlights
Immune mediated inflammatory disorders are a group of diseases that share several common features including pathologic mechanisms characterized by proliferation and accumulation of immune cells, increased release of Tumor Necrosis Factor (TNF) and other cytokines and altered tissue remodeling
While TNF blockade has proven to be a highly effective treatment for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps), three of the most prevalent immune mediated inflammatory disorders, recent evidence indicate that each disease arises by distinct pathophysiologic mechanisms
The Ps patients were younger than the RA or PsA patients and the RA patients were almost all female
Summary
Immune mediated inflammatory disorders are a group of diseases that share several common features including pathologic mechanisms characterized by proliferation and accumulation of immune cells, increased release of TNF and other cytokines and altered tissue remodeling. While TNF blockade has proven to be a highly effective treatment for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps), three of the most prevalent immune mediated inflammatory disorders, recent evidence indicate that each disease arises by distinct pathophysiologic mechanisms. Agents that target B and T cells are highly effective in RA [7] but not in PsA or Ps [8,9], and methotrexate, a cornerstone drug in RA and Ps, is not effective in PsA [8,9,10]. Molecules in the IL-23/Th17 pathway are important targets in Ps [11,12] and PsA [13] but do not show great promise in RA [14]
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