The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks.
Objective. To compare the impact of immediate and delayed introduction of anti-tumor necrosis factor therapy on inflammation and structural damage in methotrexate (MTX)-treated patients with early rheumatoid arthritis (RA).Methods. Twenty-four patients with erosive early RA (duration <3 years) who were receiving MTX were randomized to receive infliximab 5 mg/kg or placebo infusions at weeks 0, 2, and 6, and then every 8 weeks through week 46. Beginning at week 54 and thereafter, all patients received infliximab 5 mg/kg. Metacarpophalangeal joints were scanned using high-frequency ultrasonography and power Doppler imaging. Radiographs were evaluated using the modified Sharp/van der Heijde scoring system.Results. From baseline to week 54, total synovial thickness was significantly improved in the infliximab ؉ MTX group compared with the placebo ؉ MTX group (median reduction 95.8% versus 37.5%; P ؍ 0.005), as was the total color Doppler area (CDA; vascularity assessment) (median reduction 100% and 47.1%, respectively; P ؍ 0.025). From week 0 to week 110, no significant between-group difference was observed in the change from baseline for total synovial thickening or the total CDA. At week 54, greater progression in the Sharp/van der Heijde score was apparent in patients receiving placebo ؉ MTX compared with those receiving infliximab ؉ MTX. Although radiographic progression in the placebo ؉ MTX group was greatly reduced in the second year (after initiation of infliximab therapy), marked differences were observed between the infliximab ؉ MTX group (median change in the Sharp/van der Heijde score 4.0) and the placebo ؉ MTX group (median change 14.5) from baseline to week 110 (P ؍ 0.076).Conclusion. The results indicate that the efficacy of 2 years of combination therapy with infliximab ؉ MTX for inhibiting cumulative structural damage was superior to that of 1 year of treatment with MTX alone followed by the addition of infliximab.
Background: The discovery of the nod-like receptor protein (NLRP) inflammasomes in 2002 has led to the rapid identification of these unique cellular proteins as key targets for studies on innate inflammation pathways. The NLRP inflammasomes have been shown to be expressed in normal human epidermal keratinocytes (NHEK) and human dermal fibroblasts (HDF). NLRP inflammasomes in keratinocytes are interesting as these skin cells are the first living cells in the skin to contact external exogenous threats such as UV energy, chemicals, physical trauma, and bacteria and viruses. Activation of the NLRP Inflammasomes by exogenous threats results in the release of active Caspase-1 (ACasp-1), a key protease enzyme, which targets inactive forms of IL-1β, IL-18 as well as IL-1α and IL-33. Purpose: This article discusses efforts to examine the release of active Caspase-1 from NHEKs activated by various exogenous threats including UVB energy, ATP, Nigericin and Urban Dust. The work further examines if, after inflammasome activation and Caspase-1 release, certain naturally derived botanical ingredients known to have anti-inflammatory effects can function to inhibit upregulation of active Caspase-1. Methods: NHEK were treated with various doses of UVB, ATP and Nigericin and with a single dose of Urban Dust. ACasp-1 expression was measured after 3 and 20 hours using the Promega Caspase Glo-1 bioluminescent assay. After confirmation that 60 mJ/cm 2 of UVB and 5mM of ATP were effective to activate NHEK ACasp-1 release after 20 hrs, these conditions were employed to examine the influence of three botanical blends of ingredients on their ability to inhibit ACasp-1 expression. Results: Initial results demonstrate that NHEKs can be activated to release active Caspase-1 by ATP and UVB, but not by Nigericin or Urban Dust. In addition, it was unexpectedly found that, while ATP and UVB activated NHEKs, the release of ACasp-1-did not happen within the first 3 hours after exposure but did become significant after 20 hours. Additional results indicate that a blend of polysaccharides and two blends of antioxidants, one oilsoluble and the other water-soluble, known for their anti-inflammatory effects, can reduce expression of active Caspase-1 in activated NHEKs when applied extracellularly. Conclusion: Expression of NLRP activated release of ACasp-1 was found to be influenced by UVB and ATP but not by Nigericin or Urban Dust. The effects were also time dependent. Several botanical extract blends were found to reduce ACasp-1 expression in previously activated NHEKs. Links between these inflammatory effects and processes of cellular inflammaging are discussed.
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