Development and evaluation of tofacitinib transdermal system for the treatment of rheumatoid arthritis in rats.

CONTEXT: Tofacitinib tablet is approved for the treatment of rheumatoid arthritis (RA). However, tofacitinib (Tfc) faces extensive first-pass metabolism following oral administration. AIM: To develop transdermal systems of Tfc and evaluate their efficacies against RA using Freund's Complete Adjuvant immunized arthritis rat model. METHODS: These systems were prepared by solvent casting method and evaluated for texture, needle strength, skin penetrability, in vitro drug release, skin permeation, stability, and in vivo anti-arthritic activity. RESULTS AND DISCUSSION: Transdermal patch (TS) showed smooth texture, good mechanical strength, slow-release, and slow permeation through the skin. Microneedle array (MNS) showed good needle strength, with required skin penetrability. MNS and TS showed 95% and 24% drug release, and 82% and 12% drug permeation, respectively in 4 h. The developed systems were found to be stable for 90 days at very stressful conditions, that is, 40 ± 2 °C and 75 ± 5% RH. MNS and TS both reduced arthritic scores (at p < 0.01 and p < 0.001 level, respectively) and the level of inflammatory cytokines (at p < 0.05 and p < 0.01 level, respectively) significantly as compared to that of the drug solution (DS). MNS and TS were found to be effective in restoring histological alterations (annum, synovial hyperplasia, synovial constriction, and cartilage and articular erosions) toward normal. CONCLUSION: TS and MNS were found to be stable and effective for the treatment of arthritis and hence considered a good alternative for the treatment of RA with better clinical pertinence.

Serum Levels of IL-6 and TNF-α May Correlate with Activity and Severity of Rheumatoid Arthritis.

BACKGROUND We aimed to investigate the association of rheumatoid arthritis (RA) with interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) through a meta-analysis. MATERIAL AND METHODS The case-control studies that investigated the association between RA and serum levels of IL-6 and TNF-α were retrieved strictly according to the inclusion and exclusion criteria. The statistical analysis was performed using STATA statistical software (Version 12.0, Stata Corporation, College Station, TX, USA). RESULTS Fourteen studies were enrolled in our meta-analysis, with a total of 890 patients with RA and 441 healthy people as the controls. The results of this meta-analysis revealed that the serum IL-6 and TNF-α levels of RA patients were significantly higher than in the controls, and this difference was statistically significant (IL-6: SMD=2.40, 95% CI=1.57~3.24, P<0.001; TNF-α: SMD=1.93, 95% CI=1.23~2.64, P<0.001). According to ethnic subgroup analysis, the serum IL-6 and TNF-α levels of RA patients were also significantly higher compared with the controls in Asians and Caucasians (IL-6: Asians: SMD=3.64, 95% CI=2.16~5.12, P<0.001; Caucasians: SMD=0.75, 95% CI=0.47~1.02, P<0.001; TNF-α: Asians: SMD=2.74, 95%CI=1.58~3.91, P<0.001; Caucasians: SMD=0.81, 95% CI=0.50~1.11, P<0.001). CONCLUSIONS IL-6 and TNF-α may play crucial roles in the activity and severity of RA.

Nanomedicine-based combination of dexamethasone palmitate and MCL-1 siRNA for synergistic therapeutic efficacy against rheumatoid arthritis.

The main aim of this research was to design a MCL-1 siRNA and dexamethasone (DEX)-loaded folate modified poly(lactide-co-glycolide) (PLGA)-based polymeric micelles with an eventual goal to improve the therapeutic outcome in the rheumatoid arthritis (RA). Polymeric micelles encapsulating the MCL-1 siRNA and DEX was successfully developed and observed to be stable. Physicochemical characteristics such as particle size and particle morphology were ideal for the systemic administration. Folate-conjugated DEX/siRNA-loaded polymeric micelles (DS-FPM) significantly lowered the MCL-1 mRNA expression compared to either DEX/siRNA-loaded polymeric micelles (DS-PM) or free siRNA in Raw264.7 cells and macrophage cells suggesting the importance of targeted nanocarriers. Most importantly, DS-FPM exhibited a greatest decrease in the hind paw volume with lowest clinical score compared to any other treated group indicating a superior anti-inflammatory activity. DS-FPM showed significantly lower levels of the TNF-α and IL-1ß compared to AIA model and free groups. The folate receptor (FR)-targeting property of DS-FPM has been demonstrated to be a promising delivery platform for the effective delivery of combination therapeutics (siRNA and DEX) toward the treatment of rheumatoid arthritis.

A novel method to identify hub pathways of rheumatoid arthritis based on differential pathway networks.

The aim of the current study was to identify hub pathways of rheumatoid arthritis (RA) using a novel method based on differential pathway network (DPN) analysis. The present study proposed a DPN where protein­protein interaction (PPI) network was integrated with pathway­pathway interactions. Pathway data was obtained from background PPI network and the Reactome pathway database. Subsequently, pathway interactions were extracted from the pathway data by building randomized gene­gene interactions and a weight value was assigned to each pathway interaction using Spearman correlation coefficient (SCC) to identify differential pathway interactions. Differential pathway interactions were visualized using Cytoscape to construct a DPN. Topological analysis was conducted to identify hub pathways that possessed the top 5% degree distribution of DPN. Modules of DPN were mined according to ClusterONE. A total of 855 pathways were selected to build pathway interactions. By filtrating pathway interactions of weight values >0.7, a DPN with 312 nodes and 791 edges was obtained. Topological degree analysis revealed 15 hub pathways, such as heparan sulfate/heparin­glycosaminoglycan (HS­GAG) degradation, HS­GAG metabolism and keratan sulfate degradation for RA based on DPN. Furthermore, hub pathways were also important in modules, which validated the significance of hub pathways. In conclusion, the proposed method is a computationally efficient way to identify hub pathways of RA, which identified 15 hub pathways that may be potential biomarkers and provide insight to future investigation and treatment of RA.