Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis

BACKGROUND: Tofacitinib is a disease-modifying antirheumatic drug (DMARD) which was recently approved by US Food and Drug Administration (FDA). There are several randomised clinical trials (RCTs) that have investigated the efficacy and safety of tofacitinib in adult patients with rheumatoid arthritis (RA). A systematic review with a meta-analysis of RCTs was undertaken to determine the efficacy and safety of tofacitinib in treating patients with RA. METHODS: Electronic and clinical trials register databases were searched for published RCTs of tofacitinib between 2009 and 2013. Outcomes of interest include 20% and 50% improvement in the American College of Rheumatology Scale (ACR20 and ACR50) response rates, rates of infection, the number of immunological/haematological adverse events (AEs), deranged laboratory results (hepatic, renal, haematological tests and lipoprotein level) and the incidence of drug withdrawal. RESULTS: Eight RCTs (n = 3,791) were reviewed. Significantly greater ACR20 response rates were observed in patients receiving tofacitinib 5 and 10 mg bid (twice daily) versus placebo at week 12, with risk ratios (RR) of 2.20 (95% CI 1.58, 3.07) and 2.38 (95% CI 1.81, 3.14) respectively. The effect was maintained at week 24 for 5 mg bid (RR 1.94; 95% CI 1.55, 2.44) and 10 mg bid (RR 2.20; 95% CI 1.76, 2.75). The ACR50 response rate was also significantly higher for patients receiving tofacitinib 5 mg bid (RR 2.91; 95% CI 2.03, 4.16) and 10 mg bid (RR 3.32; 95% CI 2.33, 4.72) compared to placebo at week 12. Patients in the tofacitinib group had significantly lower mean neutrophil counts, higher serum creatinine, higher percentage change of LDL/HDL and a higher risk of ALT/AST > 1 ULN (upper limit of normal) versus placebo. There were no significant differences in AEs and withdrawal due to AEs compared to placebo. CONCLUSION: Tofacitinib is efficacious and well tolerated in patients with MTX-resistant RA up to a period of 24 weeks. However, haematological, liver function tests and lipoproteins should be monitored. Long-term efficacy and pharmacovigilance studies are recommended.published_or_final_versio

The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study

<p>Introduction: Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.</p> <p>Patients and Methods: 100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.</p> <p>Results: 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).</p> <p>Conclusions: This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.</p&gt

Rifampin- or Capreomycin-Induced Remodeling of the Mycobacterium smegmatis Mycolic Acid Layer Is Mitigated in Synergistic Combinations with Cationic Antimicrobial Peptides

The mycobacterial cell wall affords natural resistance to antibiotics. Antimicrobial peptides (AMPs) modify the surface properties of mycobacteria and can act synergistically with antibiotics from differing classes. Here, we investigate the response of Mycobacterium smegmatis to the presence of rifampin or capreomycin, either alone or in combination with two synthetic, cationic, α-helical AMPs that are distinguished by the presence (D-LAK120-HP13) or absence (D-LAK120-A) of a kink-inducing proline. Using a combination of high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) metabolomics, diphenylhexatriene (DPH) fluorescence anisotropy measurements, and laurdan emission spectroscopy, we show that M. smegmatis responds to challenge with rifampin or capreomycin by substantially altering its metabolism and, in particular, by remodeling the cell envelope. Overall, the changes are consistent with a reduction of trehalose dimycolate and an increase of trehalose monomycolate and are associated with increased rigidity of the mycolic acid layer observed following challenge by capreomycin but not rifampin. Challenge with D-LAK120-A or D-LAK120-HP13 induced no or modest changes, respectively, in mycomembrane metabolites and did not induce a significant increase in the rigidity of the mycolic acid layer. Furthermore, the response to rifampin or capreomycin was significantly reduced when these were combined with D-LAK120-HP13 and D-LAK120-A, respectively, suggesting a possible mechanism for the synergy of these combinations. The remodeling of the mycomembrane in M. smegmatis is therefore identified as an important countermeasure deployed against rifampin or capreomycin, but this can be mitigated and the efficacy of rifampin or capreomycin potentiated by combining the drug with AMPs

In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

Abstract Background Sustained drug delivery is a large unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. Results The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. Conclusions Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery.https://deepblue.lib.umich.edu/bitstream/2027.42/146540/1/12951_2018_Article_425.pd