Remission Duration and Long-Term Outcomes in Patients with Moderate-to-Severe Psoriasis Treated by Biologics or Tofacitinib in Controlled Clinical Trials: A 15-Year Single-Center Experience

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Comparison of the relative efficacy of different biologics in different body areas in patients with moderate to severe psoriasis receiving biologics and tofacitinib in phase 3 randomized controlled trials: a 15-year single-center experience

Focal resistant plaques are still common despite the use of biologics for psoriasis. significant impact on quality of life. We compared the relative efficacy of different biologics and tofacitinib in different body areas in 177 Asian patients with moderate-to-severe psoriasis in 10 biologics or tofacitinib trials conducted between 2004 and 2019. Pooled data were analyzed at weeks 12–16 and weeks 44–52, respectively, for total and four regional PASI 75, 90, and 100 responses. The result showed that secukinumab, ixekizumab, guselkumab, and risankizumab had more favorable efficacy, followed by adalimumab, ustekinumab, and tofacitinib, while etanercept showed the least efficacy. The regional PASI response peaked early in the head area with subsequent decline, while the lower extremities improved slowly. At week 52, the head and neck and lower extremities were less likely to achieve PASI responses compared to the trunk and upper extremities. The treatment responses of different body regions of biologics and tofacitinib were in line with the overall response. However, the head region responds fast, but total clearance at 52 weeks was similarly lower as the leg region. More subjects and prospective studies may be required to compare the efficacy of different biologics in different body regions.</p

A Linkage between SmeIJK Efflux Pump, Cell Envelope Integrity, and σ^E-Mediated Envelope Stress Response in <i>Stenotrophomonas maltophilia</i>

<div><p>Resistance nodulation division (RND) efflux pumps, such as the SmeIJK pump of <i>Stenotrophomonas maltophilia</i>, are known to contribute to the multidrug resistance in Gram-negative bacteria. However, some RND pumps are constitutively expressed even though no antimicrobial stresses occur, implying that there should be some physical implications for these RND pumps. In this study, the role of SmeIJK in antimicrobials resistance, envelope integrity, and σ^E-mediated envelope stress response (ESR) of <i>S. maltophilia</i> was assessed. SmeIJK was involved in the intrinsic resistance of <i>S. maltophilia</i> KJ to aminoglycosides and leucomycin. Compared with the wild-type KJ, the <i>smeIJK</i> deletion mutant exhibited growth retardation in the MH medium, an increased sensitivity to membrane-damaging agents (MDAs), as well as activation of an σ^E-mediated ESR. Moreover, the expression of <i>smeIJK</i> was further induced by sub-lethal concentrations of MDAs or surfactants in an σ^E-dependent manner. These data collectively suggested an alternative physiological role of <i>smeIJK</i> in cell envelope integrity maintenance and σ^E-mediated ESR beyond the efflux of antibiotics. Because of the necessity of the physiological role of SmeIJK in protecting <i>S. maltophilia</i> from the envelope stress, <i>smeIJK</i> is constitutively expressed, which, in turn, contributes the intrinsic resistance to aminoglycoside and leucomycin. This is the first demonstration of the linkage among RND-type efflux pump, cell envelope integrity, and σ^E-mediated ESR in <i>S. maltophilia</i>.</p></div

Antimicrobial susceptibilities of <i>S. maltophilia</i> KJ and its derived deletion mutants.

<p>Antimicrobial susceptibilities of <i>S. maltophilia</i> KJ and its derived deletion mutants.</p

The impact of β-lactam on the promoter activity of <i>creD</i> gene.

<p>Overnight culture of KJΔBCCreD23 was inoculated into the fresh medium to the OD₄₅₀ of 0.15. After 30-min culture, the β-lactam as indicated was added and the culture was further incubated for 3 h. The OD₄₅₀ and C23O activity were measured.</p

Growth of KJ, KJΔJ, KJΔK, and KJΔIJK in Luria-Bertani (LB) and Mueller-Hinton (MH) media.

<p>(A) Growth curves of KJ, KJΔJ, KJΔK, and KJΔIJK in LB and MH broth. (B) The growth curve of 24-h MH-cultured KJ and KJΔIJK cells subcultured into the MH or LB media.</p

Determination of <i>P_rpoE</i> activities in different strains and culture conditions.

<p>Plasmid containing a transcriptional fusion of the upstream region of <i>rpoE</i> to the <i>xylE</i> gene (pRpoE_xylE) was transferred into the wild-type KJ and its derived mutants. The C23O activities of the logarithmic-phase cultures of these strains were determined. Each bar represents the mean of three independent experiments. Error bars, where visible, indicate the average deviation. *, <i>p</i>≤0.01 significance calculated by a Student's <i>t</i>-test. (A) The impacts of <i>resA</i> mutant and <i>rseA/rpoE</i> double mutant on the promoter activity of <i>rpoE</i> gene. (B) The impacts of <i>smeIJK</i> mutant and culture media on the promoter activity of <i>rpoE</i> gene.</p

The role of SmeIJK pump in the tolerance to hypo-osomolarity and casein hydrolysate.

<p>The data are the average of the measurements made in triplicate. (A) The relative survival of KJΔIJK, KJΔJ, and KJΔK to the wild-type KJ in the LB medium containing different concentrations of NaCl. The relative survival percentage of individual mutant to the wild-type KJ, at each cultured condition, was calculated using the OD_{450 nm} of the wild-type KJ as 100%. (B) The relative survival of KJΔIJK, KJΔJ, and KJΔK to the wild-type KJ in the MH medium containing different concentrations of NaCl. The relative survival percentage of individual mutant to the wild-type KJ, at each cultured condition, was calculated using the OD_{450 nm} of the wild-type KJ as 100%. (C) The sensitivities of KJ to SDS in LB or LB containing casein hydrolysate, beef infusion, or starch were determined by the OD_{450 nm} measurement. The percentage of survival was defined as the OD_{450 nm} ratio of the SDS-additive group to the SDS-free counterpart. (D) Growth curves of KJΔIJK grown in the media of the LB, the LB without NaCl, the LB with casein hydrolysate, and the MH, respectively.</p

The C23O activity expressed by the chromosomal <i>xylE-</i>transcription fusion constructs of <i>S</i>. <i>maltophilia</i> KJ.

<p>Overnight cultures of <i>S</i>. <i>maltophilia</i> strains assayed were inoculated into the fresh LB to the <i>A</i>₄₅₀ of 0.15. Cells were grown aerobically, and the <i>A</i>₄₅₀ and C23O activity were measured every 3 h.</p

The impact of CreD on cell envelope integrity.

<p>Each bar represents the mean of three independent experiments. Error bars indicate the average deviation. *, <i>p≤0</i>.<i>05</i> significance calculated by s Student’s <i>t</i>-test. (A) Sodium dodecyl sulfate (SDS) survival analysis. The survival of KJ, KJΔCreD, and KJΔCreD(pCreD) in LB broth without or with 0.01% SDS was determined by colony forming units (CFUs) counting. The percentage of survival was defined as the CFUs ratio of the SDS-additive group to the SDS-free counterpart. (B) N-phenylanphthylamine (NPN) uptake assay. Each microtiter well was inoculated with 100 μl of the OD₄₅₀ 0.5 bacterial culture and 15 μM NPN, and incubated for 5 min. Fluorescence was monitored by fluorescence spectrophotometer at excitation and emission wavelengths of 355 nm and 402 nm, respectively.</p