Comparative Effectiveness and Durability of Biologics in Clinical Practice: Month 12 Outcomes from the International, Observational Psoriasis Study of Health Outcomes (PSoHO).

INTRODUCTION: Given the chronic nature of psoriasis (PsO), more studies are needed that directly compare the effectiveness of different biologics over long observation periods. This study compares the effectiveness and durability through 12 months of anti-interleukin (IL)-17A biologics relative to other approved biologics in patients with moderate-to-severe psoriasis in a real-world setting. METHODS: The Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of 1981 adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. The study compares the effectiveness of anti-IL-17A biologics with other approved biologics and provides pairwise comparisons of seven individual biologics versus ixekizumab. The primary outcome was defined as the proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA). Secondary objective comparisons included the proportion of patients who achieved PASI90, PASI100, a Dermatology Life Quality Index (DLQI) score of 0 or 1, and three different measures of durability of treatment response. Unadjusted response rates are presented alongside the primary analysis, which uses frequentist model averaging (FMA) to evaluate the adjusted comparative effectiveness. RESULTS: Compared to the other biologics cohort, the anti-IL-17A cohort had a higher response rate (68.0% vs. 65.1%) and significantly higher odds of achieving the primary outcome at month 12. The two cohorts had similar response rates for PASI100 (40.5% and 37.1%) and PASI90 (53.9% and 51.7%) at month 12, with no significant differences between the cohorts in the adjusted analyses. At month 12, the response rates across the individual biologics were 53.5-72.6% for the primary outcome, 27.6-48.3% for PASI100, and 41.7-61.4% for PASI90. CONCLUSIONS: These results show the comparative effectiveness of biologics at 6 and 12 months in the real-world setting.

Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues.

BACKGROUND: Atopic dermatitis (AD) is characterized by robust immune activation. Various T-cell subsets, including Th2/Th22 cells, are increased in lesional and nonlesional skin. However, there is conflicting literature on the diversity of the T-cell receptor (TCR) repertoire in lesional AD, and its relation to nonlesional skin remains unclear. METHODS: We performed high-throughput deep sequencing of the ß-TCR repertoire in 29 lesional and 19 nonlesional AD biopsies, compared to six healthy control and six cutaneous T-cell lymphoma (CTCL) samples from previously published cohorts. RESULTS: While greater T-cell infiltrates were observed in lesional vs nonlesional AD, TCR repertoire diversity was similar in lesional and nonlesional tissues, and absolute numbers of unique T-cell clones correlated with respective T-cell counts. Most (87%) top expanded lesional T-cell clones were shared with nonlesional tissues, and they were largely maintained after 16 weeks of successful treatment with topical triamcinolone. Nevertheless, both lesional and nonlesional AD showed a highly polyclonal TCR pattern, without evidence of oligoclonal expansion, or a preferred usage of certain V-ß genes in AD skin. Size of the overall T-cell infiltrate, but not the level of clonality, correlated with mRNA levels of key inflammatory mediators (e.g., IL-13, CCL17, IL23p19, CXCL10). CONCLUSION: While AD harbors a highly polyclonal T-cell receptor repertoire, and despite the lack of information on TCR antigen specificity, the sharing of top abundant clones between lesional and nonlesional skin, and their persistence after months of therapy, points to the continuous presence of potentially pathogenic skin resident memory T cells well beyond clinically inflamed lesions.

Immunoprotective effect of lentinan in combination with miltefosine on Leishmania-infected J-774A.1 macrophages.

Rejuvenation of deteriorated host immune functions is imperative for successful annihilation of Leishmania parasites. The use of immunomodulatory agents may have several advantages as they conquer immunosuppression and, when given in combination, improve current therapeutic regimens. We herein investigated the immunostimulatory potency of a ß-glucan, lentinan either alone or in combination with short dose of standard drug, miltefosine on Leishmania-infected J-774A.1 macrophages. Our study shows that infected macrophages when stimulated with 2.5 µg/mL and above concentrations of lentinan secreted significant amount of host-protective molecules. The in vitro interaction between lentinan and miltefosine showed some synergy (mean sum of fractional inhibitory concentration [mean ∑FIC] 0.87) at IC50 level. Lentinan (2.5 µg/mL) plus low-dose miltefosine (2 µM) displayed heightened level of pro-inflammatory cytokines, IL-12 (13.6-fold) and TNF-α (6.8-fold) along with nitric oxide (7.2-fold higher) when compared with infected control. In combination group, we also observed remarkably (P<.001) suppressed levels of anti-inflammatory cytokines, IL-10 and TGF-ß, than that of untreated macrophages. Additionally, in comparison with infected group, we observed significant induction in phagocytic activity of macrophages in combination with treated group. Collectively, these findings emphasize the immunostimulatory effect of lentinan alone and in combination with low dose of miltefosine against Leishmania donovani.

Cumulative Risk of Metabolic Syndrome Correlated with the Coexistence of (-1306C/T) and Altered Circulating MMP2 level.

BACKGROUND: Interindividual genetic variations and environmental factors both play pivotal roles in the pathogenesis of metabolic syndrome (MetS). The rationale of this study conducted was to analyze the association of Matrix Metalloproteinase (MMP) gene variants, MMP-1 (-1607 1G/2G) and MMP-2 (-1306 C/T) with susceptibility to MetS and its effect on serum MMP level. METHODS: Study involved 370 subjects with 1:1 distribution of cases and controls. Patients were recruited according to modified NCEP-ATP III criteria for MetS. Clinical, biochemical analysis, PCR-RFLP and ELISA methods were employed for genotyping and estimation of serum MMP level. RESULTS: Significantly (p<0.001) higher Serum MMP-2 (39.13±19.96 ng/ml) was detected in cases as compared to controls. The MMP-2 (-1306 C/T) was significantly associated with the risk of MetS. The variant genotype TT was significantly associated with increased risk of MetS. (p=0.032; OR=2.31; 95%CI=1.07-4.97). No significant association of MMP-1(-1607 1G/2G) was found with risk of MetS. CONCLUSION: Our study concluded that presence of MMP-2 (-1306 C/T) might be associated the risk of MetS. Serum MMP2 level was significantly higher in patients and correlated with clinical parameters of MetS. Clinical implication of the work may help to identify the individuals with high risk of MetS and further complications.

Removal of malachite green from dye wastewater using neem sawdust by adsorption.

Neem sawdust (Azadirachta indica) was used as an adsorbent for the removal of malachite green dye from an aqueous solution. The studies were carried out under various experimental conditions such as agitation time, dye concentration, adsorption dose, pH and temperature to assess the potentiality of neem sawdust for the removal of malachite green dye from wastewater. A greater percentage of dye removal was observed with decrease in the initial concentration of dye and increase in amount of adsorbent. The adsorption of dye on neem sawdust was found to follow a gradual process. Equilibrium isotherms were analysed by the Langmuir models of adsorption and were applicable with maximum monolayer adsorption capacity of 4.354 mg g(-1). The dimensionless factor, R(L) of the malachite green, neem sawdust isotherm revealed that the adsorption process is favourable in nature.

Effect of vitamin "A" on free radical cascade in pregnancy induced hypertension.

The role of vitamin A therapy in pregnancy induced hypertension (P.I.H.) on free radical cascade was studied in P.I.H. patients of third trimester. It was found that vitamin A therapy causes statistically significant decrease in lipid peroxidation. However it has no effect on superoxide dismutase and catalase. This indicates that vitamin A acts as chain breaking antioxidant. The present study opens a future prospective of giving vitamin A for the prophylaxis of P.I.H.

Effect of calcium channel blockers on baroreceptor reflex in anaesthetized cats.

The baroreflex-induced changes in heart rate in chloralose anaesthetized and artificially ventilated cats (2.5-4.0 kg) before and after pretreatment with calcium channel blockers (CCBs) were compared. Baroreflex mediated changes in heart rate (HR) were elicited by raising and lowering the systemic blood pressure with intravenous injections of phenylephrine and sodium nitroprusside, respectively. The effects of three CCBs, verapamil, diltiazem and nifedipine administered either intravenously (i.v.) or intracisternally (i.c.) were studied. Verapamil administration markedly inhibited the reflex bradycardia as well as the tachycardia following either i.v. or i.c. administration. Intracisternally, a relatively smaller dose of verapamil produced an effect comparable in magnitude and duration, to a higher i.v. dose. The reflex bradycardia was inhibited following i.v., but not i.c. administration of nifedipine while the reflex tachycardia was not affected significantly by either i.v. or i.c. nifedipine. Intravenous diltiazem did not appear to affect the reflex bradycardia or tachycardia significantly. It is suggested that verapamil administration interacts with central cardiovascular integrating mechanisms to reduce the gain of the baroreflex function. Nifedipine and diltiazem are relatively free from this effect.