Jacek Karczewski

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohns disease. Design In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohns disease (Crohns Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (∆CDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

New insights into the role of T cells in pathogenesis of psoriasis and psoriatic arthritis

Abstract Psoriasis is a chronic, relapsing, autoimmune disorder of the skin affecting 2–3% of general population. Approximately 30% of psoriasis patients are also affected with the psoriatic arthritis, a chronic inflammatory spondyloarthritis. The review aims to present the current knowledge on immunopathogenesis of both diseases to emphasize the involvement of various T helper cell subsets. An extensive literature search in electronic databases was performed on the topic of different Th cell subsets’ involvement in the pathogenesis of psoriasis and psoriatic arthritis. Studies were assessed and selected to present the recent progress in the area. Current data strongly suggest that both PsO and PsA are T cell-mediated diseases, with a key role of various proinflammatory cytokines in their development. The involvement of T cells is highlighted by the superior efficacy of biologic therapies targeting T cell-derived proinflammatory cytokines in both diseases. Initially, PsO and PsA were thought to be Th1-mediated diseases; however, in the last years, several studies have shown the important role of other T cell subsets, including Th17, Th22, Th9 and Treg cells, in the pathogenesis of both diseases, which has led to the development of new therapies.

The effects of the microbiota on the host immune system

Abstract The human gastrointestinal track harbors hundreds of species of commensal organisms, collectively known as microbiota. The composition of the intestinal microbiota is changeable by various factors, such as host genotype, diet, antibiotics, pathogen infections, among others. Changes in these factors can cause microbiome disruption known as dysbiosis, leading to the outgrowth of potential pathogenic bacteria or decrease in the number of beneficial bacteria. Dysbiosis has been implicated in numerous inflammatory and autoimmune diseases. This review is focused on host–microbiota interactions, specifically on influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory and autoimmune diseases.

Toxic potencies of metabolite(s) of non-cylindrospermopsin producing Cylindrospermopsis raciborskii isolated from temperate zone in human white cells.

Cylindrospermopsis raciborskii (Nostocales, Cyanobacteria) has worldwide distribution and is well known for producing the toxic alkaloid, cylindrospermopsin (CYN). Strains unable to synthesize this compound but potentially toxic were recently identified in Europe. Here, for the first time the effect of cell-free extracts of a non-CYN-producing strain of C. raciborskii was studied in human cells (neutrophils and lymphocytes) isolated from healthy donors. The observed effects were compared to those induced by CYN (1.0-0.01 μg mL(-1)). Short-term (1h) extract treatments resulted in altered viability of cells demonstrated by increased necrosis and apoptosis in neutrophils and elevated apoptosis in lymphocytes. CYN did not induce similar effects, regardless of the toxin concentration. Exposure of T-lymphocytes to 100% C. raciborskii extract in isolated and whole-blood 72 h cultures resulted in decrease of proliferation by 20.6% and 32.5%, respectively. In comparison, exposure to 1.0 μg mL(-1) of CYN caused lymphocytes proliferation to be inhibited by 91.0% in isolated cultures and 56.5% in whole-blood assay. Significant antiproliferative properties were also found for 0.1 μg mL(-1) of CYN in whole-blood culture. From the results we conclude that strains occurring in temperate zones may pose a threat to human health through the production of hitherto unknown metabolites that reveal a toxic pattern different to that of CYN. At the same time our study demonstrates that CYN is a powerful but slowly-acting toxin in human immune cells.

The role of the enzymatic antioxidant system in cylindrospermopsin-induced toxicity in human lymphocytes

Cylindrospermopsin (CYN) is known to induce cytotoxic effects in eukaryotic cells although the exact mechanism underlying these alterations is not fully explained. Given that CYN was previously found to decrease the proliferation of human lymphocytes through DNA damage and cell cycle arrest followed by an increase in the apoptotic rate, the present study evaluated the possible involvement of reactive oxygen species (ROS) and oxidative stress in these cytopathic responses. The status of enzymatic antioxidants: superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) as well as level of lipid peroxidation (LO) under CYN influence in human lymphocytes were also studied. It was found that CYN exposure (0.01-1.0 μg/ml) induces a concentration-dependent increase in H2O2 content within a time as short as 0.5h, reaching its maximum level after 3 and 6h. The highest H2O2 content was accompanied by a significant decrease of SOD and CAT activity and an elevated level of GPx. Moreover, CYN treatment resulted in a detectable increase in LO. We conclude that ROS and the products of LO play an essential role in CYN-induced toxicity in human lymphocytes. Our study helps to elucidate the sequence of events caused by CYN in eukaryotic cells and explain the background for previously observed cytopathic responses.

The effect of cigarette smoking on the clinical course of inflammatory bowel disease

Introduction Cigarette smoking is considered an important risk factor for developing Crohns disease (CD), contributing to a more severe course of the disease. Conversely, smoking is believed to have a beneficial effect on the course of ulcerative colitis (UC), a second major condition of inflammatory bowel disease (IBD). Aim To investigate the effect of tobacco use on the clinical course of IBD. Material and methods A group of 95 adults with IBD were enrolled to the study. Demographic and clinical data of patients as well as their smoking status were analysed based on their medical history. Values were considered significant when p ≤ 0.05. Results Current smokers constituted the majority of CD patients. They tended to develop a more severe course of the disease, compared to former smokers and non-smokers. Current smokers suffered a moderate-to-severe form of the disease and required immunosuppressive therapy more frequently. They were also hospitalised and underwent surgeries more frequently than patients from other investigated subgroups. The study failed, however, to fully confirm the beneficial effect of smoking on the clinical outcome of UC. The investigated non-smokers and former smokers suffered a more severe disease, but the analysis did not find any statistical differences in the frequencies of hospitalisations nor immunosuppressant usage among the investigated subgroups. Conclusions The study confirmed a detrimental effect of smoking on the outcome of CD, but failed to fully confirm its beneficial effect on UC.

Inhibitors of phosphodiesterase 4 (PDE 4): A new therapeutic option in the treatment of psoriasis vulgaris and psoriatic arthritis

Abstract Psoriasis vulgaris and psoriatic arthritis are inflammatory diseases in which inflammation and sustained inducing lesions result from immune disorders associated with overactivity of T cells that produce multiple proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin (IL): IL-2, IL-12, IL-17, IL-22 or IL-23. Modern treatment of these diseases is focused on reducing the inflammatory process responsible for the development of the disease. In recent years, the treatment of psoriasis is developing at a dynamic rate. Such therapeutic advances are contributed to the possibility of patient therapy through the use of some registered biologic agents, such as TNF-α inhibitors (infliximab, etanercept and adalimumab), and an inhibitor of the p40 subunit common to IL-12 and IL-23 (ustekinumab). In addition to the already registered medications for the indications mentioned above, there is a large group of preparations that are currently undergoing clinical trials in Europe, Canada and the United States, which provides hopes of therapy efficacy and safety.

Factors affecting response to biologic treatment in psoriasis

Psoriasis is a chronic, immune‐mediated inflammatory skin disease, affecting approximately 2–4% of the population in western countries. Patients with a more severe form of the disease are typically considered for systemic therapy, including biologics. In spite of the overall superiority of biologic agents, the treatment response may differ substantially among individual patients. As with other medical conditions, a range of factors contribute to response heterogeneity observed in psoriasis. Proper identification of these factors can significantly improve the therapeutic decisions. This review focuses on potential genetic and nongenetic factors that may affect the treatment response and outcomes in patients with psoriasis.

Biosorption of toxic metals using freely suspended Microcystis aeruginosa biomass

This paper describes the potential application of a freely suspended cyanobacterial biomass of Microcystis aeruginosa as a sorption material for toxic metals, cadmium (Cd) and lead (Pb) from aqueous solutions. In order to identify the most suitable conditions for removal of these elements (concentration range: 1–20 mg L−1), the laboratory experiments were carried out during different incubation times (1–48 h) and under various temperatures (10–40°C), pH (5–9) and with or without light irradiance. Competitive biosorption of Cd and Pb was also investigated. We found that M. aeruginosa demonstrates high efficiency in removing both of the studied metals from aqueous solutions. Sorption of Pb occurred, however, more rapidly and effectively, and was less disturbed by changes in physico-chemical conditions. Under pH=7, 25°C and light, the removal rates after 3 h and 6 h of incubation, were 90–100% for Pb and 79.5–100% for Cd, respectively. The co-occurrence of the metals decreased the rate of metal biosorption. Pb was sequestered preferentially over Cd. From the results we conclude that freely suspended M. aeruginosa can constitute a promising low-cost, easy-producible biosorbent material for toxic metals in contaminated wastewater.

Reactive oxygen species (ROS) production in human peripheral blood neutrophils exposed in vitro to static magnetic field

The aim of this study was to determine the effect of gradient static magnetic field (SMF) on reactive oxygen species (ROS) production in human neutrophils in peripheral blood in vitro. Blood samples collected from healthy individuals were incubated in an inhomogeneous SMF (in a south or north pole of the field) for 15, 30 or 45 minutes. The maximum value of induction (B max) amounted to ≈ 60 mT. To determine the strength of the ROS production, dihydrorhodamine (123DHR) as fluorophore and phorbol 12-myristate 13-acetate (PMA) as respiratory burst stimulator were used. 123DHR oxidation by ROS was measured by flow cytometry. The exposure of blood samples to SMF induced statistically significant changes in ROS production in unstimulated and PMA-stimulated neutrophils. The observed effects were highly correlated with the exposure time and depended on the orientation of the field. Although intracellular mechanisms underlying such interactions are not thoroughly understood, it could be presumed that SMF affects ROS metabolic oscillations and their formation and inactivation. This study emphasizes the importance of proper adjustment of exposure time to SMF for any potential therapeutic applications.