Are new variants of psoriasis therapy (IL-17 inhibitors) safe?

Psoriasis is a chronic, recurrent, inflammatory, and proliferative skin disease. Its etiology has not yet been fully assessed, but undoubtedly it is a multifaceted disease. The key role in its pathomechanism is played by genetic, immunologic, and environmental factors and stress. If traditional methods of psoriasis treatment (phototherapy, methotrexate, retinoids, cyclosporine A) fail, we reach for the following biopharmaceuticals - infliximab, etanercept, adalimumab, or ustekinumab. However, genetic engineering progress discovers new possibilities - the pending clinical trials involve IL-17, IL-23 antagonists, PDE4 and -3 and -1. Psoriasis etiopathogenesis mainly involves the IL-17A, IL-17F, and IL-17A/F subtypes, which affect the keratinocytes. The biological therapy molecularly oriented with the antagonists of interleukin 17 is based mainly on the influence onto the cytokine in the manner that prevents it from binding with the receptor. Three biopharmaceuticals are currently under third phase studies: two fully humanized antibodies neutralizing IL-17 - ixekizumab and secukinumab, and one human monoclonal antibody, brodalumab. The below work will be devoted to the analysis of possible undesirable symptoms, which were observed during the studies. We will try to review the latest literature concerning the most important clinical trials conducted in many centers.

Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism.

Uveitis (intraocular inflammation) is a leading cause of loss of vision. Although its aetiology is largely speculative, it is thought to arise from complex genetic-environmental interactions that break immune tolerance to generate eye-specific autoreactive T cells. Experimental autoimmune uveitis (EAU), induced by immunization with the ocular antigen, interphotoreceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing complete Freund's adjuvant (CFA), has many clinical and histopathological features of human posterior uveitis. Studies in EAU have focused on defining pathogenic CD4+ T cell effector responses, such as those of T helper type 17 (Th17) cells, but the innate receptor pathways precipitating development of autoreactive, eye-specific T cells remain poorly defined. In this study, we found that fungal-derived antigens possess autoimmune uveitis-promoting function akin to CFA in conventional EAU. The capacity of commensal fungi such as Candida albicans or Saccharomyces cerevisae to promote IRBP-triggered EAU was mediated by Card9. Because Card9 is an essential signalling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defence, we evaluated further the proximal Card9-activating CLRs. Using single receptor-deficient mice we identified Dectin-2, but not Mincle or Dectin-1, as a predominant mediator of fungal-promoted uveitis. Conversely, Dectin-2 activation by α-mannan reproduced the uveitic phenotype of EAU sufficiently, in a process mediated by the Card9-coupled signalling axis and interleukin (IL)-17 production. Taken together, this report relates the potential of the Dectin-2/Card9-coupled pathway in ocular autoimmunity. Not only does it contribute to understanding of how innate immune receptors orchestrate T cell-mediated autoimmunity, it also reveals a previously unappreciated ability of fungal-derived signals to promote autoimmunity.

[Moxalactam - a beta-lactam antibiotic in the monotherapy of severe infections in surgery. Clinico-bacteriological study of 35 patients]. / Moxalactam - ein beta-Lactam-Antibiotikum in Monotherapie bei schweren Infektionskrankheiten in der Chirurgie. Klinisch-bakteriologische Studie an 35 Patienten.

Moxalactam, a new beta-lactam antibiotic, was given to 35 patients at the Department of Surgery, Cantonal Hospital, St. Gall. The trial period started in April 1980 and ended in October. Moxalactam was not combined with any other antibiotic. The clinical course was observed closely and extensive bacteriological, mycological, and pharmacokinetic studies were carried out to evaluate the new antibiotic. Most of the patients had an intra-abdominal infectious disease and primary treatment was surgery. The antibiotic therapy was started at surgery. A total of 290 different bacteria could be isolated from the 35 patients. 220 isolates were aerobic and 7 0 anaerobic. The minimal inhibitory concentration was calculated for every isolate. In addition, the serum levels of moxalactam was determined in almost every patient. In 31 patients (88.6%) the therapy was successful, in 2 patients no evaluation was possible and in 2 patients the therapy was unsuccessful, including one patient with a primarily moxalactam-resistant Bacteroides fragilis responsible for sepsis. In some patients a massive increase in Candida was noted in the urine, stool, or wound drainage. Primarily moxalactam-resistant organisms, such as Streptococcus faecalis, were often found alone in the samples taken later in the course of therapy. An extraordinary change in the fecal flora could be observed during therapy, but no clinical complications resulted. No specific antifungal therapy nor any additional antibiotic against Streptococcus faecalis was necessary. Moxalactam was well tolerated and side effects were minimal. No impairment of renal function was noticed.