Phage therapy for hidradenitis suppurativa: a unique challenge and possible opportunity for personalized treatment of a complex, inflammatory disease.

Phage therapy is an emerging antimicrobial treatment for critical multidrug-resistant pathogens. In this review, the specific potential and challenges of phage therapy for patients with hidradenitis suppurativa (HS) are discussed. This represents a unique challenge as HS is a chronic inflammatory disease, but presenting with acute exacerbations, which have an enormous negative impact on patient's quality of life. The therapeutic arsenal for HS has expanded in the past decade, for example, with adalimumab and several other biologicals that are currently under investigation. However, treatment of HS remains challenging for dermatologists because there are individuals who do not respond to any classes of the current treatment options when used for a first or second time. Furthermore, after several courses of treatment, a patient may lose their response to therapy, meaning long-term use is not always an option. Culturing studies and 16S ribosomal RNA profiling highlight the complex polymicrobial nature of HS lesions. Despite the detection of various bacterial species in lesion samples, several key pathogens, including Staphylococcus, Corynebacterium and Streptococcus, may be potential targets for phage therapy. Using phage therapy for the treatment of a chronic inflammatory disease could potentially provide new insights into the role of bacteria and the immune system in HS development. In addition, it is possible more details on the immunomodulatory effects of phages may come to light.

A Prospective, Monocentric Case-Control Study on Uncontrolled Psoriasis as Independent Risk Factor for a Hypercoagulable State.

INTRODUCTION: Chronic inflammatory diseases, including psoriasis, are associated with development of venous thromboembolism (VTE). The clot lysis profile (CLP) provides information on both the clotting tendency and fibrinolysis activity. We hypothesized that CLP in uncontrolled psoriasis patients is disturbed towards more clotting/less lysis compared to healthy controls (HC) and that successful psoriasis treatment could normalize the CLP. In this project, we aim to compare the CLP in patients with uncontrolled psoriasis with age- and sex-matched HC and investigate the effect of anti-inflammatory treatment on CLP. METHODS: Patients with uncontrolled psoriasis [psoriasis area severity index (PASI) or body surface area (BSA) > 10] (n = 87) and HC (n = 87) were recruited at a tertiary dermatology department. Samples from patients were obtained before treatment and when disease control was obtained (PASI < 3). Amplitude, area under the curve (AUC) and 50% clot lysis time were determined. RESULTS: At baseline, psoriasis patients had higher median amplitude and AUC compared with HC (p < 0.0001). After correction for possible confounders (BMI, smoking behavior, psoriatic arthritis, arterial hypertension, diabetes and coronary artery disease), the increased amplitude in psoriasis patients compared to HC remained significant. Successful anti-inflammatory treatment resulted in a significant decrease in amplitude (p = 0.0365). CONCLUSION: This is the first prospective study comparing the CLP of psoriasis patients with that of HC. A significant increase in both amplitude and area under the curve, indicative of a hypercoagulable CLP, was observed in psoriasis patients compared to HC. After successful anti-inflammatory treatment, amplitude significantly decreased.

Effects of implementing a vaccination tool in the electronic medical record on vaccination coverage of patients with immune-mediated inflammatory diseases: a prospective cohort study.

BACKGROUND: The rising incidence of immune-mediated inflammatory diseases (IMID) requires innovative management strategies, including effective vaccination. We aimed to assess the impact of an electronic medical record (EMR)-integrated vaccination tool on vaccination coverage among patients with inflammatory bowel diseases (IBD), rheumatological and dermatological conditions. METHODS: A prospective observational study compared vaccination coverage before (2018) and after (2021) implementing the module. Vaccination data for influenza, pneumococcus, hepatitis B and tetanus, and potential predictors were collected from 1430 IMID patients (44.9% male, median age (interquartile range [IQR]) 54 (40-66) years, 789 with IBD, 604 with rheumatological and 37 with dermatological conditions). Data were analysed using McNemar, chi-square tests and multinominal logistic regression. RESULTS: Significant increases in pneumococcus (56.6% to 73.1%, p < .001) and hepatitis B vaccination (62.2% to 75.9%, p < .001) were observed. Influenza vaccination rates increased among IBD (76.2% to 80.5%, p = .006) but remained stable overall (73.1% to 73.2%, p = 1.000). Tetanus vaccination rates decreased (71.5% to 55.0%, p < .001). The proportion of fully vaccinated patients (against influenza in the past year for patients >50 years old and/or under immunosuppressive therapy, against pneumococcus in the past 5 years for patients >65 years old and/or under immunosuppressive therapy and additionally against hepatitis B for IBD patients) rose from 41.3% to 54.8% (p < .001 all using McNemar). Factors associated with vaccinations included age, immunosuppressive therapy and education level. CONCLUSIONS: Increased vaccination coverage was measured after implementing the vaccination tool. The COVID19 pandemic and the 2018 measurement might have increased vaccination awareness. Education of patients and healthcare professionals remains crucial.

Antagonistic Effects of BACE1 and APH1B-γ-Secretase Control Axonal Guidance by Regulating Growth Cone Collapse.

ΒACE1 is the major drug target for Alzheimer's disease, but we know surprisingly little about its normal function in the CNS. Here, we show that this protease is critically involved in semaphorin 3A (Sema3A)-mediated axonal guidance processes in thalamic and hippocampal neurons. An active membrane-bound proteolytic CHL1 fragment is generated by BACE1 upon Sema3A binding. This fragment relays the Sema3A signal via ezrin-radixin-moesin (ERM) proteins to the neuronal cytoskeleton. APH1B-γ-secretase-mediated degradation of this fragment stops the Sema3A-induced collapse and sensitizes the growth cone for the next axonal guidance cue. Thus, we reveal a cycle of proteolytic activity underlying growth cone collapse and restoration used by axons to find their correct trajectory in the brain. Our data also suggest that BACE1 and γ-secretase inhibition have physiologically opposite effects in this process, supporting the idea that combination therapy might attenuate some of the side effects associated with these drugs.

BACE1 levels correlate with phospho-tau levels in human cerebrospinal fluid.

Previous studies have investigated the activity and protein levels of BACE1, the ß-secretase, in the brain and cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients, however, results remain contradictory. We present here a highly specific and sensitive BACE1 ELISA, which allows measuring accurately BACE1 levels in human samples. We find that BACE1 levels in CSF of AD patients and other neurological disorder (OND) patients are slightly increased when compared to those of a non-neurological disorder control group (NND). BACE1 levels in CSF were well correlated with total-tau and hyperphosphorylated tau levels in the CSF, suggesting that the recorded alterations in BACE1 levels correlate with cell death and neurodegeneration.