Signs Of Systemic Inflammation Research Articles

Correlation of enthesial and synovial inflammation in patients with psoriatic arthritis: Data of clinical and ultrasonographic study

Objective. Assessment of clinical manifestations and ultrasonographic signs of enthesitis (En) in patients with psoriasis (PsO) and psoriatic arthritis (PsA).Subjects and methods. The study is based on the analysis of survey data from 106 patients with PsO for the period 2018–2021, which were firstly sent by dermatologists for a consultation with a rheumatologist due to musculoskeletal pain. The duration of the period of musculoskeletal pain in the observed patients did not exceed 12 months. In addition to general clinical and laboratory examination, all patients underwent ultrasonography of painful and/or swollen joints, tendons and ligaments using a linear sensor (frequency – 12–18 MHz) of MyLab 50 (Esaote, Italy) apparatus and supplemented by Doppler energy study with a pulse frequency of 6.6 MHz. The OMERACT definitions were used to identify En, synovitis and tenosynovitis.Results and discussion. The diagnosis of PsA was established in 73.6%, osteoarthritis – in 13.2%, gout – in 8.4%, fibromyalgia – in 17.9%. Ultrasonographic signs of En were found in 67.9% of patients: signs of an active inflammatory process in enthesises (decreased echogenicity, thickening and appearance of Doppler signals) were observed in 48.7%, signs of structural damage to enthesial zones (calcifications, enthesophytes and bone erosions) in 25,6% of patients. Isolated En was found in 24.4% of patients, a combination of En and synovitis – in 32.1% of patients, a combination of En and tenosynovitis – in 20.5% of patients. The correlation between the inflammatory domain values of the ultrasoundographic enthesial index MASEI (Madrid Sonographic Enthesitis Index) and the clinical enthesial index LEI (Leeds Enthesitis Index) was 0.71 [0.58; 0.77]. There were less pronounced clinical indicators of enthesial inflammation (lower LEI index values), functional disorders of the joints (lower values of the HAQ-DI index) and laboratory signs of systemic inflammation (lower CRP values) in patients with isolated En in comparison with combination of En and synovitis. Ultrasonographic signs of structural damage of enthesises were observed in 15.4% of patients without clinical and ultrasonographic signs of active En, which may indicate the possibility of a subclinical course of enthesial inflammation in patients with PsO.Conclusion. It was demonstrated that ultrasonography has diagnostic capabilities to identify the site of the inflammatory process in patients with PsA and differentiate patients with isolated En and a combination of En and synovitis in order to select a method of differentiated anti-inflammatory therapy.

MO670: Angiotensin Converting Enzyme Blockers, Angiotensin Receptor Blockers and Statins are Associated with a Reduction of Inflammation Markers Without Modification of the Peritoneal Membrane Transport Status in Peritoneal Dialysis

Abstract BACKGROUND AND AIMS Therapy with angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) as well as statins might protect the peritoneal membrane and vessels in peritoneal dialysis. The aim of this study was to analyse the effect of treatment on peritoneal transport and inflammation markers. METHOD The first two peritoneal equilibration tests in adult peritoneal dialysis patients, respectively, 6 and 12 months after dialysis start, were analysed for this retrospective study. Use of ACE, ARB and statins was registered. Serum C reactive protein (sCRP), blood leukocyte and platelet count were used as inflammation markers. Data sets of 220 examinations were acquired. Mann–Whitney U-test was performed for the comparison of therapy groups. Median patient age was 67 years. RESULTS A total of 84 measurements (38.2%) were without ACE and ARB, whereas 93 measurements (423%) without statins. Dialysate to plasma (D/P) creatinine in patients without ACE, ARB and statins was 0.64 (all median values, n = 41), respectively, in patients under therapy with ACE, ARB and statins 0.66 (n = 52). Use of ACE and ARB without statins resulted in D/P creatinine 0.64 (n = 54), whereas use of statins alone in D/P creatinine 0.63 (n = 48). The difference between groups was statistically not significant. There was a tendency of higher values of D/P creatinine (median 0.68) in patients under therapy with ACE and statins (Fig. A). sCRP was higher in patients without ACE, ARB and statins compared to patients with ACE, ARB or statins (0.60 versus 0.30 mg/dL, P < 0.05) (Fig. B). Furthermore platelet count was slightly higher in patients without ACE, ARB and statins (25 8000 versus 22 6000/mm3). Blood leukocyte count did not present significant differences (median values 6930 to 6855/mm3). CONCLUSION Our data suppose the absence of a protective effect of ACE, ARB and statins on peritoneal transport expressed by P/D creatinine despite reduced signs of systemic inflammation.

The Diagnosis and Treatment of Acute Cholecystitis

Acute cholecystitis (AC), defined as inflammation of the gallbladder, is mainly caused by gallstones. Over 90% of AC results from obstruction of the cystic duct by stones or sludge, which subsequently increases the intraluminal pressure within the gallbladder and, in conjunction with the presence of bile supersaturated with cholesterol, activates an acute inflammatory cascade. Clinical features play an important role in the diagnosis of AC. The Tokyo Guidelines 2018 for acute cholecystitis designates the presence of local inflammatory signs and systemic inflammatory signs for a suspected diagnosis. It requires confirmation by radiological imaging along with these two factors for a definitive diagnosis. Thanks to less invasiveness, easy availability, ease of use, and cost-effectiveness, ultrasound (US) is usually accepted as the first choice in suspicious AC patients. A meta-analysis comparing methods of diagnosis for AC reported that the US has 81% of sensitivity and 83% of specificity. Abdominal computed tomography is recommended for diagnosing emphysematous or gangrenous cholecystitis. Meanwhile, acute acalculous cholecystitis (AAC) is a life-threatening disease mainly in severely ill patients. It usually affects the patients hospitalized for multiple trauma, burns, cardiopulmonary bypass surgery, long-term total parenteral nutrition or sepsis. The diagnosis of AAC is quite challenging and requires a high index of suspicion. Currently, cholecystectomy is the treatment of choice for AC, although the optimal time for surgery is still controversial. Due to high morbidity and mortality in high surgical risk groups, percutaneous gallbladder drainage can be a safe and feasible alternative to cholecystectomy, particularly for patients unfit for the surgery.

Hematopoiesis, Inflammation and Aging-The Biological Background and Clinical Impact of Anemia and Increased C-Reactive Protein Levels on Elderly Individuals.

Anemia and systemic signs of inflammation are common in elderly individuals and are associated with decreased survival. The common biological context for these two states is then the hallmarks of aging, i.e., genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Such aging-associated alterations of hematopoietic stem cells are probably caused by complex mechanisms and depend on both the aging of hematopoietic (stem) cells and on the supporting stromal cells. The function of inflammatory or immunocompetent cells is also altered by aging. The intracellular signaling initiated by soluble proinflammatory mediators (e.g., IL1, IL6 and TNFα) is altered during aging and contributes to the development of both the inhibition of erythropoiesis with anemia as well as to the development of the acute-phase reaction as a systemic sign of inflammation with increased CRP levels. Both anemia and increased CRP levels are associated with decreased overall survival and increased cardiovascular mortality. The handling of elderly patients with inflammation and/or anemia should in our opinion be individualized; all of them should have a limited evaluation with regard to the cause of the abnormalities, but the extent of additional and especially invasive diagnostic evaluation should be based on an overall clinical evaluation and the possible therapeutic consequences.

P721 Faecal microbiota analysis with body composition and nutritional habits simultaneously amongst Crohn’s disease patients

Abstract Background Changes in microbiome of the gut and decreased diversity in inflammatory bowel disease(IBD) is the subject of intense researches. The exact pathophysiological connection is lacking, but the systemic inflammation due to the microbial alterations are assumed. This study aimed to perform analysis of faecal microbiota composition simultaneously with body composition by bioelectrical impedance and nutrition habits in Crohn’s disease(CD) patients to find specific microbiota profiles connected with obesity, mesenterial fat, signs of systemic inflammation, nutritional and body composition characteristics. Methods In our prospective cohort study, CD patients were enrolled. At the inclusion, demographic and clinical data, blood, and faecal samples were obtained. Clinical disease activity was assessed by CDAI, and SES-CD. Laboratory tests were made including C-reactive protein(CRP), albumin and lipids (triglyceride, cholesterol). Faecal bacterial composition was assessed using shotgun metagenomics sequencing technique. Each patient underwent a body composition analysis via bioelectrical impedance analysis. A nutritional questionnaire was filled by each subject. Results Data of 27 CD patients with different localisation was analysed in this study (mean age was 35±11 years). According to the gut inflammation, some Blautia species correlated positively with SES-CD (p=0,004), and correlated with faecal calprotectin negatively (p=0,02), while Roseburia hominis negatively with CDAI scores(p=0,01). High CDAI scores were also associated with dysbiosis. Adlercreutzia equolifaciens and Blautia hansenii associated with triglyceride(negatively p=0,04, positively p=0,05). Firmicutes has a lower, while Bacteroidetes has a higher abundance at high cholesterol level(p=0,001, p=0,023). Lower Adlercreutzia and Lactobacillus abundance were seen in patients with high visceral fat area(p=0,05, p=0,01), while Clostridia correlated with percent body fat(p=0,025).Bifidobacterium bifidum were associated in people with low body weight or low skeletal muscle mass(p=0,01, p=0,03). Beside Clostridia, Eubacteriales also correlated with waist-hip ratio(p=0,04, p=0,04). Conclusion To our knowledge this is the first study to analyse microbiota profiles by shotgun sequencing technique in CD patients depending on body composition via bioelectrical impedance and nutrition. Changes in Blautia, Lactobacillus, Adlercreutzia, Roseburia and Bifidobacterium abundances in patients with CD and obesity highlight the importance of correlations between lipid metabolism, adipose tissue mass, and chronic inflammation. Through this, it helps to develop new therapeutic approaches, such as personalized pre- or probiotics or faecal microbiota transplantation.

Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial

BackgroundThe efficacy and safety of complement inhibition in COVID-19 patients is unclear.MethodsA multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15.Results81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) − 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified.ConclusionAdministration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.

Association of structural changes of the brain with systemic immune activation in schizophrenia

The goal of this work was to investigate the associations between IL-17A levels and structural MRI findings to clarify immune factors of pathogenesis and search for biomarkers of unfavorable disease course. 45 patients with schizophrenia and 30 healthy volunteers were enrolled into the study. The levels of cytokines (IL-1β, IL-4, IL-6, IL-8, IL-17A) and inflammatory markers were determined by ELISA. MRI scans were performed on a Siemens Magnetom Verio 3T MRI scanner. It was found that elevated levels of cytokine IL-17A are associated with morphometric changes in the frontal cortex, signs of systemic inflammation and Th2 activation of the adaptive immune system in the patients. These findings make an important contribution to understanding the role of immune disorders in the pathogenesis of schizophrenia, including brain structure disorders, and indicate that IL-17A may be a biomarker of these disorders. Confirmation of correlations between structural neuroimaging and markers of inflammation may provide the basis for new interdisciplinary approaches to the diagnosis and prognosis of schizophrenia.

Biologic disease-modifying antirheumatic drugs in the treatment of major monogenic autoinflammatory diseases: literature review and clinical observation

Autoinflammatory diseases (AIDs) are a heterogeneous group of rare genetically determined conditions, the main manifestations of which are episodes of fever in combination with other signs of systemic inflammation: skin rashes, musculoskeletal and neurological disorders, damage to the organs of vision, hearing, etc., as well as acute phase markers and the absence of autoantibodies. The use of biological therapy, especially inhibitors of interleukin 1 (iIL1), in most common monogenic AIDs (mAID) – FMF, TRAPS, HIDS/MKD, CAPS – has shown its high efficiency and led to significant progress in the treatment of these patients. Currently, iIL1 are the first-line drugs for mAIDs therapy, primarily CAPS. In the case of their ineffectiveness or intolerance in certain situations, other biologic disease-modifying antirheumatic drugs can also be used – inhibitors of tumor necrosis factor α and iIL6, but this issue needs further investigation. The article describes a patient with mAID, in whom the diagnosis was made more than 40 years after the onset; administration of targeted therapy even in the late stages of the disease led to a significant improvement in many symptoms and quality of life.

Lipid profile in cardiac transplantation: a closer look at bad cholesterol

Abstract Background When it comes to lipid-lowering therapy, the primary goal is still to reduce the low-density lipoprotein levels. Although remnant cholesterol (RC), including predominantly intermediate- and very-low-density lipoproteins, is a known cardiovascular risk factor, reliable reference values, as well as therapy strategies, are yet to be validated. Additionally, the role of RC after heart transplantation is still unclear. Aim To assess the clinical and prognostic relevance of lipid profile and, in particular, of remnant cholesterol in very long-term follow-up after HTx. Methods We performed a retrospective analysis of the clinical and laboratory parameters collected at last follow-up in an outpatient setting. Additionally, remnant cholesterol levels were estimated using the formula (in mg/dL): remnant cholesterol = total cholesterol – (HLD-C + LDL-C). Results Out of 174 patients with a mean age of 45.2±15.0 years at the time of HTx and a mean follow-up of 13.1±6.5 years, 142 (81.6%) were on statin treatment. Mean cholesterol level was borderline high (184.1±48.4 mg/dL), whereas mean LDL and triglyceride values were markedly elevated (103.6±39.2 and 161.8±83.8 mg/dL, respectively). HDL results were found to be 57.1±17.5 mg/dL. Statin treatment was associated with significantly lower LDL levels (124.6±53.5 vs. 98.8±33.6 mg/dL on statins, p=0.013), but failed to show prognostic relevance in a univariate cox-regression analysis (HR 0.79, 95% CI 0.37 – 1.72, p=0.57). RC was elevated in comparison to the background population with a mean level of 23.5±17.3 mg/dL (24.2±18.1 in male and 21.3±14.8 mg/dL in female) and a tendency for lower values when on treatment with statins but without statistical significance (28.5±19.2 vs. 22.3±16.8 mg/dL on statins, p=0.07). Treatment with higher doses of statins showed no relevant influence on the RC levels (p=0.62). Additionally, elevated RC was associated with higher C-reactive protein values as a sign of systemic inflammation (CRP &amp;gt;0.5 mg/dL, OR 1.1, 95% CI 1.007 – 1.046, p=0.007). In a multivariate cox-regression analysis (adjusted for total cholesterol, LDL and triglycerides) RC was identified as a significant factor influencing mortality (HR 1.11, 95% CI 1.05 – 1.17, p&amp;lt;0.001). Conclusions When addressing dyslipidaemia in heart transplantation, statin therapy can help reduce LDL levels, but this approach seems to be insufficient in achieving clinical benefit. Remnant cholesterol is a factor, which has proinflammatory properties and can potentially influence the prognosis in HTx. The possible therapeutic alternatives for this overseen component of the lipid profile are yet to be elucidated. Funding Acknowledgement Type of funding sources: None.

Combination antibiotic therapy versus monotherapy in the treatment of acute exacerbations of chronic obstructive pulmonary disease: an open-label randomized trial

BackgroundThe role of antibiotics in the treatment of chronic obstructive pulmonary disease (COPD) exacerbations and their effectiveness in combination have not been clearly established. To determine whether using a combination of fluoroquinolones and beta-lactams improves the clinical and microbiological efficacy of antibiotics on day 20 of treatment, we conducted an open-label randomized trial based on clinical outcomes, microbiological clearance, spirometry tests, and signs of systemic inflammation in patients hospitalized with acute exacerbations of COPD.MethodsWe enrolled 139 subjects with COPD exacerbations, defined as acute worsening of respiratory symptoms leading to additional treatment. Patients were divided randomly into two groups: 79 patients using beta-lactam antibiotics alone and 60 using beta-lactam antibiotics plus fluoroquinolones. Clinical and microbiological responses, spirometry tests, symptom scores, and serum C-reactive protein (CRP) levels were evaluated.ResultsClinical success, lung function, and symptoms were similar in patients with or without fluoroquinolone administration on days 10 and 20. Combination therapy was superior in terms of microbiological outcomes and reduction in serum CRP value. Although equivalent to monotherapy in terms of clinical success, the combination showed superiority in terms of microbiological success and a decrease in CRP. The combination therapy group had a higher microbiological success rate with gram-negative bacteria than the monotherapy group with Pseudomonas aeruginosa (100% vs. 33.3%, respectively) and Acinetobacter baumanii (100% vs. 20%, respectively) (P < 0.05).ConclusionsConcomitant use of fluoroquinolone and beta-lactam antibiotics for bacterial infections during COPD exacerbations caused by gram-negative bacteria appear to be effective and should be applied in clinical practice.

Gender peculiarities of clinical and instrumental indexes in patients with acute Q-wave myocardial infarction after primary coronary intervention

The aim: to determine gender differences in the course of acute Q-wave myocardial infarction in patients after primary coronary intervention. Materials and methods. Results of clinical and instrumental examination of 58 patients with acute Q-wave myocardial infarction were analyzed. Patients were divided into 2 groups according to gender: group 1 (n = 33) – men, mean age 61.0 (55.0; 69.0) years, group 2 (n = 25) – women, mean age 69.0 (63.0; 78.0) years. All the patients underwent coronary angiography followed by angioplasty and stenting of the infarct-dependent coronary artery. Results. In men, the number of leukocytes was significantly higher (by 24.7 %, P = 0.02) and the plasma level of low-density lipoproteins was significantly lower (by 30.9 %, P = 0.007), there was a tendency towards a higher concentration of creatine kinase-MB (by 41.0 %, P = 0.11) at the time of hospital admission as compared to women. Women showed significantly increased thickness of the posterior wall of the left ventricle (LV) (by 7.31 %, P = 0.02) and a tendency towards the prevalence of the interventricular septum wall thickness (by 7.46 %, P = 0.1). The LV end-diastolic and end-systolic dimensions tended to prevail in men (by 2.41 %, P = 0.47 and by 7.81 %, P = 0.19, respectively). Men were found to have a lower peak A rate (by 23.37 %, P = 0.007), a higher E/A ratio (by 52.27 %, P = 0.009), LV diastolic dysfunction (DD) occurred less frequently (χ2 = 2.89, P = 0.08), and there was a tendency to develop eccentric LV hypertrophy (χ2 = 2.39, P = 0.12) and type 2 LV DD (χ2 = 3.82, P = 0.07). Type 1 DD was more common in women (χ2 = 5.71, P = 0.02). In men, there was a tendency to the formation of zones of LV akinesia (χ2 = 2.5, P = 0.09) and decreased LV ejection fraction (χ2 = 1.57, P = 0.31). Conclusions. In the acute period of Q-wave myocardial infarction after revascularization, in men, unlike in women, systolic dysfunction is developed more often. It is accompanied by acute left ventricular failure, eccentric left ventricular hypertrophy and type 2 diastolic dysfunction formation as well as signs of systemic inflammation. In women, in the acute period of Q-wave myocardial infarction after revascularization, concentric left ventricular remodeling occurs more frequently and is accompanied by type 1 left ventricular diastolic dysfunction.

Neutrophil extracellular traps: key drivers of severe Covid-19

In severe Covid-19, hyperinflammatory tissue-damaging, thromboembolic or immunothrombotic responses triggered by Sars-Cov-2 are major causes of respiratory failure and death. Neutrophil extracellular traps (NETS), released by activated neutrophils during a process called NETosis, can be formed in the lungs upon infection with respiratory viruses. They have the ability to promote lung damage, thrombosis and fibrosis, three cardinal features encountered in severe Covid-19. In a recent study, we sought to understand how NETosis could relate to lung immunopathological changes associated with fatal cases of the disease. We assessed whether NET structures could be identified in post-mortem lung biopsies from Covid-19 patients, and whether they were located in particular lesions and micro-anatomical lung compartments. We performed immunofluorescence staining of myeloperoxi-dase, citrullinated histone H3 and nuclear acid (DAPI) on sections of paraffin-embedded lung biopsies from four Covid-19 patients who succumbed Covid-19 and from four patients who died from a Covid-19-unrelated cause. The four patients represented prototypical severe and fatal cases of Covid-19, characterized by pneumonia and fatal respiratory distress associated with signs of systemic inflammation, neutrophilia and coagulopathy. NETs were uniquely detected in the lungs of each Covid-19 patient. Detailed histopathological analysis revealed widely distributed NET-infiltrating areas encompassing several lung compartments, including arteriolar microthrombi, neutrophil-rich inflammatory areas of lung interstitium as well as alveoli or bronchioles where they often co-localized with occluding fibrin-rich deposits. Another study published simultaneously to ours provides first experimental evidence for causality between NETosis and lung injury in severe Covid-19. However, the possible involvement of NETs in thrombogenesis remains to be addressed. Notwithstanding, these data support the hypothesis that NETs may represent drivers of Covid-19-associated severe pulmonary complications, and suggest that NET-targeting approaches could represent potential avenues for the treatment of uncontrolled tissue-damaging, thrombotic or fibrotic responses to Sars-Cov-2.

Tocilizumab in patients with COVID-19: which patient, time, and dose?

Tocilizumab (TCZ) is a recombinant anti-interleukin-6 monoclonal antibody which showed uprising evidence as an anti-inflammatory agent which modulates the cytokine storm in patients with COVID-19. However, proper use of the drug requires selection of the appropriate patient and timing. The two main factors which might improve patient selection are the degree of respiratory failure and systemic inflammation. TCZ can decrease the mortality and progression to invasive mechanical ventilation in patients with severe COVID-19 who are not yet invasively ventilated. However, its use in invasively ventilated patients did not yet gain the same level of evidence especially when administered after > 1 day from mechanical ventilation. Being an anti-inflammatory and immunomodulatory drug, TCZ was mostly used in patients with COVID-19 who have clear signs of cytokine storm. However, the drug still showed positive response in some studies which did not strictly select patients with elevated markers of systemic inflammation. Thus, it is warranted to investigate and/or re-analyze the role of the drug in patients with severe COVID-19 and with no signs of systemic inflammation. TCZ is used in a dose of 8 mg/kg which can be repeated if there was no clinical improvement. However, there are no clear criteria for judgment of the success of the first dose. Being a drug with a major effect on gross outcomes in a serious pandemic with millions of mortalities, TCZ should be meticulously investigated to reach definitive indications and number of doses to avoid drug overuse, shortage, and side effects.

Genetic and immunologic findings in children with recurrent aphthous stomatitis with systemic inflammation

BackgroundRecurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet’s disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations.ObjectiveTo investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation.MethodsSubjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score.ResultsWe enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results.ConclusionsAlthough recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

Immunoinflammatory Profile in Patients with Episodic and Continuous Paranoid Schizophrenia.

Associations of disturbances in innate and adaptive immunity during the clinical course of schizophrenia have been found in a number of studies. Yet, the relationship of immune parameters and systemic inflammation in relation to the clinical course of the disease and its prognosis, remains poorly understood, which highlights an interesting topic for further research. The goal of this study was to research the immuno-inflammatory changes in patients with clinical continuous and episodic paranoid schizophrenia, to assess the pathogenetic significance of these changes. Thirty-six patients with paranoid schizophrenia, of which 20 had episodic symptoms and 16 had continuous symptoms, consented to participate in the study, together with 30 healthy volunteers. In the study we assessed the parameters of innate immune response (serum levels of key pro-inflammatory and anti-inflammatory cytokines, C-reactive protein) and the adaptive immune response, including humoral-mediated immunity (serum immunoglobulins IgA, IgM, IgG, circulating immune complexes), as well as the cell link of adaptive immunity (key lymphocyte subpopulations). Positive and negative symptoms were assessed with the positive and negative symptoms scale; frontal dysfunction was assessed by Frontal Assessment Battery (FAB). Both patient groups had higher than normal levels of C-reactive protein and IL-8. There was a significant elevation of circulating immune complexes among patients with continuous symptoms of schizophrenia, compared to patients with episodic symptoms and healthy controls. Levels of CD45+CD3+ lymphocytes (T-cells) differed between clinical groups, with higher values identified among patients with episodic symptoms and lower values among those with continuous symptoms. In addition, patients with episodic symptoms had significantly increased levels of CD45+CD3+CD4+CD25+CD127- regulatory T-cells. Finally, the level of CD45+CD3-CD19+ B-cells was significantly higher among patients with continuous symptoms vs. patients with episodic symptoms and the control groups. Markers of activation of humoral immunity were associated with the severity of frontal disorders in these patients. Comprehensive data on the serum level of cytokines and the parameters of adaptive immunity among individuals with continuous schizophrenia, by comparison with patients with episodic schizophrenia, are practically absent in the literature. We have shown that among those with continuous schizophrenia, there are signs of systemic inflammation and chronic activation of the adaptive humoral immune response, while among patients with episodic symptoms of the disease, there are signs of systemic inflammation and certain activation of cell-mediated immunity, without significant changes in the humoral link of adaptive immunity. More studies are needed, but the data obtained in this study are important for subsequent clinical studies of new treatment methods, based on various immunophenotypes of schizophrenia.

Peri-renal adipose inflammation contributes to renal dysfunction in a non-obese prediabetic rat model: Role of anti-diabetic drugs

Diabetic nephropathy is a major health challenge with considerable economic burden and significant impact on patients’ quality of life. Despite recent advances in diabetic patient care, current clinical practice guidelines fall short of halting the progression of diabetic nephropathy to end-stage renal disease. Moreover, prior literature reported manifestations of renal dysfunction in early stages of metabolic impairment prior to the development of hyperglycemia indicating the involvement of alternative pathological mechanisms apart from those typically triggered by high blood glucose. Here, we extend our prior research work implicating localized inflammation in specific adipose depots in initiating cardiovascular dysfunction in early stages of metabolic impairment. Non-obese prediabetic rats showed elevated glomerular filtration rates and mild proteinuria in absence of hyperglycemia, hypertension, and signs of systemic inflammation. Isolated perfused kidneys from these rats showed impaired renovascular endothelial feedback in response to vasopressors and increased flow. While endothelium dependent dilation remained functional, renovascular relaxation in prediabetic rats was not mediated by nitric oxide and prostaglandins as in control tissues, but rather an upregulation of the function of epoxy eicosatrienoic acids was observed. This was coupled with signs of peri-renal adipose tissue (PRAT) inflammation and renal structural damage. A two-week treatment with non-hypoglycemic doses of metformin or pioglitazone, shown previously to ameliorate adipose inflammation, not only reversed PRAT inflammation in prediabetic rats, but also reversed the observed functional, renovascular, and structural renal abnormalities. The present results suggest that peri-renal adipose inflammation triggers renal dysfunction early in the course of metabolic disease.

Dose-Finding in the Development of an LPS-Induced Model of Synovitis in Sheep.

Models of transient synovitis that can be controlled with antiinflammatory and analgesic drugs have been used to study pain amelioration. To this end, we aimed to determine the dose of intraarticularly administered E. coli LPS that induced signs of synovitis without systemic signs in clinically healthy male castrated sheep (n = 14). In phase 1, a single dose of LPS (0.5, 1.0, 1.5, or 2.0 ng in a total volume of 0.5 mL) was administered into the right stifle joint. In phase 2, a dose of LPS (1.0 or 2.0 μg) in 0.3 mL was administered to 4 naïve sheep. In phase 3, 4 sheep from phase 1 were inoculated after a 60 d washout period with either 0.5 or 1.0 μg of LPS. During the first 48 h after LPS administration, the following were performed: assessment of clinical parameters; scoring for lameness, pain on limb flexion, and local swelling; and ultrasonography of the joints were performed. The doses tested during phase 1 produced subtle signs. During phase 2, mild to moderate lameness with no evidence of systemic signs occurred at both doses. In phase 3, clinical responses were similar between the 0.5- and 1-μg doses. Signs of swelling were not observed at any time. Therefore, we consider the 0.5-μg to be the most appropriate for this model, because it was the lowest dose tested capable of causing lameness without signs of systemic inflammation in all animals.

Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage.

Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C-terminal FGF23 circulating levels, the inactive C-terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin-NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C-terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.

Management of acute colonic diverticulitis in the general and surgical emergency departments

Acute left colonic diverticulitis is a very common disease that primarily affects the older population in the Western world. The pathogenesis of acute inflammation of the diverticula may not be as simple as once thought, and the disease cascade could involve a combination of chronic inflammation and altered gut microbiota. Several lifestyle risk factors such as obesity, low-fibre diet, smoking, use of non-steroid anti-inflammatory drugs, inadequate physical activity and others have been associated with a higher risk for diverticulitis. It has been proven that uncomplicated diverticulitis in immunocompetent patients without systemic signs of infection can be treated symptomatically. Outpatient treatment with peroral antibiotics is effective for managing patients with uncomplicated diverticulitis and signs of systemic inflammation. New, less- invasive surgical options have been recognised as appropriate for a select group of patients with complicated diverticulitis. Laparoscopic lavage and drainage are suitable for abscesses where the bowel wall is intact. Resection with primary anastomosis with or without ileostomy is now considered an option for some patients that would historically have to undergo Hartmann’s procedure. The latter still remains the most common operating option even in tertiary referral centres around the world as it is suitable for more complicated cases and critically ill patients. Current evidence does not support routine colonoscopic evaluation for uncomplicated diverticulitis in younger patients without risk factors. Recurrent diverticulitis is now understood to be more benign than was previously thought. Elective resection of the sigmoid colon is therefore no longer a standard treatment for all patients with two or more episodes of acute diverticulitis.

ANALGESIC EFFECT OF TRAMADOL IS NOT ALTERED BY POSTOPERATIVE SYSTEMIC INFLAMMATION AFTER MAJOR ABDOMINAL SURGERY.

SUMMARYTramadol is a commonly used analgesic in intensive care units (ICUs) for acute postoperative pain. Conversion of tramadol into active metabolites may be impaired in inflammatory states. Catechol-O-methyltransferase may influence pain. The aim of the study was to examine differences in the analgesic effect of tramadol between ICU patients with and without signs of systemic inflammation. Forty-three patients were admitted to ICU after a major abdominal surgery. The patients received a dose of 100 mg of tramadol intravenously every 6 hours during the first 24 hours after surgical procedure. Pain scores were measured by the Numeric Rating Scale before and 30 minutes after tramadol administration in awake patients. Systemic inflammation was considered when at least two of the following postoperative parameters were present in the first 24 hours of ICU admission: fever or hypothermia, tachycardia, pCO2 <4.3 kPa, white blood cells >12000/mm3 or <4000/mm3, or preoperative value of C-reactive protein (CRP) >50 mg/L or/and procalcitonin (PCT) >0.5 mg/L. Catechol-O-methyltransferase was analyzed postoperatively. Fifteen (34.8%) patients met the criteria for systemic inflammation. Tramadol was proven to be an effective analgesic for the treatment of postoperative pain regardless of the presence of systemic inflammation (p<0.05). Lower perception of pain before tramadol application was observed in patients with systemic inflammation, but the difference was not significant. A negative correlation was observed between the preoperative values of CRP and PCT and the analgesic effect of tramadol assessed at the second measurement point (r=-0.358, p=0.03, and r=-0.364, p=0.02, respectively). Catechol-O-methyltransferase variants were not in correlation with pain and opioid consumption. Based on our findings, tramadol is effective in lowering pain scores after major abdominal surgery irrespective of the presence of systemic inflammation.