Marcin Włodarczyk

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn's disease patients.

AIM To investigate the correlation between the appearance of skin lesions and concentration of interleukin (IL)-17A, IL-23 and interferon-γ (IFN-γ) in Crohns disease (CD) patients during anti-tumor necrosis factor-α (TNF-α) therapy METHODS A prospective study included 30 adult patients with CD of Caucasian origin (19 men and 11 women; mean age ± SD 32.0 ± 8.6 years) during biological therapy with anti-TNF-α antibodies from January 2012 to March 2013. Eighteen patients were treated with infliximab, seven with adalimumab and five with certolizumab. Inclusion criteria were exacerbation of the underlying disease, Crohns Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies. Patients with a history of psoriasis, atopic dermatitis and other autoimmune skin lesions were excluded from the study. The control group consisted of 12 healthy subjects. A diagnostic survey was carried out, blood tests and careful skin examination were performed, and the serum levels of IL-17, IL-23 and IFN-γ were measured using an enzyme-linked immunosorbent assays technique. Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by anti-TNF-α therapy. RESULTS Skin manifestations occurred in 18 of CD patients during the anti-TNF-α therapy (60%), in the average time of 10.16 ± 3.42 mo following the beginning of the 52-wk treatment cycle. Skin lesions observed in CD patients during biological therapy included psoriasiform lesions (44.4%), and eczema forms lesions (22.2%). In CD patients with drug induced skin lesions significantly higher levels of hemoglobin (13.3 ± 1.5 g/dL vs 10.8 ± 1.9 g/dL, P = 0.018) and hematocrit (39.9% ± 4.5% vs 34.3% ± 5.4%, P = 0.01), as well as a significantly lower level of platelets (268 ± 62 × 10(3)/μL vs 408 ± 239 × 10(3)/μL, P = 0.046) was observed compared with CD patients without skin manifestations. The concentrations of IL-17A and IL-23 in CD patients with skin lesions developed under anti-TNF-α therapy were significantly higher compared to those in patients without lesions (IL-17A: 39.01 ± 7.03 pg/mL vs 25.71 ± 4.90 pg/mL, P = 0.00004; IL-23: 408.78 ± 94.13 pg/mL vs 312.15 ± 76.24 pg/mL, P = 0.00556). CONCLUSION Skin lesions in CD patients during biological therapy may result from significantly increased concentrations of IL-17A and IL-23, which are strongly associated with TNF-α/Th1 immune pathways.

Clinical potential of eluxadoline in the treatment of diarrhea-predominant irritable bowel syndrome

Diarrhea-predominant irritable bowel syndrome (IBS-D) belongs to the group of functional gastrointestinal disorders and is characterized by abdominal pain in conjunction with diarrhea. The incidence of IBS-D is currently increasing, leading to a heavy economic burden for patients and health care systems worldwide. Recent studies suggest eluxadoline as an attractive new tool for the treatment of patients with IBS-D. Eluxadoline is an orally active μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, with powerful antidiarrheal and analgesic activity. Eluxadoline is believed to act locally in the enteric nervous system, and has no adverse effects in the central nervous system. In this review, we discuss the most recent findings on the mechanism of action of eluxadoline and the results of the clinical trials in patients with IBS-D. We also discuss possible side effects and analyze the potential of eluxadoline to be used in the treatment of IBS-D.

Circadian rhythm abnormalities – Association with the course of inflammatory bowel disease

Crohns disease (CD) and ulcerative colitis (UC) are the main representatives of inflammatory bowel diseases (IBD), a group of chronic, immune system-mediated inflammatory diseases of the gastrointestinal (GI) tract. The pathogenesis of the intestinal lesions in IBD is not entirely identified and understood: excessive activation of the immune system may come as a result of the interaction of various environmental and infectious factors, genetic predisposition, and the mediation of abnormal intestinal flora. The main objective of the current study is to further identify the risk factors for the development of IBD. Currently, there is very little knowledge about circadian rhythm and IBD and there are only a few studies on the relationship between sleep disturbances and the course of the disease, as well as pro- and anti-inflammatory cytokine profile and general immune system functioning. Furthermore, the relationship between the expression of circadian rhythm genes and severe course of IBD is still unknown. The aim of this review is to show the current state of knowledge about the relationship between circadian rhythm disorders, sleep disturbance and inflammation in the GI tract and to analyze the possibility of employing this knowledge in diagnosis and treatment of IBD.

Elevated risk of venous thromboembolic events in patients with inflammatory myopathies

Venous thromboembolism (VTE) is a multifactorial disease manifesting as either deep vein thrombosis or pulmonary embolism. Its prevalence makes VTE a significant issue for both the individual – as a negative factor influencing the quality of life and prognosis – and the society due to economic burden. VTE is the third most common vascular disorder in Western countries, after myocardial infarction and stroke, making it a major cause of in-hospital mortality, responsible for 5%–10% of hospital deaths. Despite many studies conducted, only 50%–60% provoking factors have been identified, while the remaining 40%–50% have been classified as idiopathic or unprovoked. Chronic inflammatory disorders, with their underlying prothrombotic state, reveal an increased risk of VTE (six to eight times) compared with the general population. Among the inflammatory disorders, we can identify inflammatory myopathies – a group of rare, chronic diseases featuring weakness and inflammation of muscles with periods of exacerbation and remission; their main classes are polymyositis and dermatomyositis. The objective of this review is to emphasize the need of VTE prophylaxis in individuals with inflammatory myopathies in order to reduce morbidity and mortality rates among those patients and improve their quality of life and prognosis.

Treatment of Perianal Fistulas in Poland

UNLABELLED A perianal fistula is a pathological canal covered by granulation tissue connecting the anal canal and perianal area epidermis. The above-mentioned problem is the reason for the patient to visit the surgeonproctologist. Unfortunately, the disease is characterized by a high recurrence rate, even despite proper management. The aim of the study was to determine the current condition of perianal fistula treatment methods in everyday surgical practice, considering members of the Society of Polish Surgeons. MATERIAL AND METHODS 1523 members of the Society of Polish Surgeons received an anonymous questionnaire comprising 15 questions regarding perianal fistula treatment in everyday practice. RESULTS Results were obtained from 807 (53%) members. After receiving answers, questionnaire results were collected, analysed, and presented in a descriptive form. CONCLUSIONS Study results showed that most Polish surgeons choose the fistulectomy/fistulotomy method. Considering treatment of perianal fistulas the most important issue is to find the correct, primary fistula canal. Further methods should be individually selected for each patient. One should also remember that every fistula is different. Surgical departments that operate a small number of perianal fistulas should direct such patients to reference centers.

Serum Cyclophilin A Correlates with Increased Tissue MMP-9 in Patients with Ulcerative Colitis, but Not with Crohn’s Disease

BackgroundCyclophilin A (CyPA) is an immunomodulatory protein, high expression of which correlates with poor outcome of patients with inflammatory diseases. However, its role in inflammatory bowel disease (IBD) has not been studied.AimThis study analyzes the correlation between cyclophilin A, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP (TIMP)/MMP-9 complexes in the inflamed and non-inflamed colon mucosa of UC and CD patients.MethodsSerum and biopsy specimens from inflamed and non-inflamed colonic mucosa of 38 patients with IBD (19 with UC and 19 with CD) and 16 controls were included in our study. We measured serum and tissue level of CyPA, and tissue level of TNF-α, MMP-9, TIMP-1/MMP-9, and TIMP-2/MMP-9 using ELISA method.ResultsOur results indicated that serum, but not tissue CyPA is increased in UC, rather than in CD patients, compared to the control. The increase correlated with higher tissue concentration of MMP-9 and TNF-α, especially in the UC group. Moreover, we observed significantly higher level of TIMP-1/MMP-9 in UC and CD group, which overlapped with the change in MMP-9. There was no change in TIMP-2/MMP-9 in the analyzed groups.ConclusionThe current study suggests that serum CyPA may be an independent additional marker of IBD, especially of UC. Higher CyPA level may be followed by increased MMP-9 in those patients. However, further studies are necessary to verify the role of CyPA in IBD development.

Pharmacology and metabolism of infliximab biosimilars – A new treatment option in inflammatory bowel diseases

Biological therapy with monoclonal antibodies to tumor necrosis factor alpha (TNF-α) was shown in large clinical trials to be effective in inducing and maintaining clinical remission in patients with moderate to severe Crohns disease (CD) and ulcerative colitis (UC). Infliximab, the first anti-TNF-α biologic drug, has significantly improved inflammatory bowel disease (IBD) treatment outcomes by preventing structural damage progression, thereby reducing complications and the need for surgery and hospitalization. The major concern associated with the use of biologics is their high cost. However, as these therapies lose patent protection, cheaper biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13. Position statements from several scientific societies and some experts in their reviews have expressed concerns to the concept of extrapolation without direct IBD clinical evidence, whereas European Medicines Agency (EMA) experts have supported extrapolation. In this review, we focus on the pharmacokinetics, pharmacodynamics properties and comparative effectiveness of anti-TNF-α biosimilars, related to their use in IBD.

Prevention and therapeutic strategies of thromboembolic events in patients with inflammatory bowel diseases: a report of three cases.

Crohns disease and ulcerative colitis belong to a group of inflammatory bowel diseases (IBD). IBD are characterized by a chronic character of inflammatory process and overlapping immunological abnormalities, which, along with therapeutic strategies are currently available, underlie an increased risk of venous thromboembolic events (VTE). The most common sites of VTE in IBD patients are deep venous thrombosis (DVT) and pulmonary embolism (PE). These complications are particularly important in clinical practice due to a very high mortality rate. Therefore, an early diagnosis of new IBD cases and the control of inflammatory process are thought to play a crucial role in risk reduction for thromboembolic events. Despite considerable evidence supporting the association between IBD and VTE, there is still a lack of recognition of this risk, with dangerous consequences for patients. In this paper authors report three cases of VTE in IBD patients and discuss the most relevant clinical studies found in MEDLINE, Cochrane Library and EMBASE regarding its prevention and management.

Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications

Long-term fluoroquinolone-associated disability (FQAD) after fluoroquinolone (FQ) antibiotic therapy appears in recent years as a significant medical and social problem, because patients suffer for many years after prescribed antimicrobial FQ treatment from tiredness, concentration problems, neuropathies, tendinopathies, and other symptoms. The knowledge about the molecular activity of FQs in the cells remains unclear in many details. The effective treatment of this chronic state remains difficult and not effective. The current paper reviews the pathobiochemical properties of FQs, hints the directions for further research, and reviews the research concerning the proposed treatment of patients. Based on the analysis of literature, the main directions of possible effective treatment of FQAD are proposed: (a) reduction of the oxidative stress, (b) restoring reduced mitochondrion potential ΔΨm, (c) supplementation of uni- and bivalent cations that are chelated by FQs and probably ineffectively transported to the cell (caution must be paid to Fe and Cu because they may generate Fenton reaction), (d) stimulating the mitochondrial proliferation, (e) removing FQs permanently accumulated in the cells (if this phenomenon takes place), and (f) regulating the disturbed gene expression and enzyme activity.

G protein-coupled receptor 30 (GPR30) expression pattern in inflammatory bowel disease patients suggests its key role in the inflammatory process : a preliminary study

BACKGROUND AND AIMS G protein-coupled receptor 30 (GPR30) is a recently de-orphanized estrogen receptor that mediates the effects of estrogens on different cells. It has been postulated that in inflammatory bowel diseases (IBD) activation of GPR30 blocks the pathways dependent on pro-inflammatory cytokines. The aim of our study was to investigate GPR30 expression in patients with IBD and its potential implication in future therapies. METHODS Fifty-seven patients were enrolled in our study: 20 subjects with Crohns disease (CD), 22 with ulcerative colitis (UC) and 15 controls. In each subject, biopsies were taken from various left-colonic locations. Gene and protein expression of GPR30 was quantified using real time RT-PCR or Western blot. RESULTS GPR30 mRNA and protein expression were detected in all tested colonic tissues. No significant differences in GPR30 gene expression were observed. In non-inflamed areas, GPR30 protein was strongly increased in CD patients, but moderately in UC patients (p= 0.014 and p=0.143, respectively, vs. controls). In CD patients, a significantly lower GPR30 protein content in inflamed than in non-inflamed tissue was observed (p=0.039). The change was independent of patient gender. CONCLUSION Our observations indicate that GPR30 may play a role in the development and progression of inflammatory lesions in IBD, thus affecting disease severity, and consequently IBD treatment. Therefore, GPR30 may become an attractive target for novel anti-IBD drugs, particularly in CD.