Agnieszka Dobrowolska

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 impact of genetic factors on response to glucocorticoids therapy in IBD

ABSTRACT Glucocorticosteroids (GCs) are used for many years as first-line drugs for the achievement of remission in exacerbations of inflammatory bowel disease (IBD). However, close to 20% of patients are resistant to GCs, and 40% of patients become dependent on GCs. The challenge of today’s personalized medicine is the anticipation of the steroid therapy effects even before the initiation of treatment. As several studies show, individually variable response to GCs in population has a genetic background and may depend on gene variability encoding proteins involved in the function and metabolism of GCs. To those genes belong: NR3C1 – responsible for the synthesis of GC receptor (GR); Hsp90, HSP70, STIP1, FKB5 – genes of GR protein complex; ABCB1 and IPO13 coding glycoprotein p170; and importin 13 – involved in GCs transport; IL1A, IL1B, IL2, IL4, IL8, IL10, TNF, and MIF – genes of the epithelial pro-inflammatory factors synthesis, which excessive activation causes steroid resistance as well as CYP3A4 and CYP3A5 – encoding GCs biotransformation enzymes. This work systematizes and sums up the state of current knowledge in the field of pharmacogenetics as well as expectations for the future in the realm of individualized medicine in IBD patients treated with GC drugs.

Usefulness of selected laboratory markers in ulcerative colitis

IntroductionThis study aimed to compare the accuracy of selected laboratory markers in assessing disease activity in patients with ulcerative colitis (UC). The analysis included serum IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ, hsCRP, peripheral regulatory T cells, as well as fecal calprotectin and lactoferrin.Patients and methodsA group of 45 adults with UC was enrolled in the study. Disease activity was assessed using the Mayo endoscopic index, while for clinical activity scoring, the Clinical Activity Index (CAI) was used. Concentrations of markers investigated were estimated by means of flow cytometry and enzyme-linked immunosorbent assays: the results were correlated with both indices.ResultsThe study demonstrated that both fecal markers, i.e. calprotectin (r = 0.880, P<0.001) and lactoferrin (r = 0.799, P<0.001) correlated closely with the Mayo endoscopic score, and might be used to evaluate the severity of UC in the clinical setting. The correlation of these markers with CAI was also significant, with r = 0.831 for calprotectin (P<0.001) and r = 0.672 for lactoferrin (P<0.05). As for the other markers investigated, only IL-6 (r = 0.598, P<0.001), IL-17A (r = 0.587, P<0.005), and TNF-α (r = 0.701, P<0.001) correlated closely with the Mayo endoscopic index. The correlation of the markers with CAI was also significant, though weaker, with r = 0.525 for IL-6 (P<0.001), r = 0.587 for IL-17A (P<0.05), and r = 0.624 for TNF-α (P<0.001).DiscussionDespite the fact, that UC is generally considered to be an IL-13-driven, Th2-like type of disease, markers of inflammation such as serum interleukin (IL)-6, IL-17, TNF-α, fecal calprotectin and lactoferrin might be useful in assessing disease activity.

Usefulness of Endoscopic Indices in Determination of Disease Activity in Patients with Crohn’s Disease

Background. Assessment of endoscopic activity of Crohns disease (CD) is of growing importance both in clinical practice and in clinical trials. The study aimed to assess which of the endoscopic indices used for evaluation of mucosal changes correlates with the currently used clinical indices for determination of disease activity and with the results of histopathological examination. Study. A group of 71 patients with CD and 52 individuals without a diagnosis of GI tract disease as a control group were investigated, considering clinical and histological severity of the disease and the severity of inflammatory changes in the bowel. Evaluation was conducted with the use of clinical, endoscopic, and histopathological indices. Endoscopic indices were then correlated with different clinical and histopathological indices with the aim of finding the strongest correlations. Results and Conclusions. Correlation between the clinical disease activity and the severity of endoscopic lesions in CD was shown in this study to be poor. The results also indicate that the optimal endoscopic index used in the diagnostic stage and in the assessment of treatment effects in CD is Simple Endoscopic Score for Crohns Disease (SES-CD).

Applicability of endoscopic indices in the determination of disease activity in patients with ulcerative colitis.

Objective The combination of clinical remission and mucosal healing represents a major goal of different treatment strategies for ulcerative colitis (UC). This study aimed to assess which of the endoscopic indices used to evaluate mucosal changes in UC are correlated with clinical indices currently used to determine disease activity, as well as which of the endoscopic indices are correlated with the Geboes Index used for histological evaluation. It also aimed to find correlations between the currently used clinical activity indices and the histological Geboes Index. Methods A group of 49 patients with a confirmed diagnosis of UC and a group of 52 individuals without a diagnosis of gastrointestinal disease, who constituted the control group, were investigated. All patients were evaluated by colonoscopy, and the severity of mucosal changes was scored in terms of nine different endoscopic indices commonly used in both pharmacological trials and clinical practice. Evaluation was also carried out using clinical and histological indices. Endoscopic indices used for UC were then correlated with different clinical and histological indices to find the strongest correlations. Results and conclusion A high correlation was demonstrated between three of the 11 evaluated clinical indices – Improvement Based on Individual Symptom Scores, Ulcerative Colitis Disease Activity Index, and Schroeder Index – and all nine endoscopic indices – Ulcerative Colitis Endoscopic Index of Severity, Baron Score, Schroeder Index, Feagan Index, Powell–Tuck Index, Rachmilewitz Index, Sutherland Index, Lofberg Index, and Lemman Index. Improvement Based on Individual Symptom Scores was the index with the highest correlation with all the endoscopic indices used for UC. The above indices are recommended for clinical evaluation of UC activity. The Ulcerative Colitis Endoscopic Index of Severity was moderately correlated with a histological index, and it is therefore recommended for routine endoscopic mucosal evaluation in patients with UC.

Prevalence of osteoporosis and osteopenia in a population of patients with inflammatory bowel diseases from the Wielkopolska Region

Introduction The incidence of osteoporosis in patients with inflammatory bowel disease (IBD) varies across different populations. Objectives The aim of this study was to evaluate the prevalence of osteoporosis in Polish patients with IBD, as well as the effect of the body mass index (BMI), disease duration, the number of hospital stays, and the use of glucocorticoids on bone mineral density (BMD). Patients and methods BMD of 208 patients with IBD (103 with Crohn disease [CD] and 105 with ulcerative colitis [UC]) and 41 healthy controls was measured using dual‑energy X‑ray absorptiometry. The association of BMD with the other parameters was analyzed using statistical methods. Results Osteoporosis of the lumbar (L2-L4) spine (T‑score) was observed in 11.7% of patients with CD and in 3.8% of those with UC, whereas that of the femoral neck (FN), in 5.8% and 2.9% of the patients with CD and UC, respectively. Osteopenia occurred in 35.9% (FN) and 36.9% (L2-L4) of CD patients, and in 25.7% (FN) and 29.5% (L2-L4) of UC patients. In CD patients, BMI was associated with lumbar and femoral BMD and with L2-L4 T‑score, whereas FN T‑score correlated with BMI. In UC patients, the cumulative glucocorticoid dose correlated with L2-L4 T‑score, FN BMD, FN T‑score, and FN Z‑score; the disease duration correlated with FN BMD, while the FN T‑score, with the number of hospital stays and FN BMD. Conclusions Osteoporosis and osteopenia are frequent in Polish patients with IBD. BMD correlated with BMI in all patients. In UC patients, BMD was associated with the cumulative glucocorticoid dose, disease duration, and number of hospital stays.

Long-range PCR libraries and next-generation sequencing for pharmacogenetic studies of patients treated with anti-TNF drugs

Biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies significantly increased the effectiveness of autoimmune disease treatment compared with conventional medicines. However, anti-TNF-α drugs are relatively expensive and a response to the therapy is reported in only 60–70% of patients. Moreover, in up to 5% of patients adverse drug reactions occur. The various effects of biological treatment may be a potential consequence of interindividual genetic variability. Only a few studies have been conducted in this field and which refer to single gene loci. Our aim was to design and optimize a methodology for a broader application of pharmacogenetic studies in patients undergoing anti-TNF-α treatment. Based on the current knowledge, we selected 16 candidate genes: TNFRSF1A, TNFRSF1B, ADAM17, CASP9, FCGR3A, LTA, TNF, FAS, IL1B, IL17A, IL6, MMP1, MMP3, S100A8, S100A9, and S100A12, which are potentially involved in the response to anti-TNF-α therapy. As a research model, three DNA samples from Crohn’s disease (CD) patients were used. Targeted genomic regions were amplified in 23 long-range (LR) PCR reactions and after enzymatic fragmentation amplicon libraries were prepared and analyzed by next-generation sequencing (NGS). Our results indicated 592 sequence variations located in all fragments with coverage range of 5–1089. We demonstrate a highly sensitive, flexible, rapid, and economical approach to the pharmacogenetic investigation of anti-TNF-α therapy using amplicon libraries and NGS technology.

C-reactive protein as a diagnostic and prognostic factor in inflammatory bowel diseases.

AIM The study aimed to evaluate high-sensitivity CRP (hsCRP) as a diagnostic and predictive marker in patients with inflammatory bowel disease (IBD). MATERIAL/METHODS Medical history of 106 patients with IBD revealed hsCRP concentrations at diagnosis and during the follow-up period. RESULTS The study showed that the majority of investigated patients had elevated hsCRP concentrations at diagnosis, although the mean concentration was much higher in the group of patients with Crohns disease (CD) than the group with ulcerative colitis (UC) (P<0.001). The overall decrease in mean hsCRP concentration observed during the follow-up period was larger in the group of CD patients. The analysis showed a correlation between hsCRP concentrations at diagnosis and risk of surgery in the group of CD patients (r=0.408, P=0.002), but not in the group of UC patients. In a logistic regression analysis, surgery in CD patients was associated with age (OR: 0.89, 95% CI: 0.8-1.0, P=0.05) and hsCRP concentration (OR: 1.02, 95% CI: 1.0-1.04, P=0.03) at diagnosis. DISCUSSION HsCRP might be a useful diagnostic marker in differentiating active IBD from other diseases. Particularly important however seems to be the predictive value of hsCRP at diagnosis in prognosing the clinical outcome of the disease in CD patients.