Retrospective study of patients with chronic spontaneous urticaria with regard to irritable bowel symptoms.

Abstract

Abstract Objectives Patients with chronic spontaneous urticaria (csU) are a heterogenic group because of the various causes and symptoms, that are presented by this patient collective. Often these symptoms are caused by gastrointestinal conditions (e.g. colonization with Helicobacter pylori or other intestinal pathogenic germs). A key role in the development of the csU is played by mast cell-released histamine, which – combined with other mediators – also influences the pathogenesis of the Irritable Bowel Syndrome (IBS), however so far not well investigated. Thus, the main objectives of this retrospective analysis were (i) to record the frequency of IBS as a comorbidity in patients with csU, (ii) to investigate a possible interaction/reactivity between the skin- and the bowel-compartment and (iii) to document the course of the disease in both compartments under guideline-conform therapy of the csU. Design and Methods The analysis was done retrospectively including samples and data of 120 patients, which were treated according to a defined clinical treatment pathway (if found Urticaria Activity Score (UAS7) ≥ 10 points at first presentation) in the outpatient clinic for patients with urticaria at the Allergy-Unit of the Department of Dermatology, University Hospital Erlangen, between February 2016 and September 2018. The evaluated treatment period was between 9 and 16 weeks (in case of further need for therapy: in specific cases up to 12 months) and a repeated set of 5 questionnaires was evaluated during this period of time. Two of these referred to the severity and impact of urticaria: the Urticaria Activity Score for 7 days (UAS7) and the Dermatological Life Quality Index (DLQI). The ROME-III-criteria were used to detect IBS. A patient presenting irritable bowel symptoms would be designated ROME+, one without ROME-. The Irritable Bowel Syndrom Severity Scoring System (IBS- SSS) evaluated the severity of IBS whereas the intensity of allergic and systemic symptoms was measured by the “Erlanger Allergiescore” (EA), which was developed to grade the reactions induced by food allergies and mast cell disorders. Further tests routinely performed and analyzed were: a skin prick test (against aeroallergens and food allergens) and in vitro parameter (tryptase, eosinophil cationic protein (ECP), C-reactive protein (CRP), total IgE and specific IgE), both, in a serum sample and in lavage material (if indicated) gained via endoscopic guided segmental gastrointestinal lavage. Finally, a histologic examination of biopsies of the lower gastrointestinal tract taken during a colonoscopy, if indicated, was performed. Observation and Results Typical symptoms of IBS were presented by 16.7% of the patients with csU, which is a slightly higher rate than the prevalence in the general population (11.2%). Within the group of urticaria patients, whose symptoms were insufficiently controlled by therapy with H1-receptor antagonists (“antihistamines”), the rate of concomitant IBS even rose to 22.6%. Under guideline-conform urticaria therapy, the UAS7 changed significantly for the whole cohort of patients (p-value 0.043). ROME- patients presented in the course of treatment a significantly decreased UAS7 (p-value 0.031), while in ROME+ patients the UAS7 also decreased, but not significantly (p-value 0.21). Regarding the different treatment options it could be shown, that under therapy with H1-receptor antagonists the urticaria-activity of ROME- patients dropped by 2.5 score points in the UAS7, while the one of ROME+ patients did not change. A more distinct impact on the disease activity was observed under therapy with Omalizumab: the UAS7 of ROME- patients dropped by 13 score points (p-value 0.25), while a decrease of 4.5 score points (p-value 0.31) could be recorded in ROME+ patients. In general, patients who needed Omalizumab in the course of therapy, always presented a higher UAS7 compared to patients, who were sufficiently treated by “antihistamines”. ROME+ patients presented a significantly higher DLQI at the beginning of their treatment compared to ROME- (p-value 0.021) and life quality was significantly better after initiating guideline-conform urticaria therapy (ROME- p-value 0.001, ROME+ p- value 0.041). A significant improvement of the gastrointestinal complaints of ROME+ patients was measured via EA (p-value 0.047), while the IBS-SSS showed a lower severity of symptoms (median decrease by 35.5 score points (25. percentile: 51; 75. percentile 149.5) only after a longer observation period (> 16 weeks -recorded in a number of patients). Treatment with Omalizumab improved in 4 out of 6 patients their irritable bowel symptoms, 3 of them even achieved a remission. In the terminal ileum of 8 out of 9 patients, the histopathological examination detected a moderate to severe mast cell infiltration, which however significantly decreased under treatment with Omalizumab (p-value 0.012). Elevated tryptase-levels as a sign of mast cell activation were only detected in a small number of patients, whereas ECP-levels, representing the activity of eosinophilc granulocytes, were elevated in the serum of 56% of the ROME- and 70% of the ROME+ patients, as well as in every patient’s lavage. Omalizumab therapy showed its biggest effect on ROME+ patients, lowering the ECP-levels in both, the serum and the gastrointestinal lavage, most effectively. Conclusion Patients with high urticaria activity and insufficient treatment response to “antihistamines” in the examined cohort benefited from a therapy with Omalizumab. Furthermore it could be shown, that these are exactly the patients that should be tested for IBS, as a disproportionately number (22.6%) of this subgroup of patients (uncontrolled by H1-receptor antagonists in their licensed or even increased dose) are affected by IBS compared to 16.7% in the whole examined cohort (n=120) of csU patients. Apart from a higher urticaria activity, this subgroup suffers of more impaired quality of life and is more difficult to medicate sufficiently. Further, best results in ROME+ were achieved under therapy with Omalizumab. Irritable bowel symptoms showed minimal change under urticaria-treatment during the observation period of 16 weeks; they decreased only after an extended time interval: Then, however, under treatment with Omalizumab even remissions were observed. Also, the rate of mast cell infiltration decreased significantly under this therapy. The high activity of eosinophilic granulocytes in csU measured in both, the blood and the intestine, could be important from a pathophysiological point of view, as mast cells and eosinophils can influence each other, and both cell populations are strongly associated with the disease entities of csU and IBS. Since Omalizumab therapy markedly reduced the eosinophil activity, in the future, ECP in blood or the intestine could be further examined as a potential biomarker for disease activity or to monitor the therapeutic effect. In our retrospective pilot study, there were some indications for a divergent pathogenesis for the subgroup of patients with csU and simultaneous IBS versus the one with csU without IBS. This, as well as the mode of action of Omalizumab in both compartments (intestine and skin) should be further explored in a larger prospective cohort with a longer observation period. Show more