Tumor necrosis factor-alpha and Fas/Fas ligand signaling pathways in chronic spontaneous urticaria.

BACKGROUND: There is increasing evidence pointing to the important role of tumor necrosis factor-alpha (TNF-α), a key inflammatory and apoptotic mediator in urticarial inflammation. However, the role of the TNF-α system and Fas/Fas ligand (FasL) in the apoptosis-inducing pathways in chronic spontaneous urticaria (CSU), remain unclear. AIM: To determine circulating concentrations of TNF-α, soluble TNF-α receptor type 1 and type 2 (sTNF-R1 and sTNF-R2, respectively) as well as soluble Fas (sFas) and FasL (sFasL) in CSU subjects. METHODS: Serum TNF-α, sTNF-R1, sTNF-R2, sFas, sFasL concentrations were measured using enzyme-linked immunosorbent assay in CSU subjects and in the healthy subjects. RESULTS: TNF-α concentrations were significantly higher in CSU subjects and moderate-to-severe CSU than in the controls, while there were no significant differences in TNF-α concentrations between subjects with mild CSU and the controls. sTNF-R1 and sTNF-R2 concentrations were significantly higher in all CSU and moderate-severe CSU subjects vs. the controls. Serum concentrations were also significantly higher in mild CSU vs. the controls, but not in moderate-severe CSU vs. mild CSU. No significant differences were observed in sFas and sFasL concentrations between CSU subjects and the healthy controls. Significant correlations were found between concentrations of TNF-α and its receptors, as well as sTNF-R1 and sTNF-R2, but not with the urticaria activity score (UAS). There was no relationship between TNF-α/sTNF-R1/sTNF-R2 and sFas/sFasL pathways in CSU. CONCLUSIONS: CSU is associated with the activation of the TNF-α/receptors signaling pathway, marked by increased circulating concentrations of TNF-α, sTNF-R1 and sTNF-R2, which are related to each other in this disease. In contrast, the circulating sFas/FasL system is not up-regulated in CSU, and sFas/sFasL may not be a useful marker of the activity/severity of urticarial processes. Considering the lack of significant changes in sFas/sFasL (mainly reflecting systemic apoptosis) in CSU patients, it appears that elevated serum TNF-α concentrations are related to its pro-inflammatory function rather than an enhanced systemic apoptotic response in CSU.

Interplay between acute phase response and coagulation/fibrinolysis in chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is associated with activation of systemic inflammatory response and coagulation/fibrinolysis. AIM: To study whether there is a relationship between the acute phase response and coagulation/fibrinolysis in chronic spontaneous urticaria (CSU) patients. METHODS: Serum concentrations of C-reactive protein (CRP) and interleukin 6 (IL-6), key markers of acute phase response and of D-dimer, a marker of fibrin turnover were investigated in 58 CSU patients assessed with the urticaria activity score (UAS) and the controls. RESULTS: Serum concentrations of IL-6, CRP, and D-dimer were significantly higher in CSU patients as compared with the controls. We found statistically significant correlations between D-dimers concentrations and the inflammatory markers: CRP and IL-6 as well as UAS. CONCLUSIONS: Markers of inflammation (IL-6 and CRP) and of fibrinolysis (D-dimer) are related to each other in CSU, suggesting a possible cross-talk between inflammation and coagulation/fibrinolysis. It might be implicated in pathogenesis of the disease and may be associated with higher risks of cardiovascular diseases in CSU patients.

Elevated plasma il-8 concentration is related to severity of systemic inflammation in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is associated with activation of acute phase response. Questions arise regarding its association with other inflammatory mediators. To determine plasma IL-8 concentration in CSU patients and its association with C-reactive protein (CRP) concentration, a nonspecific inflammatory marker of the disease activity, concentrations of plasma IL-8 and serum CRP were measured in CSU patients and compared with healthy controls. IL-8 and CRP concentrations were significantly higher in CSU patients as compared with the healthy subjects. In addition, there were significant differences in IL-8 and CRP concentrations between CSU patients with moderate-severe symptoms and the healthy subjects. Plasma IL-8 and serum CRP concentrations showed a significant correlation with urticaria activity score (UAS). Additionally, a significant positive correlation was observed between IL-8 and CRP concentrations. Up-regulations of IL-8 and its association with the marker of clinical and inflammatory activity suggest a role of this cytokine in the pathogenesis of CSU.

Decreased plasma kallikrein 5 concentrations in patients with chronic spontaneous urticaria.

Little is known about the role of the kallikrein-kinin system in chronic spontaneous urticaria (CSU). Kallikrein 5 (KLK5), a trypsin-like enzyme, is the most abundant in the skin and plays a role in itching and inflammatory reaction. In this study, we determined plasma KLK5 concentration, and its associations with acute phase response in CSU patients. Concentrations of KLK5 in plasma and CRP in serum were measured in patients with CSU of varying severity and in the healthy subjects. Plasma KLK5 concentrations were significantly lower in CSU (all) and moderate-severe CSU patients, as compared with the controls. There were no significant differences in KLK5 concentration in mild CSU patients as compared with the healthy subjects and moderate-severe CSU patients. No correlation was observed between KLK5 and CRP concentrations in the patients. It may be considered that circulating kallikrein 5 is down-regulated in CSU patients, however its potential role and the possible underlying mechanism are unknown.

The relationship between circulating concentrations of interleukin 17 and C reactive protein in chronic spontaneous urticaria.

BACKGROUND: Up-regulation of interleukin 17 (IL-17) family cytokines and acute phase response have been observed in patients with chronic spontaneous urticaria (CSU). It has been demonstrated that IL-17 stimulates C-reactive protein (CRP) expression. AIM: To determine relationship between circulating concentrations of IL-17 and CRP in CSU. METHODS: Concentrations of IL-17 in plasma and CRP in serum were measured in patients with CSU of varying severity and in the healthy subjects. RESULTS: IL-17 and CRP concentrations were significantly higher in CSU patients as compared to the healthy subjects. In addition, there were significant differences in IL-17 and CRP concentrations between CSU patients with mild, moderate-severe symptoms and the healthy subjects. CRP did not correlate significantly with IL-17. CONCLUSIONS: Increased circulating IL-17 concentration may represent an independent index of systemic inflammatory response in CSU, which is not related to increased CRP concentration.

Lower serum B12 vitamin concentrations are not accompanied by hyperhomocysteinaemia in chronic spontaneous urticaria.

BACKGROUND: Lower serum vitamin B12 concentrations have been observed in patients with chronic spontaneous urticaria (CSU). It is known that vitamin B12 deficiency is closely related to hyperhomocysteinaemia, which is associated with a proinflammatory state. AIM: To assess the relationship between vitamin B12 status and concentrations of homocysteine (Hcy) with acute phase response in patients with CSU. METHODS: Circulating concentrations of vitamin B12, Hcy and C-reactive protein (CRP) were measured in 42 patients with CSU of varying severity, and compared with 19 healthy controls (HCs). RESULTS: Significantly lower concentrations of vitamin B12 and higher concentrations of CRP were observed in the serum of the patients with CSU compared with HCs (P < 0.01 and P < 0.001, respectively). However, there were no significant differences in plasma Hcy concentrations between the investigated groups. In addition, no correlations were found between the concentrations of vitamin B12, Hcy and CRP. CONCLUSIONS: Lower values of vitamin B12 concentration in patients with CSU were not associated with higher Hcy concentrations, suggesting that such patients do not have functional vitamin B12 deficiency.

Evaluation of platelet function using PFA-100® in patients treated with Acetylsalicylic acid and qualified for Trauma and Orthopedic surgery procedures.

The phenomenon of high on-acetylsalicylic acid (ASA) treatment platelet (PLT) reactivity - HATPR - and its clinical implications have not been fully understood. Little data is available on assessing PLT activity based on the severity of intra- and postoperative bleeding in a population of orthopedic patients with normal closure time (CT) measured by a PLT function analyzer PFA-100®, despite being given long-term ASA therapy. The aim is to assess PLT function using PFA-100® in patients with ASA therapy and qualified for trauma and orthopedic surgery procedures. The retrospective analysis covered 384 patients whose PLT reactivity was assessed using PFA-100®. Out of those, 198 had been taking ASA with a 75 mg dose until hospital admission. In addition, a group of 70 patients with a proximal femoral fracture surgically treated using the dynamic hip screw (DHS) was selected, in whom severity of bleeding was assessed by HIP ASA (+). The reference group comprised 52 patients (without ASA therapy) who were operated on due to the same indications. Normal CT was found in 37% of ASA-receiving patients. Patients with normal CT, despite ASA therapy, exhibited significantly more intense bleeding after DHS surgery. A similar number of patients required red blood cells (RBCs) transfusion in HIP ASA (+) and HIP ASA (-). Increased risk of complications in HIP ASA (+) group was not found. CONCLUSIONS: Normal PLT function assessed using PFA-100® is a common phenomenon in patients with long-term ASA treatment and who are qualified for trauma and orthopedic surgery procedures. In many cases, it seems that inadequate response to ASA is only a laboratory phenomenon.

Evaluation of circulating vascular endothelial growth factor and its soluble receptors in patients suffering from persistent allergic rhinitis.

BACKGROUND: Overexpression and enhanced release of vascular endothelial growth factor (VEGF) have been detected in various types of allergic inflammation, including asthma. AIM: To further evaluate the pattern of systemic release of VEGF in atopic allergy, free circulating VEGF was measured in patients with persistent allergic rhinitis (PAR). METHODS: The concentrations of VEGF and its soluble receptors (sVEGF-R1 and VEGF-R2) in plasma were measured in patients with PAR sensitized to house dust mites and the healthy subjects. RESULTS: No significant differences were found between PAR patients and healthy subjects with respect to plasma levels of VEGF and its receptors. CONCLUSIONS: It seems that free circulating VEGF may not be elevated in PAR patients. Moreover, on the basis of the present study as well as the earlier ones, it appears likely that systemic release of VEGF varies among patients with distinct clinical manifestation of atopy; may depend on severity/activity and the extent of inflammatory response.

Involvement of the histaminergic system in the resuscitating effect of centrally acting leptin in haemorrhagic shock in rats.

Leptin, acting centrally as a neuromodulator, induces the activation of the sympathetic nervous system, which may lead to a pressor action in normotensive animals. In haemorrhagic shock, leptin administered intracerebroventricularly (icv.) evokes the resuscitating effect, with long-lasting rises in mean arterial pressure (MAP) and heart rate (HR), subsequent increase in peripheral blood flows, and a 100% survival at 2 h. Since leptin is able to activate histaminergic neurons, and centrally acting histamine also induces the resuscitating effect with the activation of the sympathetic nervous system, in the present study, we investigated an involvement of the histaminergic system in leptin-evoked cardiovascular effects in haemorrhagic shock. The model of irreversible haemorrhagic shock, with MAP decreased to and stabilised at 20 - 25 mmHg, has been used. Leptin (20 µg) given icv. at 5 min of critical hypotension evoked 181.5% increase in extracellular hypothalamic histamine concentration during the first 10 min after injection. Rises in MAP, HR and renal, mesenteric and hindquarters blood flows induced by leptin were inhibited by icv. pre-treatment with histamine H1 receptor antagonist chlorpheniramine (50 nmol). In contrast, there was no effect of H2, H3 and H4 receptor antagonists ranitidine (25 nmol), VUF 5681 (25 nmol) and JNJ 10191584 (25 nmol), respectively. In conclusion, the histaminergic system is involved in centrally-acting leptin-induced resuscitating effect in haemorrhagic shock in rats.

Circulating soluble receptor for advanced glycation end products is decreased and inversely associated with acute phase response in chronic spontaneous urticaria.

BACKGROUND: Activation of receptor for advanced glycation end products (RAGE) leads to the proinflammatory response and the release of its soluble form (sRAGE) which appears to function as an anti-inflammatory feedback mechanism. AIM: To determine serum sRAGE concentration in CSU patients and its association with C-reactive protein (CRP) concentration, a nonspecific inflammatory marker of the disease activity. METHODS: Concentrations of sRAGE and CRP were measured in serum of CSU patients and compared with the healthy controls. RESULTS: Serum sRAGE concentrations were significantly decreased in CSU patients, especially those more severely affected. In addition, significant inverse correlations were observed between sRAGE and CRP concentrations. CONCLUSIONS: Down-regulation of sRAGE and its association with acute phase response suggest a role for RAGE activation in the pathogenesis of CSU. It seems that lower serum sRAGE concentration may enhance the urticarial processes.

Effective treatment of different phenotypes of chronic urticaria with omalizumab: Case reports and review of literature.

Despite the excellent efficacy and safety profile of omalizumab in chronic spontaneous urticaria (CSU), there are scarce data concerning its role in the treatment of refractory cases with different phenotypes of urticaria. We describe our experience with the therapy of nine patients with CSU co-existing with delayed pressure urticaria (DPU) or angioedema or both and refractory to treatment with high-dose antihistamines. The first patient, with severe CSU and recurrent angioedema, did not respond well to cyclosporine A or corticosteroids and suffered from numerous side effects of long-term corticosteroid therapy. The second patient presented with severe symptoms of DPU, which first of all prevented any daily activities of the professional routines. Both patients showed a complete remission of urticaria after the first injection of omalizumab. The third patient with CSU and severe DPU had been ineffectively treated for more than 20 years with various medications. Following the administration of omalizumab, the symptoms of CSU subsided but those of DPU intensified, and the drug was withdrawn after two cycles. In another four patients with refractory CSU and angioedema, the symptoms subsided after the first administration of omalizumab, and the patients have been in remission for about 5 weeks. In the remaining two patients, the symptoms did not resolve despite four 300 mg doses of omalizumab. It is important to establish a therapeutic regimen with omalizumab (150-300 mg; every 4-8 weeks) tailored to individual patient's needs and dependent on the type of urticaria; this may minimize unnecessary the medication exposure, adverse drug effects, and healthcare costs.

Pentraxin-3 as a local inflammatory marker in chronic spontaneous urticaria.

BACKGROUND: The pentraxin family plays an important role in the acute phase response to immune-inflammatory processes. The short pentraxin, C-reactive protein (CRP) is a marker of chronic spontaneous urticaria (CSU) activity, reflecting the systemic effects of inflammatory mediators associated with the disease. It is known, that the long pentraxin, pentraxin 3 (PTX3) is produced at the sites of inflammation, therefore may better reflect activity of the local inflammatory processes. To assess the relevance of PTX3 in CSU patients and its association with CRP. METHODS: Plasma PTX3 and serum CRP concentrations were measured in patients with CSU of varying severity as well as in the healthy subjects. RESULTS: The concentrations of PTX3 and CRP were significantly increased in more severe CSU patients, when compared to mild CSU and the healthy controls. There was a significant correlation between concentrations of PTX3 and CRP. CONCLUSIONS: In contrast to CRP, PTX3 is produced at the sites of inflammation, therefore it seems that elevated PTX3 may result from activation of cells involved in local urticarial processes. Finally, the correlation between these two pentraxins suggests that they may be upregulated by the same mechanisms associated with acute phase response in CSU.

Is delayed pressure urticaria associated with increased systemic release of sCD40L?

BACKGROUND: Elevated levels of soluble CD40 Ligand (sCD40L) were found in serum but not in plasma of patients with chronic spontaneous urticaria (CU). What is important is that sCD40L has proinflammatory properties, and its elevated plasma level may indicate increased risk of cardiovascular events. These observations should stimulate further evaluation of sCD40L in different forms of urticaria. AIM: In the present study, sCD40L plasma level was investigated in delayed pressure urticaria (DPU). METHODS: As platelets are predominant and variable sources of sCD40L, we investigated sCD40L concentration in platelet-poor plasma (PPP), which seems the best way to minimize the potential contribution of these cells to the ligand level. RESULTS: Plasma sCD40L concentration was significantly increased in the DPU group compared to the healthy controls. CONCLUSIONS: It seems that DPU is associated with increased systemic release of sCD40L, which is believed to derive predominantly from activated platelets. The present study as well as the earlier contributions suggest that distinct cells activity, including platelets, may be identified in different types of urticaria.

Acute phase inflammatory markers in patients with non-steroidal anti-inflammatory drugs (NSAIDs)-induced acute urticaria/angioedema and after aspirin challenge.

BACKGROUND: Active chronic urticaria, identified as a mast cell- and basophil-dependent inflammatory disorder of the skin is able to elicit acute phase response (APR). However, systemic inflammatory response in different types of urticaria is poorly characterized. AIM: To determine APR pattern in a clearly defined group of patients with acute urticaria and/or angioedema - induced by NSAIDs. METHODS: Plasma IL-6 and serum C-reactive protein (CRP) concentrations were studied in 17 patients with NSAIDs-induced acute urticaria/angioedema (NSAIDsAU) and in 20 healthy controls. Eleven patients who used NSAIDs were presented at the emergency room with acute urticaria/angioedema while the remaining six manifested the symptoms during the aspirin challenge test. Patients were examined in a dynamic manner: during the acute phase, and next, after subsidence of the symptoms. RESULTS: CRP and IL-6 concentrations increased significantly in patients with NSAIDsAU as compared with their asymptomatic period and the healthy subjects. In addition, NSAIDsAU patients showed elevated concentration of the biomarkers following aspirin provocation with the baseline values recovered in the asymptomatic period. CONCLUSION: These results indicate that an acute systemic inflammatory response is activated in patients with NSAIDs-induced urticaria and/or angioedema. The study supports the evidence proving that up-regulation of CRP and IL-6 in urticaria/angioedema does not necessarily reflect any concomitant infection or other inflammatory processes, but may be due to the disease itself.

Analysis of procalcitonin and CRP concentrations in serum of patients with chronic spontaneous urticaria.

BACKGROUND: Our previous findings showed the importance of analysing the peripheral markers of acute phase response (APR) activation, C-reactive protein (CRP) and IL-6 in the context of urticaria activity and severity. However, these biomarkers do not reliably differentiate between APR to infectious and the disease severity. AIM: In order to investigate a possible association between the immune-inflammatory activation markers CRP and procalcitonin (PCT). METHODS: Serum PCT and CRP concentrations were measured in patients with CU of varying severity as well as in healthy subjects. RESULTS: Serum PCT and CRP concentrations were significantly increased in more severe CU patients when compared to healthy controls and mild CU, and within the CU population there was a significant correlation between concentrations of PCT and CRP. Serum PCT concentrations remained within normal ranges in most CU patients and were only slightly elevated in some severe CU cases. CONCLUSIONS: PCT serum concentration may be only slightly elevated in some cases of severe CU. Upregulation of PCT synthesis accompanied by parallel changes in CRP concentration reflects a low-grade systemic inflammatory response in CU. PCT should be considered as a better marker than CRP to distinguish between APR to infection and an active non-specific urticarial inflammation.

Interleukin 1-ß, interleukin-1 receptor antagonist, and interleukin 18 in children with acute spontaneous urticaria.

UNLABELLED: Very little is known about the role of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in urticaria. MATERIAL AND METHODS: Serum levels of IL-1ß, IL-1 receptor antagonist (IL-1RA), and IL-18 were measured in 56 children with urticaria and in 41 healthy subjects. RESULTS: Serum IL-1ß did not differ between children with acute urticaria and controls. Children with single episode of urticaria had higher levels of IL-1RA and IL-18 than healthy subjects. In children with single episode of urticaria, level of IL-1RA correlated with C-reactive protein (CRP), D-dimer, and IL-1ß levels. In subjects with recurrence of urticaria IL-1RA was positively correlated with WBC and D-dimer levels. No correlation of cytokine levels and urticaria severity scores (UAS) in all children with urticaria was observed. In children with single episode of urticaria UAS correlated with CRP level. In the group with single episode of urticaria and in children with symptoms of upper respiratory infection, IL-1RA and IL-18 levels were higher than in controls. The former was higher than in noninfected children with urticaria. In conclusion, this preliminary study documents that serum IL-1RA and IL-18 levels are increased in some children with acute urticaria. However further studies are necessary to define a pathogenic role of IL-1ß, IL-1RA, and IL-18 in urticaria.

Increased plasma concentration of vascular endothelial growth factor in patients with atopic dermatitis and its relation to disease severity and platelet activation.

BACKGROUND: Overproduction of vascular endothelial growth factor (VEGF) in atopic dermatitis (AD) lesions has previously been observed. It is also known that platelet is an important source of VEGF and platelet factor 4 (PF-4), a potential marker of AD severity. AIM: To evaluate concentrations of VEGF and its soluble receptors (sVEGF-R1 and sVEGF-R2) in the plasma of AD patients and to examine its possible correlation with disease severity and plasma concentrations of PF-4, a platelet activation marker. METHODS: Plasma concentrations of VEGF and its receptors and levels of PF-4 were measured by an immunoenzymatic assay in 51 AD patients and in 35 healthy non-atopic controls. The severity of the disease was evaluated using the eczema area and severity index. RESULTS: AD patients showed significantly increased VEGF and PF-4 plasma concentrations as compared with the controls. Plasma concentrations of sVEGF-R1 and sVEGF-R2 did not differ between the groups. There were no remarkable correlations between plasma VEGF concentration and disease severity or between VEGF and PF-4 concentration. CONCLUSIONS: This study shows that plasma concentration of VEGF may be increased in patients suffering from AD. It seems that plasma VEGF concentration is not a useful marker of disease severity and, apart from platelets, other cells might also release the cytokine.

Acute-phase response in chronic urticaria.

The patterns of acute-phase response (APR) biomarkers differ upon various inflammatory conditions. Little information is available on the systemic inflammatory response in urticaria/angio-oedema. It has been shown that concentrations of circulating APR biomarkers, IL-6 and C-reactive protein (CRP), are elevated more in severe chronic urticaria (CU) than in patients showing milder urticarial symptoms. It is not clear whether the increase of IL-6 and CRP is merely an epiphenomenon or may contribute to the pathogenesis of CU. It is tempting to speculate that mediators of APR may enhance urticarial inflammation. In addition, there is some association between APR and activation of coagulation/fibrinolysis in CU. It is well known that even slight elevation in CRP baseline concentration is enough to produce significant increase in cardiovascular risk. In this light, one should ask whether CU patients, in particular those showing stronger systemic inflammatory response and long-lasting course are more vulnerable to the cardiovascular events. Apart from highly troublesome symptoms and low quality of life, CU may then involve some remote, serious systemic consequences. Taken together, CU can be identified as a mast cell- and basophil-dependent inflammatory disorder of the skin, which is accompanied by APR. Characterization of APR in CU may appear essential for an insight into the activity of this disease and for assessment of the inflammation degree. Moreover, measurement of these biomarkers might be particularly relevant while assessing CU patients demanding an anti-inflammatory or immunosuppressive therapy. This review summarizes information regarding APR in the course of urticaria/angio-oedema.