Kynurenine Pathway in Psoriasis-a Promising Link?

Psoriasis is a common dermatosis which affects the patient's skin and general well-being because of its link to diseases such as depression, kidney disease and metabolic syndrome. Pathogenesis remains unknown; however, genetic, environmental and immunological factors seem to play a role in the development of the disease. Due to a lack of complete understanding of the psoriasis pathology, effective treatment is yet to be developed. The kynurenine pathway is one of the ways amino acid tryptophan is metabolised. In comorbidities typical for psoriasis such as chronic kidney disease, depression and atherosclerotic alterations in the activation of the kynurenine pathway were observed, which were mainly characterised by higher activity compared to that in healthy individuals. However, the kynurenine pathway has not been thoroughly studied among patients with psoriasis even though increased levels of L-kynurenine, one of the enzymes in the kynurenine pathway, were found in psoriatic skin lesions. Given the unknown pathogenesis of the disease, this finding seems to be a potential new field of study and shows a possible link between psoriasis and its comorbidities that could also lead to novel effective treatment for this chronic condition.

Effect of psoriasis activity and topical treatment on plasma epidermal growth factor (EGF) and its soluble receptor (sEGFR).

BACKGROUND: Pathogenesis of psoriasis involves epidermal growth factor (EGF) that participates in keratinocyte proliferation, angiogenesis and cell differentiation through binding to soluble epidermal growth factor receptor (sEGFR). It is synthesised by, among others, keratinocytes, especially within psoriatic skin. OBJECTIVE: To evaluate EGF and sEGFR plasma concentrations during topical psoriatic treatment. METHODS: Blood samples were collected from 51 patients with plaque psoriasis. EGF and sEGFR plasma concentrations were examined with immunoenzymatic method prior and 14 days after topical treatment. The outcomes were analyzed with respect to PASI. RESULTS: Mean EGF concentration was higher in the plasma of psoriatic patients compared to the control group (p = .401) while mean sEGFR concentration was over twofold lower compared to the control group (p < .001). After the therapy, an insignificant decrease in EGF plasma concentration (p = .835) and a significant increase in sEGFR concentration (p = .017) compared to initial values were observed. The coefficient of EGF/sEGFR concentration calculated for each individual had similar values before and after the treatment (p = .009), both of which were significantly higher compared to control group (respectively p < .001, p < .008). CONCLUSION: Epidermal growth factor and its soluble receptor may be a useful markers in monitoring clinical course of psoriasis and the effectiveness of therapy.

Influence of narrowband ultraviolet B phototherapy on serum tumour necrosis factor-like weak inducer of apoptosis (TWEAK) in patients with psoriasis.

Psoriasis is characterized by keratinocyte resistance to apoptosis. We recently demonstrated an increase in serum tumour necrosis factor-like weak inducer of apoptosis (TWEAK) in patients after topical treatment for psoriasis. We decided to verify whether narrowband ultraviolet B (NB-UVB) has a similar effect. Serum concentration of TWEAK was estimated in patients with exacerbated plaque psoriasis treated with NB-UVB. Baseline TWEAK levels were similar in patients with psoriasis and healthy controls, and Psoriasis Area and Severity Index (PASI) correlated inversely with TWEAK levels. Treatment with NB-UVB caused a significant reduction in PASI and concurrent increase in serum TWEAK. This finding may be due to increased expression of TWEAK receptor in psoriatic skin, which has been reported previously, with consequent binding of excess soluble TWEAK during treatment and subsequent release after treatment. Severity of plaque psoriasis and its improvement after NB-UVB treatment may be associated with TWEAK concentrations. The importance of our findings remains to be established.

Effect of psoriasis activity and topical treatment on serum lipocalin-2 levels.

OBJECTIVE: Psoriasis has been considered as systemic disorder. Lipocalin-2 might be a link between psoriasis and its comorbidities. Aim of the study was to investigate the associations between serum lipocalin-2 levels and the disease activity, markers of inflammation or metabolic disturbances and changes after topical treatment in psoriatic patients. METHODS: Thirty-seven individuals with active plaque-type psoriasis and 15 healthy controls were recruited. Blood samples were collected before and after 14 days of therapy. Serum lipocalin-2 concentrations were examined by enzyme-linked immunosorbent assay. The results were correlated with Psoriasis Area and Severity Index (PASI), body mass index (BMI), inflammatory and biochemical markers, lipid profile and with effectiveness of topical treatment. RESULTS: Lipocalin-2 serum levels were significantly increased in psoriatic patients in comparison to the controls (p = 0.023). No significant correlations with indicators of inflammation, nor BMI or PASI were noted. A statistical association between lipocalin-2 and low-density lipoprotein-cholesterol was shown. After topical treatment serum lipocalin-2 level did not significantly change (p = 0.9), still remaining higher than in the controls, despite clinical improvement. CONCLUSIONS: Lipocalin-2 might be a marker of psoriasis and convey cardiovascular or metabolic risk in psoriatic patients, but may not be a reliable indicator of inflammation, severity of psoriasis nor efficacy of antipsoriatic treatment.

Serum Fatty Acid-Binding Protein 4 is Increased in Patients with Psoriasis.

Psoriasis is associated with metabolic syndrome and cardiovascular disease. Fatty acid-binding proteins (FABP) have been recognized as predictors of these systemic disorders. The aim of this study was to assess correlations between levels of serum heart and adipocyte fatty acid-binding proteins (FABP3, FABP4) and disease severity, indicators of inflammation or metabolic disturbances, and topical treatment in psoriatic patients. Thirty-seven patients with relapse of plaque-type psoriasis and 16 healthy volunteers were recruited. Blood samples were collected before and after 14 days of therapy. Serum FABP concentrations were examined by enzyme-linked immunosorbent assay for correlation with Psoriasis Area and Severity Index (PASI), body mass index (BMI), inflammatory or metabolic parameters, and treatment used. The median FABP4 serum levels were significantly increased (p = 0.038) in psoriatic patients, while FABP3 levels did not differ (p = 0.47) compared to the controls. No significant correlations were noted between the proteins and PASI, C-reactive protein (CRP), BMI, or levels of glucose or lipids. FABP3 significantly correlated with white blood count (p = 0.03) and aspartate aminotransferase (p = 0.04). After topical treatment, there was no significant change in serum FABP3 [11.5 (4.9-30.3) vs. 12.9 (3.5-30.3) ng/ml] (p = 0.96), whereas FABP4 was decreased [27,286 (20,344-32,257) vs. 23,034 (18,320-29,874) pg/ml] (p = 0.12), losing its basal significance. FABP4 may be a marker of psoriasis, and FABP3 may be associated with inflammation or liver disorders in psoriatic patients. FABP do not appear to be useful for determining disease severity or the effectiveness of antipsoriatic treatment.

The effect of topical treatment and psoriasis severity on serum retinol-binding protein-4 levels.

OBJECTIVE: Psoriasis has been considered as chronic systemic disease. Retinol-binding protein-4 (RBP-4) might play a role in psoriasis and its comorbidities. The aim of this study was to investigate the associations between serum RBP-4 levels and disease severity, indicators of inflammation or metabolic syndrome and changes after topical treatment in psoriatic patients. METHODS: Thirty-seven patients with relapse of plaque-type psoriasis and 16 healthy volunteers were examined. Blood samples were collected before and after 14 days of therapy. Serum RBP-4 concentrations were examined by enzyme-linked immunosorbent assay for correlation with psoriasis area and severity index (PASI), body mass index (BMI), inflammatory and biochemical markers and with efficacy of topical treatment. RESULTS: RBP-4 serum levels were increased in psoriatics compared to the controls, but without statistical significance (p = 0.2). No significant correlations between investigated adipokine and several indicators of metabolic disorders, nor BMI or PASI were found. A significant negative correlation with CRP was noted. After topical treatment serum RBP-4 level did not significantly change (p = 0.3), despite clinical improvement. CONCLUSION: RBP-4 might have a protective role in terms of chronic inflammation and comorbidities of psoriasis. The adipokine is presumably not useful in determining severity and the effectiveness of antipsoriatic treatment.

Serum adiponectin and leptin levels in psoriatic patients according to topical treatment.

OBJECTIVES: Psoriasis has been considered as a systemic disease associated with obesity, cardiovascular diseases and metabolic syndrome. Adipokines have influence on many metabolic processes. Aim of this study was to evaluate the effect of conventional topical treatment on serum adiponectin and leptin levels in patients with psoriasis. METHODS: Forty-nine patients with relapse of plaque-type psoriasis and 16 healthy controls were examined. Blood samples were collected before therapy and after 14 days of application. Serum adiponectin and leptin concentrations were examined by enzyme-linked immunosorbent assay for correlations with effectiveness of topical treatment. RESULTS: Adiponectin and leptin serum levels were significantly decreased in psoriatic patients in comparison to the controls. As a result of the topical treatment, serum adiponectin level did not significantly change. Serum leptin level increased significantly, still remaining lower than in the controls. CONCLUSIONS: Leptin might be a useful marker in assessing the efficacy of the treatment for psoriasis.

Effect of psoriasis activity on epidermal growth factor (EGF) and the concentration of soluble EGF receptor in serum and plaque scales.

BACKGROUND: Epidermal growth factor receptors (EGFRs) are overexpressed in psoriatic keratinocytes, and regulate cell growth, proliferation and differentiation through binding to epidermal growth factor (EGF). The role of EGF and EGFRs in the pathogenesis of psoriasis and the contribution of their measurement to psoriasis management are still unknown. AIM: To evaluate serum concentrations of EGF, soluble (s)EGFRs and EGF content in psoriatic scales of patients with severe psoriasis, and to analyse their association with the clinical activity of the disease. METHODS: Serum samples and plaque scales were collected from 51 patients with plaque-type psoriasis. Concentrations of EGF and sEGFR in serum and of EGF in scales were measured using enzyme immunoassay. Data were analysed with respect to baseline Psoriasis Area and Severity Index (PASI). RESULTS: Mean serum EGF concentration in patients was higher than in controls (701 ± 72 vs. 586 ± 63 pg/mL), but the difference was not significant. Mean serum concentration of sEGFR was significantly lower than controls (40.8 ± 1.4 vs. 86.4 ± 11.3 ng/mL, P < 0.001). Serum levels of EGF showed a significant positive correlation and EGFR showed a significant negative correlation with PASI (P < 0.05). No correlation was seen between PASI and EGF content in scales or between EGF and sEGFR levels. Serum EGF concentrations reached the highest mean level (914 ± 138 pg/mL) in patients with PASI > 20, and this was significantly higher than the mean of 414 ± 82 pg/mL in the group with PASI < 10. Mean sEGFR serum concentrations remained significantly lower than those of controls, irrespective of disease severity. CONCLUSIONS: Compared with controls, patients with psoriasis had increased EGF and decreased sEGFR levels in serum. EGF and sEGFR levels correlated with disease severity.

Effect of psoriasis therapy on VEGF and its soluble receptors serum concentrations.

BACKGROUND: Vascular endothelial growth factor (VEGF) is recognized a pivotal pro-angiogenic factor responsible for new blood vessels formation in psoriatic lesion. OBJECTIVES: The aim of the study was to analyse serum concentrations of VEGF and its soluble receptors (sVEGF) R1 and R2 in psoriatic patients before and after treatment. METHODS: Serum samples were collected before and after 14 days of standard topical therapy, from 44 patients with exacerbated chronic plaque-type psoriasis and VEGF, sVEGF R1 and sVEGF R2 concentrations were measured using an enzyme immunoassay. Data were analysed with respect to baseline values of the psoriasis area severity index (PASI). RESULTS: Baseline mean serum levels of VEGF and sVEGF R1, but not sVEGF R2 were significantly higher in patients than in healthy controls. VEGF demonstrated significant correlation with PASI score. Treatment resulted in significant reduction of VEGF serum concentration, particularly in patients with severe course of the disease (PASI >20) and increase in sVEGF R1 concentration in patients with mild disease activity (PASI <10). Moreover, serum sVEGF R1 level after treatment termination was significantly higher in patients with mild than severe course of psoriasis. CONCLUSIONS: We confirmed the association between psoriasis activity and serum VEGF concentrations, which can be recognized as an indicator of the disease severity. However, the increase of serum sVEGF R1 concentrations can predict amelioration of clinical signs.

Plasma and scales levels of interleukin 18 in comparison with other possible clinical and laboratory biomarkers of psoriasis activity.

The aim of the study was to assess plasma and scales levels of interleukin (IL) 18 collected from psoriatic patients with different disease activity. IL-18 concentrations were measured using an enzyme immunoassay in the plasma and scales of 34 patients with chronic plaque type psoriasis. IL-18 levels were analysed with respect to plasma-transforming growth factor beta1 (TGF-beta1), the disease duration and the duration of the present relapse, and psoriasis area and severity index (PASI). Plasma IL-18 concentration varied from 90 to 1300 pg ml-1 and means (368.2 +/- 42.4 pg ml-1) were significantly elevated in comparison with healthy controls (205.9 +/- 31.8 pg ml-1). The presence of IL-18 was also demonstrated in scales from skin lesions. Treatment caused a significant decrease of plasma IL-18 concentration to 250.2 +/- 13.8 pg ml-1. There was a significant correlation between plasma IL-18 levels and PASI values (r = 0.554). There was no correlation between IL-18 concentration in scales and PASI, between IL-18 concentrations in plasma and scales, and between plasma IL-18 and the disease duration or duration of present relapse. Plasma TGF-beta1 concentration demonstrated a significant correlation with PASI (r = 0.353), but not with IL-18 levels in plasma (r = 0.063) and scales (0.141). The sum of plasma levels of IL-18 and TGF-beta1 divided by the optimal coefficient demonstrated a statistically significant correlation with the highest r-value. The findings confirm an association between plasma IL-18 concentration and psoriasis severity. Moreover, it was shown that combined measurement of IL-18 and TGF-beta1 in plasma can be considered as a possible biomarker of psoriasis activity.

Effect of psoriasis treatment on plasma concentrations of metalloproteinase-1 and tissue inhibitor of metalloproteinases-1.

AIM: The aim of this study was to evaluate the effect of psoriasis treatment on plasma concentrations of metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) with respect to disease severity. METHODS: MMP-1 and TIMP-1 were measured using an enzyme immunoassay in plasma of 32 patients before and after topical treatment. Data were analysed with respect to baseline values of the Psoriasis Area and Severity Index (PASI). RESULTS: Baseline plasma concentrations of both TIMP-1 and MMP-1 (1487 +/- 102 and 21.0 +/- 2.5 ng/mL, respectively) were significantly higher (P = 0.02 and 0.03, respectively) than normal. Both TIMP-1 and MMP-1 decreased significantly after completion of treatment to values similar to normal (1112 +/- 127 and 11.3 +/- 1.3 ng/mL, respectively). There was a significant positive correlation (r = 0.522) between baseline PASI and TIMP-1 values. Significant differences were observed between baseline TIMP-1 concentrations in groups with PASI < 15 and PASI > 20. Baseline values (1697 +/- 162 ng/mL) in patients with severe course of the disease (PASI > 20) were significantly elevated in comparison to normal values. Treatment caused a decrease in TIMP-1 plasma concentrations in all groups, but a significant difference was noted only in patients with pretreatment PASI > 20. Baseline MMP-1 concentrations exceeded significantly normal values only in patients with PASI < 15 (27.2 +/- 6.3 ng/mL) and 15-20 (18.4 +/- 1.4 ng/mL). Treatment caused a significant decrease in MMP-1-values in all groups to levels similar to normal. CONCLUSIONS: Our results confirm the role of TIMP-1 and MMP-1 in the pathogenesis of psoriasis. Pretreatment plasma TIMP-1 increased whereas MMP-1 decreased in patients with a more severe course of the disease. However, successful treatment causes normalization of these plasma protein concentrations irrespective of psoriasis baseline activity.

[Antibodies against Borrelia afzelli in patients with an early stage of Lyme disease]. / Przeciwciala przeciw Borrelia afzelii u chorych we wczesnym okresie kretkowicy kleszczowej.

The aim of the study was evaluation of specific immune response against Borrelia afzelii in patients with erythema migrans, as a sign of an early stage of Lyme borreliosis. The study was performed in 42 patients, residents of Podlasie province, who were initially evaluated by indirect immunofluorescence assay as a seropositive for Borrelia burgdorferi sensu lato. Antibodies against particular antigens of B. afzelii were demonstrated using a Western-blot technique. Evaluation of results showed the most frequent prevalence of antibodies against 41 kDa antigen in majority of patients, which were predominantly of IgM class in patients with short-lasting lesions, and IgG class in patients with long-lasting lesions. Results of IgM blots were recognized as a positive in 26 patients, and IgG blots in 22 patients. Positive result in at least one class of antibodies was noted in 34 patients (81%), and in both classes in 14 (33%). IgM antibodies against 21 kDa antigen, and IgG antibodies against 43 kDa antigen were two fold more frequent in patients with short-lasting lesions. These results confirm the diagnostic usefulness of determination of antibodies against B. afzelii antigens in Poland. The most important for an early diagnosis can be simultaneous demonstration of IgM antibodies against 21 and 41 kDa antigens.

Clinical features and specific immunological response to Borrelia afzelii in patients with acrodermatitis chronica atrophicans.

Acrodermatitis chronica atrophicans (ACA) occurs mostly in Europe. Borrelia afzelii is considered to be responsible for this manifestation of Lyme borreliosis. The aim of the study was to observe the clinical features of the ACA and evaluate the specific immunological response to Borrelia afzelii. Nine patients from an endemic Lyme borreliosis region in northeastern Poland were studied. The serum samples were tested routinely with IFA and EIA and, following testing, with immunoblots using Borrelia afzelii antigens. ACA was located mainly on the skin of the arms, forearms, thighs and chest. The only extracutaneal manifestation of Lyme borreliosis was paresis of the brachial plexus observed in one patient. Analysis of the immunoblot-banding pattern revealed positive reactions in all patients against flagellar antigen (41 kDa). Interpretation of the immunoblots revealed positive IgG results in all cases and IgM in five of them. Concluding, ACA develops not only on the extremities, but also on the trunk. The immunoblot technique using Borrelia afzelii antigens is of value in the diagnosis of ACA.

Epidemiology of erythema migrans in north-eastern Poland.

The aim of the study was to evaluate erythema migrans (EM) prevalence and treatment in north-eastern Poland during the last 25 years. The material for the study consisted of data sent to the Department of Dermatology by physicians from fifteen regional out-patient clinics. They were collected according to specially prepared questionnaires. The data were analysed with respect to the total number of EM cases, patients' age, seasonal prevalence of the disease, dynamics of its prevalence and treatment methods in successive years. Of the 262,421 case histories, retrospectively analysed 1235 EM cases (0.4%) were found. The age of the patients varied from 4 to 78 years. The highest incidence was observed between August and October (57.7% of all cases). The annual number of cases increased from only a few, in the years 1969-76, to over 436 in 1993. Penicillin or erythromycin were preferred for the treatment of EM before 1981, tetracycline or ampicillin between 1982-90, and amoxicillin or doxycycline in the last three years. Our results showed a significant increase in the number of EM cases in the dermatological clinics of north-eastern Poland in recent years. The treatment of the disease applied at present, complies with the generally accepted guidelines.

[Late consequences of untreated lyme borreliosis]. / Odlegle nastepstwa nie leczonej boreliozy z Lyme.

The study aimed to evaluate late clinical symptoms and serological changes in persons with erythema migrans (EM) diagnosed 4-11 years ago who were not treated with antibiotics. Among initially included into the study 28 untreated EM cases, twelve persons responded for invitation to the Department. The symptoms and signs which could be related to previous Borrelia burgdorferi infection were present in 9 (75%) untreated patients. They included ischialgia (42%), arthritis (33%) and positive serological tests results (33% of patients, including 2 with clinical signs). These results demonstrate that lack of antibiotic treatment in the early LB stage can result in the development of late disease manifestations.

Study on clinical picture of erythema migrans.

Clinical picture of erythema migrans (EM) was evaluated in 83 patients from north-eastern Poland. Patients were in mean age of 42,8. Most of patients (71%) were women. Tick bite remembered 64% patients. Mean incubation period of EM was 33 days. The mean diameter of the skin lesions was 14.8 cm. They persisted for 2-270 (mean-54) days. Lesions were located mostly on the skin of lower extremities. The largest lesions were found on trunk and the smallest on lower extremities. EM of diameter exceeding 20 cm were observed in patients with longer history of the disease. Specific antibodies were found in 53% of cases and were present more frequently (78%) in patients with shorter incubation period (< 30 days).

[Seasonal prevalence of antibodies against Borrelia burgdorferi in Bialowiez inhabitants]. / Sezonowosc wystepowania przeciwcial przeciw Borrelia burgdorferi wsród mieszkanców Bialowiezy.

The aim of study was evaluation of seasonal prevalence of antibodies against Borrelia burgdorferi in Bialowieza area, that is Lyme borreliosis endemic region. IgM and IgG antibodies against 41-kDa antigen of Borrelia burgdorferi B31 strain were investigated with ELISA in sera of 300 Bialowieza inhabitants between September 1993 and May 1994. Moreover in 40 asymptomatic persons, that were seropositive in September 1993, additional control was performed in May 1994. The highest prevalence of IgM antibodies was observed in September 1993 (43.4%), with decrease during winter and spring (down to 15.7% in April) and accompanying the highest prevalence of IgG antibodies (17.7%) in April 1994). From 33 persons, that revealed IgM antibodies in September 1993, 3 (9%) were still seropositive, 4 (12%) cleared IgM antibodies and became IgG-seropositive, and remained 26 (79%) had no antibodies. Specific IgG antibodies found in 7 persons in September, were still present in 4. Obtained results indicate necessity of taking into consideration seasonal dynamics, when results of seroconversion against Borrelia burgdorferi between different areas and different populations are compared.

[Endemic threat of Lyme borreliosis in Bialowicza forestry area]. / Zagrozenie endemiczne borelioza z Lyme w regionie Puszczy Bialowieskiej.

Lyme Borreliosis is a serious diagnostical and therapeutical problem in regions with high exposure of residents to ticks, which are Borrelia burgdorferi vectors. The aim of this study was to estimate occurrence of specyfic antibodies and symptoms of Lyme Borreliosis in Bialowieza area, as a region of potential endemic presence of this disease. Antibodies against B. burgdorferi were found, with an immunoenzymatic assay, in 71 from among 143 of examined persons (49.7%). Diagnosis of Lyme Borreliosis was established in 54 persons (37.7% of examined population) according to criterions of Lyme Disease Foundation and Centers for Diseases Control. Symptoms of joints involvement (polyarticular or restricted to knee joints) and peripheral nervous system involvement (predominantly radiculalgia lumbosacralis) were most frequently observed in clinical picture. These results motivate to recognize Bialowieza region as an endemic area of Borrelia burgdorferi infections.