Baseline serum levels of mast cell tryptase are raised in hemodialysis patients and associated with severity of pruritus

Background: The pathogenesis of pruritus in renal disease is not yet understood. Evidence suggests that mast cells play a role; for example, the number of dermal mast cells is increased in patients on hemodialysis. Patients and methods: To investigate a possible role of mast cell tryptase in pruritus of patients undergoing chronic hemodialysis, serum mast cell tryptase concentrations were measured in blood samples taken from 93 such patients, 53 of whom also recorded the severity of their pruritus on a visual analogue scale. Results: Serum mast cell tryptase levels were above 11.4 µg/l (95^th percentile) in 84 of 93 hemodialysis patients (90.3 %). The intensity of pruritus correlated significantly (p = 0.014) with the tryptase levels, an associated not yet shown for other mast cell‐related parameters. Conclusions: Mast cells or even tryptase itself may be involved in the pathogenesis of pruritus of hemodialysis patients.     

Elevated Plasma Histamine in Chronic Uremia Effects of Ketotifen on Pruritus

A role for histamine in the pathogenesis of uremic pruritus was investigated in maintenance hemodialysis patients. Venous plasma histamine levels, as determined by radioenzymatic assay, were significantly higher (p less than 0.05) in hemodialysis patients with pruritus (368 +/- 103 pg/ml [mean +/- SEM], n = 6) than in those without pruritus (146 +/- 22 pg/ml, n = 5) and in normal controls (142 +/- 16, n = 5). Arteriovenous fistula histamine levels (202 +/- 52 pg/ml, n = 6) were significantly lower (p less than 0.05) than simultaneously drawn venous samples. Markedly elevated histamine-degrading enzyme (histaminase) activities were found in both hemodialysis patients with (2.95 +/- 0.18 pg histamine degraded/minute) and without (2.44 +/- 0.28) pruritus, but was undetectable in normal controls. Histaminase activities did not significantly differ in simultaneously drawn venous and fistula samples. With hemodialysis, histaminase activities fell significantly (p less than 0.01), whereas plasma histamine did not change. We further examined the effects of ketotifen, a putative mast cell stabilizer, on severe uremic pruritus. Five of five patients had significant (p less than 0.01) reductions in pruritus, as judged on a six-point pruritus index, after 8 weeks of drug (x = 2.3), as compared to conventional therapy (x = 5.9). Despite these improvements, no significant differences were noted in pre- versus post-drug plasma histamine levels, histaminase activities, or the histamine content per gram of skin biopsy specimen. These data support prior hypotheses that mast cell activation contributes to the pruritus of uremia.     

Density of mast cells and intensity of pruritus in psoriasis vulgaris: a cross sectional study

Background:Psoriasis is a chronic and prevalent disease, and the associated pruritus is a common, difficult-to-control symptom. The mediators involved in psoriatic pruritus have not been fully established.Objective:To evaluate associations between the number of mast cells in psoriatic lesions and the intensity of pruritus.Methods:29 patients with plaque psoriasis were recruited. In all participants, Psoriasis Area and Severity Index and Body Surface Area were assessed. A questionnaire was administered to obtain clinical information and the Dermatology Life Quality Index. Pruritus was assessed using a visual analog scale and skin biopsies were performed for staining with Giemsa and Immunohistochemistry with C-Kit.Results:Pruritus was observed in 91.3% of our patients. Median VAS was 6 (p25-75: 2-8). The immunohistochemical method revealed a mean of 11.32 mast cells/field and Giemsa staining revealed a mean of 6.72 mast cells/field. There was no correlation between the intensity of pruritus and mast cell count, neither in Immunohistochemistry (p = 0.15; rho = -0.27) nor in Giemsa (p = 0.16; rho = -0.27). Pruritus did not impact on the Dermatology Life Quality Index (p = 0.51; rho = -0.13).Study limitations:The small sample size may be considered the main limitation of our study.Conclusions:Although mast cells are mediators of pruritus in many cutaneous diseases, our findings support that psoriatic pruritus is a complex disorder with multifactorial, complex pathophysiology, involving pruritogenic mediators others than mast cells.     

Demonstration by S-100 protein staining of increased numbers of nerves in the papillary dermis of patients with prurigo nodularis.

BACKGROUND: We hypothesized that hyperplasia of papillary dermal nerves was a constant feature of prurigo nodularis. OBJECTIVE: We tested this hypothesis by examining sections from 25 cases of prurigo nodularis, 25 cases of skin lesions characterized by epidermal hyperplasia without clinical pruritus, and 22 cases of clinically pruritic dermatoses with variable degrees of epidermal response for the presence of papillary dermal nerves. METHODS: We used a standard immunohistochemical assay with an antibody to S-100 protein as a means of identification of nerves. RESULTS: In 24 of 25 cases of prurigo nodularis, papillary dermal nerves were identified by immunostaining. Cutaneous nerves were present in 1 of 22 cases of epidermal hyperplasia with pruritus and were absent in the papillary dermis in nonpruritic cases. CONCLUSION: We conclude that hypertrophy of cutaneous papillary dermal nerves is a relatively constant feature of prurigo nodularis. The presence of papillary dermal nerves suggests a neurocutaneous component in the pathogenesis of prurigo nodularis.     

Cutaneous mononuclear cells and eosinophils are significantly increased after warm water challenge in pruritic areas of polycythemia vera

BACKGROUND: Increased cutaneous cells following warm water challenge in pruritus-related polycythemia vera (PV) have been reported, but their nature and magnitude are not known. METHODS: Qualitative and quantitative assessments (digital image analysis) of the cutaneous mononuclear cells, eosinophils and mast cells were carried out in PV patients and healthy controls (n = 10 each) following exposures to water at room temperature and warm water. RESULTS: Infiltration of the spongiotic epidermis and dermis by mononuclear cells and eosinophils together with edema and vasodilatation of upper dermis following warm water contact was clearly observed only in PV patients. In contrast to controls, significant increase in numbers of mononuclear cells and eosinophils in comparison with exposure to water at room temperature at the dermal-epidermal junction (p < 0.01), papillary dermis (p < 0.01) and perivascular area (p < 0.05) was found. Obvious mast cell degranulation was seen in PV sections after warm water contact, but no significant increase of their numbers was observed whether among PV patients or healthy controls (p > 0.05). However, the numbers of papillary dermal mast cells in specimens obtained from PV patients following room temperature water exposure were significantly more than those of healthy controls (p < 0.05). CONCLUSIONS: PV represents an invisible dermatosis in which the infiltrating mononuclear cells and eosinophils may have a role in warm water-induced pruritus.     

Pathogenese der Prurigo nodularis

Background

Prurigo nodularis is a chronic reaction pattern associated with severe pruritus that markedly affects the quality of life in patients.

Pathogenesis

The pathogenesis of prurigo nodularis is not completely clear. Patients have an increased number of substance P and calcitonin gene-related peptide positive nerves in the dermis. Eosinophils and mast cells are in close vicinity to peripheral nerves and increased in numbers in the inflammatory infiltrate in prurigo nodularis. Nerve growth factor (NGF) is increased in lesional skin of patients and can be released by mast cells and eosinophils. In addition, NGF modulates the functional activity of mast cells and eosinophils. Recently, higher levels of the novel pruritic cytokine IL-31 were found in the skin of patients with prurigo nodularis than other pruritic skin diseases.

Conclusion

The pathogenesis of prurigo nodularis seems to be regulated by immunological and neuronal plasticity which will be highlighted in the current article.     

Aktuelles zur kutanen Neurobiologie von Pruritus

The pathogenesis of chronic and acute pruritus is not yet completely understood. Interactions of neurons with resident and nonresident skin cells seem to play an important role in the regulation of pruritus. Neuronal cells which express specific receptors and are capable of releasing neuromediators play an active role in this interaction. Furthermore, released neuromediators can activate immune cells including mast cells and eosinophils, which are increased in the inflammatory infiltrate of many pruritic skin diseases. Mast cells and eosinophils express receptors for neuromediators themselves. In addition, they can release neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and cytokines including interleukin (IL)-31 which correlate with disease activity in patients with inflammatory skin diseases including atopic dermatitis and induce neuronal outgrowth. In part, a correlation of these mediators has also been described with pruritus. Although the interplay between transient and resident cells in the skin with peripheral nerves, mast cells, and eosinophils plays an important role in the mutual activation, the neurobiological mechanisms that lead to pruritus are not completely clear yet.     

A randomized two‐sided placebo‐controlled study on the efficacy and safety of atmospheric non‐thermal argon plasma for pruritus

Background To look into new potential indications for physical plasma and because some reports suggest plasma having antipruritic effects, we investigated the treatment of pruritus that often represents a therapeutic challenge. Objectives To assess the efficacy and safety of cold atmospheric argon plasma as add‐on‐therapy in pruritic diseases. Methods We treated 46 patients with various pruritic diseases with cold plasma for 2 min daily in addition to standard treatment. All patients served as their own control, when their pruritic disease was treated with argon gas (placebo). The outcome measure was a long‐term and short‐term reduction in itching measured by means of a visual analogue score (VAS). Results The VAS scores at baseline were comparable (plasma 4.57, SD 2.38, argon 4.34, SD 2.35). We did not find any significant differences in VAS reduction between plasma and argon: long‐term VAS difference of 1.97 (SD 1.33) for plasma and 1.74 (SD 2.37) for argon [P = 0.224, 95% CI: (?0.15; 0.60)], short‐term VAS difference of 1.92 (SD 1.33) for plasma and 1.97 (SD 1.29) for argon [P = 0.544, 95% CI: (?0.21; 0.11)]. In both groups, patients experienced a significant reduction of pruritus at the end of therapy compared to baseline [plasma 1.97 (P < 0.0001), placebo 1.74 [P < 0.0001)]. No relevant side effects occurred, and treatment was well tolerated. Conclusions Treatment with cold plasma did not result in higher pruritus reduction than treatment with placebo. A significant reduction of pruritus compared to no effect was found at the end of therapy in both groups. Both treatment options had similar safety profiles.     

Pathogenesis of pruritus

The pathogenesis of acute and chronic (> 6 weeks duration) pruritus is complex and involves in the skin a network of resident cells (e. g., mast cells, keratinocytes, sensory neurons) and transient inflammatory cells (e. g., eosinophils). Though pruritus and pain show overlapping mechanisms, recent studies have provided evidence that pruritus and pain pathogenesis differ in important points. In the skin, the sensory C‐nerve fibers have been investigated intensively. Several classes of histamine‐sensitive or histamine‐insensitve C‐fibers have been described. Epidermal and dermal sensory nerve fibres are now assumed to be of major importance in pruritus induction. They interact with keratinocytes, inflammatory cells such as T lymphocytes, eosinophils and basophils which have been shown to release multiple pruritogenic mediators (e.g., nerve growth factor, interleukin‐31) which lead to activation, sensitization and sprouting of skin nerves. Specific receptors have been discovered on cutaneous and spinal neurons to be exclusively involved in the processing of pruritic signals. Just recently, the gastrin‐releasing peptide receptor (GRPR) was identified on spinal neurons that are crucially involved in pruritus but not pain processing. Chronic pruritus is notoriously difficult to treat. Newer insights into the underlying pathogenesis of pruritus have enabled novel treatment approaches that target the pruritus‐specific pathophysiological mechanism. For example, kappa‐opioid receptor agonists and neurokinin‐1 antagonists have been found to relieve chronic pruritus.     

Possible contribution of stem cell factor in psoriasis vulgaris

It is suggested that mast cell is implicated to play a role in the pathogenesis of psoriasis. In this study, to determine the role of stem cell factor (SCF), which is a growth factor of mast cells, we have examined the immunohistochemical localization and serum level of SCF in patients with psoriasis vulgaris. Immunohistochemical analysis revealed diffuse staining for SCF on keratinocytes in acanthotic epidermis in psoriasis, along with endothelial cells and fibroblasts. Serum SCF level, which was measured by enzyme-linked immunosorbent assay (ELISA), was significantly increased in patients with psoriasis vulgaris (1033+/-334 pg/ml) (n=24) than that of normal subjects (666+/-196 pg/ml) (n=15) (P<0.05). However, serum SCF did not show a correlation with the disease severity assessed by psoriasis activity and severity index (PASI) score. As patients with psoriasis vulgaris occasionally complain itching, next we divided 20 patients into two groups, those with itching (Group I) (n=8) and those without (Group II) (n=12), and compared the mast cell number located in the papillary dermis between thickened psoriatic epidermis, serum SCF and plasma histamine levels. Results showed that mast cell numbers (56.3+/-22.3/mm(2) in Group I vs 31.5+/-10. 3/mm(2) in Group II, P<0.05) and plasma histamine level (1.5+/-0.59 ng/ml vs 0.39+/-0.15 ng/ml, P<0.01) were significantly higher in patients of Group I than those of patients of Group II, however, the difference of serum SCF level (1132+/-368 pg/ml vs 890+/-373 pg/ml) did not reach a statistical significance. Finally, in a separate experiment, we examined whether exogenous SCF is capable of inducing psoriatic architecture on the transplanted uninvolved psoriatic skin onto severe combined immunodeficient (SCID) mice. SCF injection for 2 weeks could not induce a psoriasiform architecture such as acanthosis on the transplanted uninvolved psoriatic skin, although mast cells were increased in number. These results raised a possibility that keratinocyte-derived SCF plays a role, in part, in the increased number of mast cells in the papillary dermis of psoriasis, which may lead pruritus associated with psoriasis. Elevated serum SCF level may also be responsible for increment of mast cells in psoriasis vulgaris. Mast cell-derived factor stimulated by exogenous SCF could not induce psoriatic epidermis, suggesting that other factors such as activated lymphocytes or macrophages are further required for the development of psoriatic lesions.     

Transcutaneous electrical nerve stimulation for reduction of pruritus in macular amyloidosis and lichen simplex

Lichen simplex (LS) is characterized by circumscribed, lichenified, pruritic patches that may develop on any part of the body. Macular amyloidosis (MA) is the form of primary localized cutaneous amyloidosis. Transcutaneous electrical nerve stimulation (TENS) uses a pulsed electric current generated transcutaneously by a device to cause impulses to be carried along large-diameter afferent nerves. In this article, we report the effects of TENS on the Dermatology Life Quality Index (DLQI) measures and visual analogue scale (VAS) scores in patients with pruritus, in whom LS and MA were diagnosed. All patients with MA and six (75%) patients with LS had relief of their pruritus with TENS therapy. At week 2, there was a significant difference in median VAS scores between baseline in the group of LS (P = 0.007). At 4 weeks of therapy, statistically significant differences were observed compared with the baseline and week 2 in the median VAS scores in the group of MA (P < 0.001). There was also a statistically significant improvement in median DLQI total scores with respect to baseline, which was achieved as early as week 2 in patients with LS and MA who were on the TENS treatment (P = 0.006, P = 0.001, respectively).     

Mast cells in the cutaneous lesions of sarcoidosis: their subtypes and the relationship to systemic manifestations

Possible involvement of mast cells in pulmonary sarcoidosis has been suggested, however whether mast cells are involved in cutaneous sarcoidosis remains unknown. We undertook a morphological study of mast cells in the lesional skin from 17 patients with cutaneous sarcoidosis using immunohistochemical methods. Mast cells were present in non-parenchymal fibrous areas, but not in granulomatous areas, in the biopsy specimens from the cutaneous lesions. However, there were no significant differences between the number of mast cells in the lesional skin and that in non-lesional skin from the patients. Mast cells containing substantial quantities of both tryptase and chymase (MC(TC) cells) were present in 41% of the patients, and cells containing tryptase but not chymase (MC(T) cells) were present in 59% of patients. All patients of the former group showed systemic manifestations of the disease concomitantly. Serum angiotensin I-converting enzyme levels were elevated in 71.4% of the former group, and in 30% of the latter group. This study for the first time demonstrated that mast cells were present in non-parenchymal fibrous areas of the cutaneous lesions of sarcoidosis, and the mast cell subtypes may be related to systemic manifestations.     

Hemodialysis-related pruritus and associated cutaneous manifestations

BACKGROUND: Uremic pruritus is one of the most common disabling problems in patients with chronic renal failure. Few studies have evaluated itching and cutaneous manifestations in hemodialysis-dependent patients. OBJECTIVES: The aim of this prospective study was to identify the prevalence of pruritus and cutaneous changes affecting patients undergoing hemodialysis. METHODS: The degree of itching in 70 patients treated at the Haemek Medical Center Hemodialysis Unit, in northern Israel, was scored according to presence and severity. We examined the relationship between the quality of dialysis and the frequency of pruritus, and identified concurrent cutaneous disorders. RESULTS: Pruritus was a common problem in the study cohort and affected 74.3% of hemodialysis patients at some point. The main characteristics of pruritus were a general pattern in 65.7% and mild intensity in 78.3% of observed patients. Duration of hemodialysis varied between 3 months and 13 years. There was no correlation between occurrence of pruritus and demographic or medical parameters (sex, type of kidney disease, regular medications or duration of hemodialysis) of the patients. Higher dialysis efficacy, as expressed by dialyser clearance, volume distribution of area, dialysis duration (Kt/v), may reduce the prevalence of pruritus (P < 0.02). None of the blood and chemical values considered (hemoglobin, creatinine, urea, phosphorus, calcium, albumin, parathormone and alkaline phosphatase) revealed any statistically relevant differences between pruritus groups. The appearance of foot ulcers was different between diabetic and nondiabetic individuals undergoing hemodialysis (P < 0.001). CONCLUSIONS: Pruritus is still a common problem in hemodialysis-dependent patients. The prevalence of xerosis and excoriations was high in patients undergoing replacement therapy. Efficient replacement hemodialysis may provide a clinical benefit.     

Plasma neuropeptides and perception of pruritus in psoriasis

The aim of this study was to evaluate the influence of selected neuropeptides on itching in psoriatic individuals. Fifty-nine patients (43 pruritic and 16 non-pruritic) with psoriasis were included in the study. The severity of psoriasis, measured using the Psoriasis Area and Severity Index scale, ranged between 2 and 43.7 points. The intensity of pruritus was evaluated using a Visual Analogue Scale. The plasma levels of substance P, vasoactive intestinal peptide, calcitonin gene-related peptide and neuropeptide Y were measured radioimmunologically. The plasma level of neuropeptide Y was significantly decreased in patients with pruritus compared with those without pruritus (21.6 +/- 39.6 pg/ml and 144.3 +/- 385.7 pg/ml, respectively; p=0.03). Levels of other neuropeptides did not differ significantly between pruritic and non-pruritic patients; however, a tendency to lower plasma levels of substance P and vasoactive intestinal peptide in patients with itching was noted. Moreover, a significant negative correlation was observed between pruritus severity and levels of substance P (r = -0.36; p=0.02), as well as between pruritus severity and plasma levels of vasoactive intestinal peptide (r = -0.34; p=0.03). The imbalance of neuropeptide activity in the sera of pruritic subjects may suggest a role for neuropeptides in perception of itching in psoriatic individuals.     

Brachioradial pruritus: a case report and review of the literature

Brachioradial pruritus is an enigmatic pruritic sensation that characteristically involves the proximal lateral forearm of middle-aged women residing in tropical to temperate climates. There are often no associated cutaneous signs. The pathophysiology has been debated but is believed to involve UV radiation and/or cervical spine disease. We present a patient with brachioradial pruritus and a review of the literature. Brachioradial pruritus should be suspected in patients with intractable pruritus overlying the brachioradialis muscle of the forearm that is recalcitrant to standard therapies. These patients commonly report a history of chronic solar damage and/or cervical spine disease.     

Prospective, single-blind, randomized, controlled study to assess the efficacy of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel sheeting in hypertrophic scar treatment.

OBJECTIVE: To determine the efficacy of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel sheeting in the treatment of hypertrophic scars in lighter- and darker-skinned patients. DESIGN: Prospective, single-blind, randomized, internally controlled, comparison investigation. SETTING: Large academic dermatology department. PATIENTS: Twenty patients with hypertrophic scars (19 completed the laser treatments and 18 completed the silicone gel sheeting treatments). MAIN OUTCOME MEASURES: Clinical measurements included hypertrophic scar blood flow, elasticity, and volume. Patients' subjective complaints of pruritus, pain, and burning were also monitored. Histological assessment of fibrosis, number of telangiectasias, and number of mast cells was performed. Statistically significant improvements in clinical measurements and patients' subjective complaints determined treatment success. RESULTS: Mean scar duration was 32 months (range, 4 months to 20 years). There was an overall reduction in blood flow, volume, and pruritus over time (P = .001, .02, and .005, respectively). However, no differences were detected among treatment and control groups. There was no reduction in pain or burning (0-40 weeks), elasticity (8-40 weeks), or fibrosis (0-40 weeks, n = 5 biopsies) in the treated or control sections of the scars. Unlike in a previous study, the number of mast cells in the scars was similar to the number of mast cells in healthy skin. CONCLUSION: Clinical results demonstrate that the improvements in scar sections treated with silicone gel sheeting and pulsed-dye laser were no different than in control sections.     

The efficacy of omalizumab in Cutaneous Mastocytosis: A case series

Background: Mastocytosis describes a heterogeneous group of disorders arising from a clonal proliferation of mast cells. Given the lack of curative treatments for the cutaneous form, there is a significant need for superior therapies. Omalizumab is a recombinant DNA‐derived humanized IgG monoclonal antibody that selectively binds to human immunoglobulin E (IgE). It represents a potential treatment for the management of cutaneous mastocytosis, which currently has no standard treatment. Methods: Two patients were treated with subcutaneous omalizumab 300 mg every 4 weeks. Discussion: Patient 1 experienced 50% reduction in cutaneous infiltration and moderate improvement in pruritus. Patient 2 underwent 90% complete clearance of cutaneous lesions and reported full resolution of pruritus. The median duration of treatment was 24 weeks and time to response was 8 weeks. No significant changes in tryptase levels were observed. Both patients experienced injection site reactions. Conclusion: We provide evidence from two cases supporting the efficacy of IgE‐mediated therapy in the treatment of cutaneous mastocytosis. Even at a higher‐than‐standard dose (300 mg vs. 150 mg), the drug was well‐tolerated. As we await the results of pivotal clinical trials, omalizumab appears to be a promising treatment option in patients with cutaneous mastocytosis unresponsive to traditional therapies.     

EFFECTS OF AZELASTIN ON PRURITUS AND PLASMA HISTAMINE LEVELS IN HEMODIALYSIS PATIENTS

Background. Persistent pruritus is the most common symptom in hemodialysis patients. Its causes are poorly understood and there is no effective treatment. We have studied the effect of azelastin HCL on the plasma histamine concentrations and pruritus in maintenance dialysis patients with or without erythropoietin therapy. Patients. Twenty-eight hemodialysis patients were divided into four groups according to the presence or absence of pruritus and whether or not they received erythropoietin therapy. Results. Histamine concentrations in the patient groups were significantly higher than in healthy volunteers, but a significant difference could not be found among the four groups. The patients with pruritus showed no change in their histamine concentration during treatment with azelastin HCL, but their pruritus scores decreased remarkably. Conclusions. The present data do not support the thesis that the increased plasma histamine concentration is causally related to pruritus in hemodialysis patients or that the antiallergic drug, azelastin HCL, alleviates the pruritus of dialysis patients by decreasing plasma histamine levels. The possible role of the increased tissue levels of histamine remains to be studied.     

Ultraviolet irradiation induces apoptosis in human immature, but not in skin mast cells

As diverse pruritic cutaneous diseases respond to ultraviolet treatment, we have examined whether ultraviolet light is capable of inducing apoptosis in mast cells. Human mast cell line 1 (HMC1) derived from a patient with malignant mastocytosis and purified skin mast cells were irradiated with single doses of ultraviolet B or ultraviolet A1, or pretreated with 8-methoxypsoralen prior to ultraviolet A1 exposure. After 0 to 48 h of incubation, the percentage of apoptotic and dead cells was assessed. In HMC1 cells, morphologic features of apoptosis were further evaluated by electron microscopy. All ultraviolet treatment induced apoptosis of HMC1 cells in a time- and dose-dependent manner. Apoptosis was associated with activation of caspase-3, release of cytochrome C, cleavage of poly(ADP-ribose)-polymerase, and nuclear accumulation of p53. In contrast, resting skin mast cells were resistant to ultraviolet light induced apoptosis. After incubation with stem cell factor and interleukin-4 for 2 wk, however, slowly proliferating skin mast cells also underwent apoptosis in response to ultraviolet light. In conclusion, these data demonstrate that ultraviolet light directly affects mast cells, but mainly aims at the proliferating mast cells as found in mastocytosis and mast cell dependent pruritic diseases, where increased numbers are observed due to the recruitment mast cell precursors from the blood.