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Address correspondence to: George N. Konstantinou, MD, PhD, MSc, MC (Army), FAAAAI, Department of Allergy and Clinical Immunology, 424 General Military Training Hospital, 11 Eleftheriou Venizelou St, Kalamaria, Thessaloniki 55 133, Greece.
It has been observed that certain patients with chronic spontaneous or idiopathic urticaria (CSU/CIU) have a personal history of a significant stressor before urticaria onset, while the prevalence of any psychopathology among these patients is significantly higher than in healthy individuals. Research has confirmed that skin is both an immediate stress perceiver and a target of stress responses. These complex interactions between stress, skin, and the nervous system may contribute to the onset of chronic urticaria. This systematic review investigated the association between CSU/CIU and neuroimmune inflammation with or without evidence of co-existing psychological stress from in vivo and ex vivo studies in human beings.
Methods
PubMed and Scopus were searched to September 2019 for reports in human beings describing neuroimmune inflammation, stress, and CSU/CIU. A comprehensive search strategy was used that included all the relevant synonyms for the central concept.
Findings
A total of 674 potentially relevant articles were identified. Only 13 satisfied the predefined inclusion criteria and were included in the systematic review. Five of these 13 studies evaluated the correlation between CSU/CIU, stress, and neuro-immune-cutaneous factors, while the remaining 8 focused on the association between CSU/CIU and these factors without examining any evidence of stress.
Implications
The complex neuro-immune-cutaneous model that involves numerous neuropeptides and neurokinins, inflammatory mediators and cells, hypothalamic-pituitary-adrenal axis hormones, and the skin may better explain the underlying pathophysiological mechanisms involved in the onset of urticaria. In addition, the elevated psychological stress level that has been closely related to CSU/CIU could be attributed to the imbalance or irregularity of this neuro-immune-cutaneous circuit. It is still unclear and must be further investigated whether any psychological stress results in or triggers CSU/CIU onset on top of a preexisting neuroimmune dysregulation. Nevertheless, new psycho-phenotypic or neuro-endotypic CSU/CIU subsets should be considered as the era of personalized treatment strategies emerges. A better understanding of CSU/CIU pathophysiology and consideration of the patient as a whole is vital for identifying targets for new potential treatment options
Chronic spontaneous or idiopathic urticaria (CU) is the occurrence of daily or frequent wheals with or without pruritus for at least 6 weeks with no identifiable cause. In clinical practice, it has been observed that a significant proportion of patients with CU have a history of a significant life stressor in the period before the onset of urticaria symptoms and signs
Posttraumatic stress disorder, emotional suppression and psychiatric co-morbidity in patients with chronic idiopathic urticaria: a moderated mediation analysis.
Stress occurs when homeostasis is threatened by internal or external adverse forces known as stressors (eg, threats). Homeostasis is necessary for maintaining the complex dynamic equilibrium maintained by living systems. Neuroendocrine hormones are pathophysiologically involved in several disorders as major regulators not only for the basal homeostasis but also for responses to threats. The response to stress is regulated by the stress system that is located both in the central nervous system (CNS) and the peripheral organs. Hypothalamic hormones (eg, corticotropin-releasing hormone [CRH], vasopressin, pro-opiomelanocortin–derived peptides), along with locus coeruleus, the major source of norepinephrine in the dorsal pontine tegmentum, and autonomous norepinephrine centers in the brainstem, are significant effectors in the CNS. Unnecessary upregulation or downregulation of this system's basal activity and responsiveness could cause a homeostatic imbalance that may lead to several pathologic conditions.
Emerging research has shown that skin actively participates in the response to stress through a local hypothalamic-pituitary-adrenal (HPA) axis, peripheral nerve endings, and immune system skin-homing cells, including keratinocytes, mast cells, and T cells.
Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects.
There are feedback and crosstalk mechanisms between the brain and skin as well. Preinflammatory and proinflammatory cytokines and inflammatory neurogenic pathways play significant roles in the mediation of such responses.
In a recent meta-analysis, the overall prevalence of any psychopathological condition among patients with CU was estimated to be 31.6%, significantly higher than in healthy subjects.
However, whether psychiatric conditions predispose the onset of CU or emerge during CU remains undetermined. Treatment with antidepressants has been shown to be beneficial in common inflammatory skin disorders, including CU. According to another systematic review, there is substantial evidence of anti-inflammatory properties in antidepressant agents.
The complex interactions between stress, numerous neuropeptides and neurokinins, inflammatory mediators and cells, and the skin may contribute to the development of CU. We therefore undertook a systematic review to summarize evidence from in vivo and ex vivo studies in human beings related to the association between CU and neuroimmune inflammation with or without evidence of co-existing psychological stress.
Materials and methods
This systematic literature review was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Figure 1). PubMed (for the MEDLINE database) and Scopus were searched by using a comprehensive search strategy [(neurotransmitters OR neurokinins OR stress OR neuropeptides OR neuroinflammation OR “central nervous” OR neuroimmune) AND “chronic urticaria.” Filters: Publication date to September 2019]. Inclusion criteria were: (1) clear distinction between urticaria versus other allergies; (2) clear distinction of chronic spontaneous or idiopathic urticaria (abbreviated as CU in the present article) as opposed to acute urticaria; (3) clinical studies in human beings; and (4) published articles written in the English language. Additional potentially relevant studies were scrutinized in the reference lists of the eligible publications.
Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram.
Eligible articles could be randomized clinical trials, uncontrolled studies, case-control studies, case series, and case reports in human beings related to the association between CU and neuroimmune inflammation with or without evidence of co-existing psychological stress. An initial selection process was conducted based on the titles and abstracts of articles returned by the initial search. Duplicate entries were excluded. The study authors independently reviewed the full texts of all potentially eligible studies, assessed their eligibility against the predefined criteria for inclusion and quality, and extracted all data. Any discrepancy was resolved by consensus. The quality of the studies was evaluated independently by the authors according to the Cochrane Handbook for Systematic Reviews for Interventions for assessing bias.
Results
A total of 674 potentially relevant published articles were identified. Only 13 of these studies satisfied the predefined inclusion criteria and were included in the systematic review (Figure 1). Five of these 13 studies evaluated the association between CU, stress, and neuro-immune-cutaneous factors, while the remaining 8 focused on the relation between CU and these factors without examining any evidence of stress (Table 1).
Table 1Studies included in the systematic review suggesting associations: (1) among chronic spontaneous/idiopathic urticaria (CU), stress, and neuro-immune cutaneous factors; and (2) between CU and neuro-immune-cutaneous factors without examining any evidence of stress.
Study
Patients
Control Group
Results
Studies suggesting association among neuro-immune-cutaneous factors, stress, and CU.
Both CRF and ACTH were shown to activate basophils. No significant difference was found between numbers of CU patients and controls responding to CRF, ACTH or cortisol. CU patients had higher serum cortisol levels.
The involvement of serum stem cell factor, SP, and NPY in CU pathogenesis among selected neuropeptides was reported. A novel finding of this investigation was revealing NPY as the most important peptide predictive of APST positivity.
Mean β-endorphin levels of CU patients were significantly elevated compared to control subjects. It is suggested that the opioid system of CU patients is strongly activated in the chronic stage of the disease.
Studies suggesting association between neuro-immune-cutaneous factors and CU independently of stress.
Basal NGF levels were significantly lower in CU patients whose symptoms persisted despite treatment compared with drug-responsive patients and control group. NGF in treatment-responsive patients increased after the symptoms were suppressed.
9 delayed pressure urticaria patients, 9 patients with CU
9 healthy individuals
CU patients have enhanced wheal and flare reactions induced by SP and CGRP. CGRP provoked an immediate response of wheal and flare followed by prolonged erythema. H1-antihistamines partially affected both the SP-induced wheal and flare reactions but only the CGRP induced flare, an effect that was more pronounced in CU patients compared with controls.
Upregulated expression of substance P in basophils of the patients with chronic spontaneous urticaria: induction of histamine release and basophil accumulation by substance P.
SP plasma level and numbers of basophil in CU patients were higher compared with controls. SP inhibitors and NK1R blockers are potentially useful agents to treat CU.
A significant increase in VIP-induced wheal was observed in CU patients suggesting an increased sensitivity of VIP microvasculature in these patients with CU.
16 patients in an eczema-free interval, 16 acute atopic eczema patients, 16 patients with CU, 16 patients with psoriasis
16 healthy individuals
CU patients exhibited a decreased axon-reflex erythema after histamine iontophoresis in the skin, suggesting a downregulation of C-fiber responsiveness to histamine. This could be explained either by reduced release of neuropeptides, or downregulation of their receptors, or impaired histamine metabolism.
indicated that chronic stress could potentially tangle with and intensify the vicious cycle of CU pathogenesis. They observed signiflcant stress scores, systemic inflammation, and increased interleukin (IL)-18 and high-sensitivity C-reactive protein (CRP) levels. Interestingly, patients with CU had lower basal cortisol levels compared with healthy individuals. This finding was more pronounced in those with autoimmune disease and increased severity. Stress scores did not significantly vary between patients with negative and positive autologous plasma skin test results.
investigated any potential link between psychological stress and CU by comparing basophil activation and serum cortisol, corticotropin-releasing factor (CRF), and adrenocorticotrophic hormone levels in healthy individuals and in patients with CU. The baseline basophil activation level did not differ. However, there was a correlation between basophil responses to serum CRF or adrenocorticotropic hormone and cortisol in volunteer control subjects that was not observed in patients with CU who had higher serum cortisol levels. This finding suggests an abnormality of the HPA axis in CU.
determined elevated serum stem cell factor, substance P (SP), and, to a lesser extent, neuropeptide Y levels in patients with CU compared with control individuals, suggesting they are essential neuropeptides involved in CU pathogenesis. Interestingly, neuropeptide Y was found to be predictive of autologous plasma skin test positivity, indicating a role for this neuropeptide in autoreactive urticaria and potentially in autoimmune urticaria.
found that brain-derived neurotrophic factor is increased in serum and diseased skin of patients with CU. They proposed a role of neurotrophins in the pathophysiology of this chronic inflammatory skin disease.
observed that β-endorphin levels of patients with CU were elevated compared with those of control subjects. This increased activity of the endogenous opioid system could be explained by a neuro-endocrine hyperreactivity that may be a characteristic of patients with CU, by an imbalanced negative feedback mechanism in HPA axis activation, or by a modified pro-opiomelanocortin–synthesizing activity that can cause an enormous release of β-endorphin from the readily disposable pool presented in the pituitary gland. Nevertheless, they suggest that an anti-opioid agent might be therapeutically beneficial in these patients.
Studies Suggesting Association Between Neuro-Immune-Cutaneous Factors and CU independently of stress
investigated the important role of nerve growth factor (NGF) in CU, which indicated that neurotrophin deregulation might contribute to the pathophysiology of urticaria. In this study, NGF levels in patients with refractory CU to intensive therapy using antihistamines were significantly lower than antihistamine responsive patients and healthy controls. In addition, NGF rates continued to increase after drug therapy in patients who had reacted well to treatment, whereas no improvement was observed in those patients who were resistant to treatment.
investigated the cutaneous responses to SP and calcitonin gene–related peptide (CGRP) in patients with delayed pressure urticaria and patients with CU compared with healthy adults; they also evaluated the effect of H1-antagonists on these responses. Based on their results, patients with CU have enhanced wheal and flare reactions induced by SP and CGRP. CGRP provoked an immediate response of wheal and flare followed by prolonged erythema. H1-antagonists partially affected the SP-induced wheal and flare reactions, but only the CGRP induced flare, an effect that was more pronounced in patients with CU as opposed to healthy individuals.
assessed the serum SP levels in patients with CU, atopic subjects, and healthy individuals. The mean concentration of serum SP was not significantly different among patients with CU and healthy subjects. Conversely, Metz et al
found a significant increase in SP levels in patients with CU compared with healthy control subjects and reported a direct correlation between SP concentration and disease activity.
Upregulated expression of substance P in basophils of the patients with chronic spontaneous urticaria: induction of histamine release and basophil accumulation by substance P.
confirmed the increase of circulating SP in patients with CU, suggesting a potent proinflammatory role of SP in the pathogenesis of CU. Patients with CU had more blood basophils expressing SP receptor, a fact that could explain the increased releasability observed after basophil stimulation with SP ex vivo.
assessed the effect of systemic H1-antihistamines on serum levels of selected neuropeptides, including SP, in patients with CU for 1 week. The treatment responses were not consistent for all examined neuropeptides. There was no difference between pretreatment and posttreatment levels of SP, whereas stem cell factor, neuropeptide Y, and vasoactive intestinal peptide decreased and CGRP increased after treatment with antihistamines.
found a significant increase in vasoactive intestinal polypeptide (VIP)-induced wheal, but not flare or cutaneous blood flow, in urticaria patients compared with healthy control subjects. Such data indicate an increased vulnerability of microvasculature to VIP in patients with CU.
Taking into account itch and flare reactions in patients with atopic eczema after histamine application, Heyer et al
tried to determine such reactions in patients with CU. They concluded that neurogenic inflammation in CU is impaired compared with healthy control subjects, as suggested by the smaller axon-reflex erythema (caused by the afferent C-group nerve fibers) but unaffected pruritus. These observations could be attributed to histamine and SP receptor downregulation on different target structures causing decreased C-fiber responsiveness.
Discussion
This systematic review identified explicit, direct, or indirect evidence of a significant association between CU, neuroimmune inflammation, and stress. It is not clear, however, which is the underlying, pre-existing, or induced critical causal factor that, if eliminated, would have either prevented CU onset or reduced its severity.
Thus far, only 5 studies have suggested that stress could be implicated in CU pathomechanisms and that stress can intensify and regenerate CU underlying pathomechanisms in the pathogenesis of CU.
It would have been particularly interesting if it were possible to subgroup these patients into different CU-related psycho-phenotypes. Unfortunately, there are no stress-related biomarkers of clinical importance that could help in this direction, or even reveal those who will be susceptible to develop CU after the occurrence of a critical psychological stressor.
Eight studies, however, have examined the increased or decreased serum concentration of neuro-immune-cutaneous factors of inflammation or neurotransmission in patients with CU (eg, SP, CGRP, NGF, IL-6, IL-18).
Upregulated expression of substance P in basophils of the patients with chronic spontaneous urticaria: induction of histamine release and basophil accumulation by substance P.
Similarly, identifying CU neuro-endotypes would have been of great importance in understanding the CU pathomechanisms and the complex psycho-neuro-endocrine-immuno-cutaneous crosstalk, subgrouping those patients according to the impaired pathophysiological pathway and then treating accordingly.
CU pathophysiology is still poorly understood, although there is increasing evidence that stress, immunity, and inflammation can eventually lead to degranulation of the mast cell and basophil, and therefore wheal formation. The association with stress dictates the potential role of the neuroendocrine system in the etiopathogenesis of CU via inflammatory and neurotransmission dysregulation.
Temporary activation of the HPA axis occurs at the early stages of stress. The consequent physiological pathways include cortisol secretion, upregulation of anti-inflammatory cytokines, and downregulation of proinflammatory cytokines. Moreover, stress also results in IL-18 secretion, which may exhibit both immunomodulatory and proinflammatory properties from the adrenals and the anterior pituitary during the HPA-axis activation process. IL-18 and cortisol modulate the HPA axis by inhibiting CRH secretion in a negative feedback manner.
However, longstanding exposure to stress augments the central tone of the HPA axis. As a consequence, HPA axis fatigue occurs, leading to hypocortisolism.
In addition, an increased release of proinflammatory cytokines, including IL-6 and IL-18, is observed. In the paradigm of autoimmune urticaria, keratinocytes have been implicated for this increase, which, in turn, retains the chronic skin inflammation and the subsequent chronic stress. This contributes further to the difficult cycle of HPA-axis fatigue and worsening hypocortisolism.
Study of serum interleukin (IL) 18 and IL-6 levels in relation with the clinical disease severity in chronic idiopathic urticaria patients of Kashmir (North India).
It was shown in earlier studies that patients with CU experience secondary insomnia due to pruritus and stress, which can interrupt the circadian rhythm of cortisol secretion and aggravate CU.
Apart from the central HPA axis, there is evidence suggesting that there is a peripheral HPA axis, analog to the central one, in the skin. Effector cells in this axis are the mast cells and the epidermal and hair follicle keratinocytes, which express CRH receptor 1 (R1) receptors and secrete CRH and IL-18 in response to stress. The CRH-R1 plays an essential role in orchestrating the neuroendocrine, behavioral, and autonomic responses to stress, whereas IL-18 contributes to induction of severe cutaneous inflammation. Hence, the cutaneous HPA axis regulates the local inflammatory cytokine equilibrium,
which, because of the imbalance secretion, results in increased CRH production.
CRH has been shown to have proinflammatory properties by inducing degranulation of the mast cells and increasing in vivo vascular permeability in rat skin.
Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects.
CRH can also cause increased secretion of IL-6. This activation of skin mast cells induced by CRH through a CRH-R1–dependent mechanism is responsible for vasodilation and increased vascular permeability, which is a pathogenetic characteristic of urticaria. Stress can exacerbate or precipitate these phenomena.
Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects.
Expression of high levels of the mast cell–related gene histidine decarboxylase and of CRH-R1 was found in patients with CU involving the CRH receptors.
Investigation of dermatology life quality index and serum prolactin and serum dehydroepiandrosterone sulphate levels in patients with chronic urticaria.
Although mast cells are expected to be inflammatory, they can also respond in inflammatory processes to neuropeptides. In response to various challenges, mast cells secrete many proinflammatory, vasoactive, and nociceptive molecules.
Each one of these molecules has more than one function and overlap biological effects. Mediators such as histamine and serotonin are stored in mast cells and released during degranulation of the mast cells. Furthermore, mast cells release, inter alia, numerous cytokines such as interferon-γ, tumor necrosis factor-α, IL-1, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-16, inter alia, nitric oxide, vascular endothelial growth factor, transforming growth factor-β, basic fibroblast growth factor, and NGF.
Joint capsule mast cells and neuropeptides are increased within four weeks of injury and remain elevated in chronic stages of posttraumatic contractures.
J orthopaedic Res: Off Pub Orthop Res Soc.2008; 26: 1313-1319
Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution.
Mast cells can also express receptors for neuropeptides such as CRF, pituitary adenylate cyclase–activating polypeptide, VIP, neurotensin, proopiomelanocortin, neuropeptide Y, CGRP, SP, neuromedin U, and galanin.
This inflammation cascade can easily explain not only the evidence of systemic inflammation (eg, elevated CRP and IL-6) suggested by many studies in patients with CU but also their positive correlation with disease severity.
showed that human mast cells constitutively express neuropeptide receptors and respond to neuropeptides by generating chemokines. It is clear that the homeostatic role of mast cells that exist in every single organ, to produce and secrete multiple molecules, express a huge variety of receptors, and interact peripherally and centrally with the nervous system, is crucial for retaining physiology.
Neuropeptides are a type of neurotransmitter. They are produced and released by neurons of both the peripheral system and the CNS but also by mast cells. Neuropeptides are small molecules up to 36 amino acids in length that influence their effector cells in a receptor-dependent manner.
These cells, in turn, release other bioactive substances such as prostaglandins, cytokines, carbon monoxide, and nitric oxide, which interact with nerve terminals and fibers. The role of neuropeptides in the skin is pleiotropic because, apart from direct cytokine release from mast cells and lymphocytes, they can modulate vessel extravasation and cutaneous edema, recruitment, and proliferation of inflammatory cells. The realization of the interplay between the nervous system, via the secreting neuropeptides, and the mast cells, via the expression of relevant receptors and the production of bioactive byproducts, introduced the concept and the model of neurogenic inflammation.
Neurokinins, a family of peptides that includes SP, neurokinin A, and neurokinin B, are among the major neurotransmitters released during nerve stimulation. Along with other neurogenic inflammatory mediators such as CGRP and VIP, neurokinins exert their responses.
There is evidence supporting the involvement of neurokinins in sensory transmission as well as in most immunological and inflammatory states through their action as trophic and mitogenic substances with respect to their role in inflammatory processes.
Neurokinins act either directly or indirectly via the secondary development of inflammatory mediators, mainly histamine, nitric oxide, and other kinins.
Recent studies have shown that circulating SP levels in patients with CU are positively correlated with CU severity and the upregulation of SP-positive basophils.
According to current knowledge, the underlying pathophysiology for CU includes the degranulation of histamine and other inflammatory mediators in the skin by mast cells and basophils. Recent evidence suggests that CU cutaneous inflammation can result from complex neuroendocrine pathways, which could explain the clinical responsiveness heterogeneity and the variable treatment responses.
Continuous administration of regular or even higher up to fourfold doses of H1-antihistamines is the basis of CU treatment and is efficacious in many patients with CU. Treatment with omalizumab is the next option in CU refractory to antihistamines and, fortunately, many patients respond. However, there are still patients who do not benefit or tolerate these therapies, or need these medications for many years, if not lifelong.
The complex neuro-immune-cutaneous model that involves numerous neuropeptides and neurokinins, inflammatory mediators and cells, hormones, and the skin may better explain the underlying pathomechanisms involved in the onset and maintenance of urticaria. In addition, the elevated psychological stress level that has been closely related to CU could be attributed to the imbalance or irregularity of this neuro-immune-cutaneous circuit. It is still unclear, and requires further investigation, whether any psychological stress results in or triggers CU onset on top of a preexisting neuroimmune dysregulation. Nevertheless, new psycho-phenotypic or neuro-endotypic CU subsets should be considered as the era of personalized treatment emerges. A better understanding of CU pathophysiology and consideration of the patient as a whole is vital for identifying targets for potential new therapies not only to treat but also to prevent onset of urticaria.
Disclosures
The authors have indicated that they have no conflicts of interest regarding the content of this article.
Acknowledgments
Both authors performed the literature search of electronic databases, screened articles for eligibility based on the inclusion criterion and assessed the risk of bias, reviewed and extracted information from the eligible full-text articles, and contributed to the analysis of the results and the writing of the manuscript. Both authors read and approved the final manuscript.
References
Chung M.C.
Symons C.
Gilliam J.
Kaminski E.R.
Posttraumatic stress disorder, emotional suppression and psychiatric co-morbidity in patients with chronic idiopathic urticaria: a moderated mediation analysis.
Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects.
Upregulated expression of substance P in basophils of the patients with chronic spontaneous urticaria: induction of histamine release and basophil accumulation by substance P.
Study of serum interleukin (IL) 18 and IL-6 levels in relation with the clinical disease severity in chronic idiopathic urticaria patients of Kashmir (North India).
Investigation of dermatology life quality index and serum prolactin and serum dehydroepiandrosterone sulphate levels in patients with chronic urticaria.
Joint capsule mast cells and neuropeptides are increased within four weeks of injury and remain elevated in chronic stages of posttraumatic contractures.
J orthopaedic Res: Off Pub Orthop Res Soc.2008; 26: 1313-1319
Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution.
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