Urticaria-Nomenclature and Classification
Urticaria is derived from the two latin words “urtic” which means nettle and “uere” that means burn. The name suffices the stinging or burning itchy sensation produce by the urticarial rash. The incidence of urticaria ranges from 0.5 to 1.0 % of population and although can be seen in any age group although acute criteria is more common in children the chronic urticaria is most commonly seen in people in 20–40 years of range, and affect more females. The typical lesion is called wheal or hive which appears as smooth raised soft erythematous plaques caused by the swelling in superficial layers of skin resulting from mast cell degranulation. The urticarial lesions are highly pruritic and may last for several hours, they heal without any scarring .
Urticaria is mainly divided in two classes based on onset and recurrence, acute urticaria and chronic urticaria.
The urticaria when last less then 6 weeks is called acute urticaria. The acute urticaria is usually a reaction to an identifiable etiological agent and is further classified based on type of the etiology. Acute urticaria may occur in absence of any triggering agent and in that case is called acute spontaneous urticaria. The urticarial lesions can appears in close temporal relationship with the etiological agent sometimes within hours and getting a good history may help delineate the causative factors. Common causative agents are food, chemicals, medications and viral infections. Acute urticaria usually resolves in few days and if recurrent my resolve completely in less than 6 weeks with no further recurrence .
The chronic urticaria is a relapsing and remitting condition lasting for 6 weeks or more. About 2–3 % of population suffers from chronic urticaria. The etiology of the chronic urticaria can be multifactorial but stress plays a significant role. The relationship of stress with urticaria is bidirectional. Psychological stress is known to play a major etiological role in chronic urticaria and having chronic urticaria and it’s symptoms like recurring wheals, pruritus and it’s impact on quality of life can cause further create psychological stress .
Chronic urticaria is further classified in two main classes: chronic spontaneous and chronic inducible urticaria. The chronic spontaneous urticaria has no identifiable causative agent while chronic inducible urticaria occur in response to an identifiable causative agent. Common agents known to cause chronic inducible urticaria are more physical in nature like application of pressure, exercise, exposure to heat or cold, solar or water exposure. Although not classified separately psychological stress can be a major factor contributing to the onset of continuation of chronic urticaria (Fig. 18.2) .
Classification of urticarias
Stress, Skin and Neuroendocrine System
Stressful events activate the HPA axis, starting with the release of Corticotrophin-releasing hormone. CRH is the key component considered as the conductor of this orchestra of HPA-Axis hormonal symphony. CRH is produced in the paraventricular nuclei of the hypothalamus and in turns it controls the release of proopiomelanocortin (POMC) and different POMC-derived peptides including adrenocorticotrophin releasing hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH) from the anterior pituitary gland [5, 6]. Activation of ACTH by CRH in turn leads to stimulation if adrenal cortex causing release of glucocorticoids, which returns to its base line when stressful event has passed and HPA axis activation subsides. The ACTH is released in a diurnal fashion with peak secretion in mornings and reaches a trough at midnight. This diurnal secretion gets disrupted when the CRH-ACTH system is under stress. ACTH exerts its action by binding with melanocortin receptors 2 (MC2) and stimulating adenyl cyclase, and generating cAMP that activates downstream enzyme pathways in steroidogenesis [5–7]. Glucocorticoid synthesis mainly takes place in the zona fasciculata of the adrenal cortex and is responsible for activating the negative feedback loop to terminate the stress response at suprahypothalamic centers, hypothalamus, and pituitary gland [5–7].
In cases when stress is chronic and gives rise to continual hypersecretion of CRH, perpetuating an unrelenting activation of the HPA axis a syndromal state characterized by physical changes leading to disease traits and states causing central obesity, diabetes mellitus, metabolic syndrome, hyperthyroidism, osteoporosis, atherosclerosis, chronic immunosuppression leading to increased susceptibility to infectious and even neoplastic diseases. This chronic stress induced altered homeostasis is also responsible for many neurovegetative symptoms like lack of appetite, insomnia, low energy, chronic fatigue and psychological difficulties like anxiety disorders, depression, anorexia nervosa [6, 7].
Persistent or frequent stimulation of HPA axis due to stress leads to elevation of glucocorticoids. It has been postulated that constant or more frequent elevation of glucocorticoids can be damaging to the cells leading to insulin resistance, release of proinflammatory cytokines release and increasing the organism susceptibility to disease [8, 9]. CRH is also mediating the stress response via another system by activating locus coeruleus in the brain stem releasing arginine vasopressin (AVP) and other nonapeptides [6, 7].
Pathophysiology of Urticaria: The Skin HPA-Axis
It has been postulated that skin has its own HPA-axis equivalent to the central HPA-Axis. Unlike most other body cell the skin cells especially keratinocyte, melanocyte, and mast cells can secrete CRH in response to a stress full situation. Skin cells also have abilities to induce expression of specific receptors on their surface to engage molecules of ACTH, CRH, urocortin, α-MSH and β-endorphin all of which are important players in the skin response to stress. CRH action is mediated through two different types of receptors CRH-1 and CRH-2. CRH manage the different skin cells by inducing proliferation, and differentiation of cells while on the other hand it can also inhibit the proliferation and inducing apoptosis of different skin cell lines. It also induces proinflammatory changes by activating mast cells [10–13].
The mast cells plays such a critical role that they are called as “central switchboard” of skin-stress response . Skin mast cells are regulated by various factors; they are activated and promoted by stress mediators such as CRH, ACTH, NGF (nerve growth factor), SP (substance P), and stem-cell factor; they are inhibited by glucocorticoids and catecholamines [13, 14].
The CRH-1 receptors located on mast cells when activated cause mast cells to degranulate and release histamine. CRH also induces the release of IL-4, IL-6, IL-10, and IL-13 from mast cells. CRH and mast cells plays a major role in delayed hypersensitivity reaction. The self-regulatory nature of the CRH-Glucocorticoid cycle prevents adverse consequences of prolonged adaptive changes like catabolism and immunosuppression that initially are a integral response to deal with stress can become harmful for the body [5–7].
Stress can cause the HPA-axis to become over burdened especially if stress is prolonged, this is called allostatic overload . When compromised due to allostatic overload the HPA-axis is not able to respond to the new stressors resulting in various levels of dysregulation ranging from inflammation to immunosuppression . Skin mast cells are crucial in maintaining an allostatic balance. Skin mast cells also express several neuropeptides receptors on their surface leading them to orchestrate the different aspects of this localized psycho-immuno-neuro-endocrine axis. Skin mast cells produce different pro-inflammatory and vasoactive peptides beside histamine. The release of histamine, bradykinin, leukotriene C4, prostaglandin D2, leads to extravasation of plasma producing the urticarial lesions . Keratinocytes produces Interleukin -8 (IL-18) a proinflammatory cytokines that is known to play a role during state of stress . Any stressful event leading to psychological stress can easily cause a fare up of urticaria perpetuating this chronic cycle of suffering [15, 16]. Unrelenting pruritus can cause significant anxiety and mood problems .
Mast cell degranulation is prominent in physical urticaria induced by temperature changes, sun or water exposure as well as cholinergic or dermatographic urticaria. In urticaria, histamine-releasing autoantibodies have shown to activate mast cells and basophils via activation of complement system and thus causing histamine release. Mast cells and basophils both play an important role in intensity and duration of urticarial episode . Oxidative stress may play a role in chronic spontaneous urticaria .
Pathophysiology of Urticaria: The Psychological Stress
The relationship between stress and urticaria is well known but still vaguely understood when it comes to direct cause and effects. It has been postulated that certain early life events predispose people to develop particular personality traits in adult life making them at high risk of responding to psychological stress with conditions like urticaria. Patient with urticaria are shown to have high likelihood of having a major psychological stressful event in preceding 6–12 months, with maximal events occurring in month preceding the onset or recurrence of urticaria . Various studies have found different level of association of stressful events and urticaria ranging from 16 % to as high as 51 % in different samples [18–20]. The most likely stressor reported was death of a loved one followed by interpersonal conflict in family, financial stressors, illness is a family member, work related challenges, extramarital affairs, and sexual difficulties. Interestingly, presumably positive life events such as traveling for pleasure, or getting engaged or married, were equally likely to predispose people to develop uticaria within a year of the event. .
Chronic Urticaria and Psychiatric Comorbidity
Chronic urticaria is known to cause profound psychological impact on patients leading to significant negative impact on functional abilities and expression of different psychiatric illness. Shoemaker RJ et al. postulated a few decades ago that patients suffering from chronoic urticaria are replaying the dependency traits learned from adverse childhood events and in face of psychological stress they are unable to utilize mature ego defences and tend to have more emotional dependency needs which when unmet or are feared to not be met create a emotional climate for an episode of urticaria .
It has been reported that patients suffering from chronic urticaria for many years may develop psychological traits such as alexithymia and repression that can lead to development of long-term psychiatric difficulties. There is increased risk of developing comorbid anxiety disorders including posttraumatic stress disorder, somatoform disorders and depression in patients with chronic urticaria. Adolescents who suffered from non infective urticaria were found to have higher risks of developing major depressive disorder when compared to the age matched control who did not suffer from urticaria [22–26].
Stubach P et al. studied relationship of the psychiatric disorders and urticaria in 100 patients . The patients were evaluated with validated scales to establish the diagnosis and severity of urticaria and using the The Mini-DIPS, a shortened German version of the common international diagnostic interview for mental disorders (DIPS) based on the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) along with well validated scales like Hospital Anxiety and Depression Scale (HADS) for anxiety and depression and the Symptom Check List (SCL-90R) for assessment of level of emotional distress and somatoform disorders . Patients were also thoroughly evaluated to identify underlying causes of CSU to identify any triggering stimulus causing urticaria like food and other allergens, histamine intolerance and autoreactivity any underlying autoimmune diseases, chronic infection or any other medical condition that can including sensitize a person to type I allergens. Patients in whom no definitive causative stimulus was identified were classified as having chronic idiopathic urticaria (CIU). The study concluded that the out of the 100 patients studied (69 females, mean age 43.8 years) 48 patients were found to be suffering from one or more psychiatric disorders . Anxiety disorders were among the most common, comprising 30 % of the patients followed by depressive disorders 17 %, and somatoform disorders 17 % .The commonest anxiety disorder was agoraphobia followed by social and specific phobia and panic disorder. Major depressive disorder recurrent and dysthymic disorder were equally prevalent in the depressed patients followed by adjustment disorder. In the somatoform group, somatization disorder and somatoform autonomic function were followed by undifferentiated somatoform disorder . Other disorders seen in this population were alcohol and other substance use or multiple substance dependence in about 1–3 %. The patient who were found to have psychiatric disorder and CSU were also likely to report higher level of emotional distress .
The prevalence of axis I and axis II psychiatric disorders was explored by another study in 89 patients of CIU and compared with a control group . The study utilized the standardized an validated tools of Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (SCID-I) for axis I disorders and the Structured Clinical Interview for DSM, Revised Third Edition Personality Disorders for diagnosis of axis II disorders . Overall study found the about half of the patients (49.4 %) with CIU had an axis I or axis II disorder compared to only 12.5 % of control group. The most prevalent disorder in this population was obsessive compulsive Disorder affecting a quarter (25.8 %) of patients . The depressive disorder including major depression 13.5 % and dysthymic disorder at 9 % were the second commonest disorder along with social phobia at 9 % . The personality disorders were also much commoner in the group with CIU at 44.9 % with commonest personality disorder being obsessive compulsive personality disorder at 30.3 % followed by avoidant personality disorder at 18 % . The patients with CIU and axis I psychiatric disorders were also more likely to have a personality disorder (Ungz 2008). The authors recommended routine screening for psychiatric disorder in CIU patients in out patient dermatological setting to optimize their treatment with psychiatric referrals when indicated .