Tyler Chen '24

Pathophysiology, Diagnosis, and Treatment of Heat-Induced Hives: Cholinergic Urticaria

BY TYLER CHEN '24

Cover Image: On the le is the general immune response that leads to wheal formation – the characteristic symptom of chronic urticaria. With cholinergic urticaria, increases in body temperature lead to this immune response through multiple mechanisms. On the right is the ribbon for chronic urticaria awareness.

Image Source: Wikimedia Commons Introduction

ere are not many conditions that are both as commonplace yet largely unheard of as cholinergic urticaria (CU). In fact, it wasn’t until 1924 when CU – referred to as “urticaria calorica” at the time – was rst documented by Duke (Duke, 1924). In essence, CU is the abnormal sensitivity to heat. ose a icted with CU will produce numerous small (usually <5mm in diameter) short-lived pruritic wheals (itchy hives) – most frequently on the upper trunk and proximal limbs – when the body’s core temperature rises from some sort of heat stimulus (examples include physical or mental exertion, eating spicy foods, and taking hot showers) (Kim et. al, 2014). e symptoms subside quite quickly – typically within an hour or so – a er the core body temperature lowers. But, even then, it may signi cantly impair quality of life, especially for athletes whose body temperatures frequently elevate due to routine physical exertion through their sports. Due to its characteristic clinical presentations, diagnosis of CU has become quite easy. However, the underlying pathophysiology behind CU still remains uncertain. subcategories: 1) CU with Poral Occlusion (CuPO), 2) CU with Acquired, Generalized Hypohidrosis (CuAGH), 3) CU with Sweat Hypersensitivity (CuSH), and 4) idiopathic CU (iCu) – all of which are further detailed over the course of the paper. ese four subtypes all have unique presentations and underlying pathophysiologies that lead to the urticarial reaction. In all cases, CU can be generally diagnosed fairly easily through either an exercise test or some other heat stimulus (Commens & Greaves, 1978). However, further distinguishing between the four types for CU requires additional diagnostic tools. Moreover, due to the varying pathophysiologies behind all four conditions, treatments for each are distinct as well, necessitating the precise diagnosis of the speci c type of CU.

e disease itself is fairly common across the general population, with most cases being seen among young adults. Di erent studies have aimed to determine the prevalence of CU among the young adult population, but there is no consensus on the real gure. For example, a study on university and high school students in Germany found that 11.2% of the young adult population displayed whealing consistent with

CU following a heat stimulus (Zuberbier et al., 1994) – a gure that vastly di ers from that of a study on the young adult population within India that found an overall prevalence of 4.16% (Godse et al., 2013).

is article seeks to document the current collective understandings of the underlying pathophysiologies of CU, the various diagnostic tools used to diagnose and di erentiate between the four categories of CU, and the present methods available to treat CU.

Pathophysiology

e current pathophysiology surrounding CU remains largely unclear. However, insights have been derived for each subtype of CU.

a. Cholinergic Urticaria with Poral Occlusion (CuPO)

ere have been a few cases that suggest that CU can be caused by poral occlusion (PO) (when sweat pores get clogged). In these cases, histological examinations of skin cells surrounding the wheals consistent with CU revealed occlusion of the upper parts of the sweat ducts. is occlusion was seen to be largely due to both hyperkeratinization – formation of keratotic plugs in the super cial acrosyringium (intraepidermal portions of the sweat ducts) – and dilatation of the sweat ducts themselves (Chinuki et al., 2011; Nakamizo et al., 2012). From this, it is hypothesized that PO causes sweat to leak out of the sweat ducts and into the surrounding dermis. e contents of sweat – which include numerous enzymes, a renin-like substance, secretory IgA, IgE, and cytokines that include interleukin α and β, and interleukin 8 – then induce a local in ammatory response which in turn produces the wheals consistent with CU (Kobayashi et al., 2002). In cases such as these, those a ected with CuPO consistently see a seasonal trend with their symptoms, with a peak in symptoms during the winter and a low during the summer (Rho, 2006). is can be attributed to dryer skin during the winter due to lower temperatures. It may be that with dryer skin due to lower temperatures and humidity, the skin hyperkeratinizes (the process in which excess keratin results in increased cohesion between and accumulation of dead skin cells, leading to the obstruction of the super cial acrosyringium) in order to protect the skin, leading to higher incidences of PO and thus CU. e ip side is also true: higher temperatures and humidity during the summer reduce the amount of hyperkeratinization of the intradermal portions of the sweat ducts, resulting in a lower incidence rate of CU.

b. Cholinergic Urticaria with Acquired, Generalized Hypohidrosis (CuAGH)

CU has also long been associated with acquired, generalized hypohidrosis (AGH) – a condition in which individuals have di culty sweating. Autoimmunity to sweat glands, autoimmunity to acetylcholine receptors [acetylcholine binds to the M3-muscarinic acetylcholine receptors (M3MARs) in the eccrine glands, which produce an immediate sweat response], degeneration of post-ganglionic sympathetic skin nerve bers (nerve bers that carry the sympathetic signals for acetylcholine release), or even PO (as previously discussed) have all been proposed as potential causes of AGH (Hu et al., 2018; Nakamizo et al., 2012). But, even with these hypotheses, the general pathophysiology surrounding the involvement of AGH with CU remains unclear. Although the exact mechanism is unclear, recent studies looking into the association between AGH and CU have shed more light on the roles and functions of M3MARs within the eccrine glands.

Looking at patients with CU with hypohidrosis/ anhidrosis, there seems to be a lower expression of acetylcholinesterase – an enzyme responsible for the breakdown of acetylcholine into acetic acid and choline – and M3MAR in eccrine gland epithelial tissue (Sawada et al., 2014). In normal patients, acetylcholine released within eccrine gland epithelial tissue will either bind to the M3MARs on the sweat ducts to stimulate the secretion of sweat or bind to acetylcholinesterase to get broken down. However, those with

Image 1: A male patient is seen here displaying CU on the volar aspect of his forearm. e characteristic pinpoint-sized, numerous, pruritic wheals are seen clearly across the arm, along with some mild erythema (redness) in response to a heat stimulus.

Image Source: Wikimedia Commons

"Clinically, we can categorize CU into 4 subcategories: 1) CU with Poral Occlusion (CuPO), 2) CU with Acquired, Generalized Hypohidrosis (CuAGH), 3) CU with Sweat Hypersensitivity (CuSH), and 4) idiopathic CU..."

"... CU is ultimately rooted in the body’s hypersensitivity to heat..."

Image 2: A cross-section of skin, with sudoriferous glands (sweat glands). Here, the sweat glands are all speci cally eccrine sweat glands, since the glands themselves open directly to the surface of the skin via the sweat ducts, as opposed to apocrine sweat glands which open to the hair follicle. e ve layers Stratum corneum, Stratum lucidum, Stratum granulosum, Stratum mucosum, Stratum germinativum form the epidermal layer of the skin, and the portion of the sweat duct located within these layers is known as the acrosyringium. e super cial acrosyringium refers to the portion of the acrosyringium that is near the outer surface of the skin, or within the top portions of the Stratum corneum. In patients with CuPO, elevated keratin levels result in higher cohesion between keratinocytes (90% of skin cells) in the Stratum corneum, leading to an overaccumulation of skin cells surrounding the super cial acrosyringium. With a large enough accumulation of keratinocytes, they cap the opening to the outer surface of the skin – forming a keratotic plug. Image Source: Wikimedia Commons anhidrosis have skin with lower expression of both of these receptors. As a result, acetylcholine fails to bind to the M3MAR due to its reduced expression, and also fails to become fully degraded due to the lower amount of acetylcholinesterase available. is excess acetylcholine then over ows into adjacent mast cells, which store a variety of di erent chemical mediators and are responsible for controlling local in ammatory responses such as allergy or hypersensitivity reactions. In response to the presence of acetylcholine, mast cells degranulate, or release their chemical mediators, which stimulates the in ammatory response and produces the wheals that are characteristic of CU (Takahashi et al., 1992). However, some individuals a icted with this type of CU also see no expression of M3MAR even on mast cells (Nakamizo et al., 2012). is indicates that there may be other molecules beyond acetylcholine that are involved in CU.

e cause of this underexpression of both M3MAR and acetylcholinesterase remains unknown, but it does appear to be related to the concentration of several chemokines associated with Atopic Dermatitis – another skin condition that is closely related to CU. Speci cally, expression of the chemokines CCL2/MCP-1, CCL5/RANTES, and CCL17/TARC within the eccrine gland epithelial tissue a ected by Atopic Dermatitis was signi cantly higher, which thus attracts CD4+ and CD8+ T cells and mast cells to the eccrine gland epithelial tissues (Sawada et al., 2014). In turn, the presence of these T cells is thought to cause the eccrine glands to limit the expression of M3MAR and acetylcholinesterase, which thus promotes the urticarial condition alongside the increased presence of mast cells.

e cause of this underexpression of both M3MAR and acetylcholinesterase remains unknown, but it does appear to be related to the concentration of several chemokines associated with Atopic Dermatitis – another skin condition that is closely related to CU. Speci cally, expression of the chemokines CCL2/MCP-1, CCL5/RANTES, and CCL17/TARC within the eccrine gland epithelial tissue a ected by Atopic Dermatitis was signi cantly higher, which thus attracts CD4+ and CD8+ T cells and mast cells to the eccrine gland epithelial tissues (Sawada et al., 2014). In turn, the presence of these T cells is thought to cause the eccrine glands to limit the expression of M3MAR and acetylcholinesterase, which thus promotes the urticarial condition alongside the increased presence of mast cells.

c. Cholinergic Urticaria with Sweat Hypersensitivity (CuSH)

Some cases have also detailed patients with CU displaying a hypersensitivity to their sweat. is indicates that, in some cases, the onset of CU may be rooted in the individual’s allergic reaction to their sweat. Upon intradermal injections of their sweat, patients with CuSH had an immediate skin reaction, indicating that there is a high association between this subtype of CU and hypersensitivity to sweat (Adachi et al., 1994). is hypersensitivity to autologous sweat antigen has been well-documented among patients with Atopic Dermatitis (eczema). In fact, it has been noted that the hypersensitivities to sweat between those with CU and Atopic Dermatitis seem to be virtually the same, leading to the belief that the exact mechanism behind the presence of the urticarial reaction may be similar to that of Atopic Dermatitis (Tanaka et al., 2006). In patients with Atopic Dermatitis, a speci c IgE for the sweat antigen led to the degranulation of basophils and mast cells, which thus induced the in ammatory response and urticarial reaction. A similar mechanism is also projected for CuSH, suggesting that both CU and Atopic Dermatitis may share hypersensitivities to the same antigens within sweat – even if their clinical presentations are distinct (Takahagi et al., 2009).

d. Idiopathic Cholinergic Urticaria (iCu)

Although most individuals with CU can be diagnosed with one of the three aforementioned subtypes, there are some cases in which the urticarial reaction cannot be pinpointed to any one of the causes previously mentioned. In this case, methods used to di erentiate between PO, AGH, and sweat hypersensitivity have been exhausted, and the patient is diagnosed with iCu (Nakamizo et al., 2012). Clinical Diagnosis

a. Diagnosis of Cholinergic Urticaria

Since CU is ultimately rooted in the body’s hypersensitivity to heat, the diagnosis for CU in the most general sense (i.e., without distinguishing between subtypes) can be carried out fairly easily. As is common amongst other forms of hypersensitivity testing, provocation testing is used to determine the presence of CU. Patients are typically placed in a hot bath, asked to perform a certain exercise, or placed in a hot box to elevate their body temperature and their physical response is noted (Fukunaga et al., 2018).

However, even when given a response that is consistent with CU (pinpoint-sized wheals, erythema, etc.), CU must still be di erentiated from Food-Dependent Exercise-Induced Anaphylaxis (FDEIA) and Localized Heat Urticaria (Fukunaga et al., 2018). Di erentiating between FDEIA and CU is relatively simple, as the former requires the ingestion of food and a speci c IgE response to the causative food antigen. To measure these conditions, skin prick tests, measurements of the particular IgE, and other provocation methods can be used to distinguish between FDEIA and CU. Di erentiating between Localized Heat Urticaria and CU is rather simple as well. While CU is a more systematic urticarial reaction due to a signi cant increase in core body temperature, Localized Heat Urticaria is the development of itchy wheals limited only to the portions of skin that were exposed to heating (Fukunaga et al., 2002). As a result, Localized Heat Urticaria can be tested through more localized heat provocation testing, typically involving cylinders of hot water that heat a speci c area rather than general heat stimuli aimed at elevating the body’s core temperature.

Image 3: An insight into the pathways surrounding the urticarial reaction in CuAGH. Dysfunctional and/or underexpressed M3MAR not only leads to decreased sweating but also results in an over ow of acetylcholine into nearby mast cells, which then stimulates the degranulation of said mast cells and leads to the urticarial reaction. Additionally, some patients report pain – not just pruritus – with CuAGH, which can also be seen to be the result of acetylcholine over ow as well. Excess acetylcholine stimulates sensory nerves – causing pain. Image Source: Wikimedia Commons

Image 4: A visual depiction of the mast cell degranulation process within the sweat allergy pathway. 1. Antigen (sweat antigen). 2. Immunoglobulin E antibody (IgE). 3. High-a nity IgE receptors on mast cells (FcεRI receptors). 4. Preformed mediators (e.g. histamine, proteases, chemokines, and heparin). 5. Granules. 6. Mast cell body. 7. Newly formed mediators (e.g. prostaglandins, leukotrienes, thromboxane, PAF). IgE antibodies speci c to a particular sweat antigen rst bind to the sweat antigen, and then bind to FcεRI receptors on mast cells or basophils, driving the degranulation of di erent mediators – histamine in particular – which stimulates the in ammatory response and results in the urticarial reaction. In addition to using heat stress methods, 0.05mL intradermal injections of 0.02% methacholine chloride (Acetyl-β methylcholine chloride) are used to induce an urticarial reaction in those with CU (Commens & Greaves, 1978). Methacholine itself has a similar structure to acetylcholine – the neurotransmitter thought to be the primary substance triggering CU. However, since acetylcholine itself is unstable in solution, methacholine is the more suitable option for routine CU testing. When injected into the skin, the formation of the characteristic wheals is used to establish a diagnosis of CU. However, only around 51% of cases present with wheals upon methacholine injection, implying that a lack of are-up cannot de nitively rule out CU. Likewise, 0.05mL intradermal injections of 0.002% carbamylcholine chloride (carbachol) can be used to a similar e ect (Schwartz, 2021).

b. Di erential Diagnosis between Subtypes of Cholinergic Urticaria

Beyond the con rmation of CU, it is necessary to pinpoint which type of CU a icts the patient, as that will guide the treatment plan. Due to the di erences between the underlying pathophysiologies for the four subtypes of CU, there are several methods to di erentiate between the categories:

i. Intradermal Injection of Autologous Sweat

An intradermal injection of a diluted sample of the patient’s sweat can provide insight into what kind of CU the patient might be facing. e pathophysiology surrounding CuAGH relies more on the leakage of acetylcholine and other substances into nearby tissue, and not on a direct immune response to the sweat itself. For those with CuSH, an intradermal injection of a diluted sample of autologous sweat will produce an in ammatory response. e sample must be diluted to below 1/10, as even healthy individuals will occasionally produce an in ammatory and urticarial response to intradermal injections of autologous sweat that are more highly concentrated (Fukunaga et al., 2005). us, a positive reaction (de ned by the development of a wheal and/or erythema of a signi cant size predetermined by the dosage and dilution of the injection) to an intradermal injection of autologous sweat implies hypersensitivity to sweat and can be used to support the diagnosis of CuSH.

ii. Intradermal Injection of Cholinergic Agents

Acetylcholine is a very large proponent of some types of CU (CuAGH in particular). As such, an intradermal injection of a cholinergic agent (molecules with the structure of acetylcholine) can be expected to produce an urticarial response in certain cases of CU. In using this method of diagnosis, both CuAGH and CuSH produce an urticarial reaction (Nakamizo et al., 2012). On the contrary, there will be typically no urticarial reaction among those with CuPO, since it is the sweat content itself that leads to the urticarial reaction, not the presence of acetylcholine or other cholinergic agents.

iii. Hypohidrosis/Anhidrosis Testing

As evident in its name, CuAGH presents with hypohidrosis. is can be used as a di erentiating factor with the other subtypes of CU, since CuSH does not present with hypohidrosis. To diagnose hypohidrosis, a simple sweat test is carried out. Sweat can be easily visualized through topical indicators such as iodinated starch and sodium alizarin sulphonate (Chia & Tey, 2013). ese substances undergo a dramatic color change when they encounter the moisture of sweat. A er the topical indicator is applied to the patient, a thermoregulatory sweat test is carried out. During this test, the patient will be placed in a hot box, placed under a thermal blanket, or will exercise. If the topical indicator fails to change color a er some time, it indicates that the patient has hypohidrosis. Hypohidrosis itself is also a separate disorder, and further actions can be taken to localize and pinpoint the cause of the patient’s hypohidrosis.

iv. Histological Examination

Histological examination of the skin tissue surrounding the wheals/urticarial reaction can also provide valuable insights into the subtype of CU that the patient has. is method is primarily useful for CuPO, as the main pathophysiology behind this type of CU is the hyperkeratinization of the super cial acrosyringium and the dilatation of the sweat ducts themselves. Histological examination of the epidermal layer of the skin around the wheal can verify whether the super cial acrosyringium is being obstructed by a keratin plug, which would indicate CuPO. Furthermore, within cases of CuAGH, the sweat glands themselves are also occasionally atrophic – which can be veri ed through histological examination of the sweat glands themselves (Nakamizo et al., 2012).

v. Idiopathic Cholinergic Urticaria (iCu)

e previous four methods are e ective in verifying or a rming a certain subtype of CU within patients. However, under circumstances when intradermal injections of autologous sweat and cholinergic agents don’t elicit a response, the patient is veri ed to not have hypohidrosis, and the histological examination of local epithelial tissue reveals nothing indicative, the patient is diagnosed with iCu.

Treatments

a. Cholinergic Urticaria with Poral Occlusion (CuPO)

Since the main cause of CuPO is the PO itself, steps should be taken to reduce the hyperkeratinization that ultimately leads to the urticarial reaction. Taking a hot bath and exercising can help the body sweat more, which in turn can help improve the symptoms of this type of CU (Kobayashi et al., 2002). Repeated sweating prevents the formation of keratotic plugs in the intraepidermal portions of the sweat ducts, and thus prevents the onset of CU. In fact, the seasonality of CuPO is largely tied with this, as increased sweating during the summer deters the hyperkeratinization of the sweat ducts, leading to a lower incidence of CuPO during the summer months. In addition to bathing or inducing more sweating, individuals can also apply keratolytic agents, which deter the formation of keratotic plugs (Nakamizo et al., 2012).

b. Cholinergic Urticaria with Acquired, Generalized Hypohidrosis (CuAGH)

Combating CuAGH is more nuanced. e onset of AGH plays a big role in the pathophysiology of this CU, so treatments can range depending on the cause of it. When the cause of AGH is the destruction of sweat glands due to autoimmune disease, a high dosage of corticosteroids can be e ective (Bito et al., 2012). Although the exact mechanism surrounding the e ects of corticosteroids on improving symptoms remains unclear, it is thought that this treatment leads to the decrease in lymphocyte in ltrate around the sweat glands, allowing the M3MARs to re-express. is, in turn, would then lead to improvements in sweating and CU.

Beyond systemic steroid therapy, the cornerstone of pharmacological treatment for CuAGH is antihistamine drugs. e rst line of therapy typically involves H1-antagonists, although patients typically only see a mild to moderate

Image 5: Methacholine (le ) vs. Acetylcholine. But have very similar structures except for methacholine having an extra methyl group. is extra methyl group allows methacholine to be selective towards muscarinic acetylcholine receptors compared to nicotinic acetylcholine receptors, thus allowing for the selective stimulation of receptors compared to direct injection of acetylcholine. Additionally, the structural change makes methacholine signi cantly less susceptible to hydrolysis and breakdown compared to acetylcholine. Acetylcholine can be broken down by several non-speci c cholinesterases, including acetylcholinesterase. However, methacholine can only be hydrolyzed by acetylcholinesterase, and at a much lower rate than acetylcholine gets hydrolyzed. Image Source: Wikimedia Commons

"... it is necessary to pinpoint which type of CU a icts the patient, as that will guide the treatment plan."

"Overall, further investigation into CU and the e cacy of di erent drugs against CU can help elucidate some of the uncertainty surrounding treatment plans and improve the current understanding of the rst three subtypes of CU, as well as provide insight into the pathophysiology of iCu."

Image 6: e chemical structure of the antihistamine cetirizine, also known as Zyrtec (shown on the right). Cetirizine itself is a highly-selective H1-antagonist – meaning that it speci cally targets histamine H1-receptors, outcompeting histamine in binding to the receptor (Portnoy & Dinakar, 2004). More speci cally, it is an inverse agonist to the receptor, meaning that when it binds to the histamine H1-receptor, it produces an e ect that is opposite to the e ect that would have ensued if histamine had bound to the histamine H1-receptor. Additionally, it is seen that cetirizine also has some anti-in ammatory responses independent of that of the H1receptor. Speci cally, it is seen that cetirizine also regulates the release of chemokines and cytokines, which thus regulates the in ammatory response (Walsh, 1994; Albanesi et al., 1998). Additionally, cetirizine has also been seen to limit eosinophil chemotaxis as well, further regulating/limiting the in ammatory response (Boone et al., 2000). Zyrtec itself is a combination of cetirizine and pseudoephedrine, with the former providing allergy relief and the latter being a decongestant. Image Source: Wikimedia Commons improvement in symptoms from standard doses (Fukunaga et al., 2018). Even still, they are generally considered to be e ective. Speci cally, the H1-antagonist cetirizine (also called Zyrtec) was found to be particularly e ective in relieving CU, leading to signi cant reductions in wheal formation, pruritus, and erythema (Zuberbier et al., 1995). Additionally, increasing the dosage of H1-antagonists can further improve symptoms, though this e ect was seen in fewer than half of patients. When increasing the dosage did not provide any further relief, lafutidine – an H2antagonist – was also found to be e ective in those with refractory CU (Hatakeyama et al., 2016).

Further studies into di erent anticholinergic drugs and treatments were also proven to be potentially e ective. One study found the oral administration of scopolamine butylbromide (an anticholinergic drug) to be e ective in cases where patients were found to be resistant to H1-antagonists and other conventional antihistamines (Tsunemi et al., 2003). Another case found that a combination of propranolol (a β2-adrenergic blocker), cetirizine, and montelukast to be e ective in treating CU when an antihistamine-only treatment regimen failed to produce long-term relief (Feinberg and Toner, 2008). Botulinum toxin injections were also found to be e ective in possibly treating CU, with one individual nding relief from CU following a Botox injection (Sheraz & Halpern, 2013). However, this relief was only temporary, as the neuromuscular blocking e ects of Botulinum toxin resulting in a decreased release of acetylcholine wears o over time as new axons regenerate and new neuromuscular connections form, leading to a resurgence in acetylcholine levels and CU. Danazol was also found to be very e ective in treating CU. Speci cally, multiple studies have indicated that Danazol therapy greatly reduces rates of whealing in young men a icted with CU (Wong et al., 1987). Within individuals with CU, it is observed that serum levels of α1-antichymotrypsin – a protease inhibitor responsible for inhibiting mast cell chymases and the neutrophil proteinase cathepsin G – are depressed, which is thought to promote CU through the delayed inactivation of these in ammatory proteases (Kalsheker, 1996). Danazol itself can greatly increase the serum level of several protease inhibitors, with serum levels of α1-antichymotrypsin also seen to increase signi cantly a er taking Danazol – alongside signi cant symptomatic improvements as well. In addition to further establishing Danazol’s e ectiveness, this also implies that the depressed levels of α1-antichymotrypsin are linked pathologically with the release of histamine and the subsequent development of wheals and pruritus (Alsamarai et al., 2012). But despite Danazol’s e ectiveness in mitigating CU, it should be avoided entirely or given with extreme caution to females and children, since it is an attenuated androgen, or a hormone responsible for regulating the development of male characteristics (e.g. testosterone).

c. Cholinergic Urticaria Associated with Sweat Hypersensitivity (CuSH)

Treatments for CuSH largely resemble that of CuAGH from a pharmacological perspective. However, the rst line of treatment is typically a desensitization protocol to autologous sweat in order to reduce the severity of the urticarial response: the sweat antigen to which the individual is highly sensitive to is puri ed and then used in a rapid desensitization process that is commonly used with other kinds of hypersensitivities (Kozaru et al., 2011). Beyond the normal procedure of allergen desensitization, the treatment options for CuSH closely resemble the typical pharmacological treatments used to treat CuAGH.

In some cases of CuSH, anti-IgE therapy can be e ective in reducing symptom severity. A well-known example of this anti-IgE therapy is omalizumab, a recombinant humanized

monoclonal antibody that has been seen to be potentially e ective in treating CuSH among other urticarias (Metz et al., 2008). Omalizumab binds to the same site on IgE that binds with the high-a nity IgE receptors, or FcεRI, located on mast cells, basophils, and antigen-presenting dendritic cells (Chang et al., 2007). As a result, sweat antigen-IgE complexes are unable to bind to FcεRI, which prevents the cross-linking of FcεRI via the sweat antigen-IgE complexes and thus prevents the granulation of basophils and mast cells (Siraganian, 2004). is inhibition of the degranulation of basophils and mast cells, in turn, prevents the urticarial reaction. However, while the e cacy of omalizumab is high within several studies, the overall collection of literature surrounding the use of omalizumab to treat CU remains mixed regarding its e ectiveness. Omalizumab has also been documented to be ine ective in treating CU within some patients who were H1-antagonist resistant (Sabroe, 2010). us, omalizumab is a potentially e ective treatment for CuSH, but further research must be conducted to identify which populations are most likely to respond positively to it.

d. Idiopathic Cholinergic Urticaria (iCu)

Just as the diagnosis for iCu remain unclear, the treatments options for iCu also remains generic. As mentioned with the previous subtypes of CU, the primary pharmacological treatment for CU is mainly antihistamine drugs, with H1-antagonists being within the primary option of these drugs (Fukunaga et al., 2018). Alongside antihistamine drugs, other common treatments for CU in general also include leukotriene inhibitors (e.g. montelukast) and immunosuppressive drugs (e.g. prednisone). Overall, there is not a single treatment that is universally e ective in all cases of CU (Alsamarai et al., 2012). Similarly, extensive study into all the di erent combinations of antihistamines, anticholinergic drugs, etc. have also revealed that no one combination is e ective for all patients. us, the most comprehensive treatment plan lies within personalization and a trial-and-error process with existing treatments that are e ective for a good portion of the population.

Conclusion

e current literature surrounding CU is relatively sparse given its sizable prevalence across the population. As such, present understanding of the disease’s underlying pathophysiology remains uncertain as well. What is currently understood about CU is that it typically presents in the form of four variants: Cholinergic Urticaria with Poral Occlusion (CuPO), Cholinergic Urticaria with Acquired, Generalized, Hypohidrosis (CuAGH), Cholinergic Urticaria Associated with Sweat Hypersensitivity (CuSH), and Idiopathic Cholinergic Urticaria (iCu). Treatments for each of these types of CU remain generalized. Antihistamine drugs are the most common pharmacological treatments for all subtypes, while systemic steroid therapy and autologous sweat desensitization are prominent treatments for CuAGH and CuSH as well. Overall, further investigation into CU and the e cacy of di erent drugs against CU can help elucidate some of the uncertainty surrounding treatment plans and improve the current understanding of the rst three subtypes of CU, as well as provide insight into the pathophysiology of iCu.

Image 7: A breakdown of how omalizumab, or any Anti-IgE, reduces the severity of the allergic immune response. Omalizumab/ Anti-IgE (antibodies with the dark green heavy chains) bind to free- oating IgE, preventing the IgE from binding to the FcεRI receptors found on mast cells, basophils, and antigenpresenting dendritic cells. is in turn prevents the degranulation of mast cells and basophils, which in turn reduces the urticarial reaction. Additionally, the reduction of IgE bound to FcεRI receptors also leads to the decreased expression of FcεRI receptors on the surface of mast cells, basophils, and antigenpresenting dendritic cells. IgE levels are already the lowest of all the immunoglobulins, so reducing the expression of FcεRI receptors also decreases the chance of capturing free- oating IgE, and thus lowers both the strength and chance of mast cell and basophil degranulation (Rios & Kalesniko , 2015). Lower FcεRI receptor expression could also decrease the quantity of allergen (sweat antigen in the case of CuSH) presented on the surface of antigen-presenting dendritic cells to T cells, which can reduce tissue in ltration by T and B cells, eosinophils, mast cells, and basophils (Segal et al., 2008). Image Source: Segal et al., 2008, Creative Commons License

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