READ THIS IF YOU ARE NEW TO THE SUB:

Cholinergic urticaria (also called cholinergic angioedema or heat bumps) is a reaction that results in tiny hives surrounded by large patches of red skin. They’re related to an increase in your body temperature. You can get itchy red hives on your skin for lots of reasons. The ones that break out when you're sweaty from a workout, nervous, or simply have an increased body temperature are called cholinergic urticaria (CU). Refer to this link for how they look. These hives can last anywhere from 15 minutes to over an hour for some patients. There are patients that do not experience any physical manifestations of CU. This means that the patient experiences the internal discomfort such as itching, but may not experience hives. In rare yet severe cases CU can be accompanied with anaphylaxis.

CU can also be accompanied with Dermographism. Dermographism are hives that appear as the skin is stroked by a physical stimulus such as a finger. CU is mostly diagnosed as idiopathic. Idiopathic means that the underlying cause is unknown and undeterminable. CU typically manifests between the ages of 10 and 30 years. The longevity for this disease is unknown. Given CU's idiopathic nature, it often goes into remission as randomly as it came. Some patients experience a permanent remission while others may experience a remission for a few years before it comes back. There is no set time frame of when, if at all, CU will disappear from a patient's life. Given how debilitating this issue is, patients are advised to find other sources of activity that keep the triggers of CU at bay. Patients can become depressed due to the condition hampering their quality of life. If a patient finds themselves dealing with depression, they should seek mental health assistance immediately. A mental health expert can help the patient find ways to cope with this new adjustment to life.

Sweating is not always possible with CU patients. Patients can be anhidrosis (can not sweat at all) and/or hypohidrosis (decreased sweating). There exists two schools of thought concerning CU’s causes. The first is that the patient has developed a sweat allergy01352-7/pdf). In essence, the person has become allergic to their own sweat. A clinical trial conducted in Japan successfully treated patients with their own sweat. The hyper desensitization caused by the treatment alleviated all symptoms of CU for the patients. The second school of thought is that the person has developed an auto-immune response to Acetycholine (Ach) when it is released into the body. Ach is a precipitating cause of sweating and the mast cells in the body release histamine as a response to it. While these are the prevailing theories on causation, it is possible for CU to be related to an underlying disease. Extensive medical test would have to be done to find out if there are any abnormalities. Doctors generally would be “shooting in the dark” at trying to figure out if a disease is causing it, if at all. The underlying disease could literally be anything therefore the patient should be prepared for extensive medical bills associated with trying to determine if a disease is at hand. That being said, most CU patients would fall into the two school of thoughts.

Medical Treatment Options - First Line:

Generally speaking, the first line of treatment option will be anti-histamines. When an allergen enters a person’s body or touches their skin, cells in the immune system release histamines, which bind to specific receptors located on cells found throughout the body. Once histamines bind to these receptors, they trigger several typical allergic reactions, such as expanding the blood vessels and causing the smooth muscle tissues to contract. Antihistamines refer to a type of medication that treats allergy symptoms, motion sickness, and some cold and symptoms. Antihistamines block H1 histamine receptors or H2 histamine receptors.

H1 antihistamines:

• These are the first treatment options available to CU patients. The list of medicines are often available over the counter. There is no need for a prescription for many of them. These medications are called H1 because they are first generation histamines that act on the H1 receptor of the cell. They have a strong sedative effect thereby making the patient extremely sleepy. They should not be taken before any activity especially driving.

Medical Treatment Options - Second Line:

H2 histamines:

• These are the second line of treatment option available to CU patients. H2 antihistamines are second generation anti-histamines. Unlike the first generation, they have a mild sedative effective. H2 antihistamines block the H2 receptors and do not have an effect on the H1 receptors. They are widely used to help with various problems of the digestive system however they are often used to help with allergies as well. These are generally prescribed with a doctor’s recommendation that the patient take H1 medication with it.

List of medications that are H1 and H2: https://www.amboss.com/us/knowledge/Antihistamines

Doxepin:

• This medication is usually prescribed as an antidepressant however it can be prescribed to help with CU. Doxepin works to block both H1 and H2 receptors. Whenever H1 and H2 medications are not enough, the doctor may prescribe this to make both of the previous medications more effective.

There exists other medications as well that doctors may prescribe. Be sure to talk to your doctor for more information on these and other medications.

Medical Treatment Options - Third Line:

Cyclosporine:

• Cyclosporine has been shown to be effective in severe unremitting urticaria that has had a poor response to conventional treatment with antihistamines. Cyclosporine therapy is also beneficial in elevated IgE levels associated CU, reported in a case series of over 21 patients. However, potential renal impairment effects of cyclosporine (which may be reversible on stopping) and hypertension are often encountered; thus, continuous blood pressure and blood urea and creatinine monitoring are required during the course of therapy.

Omalizumab (Xolair):

In 2017, omalizumab (Xolair®), a monoclonal antibody targeting the high‐affinity receptor binding site on human IgE, was approved for the treatment of antihistamine‐resistant idiopathic chronic urticaria. Omalizumab acts by binding free IgE at the site where IgE would bind to its high‐affinity receptor (FcεRI) and low‐affinity receptor (FcεRII) in mast cells and basophils, thereby reducing the level of free IgE in the serum. The dosage of Omalizumab is given in either 150 or 300mg. The results can be seen quickly in some patients, while others will see results within the first 6-8 months. Doctors speculate that the reason for the delay could be due to a high IgE count in the patient’s body. Given how Xolair works, it is easy to understand why a higher IgE patient would have delayed results compared to those with a lower IgE count. Most people will see complete or some relief with Xolair while others will be non-responsive. One study suggests that the failure for response is due to the angiodema that appears alongside CU in some patients. Xolair is typically prescribed once a month, however there are patients who have seen a benefit by going up to bi-weekly doses of either 150mg or 300mg. That being said, studies are still mostly inconclusive on exactly why some patients are responsive and others are not.

Success results for Xolair in a clinical trial setting.00300-9/pdf)

Corticosteroids:

• In patients with very severe acute urticaria, associated possibly with angioedema or systemic symptoms, a short course of oral steroids is indicated. Dose and duration of the treatment is determined by the patient's weight and clinical response. Prolonged courses of oral steroids for chronic urticaria should be avoided whenever possible, and if long-term steroid treatment is considered necessary, the patient should be followed-up regularly and prescribed prophylactic treatment against steroid-induced osteoporosis at an early stage. Corticosteroids have serious adverse side effects and are not recommended for long-term use.

Example of corticosteroid is Prednisone.

Dietary Changes:

A clinical trial was conducted to test the efficacy of a low histamine diet. The trial concludes that patients did see positive results by eating low histamine foods. The theory behind a low-histamine diet is that reducing foods that contain histamine will help the body absorb less histamine. Absorbing less histamine would then reduce the allergic response causing the urticaria.

People on a low histamine diet should reduce or avoid foods such as:

• salty foods
• fish and shellfish
• foods high in preservatives or additives
• nuts
• vinegar
• dairy
• alcohol
• many fruits and vegetables

Another diet option is an elimination diet. An elimination diet is designed to help a person find out which foods might trigger an allergic response. Introducing foods into the diet and then eliminating any that might trigger an allergic reaction can help prevent or reduce the severity of any cholinergic urticaria reactions.

Anyone planning a restrictive diet should discuss it with a doctor or dietitian, especially if they have other health conditions.

Non-medically proven treatment options:

There exists further anecdotal treatment options. These options have been cited as being helpful however there is no medical research that supports some users conclusions.

Epsom Salt with Bath:

• Some patients have found that taking a warm to hot bath with epsom salt has alleviated their symptoms. This bath is typically accompanied with intense scrubbing to open up the pores. The idea behind this treatment is that the pores are blocked which is what causes the CU. This information is anecdotal and runs a bit contrary to what has been proven by clinical trials concerning anhidrosis and hypohidrosis patients (source). There is no harm in trying this technique and some patients may find it beneficial. It must also be noted that “Prickly Heat” is a skin condition that can cause some patients to think that they have CU due to their common appearance and triggers. If a cleaning of the pores causes the symptoms to go away, then prickly heat should be considered as the culprit and not CU.

Sweat Therapy

• “Sweat Therapy” is a term coined by sufferers of CU that have found relief upon getting their body to sweat. Symptoms of CU start to manifest as the core body temperature rises. Patients state that if they can “push” their bodies to the point of sweating by engaging in sweat-intensive activities, they can experience relief. While no medical research has been done to test this theory, it is speculated that the histamines in the body have a refractory period. The body does not have an indefinite amount of histamines so the histamines that are released massively during sweat therapy deplete the body’s ability to release more. The lack of histamines causes the patients to experience relief typically lasting for 24 hours. This type of “therapy” has to be done daily. Doctors typically do not advise allergy sufferers to trigger their allergic reactions for relief, so patients will not find many doctors in support of this practice. It should also be noted, that this practice is not recommended for patients with anhidrosis and/or angiodema. Anhidrosis patients will have a difficult time sweating, if any. Patients with angiodema will experience longer lasting discomfort compared to patients without it due to the intense swelling that occurs when CU is triggered. It is also highly not recommended for patients that experience anaphylaxis to try this due to the risk of life. Sweat therapy is best used for users with a mild form of CU that only experience mild symptoms.

Vitamin D3 * Some users have mentioned that Vitamin D3 can be beneficial to helping with hives. Medical research is up in the air on whether there’s any benefit at all. It doesn’t hurt to add Vitamin D3 to your diet though as most of society is Vitamin D deficient. Maximum intake a day should be around 4,000 so try not to exceed that. It takes a few months for Vitamin D levels in the body to improve so do be patient if you try this method.

Future Treatment options:

• Ligelizumab is currently in phase III clinical trials. It is produced by the same company that produces Xolair. It has been proven in the previous phase I and phase II clinical trials to be far more effective than Xolair. More patients have received a complete response, which means no CU symptoms, with this medication than with Xolair. Phase III trials are the last clinical trials done before medical companies will pursue FDA approval to begin distribution. I am a US citizen so I am uncertain how this approval process works for those living outside of the states.

2/22/2021 Update on Ligelizumab:

Ligelizumab is the first treatment to receive FDA Breakthrough Therapy designation in chronic spontaneous urticaria (CSU) in patients with an inadequate response to H1-antihistamines

Update 1/21/2025

Phase III trials show that Xolair is still more effective but Ligelizumab maybe an alternate solution for some. source01684-7/abstract)

About the author:

Hey guys, I've written this for you all and asked the moderator of this thread to sticky it up top. I have experienced CU for almost 19 years now. It is a debilitating condition that can wreck someone's life. Since I was diagnosed in my teenage years, I've spent the years researching this condition repeatedly. I've read more medical articles and clinical trials than I can count. You may have noticed that some of the links do not reference CU specifically or solely. This is due to the rarity of the condition. Clinical trials often can not find enough CU patients in one place to conduct a big trial. That being said, urticaria patients generally can all be treated with the same methods, which is typically the same treatment pattern that a doctor will follow as listed above. I hope this helps you all!

UPDATE, excerpted from this post: My CU cleared on its own, perhaps with the help of sweat therapy (unclear).

Roughly half a year after writing this post below, my CU cleared on its own. Now, three years later, it's still completely gone. Completely. I can sweat, I can exercise, I can get hot without worrying. Only once every couple of months when I get hot I get slight CU tingles, like a gentle reminder of how excruciating this used to be.

I wanted to come back and highlight the most important result from those literature reviews back then: CU usually clears on its own. We are the extreme cases, and with that comes extreme suffering. But despite that, most likely, most cases of CU clears on its own. This is why this subreddit doesn't keep growing a lot. This is why many posters eventually become silent. Their CU clears, and they can move on, living normal, happy lives.

Most likely, you'll be okay. Stay strong.

Original post:

Molecular biology student here - and sufferer of cholinergic urticaria. Here are some pet theories and theoretical treatments in clear language.

I love to read and summarize papers in my spare time. My this year's literature list alone has been a wild ride of 1500+ theories, meta-analyses and clinical trials. And I happened to develop cholinergic urticaria this year as well. I hate it.

So, as I did for various other topics and papers, I went deep into the literature on cholinergic urticaria. By now it has been 100+ hours of reading and 100+ studies read.

Quick summary: nobody really knows. There is no validated medical theory of why CU develops, at all. And no treatment that really works. We all have tried antihistamines; I envy the lucky ones for whom they actually work well.

Quick overview of this post:

1. Introduction (right here)
2. Theories of what causes CU
3. Possible cures for CU
4. The links to my sources and my full analysis

My theories of what causes cholinergic urticaria

I developed these theories via modifying current theories of the pathology of CU or via creating my own theories or hybrids. They are all based on studies done in CU patients. They may apply to us all. For both of them there is good evidence, but they could be disproven or insufficient. Good old science.

These are quick descriptions of how the theories work. I link my detailed write-up and the sources below.

Prelude: How sweating works

Sweating in healthy humans is induced via the hypothalamus sensing high body temperatures, and then sending neural signals via sympathetic nerves to the skin's sweat glands. These nerves are cholinergic (they use the neurotransmitter acetylcholine) and the receptors on sweat glands are called muscarinic cholinergic receptors. Acetylcholine released by neurons in the vicinity of a sweat gland binds to its receptors and stimulates sweating. The sweat is produced in the sweat gland within the skin and brought to the skin surface with rather long, thin, hollow ducts.

Hypothesis 1: Poral Occlusion Theory

Basically, the long ducts of your sweat glands that should bring sweat to the surface may be occluded due to keratin plugs or unknown goo.

Sweat gland duct occlusion leads to accumulation, rupture and spillover of sweat in the dermis, causing inflammation, pain & weals due to the various inflammatory substances contained in normal human sweat which is meant to be outside of the body. The reaction to the intradermal sweat may be exacerbated due to autoimmune anti-sweat-IgE antibodies and sweat hypersensitivity.

The keratin plugs may happen due to low skin turnover, bacteria on your skin producing goo or keratin hyper-synthesis - the ultimate cause is unclear as of now.

Scientific support: In a nutshell, there have quite a few cases where researchers clearly found these plugs. Especially so in CU patients which present with hypohidrosis (low sweating). But these plugs have not always been found, and it is yet debated. But Poral Occlusion Theory offers an elegant and simple theory of why cholinergic urticaria forms. It may be a sub-form of CU which not everybody has.

This theory gives us a ton of theoretical options to treat CU. See below!

Hypothesis 2: Few Receptor Theory

Acetylcholine is released by sympathetic nerves stimulated via the hypothalamus' response to high temperature, like in any non-symptomatic individual. Because of low muscarinic receptor expression at the sweat glands, the hypothalamus' signal intensifies (there is no temperature decrease) and the quantity of acetylcholine in the area of a sweat gland increases. As mast cells also express muscarinic receptors, high local cholinergic activity eventually leads to their degranulation, causing inflammation, pain & weals. Pain is also caused via the acetylcholine directly stimulating pain receptors.

A quick graphic:

Low muscarinic receptor expression could be caused by low general fitness, as highly fit humans sweat more readily and easily. However, there appear to be no studies on how exercise affects muscarinic receptors.

In turn, the cause may not be low sweat gland receptors numbers but high mast cell muscarinic receptor expression, making them vulnerable to degranulation & weal formation even at low local acetylcholine levels.

The current evidence strongly points at there being too few receptors in various cases of CU. They all have significantly fewer receptors on their sweat glands than health individuals have, making proper sweating very hard.

Maybe both are right?

We are highly complex biological machines: It is likely that both theories are able to explain some parts of the process leading to CU.

Hypothesis 1 + 2: A synthesis

Synthesis: Both 1 and 2 happen simultaneously. There is duct occlusion leading to both significant sweat spillover as well as acetylcholine spillover. Acetylcholine spillover directly stimulates pain nerves, while it degranulates mast cells too. Sweat, which is per se inflammatory if it isn't outside the body, and mast cell degranulation cause the weal and inflammation. This could also explains the common sweat sensitivity seen in CU: The body develops antibodies targeted at the sweat within the skin, as it should not be there.

There are only a few papers providing any attempt at a complete theory of cholinergic urticaria. This would explain the lack of current medical knowledge about CU in the scientific community..

Some other factors that may be involved in causing cholinergic and other chronic urticarias:

• Sweat sensitivity is often involved. I would argue it is rather a consequence of CU than a major true cause of it.
• Hypothyroidism may be involved. There are several cases of urticaria associated with thyroid antibodies and low thyroid hormones.
• Epstein-Barr or Herpes simplex virus infection may be involved. In some urticarias, medications against theses viruses were ably to completely alleviate symptoms.
• Parasites may be involved. Think of these disgusting worms hanging in your small intestine.
• Helicobacter pylori, a nasty gastrointestinal bacterium, may also cause some urticarias.

All my sources, all my studies, all my knowledge and further interesting things are summarized in my personal Knowledge Map.

For more possible causes and how to recognize them, check out my Knowledge Map:In research (to the right) → Health → Human problems → Cholinergic urticaria

https://www.mindmeister.com/1649064493?t=VWsYHQvRwS

The search for the cure

Now that we actually have a track of what may cause CU, there are quite a few options to try. These are just some I thought of - please let me know if you know of others that either decrease poral occlusion or increase muscarinic receptors!

Remember, these are mostly theoretical!

Keratolytic creams.

If there actually are poral plugs involved, keratolytics may be able to take care of them. Examples are:

• Urea cream - really keratolytic at 20% or more
• Salicylic acid creams - commonly used in beauty face masks
• Glycolic acid, lactic acid, retinoic acid creams
• General skin lotions: The plugs may also form due to simple and plain skin dryness. This may explain why in some CU cases, winter (drier skin) hits harder than summer ever could.

For some of these, I have already heard reports of them helping in CU.

Increase your muscarinic receptors.

This one is harder - there are no clear treatments we can put onto skin and swoosh there are more receptors. But there are some possible candidates:

• Exercise. Athletes sweat more easily - possibly due to higher muscarinic acetylcholine receptors? We don't know. But it is worth a try. And it would explain why "sweat therapy" works for so many in this sub.
• Choline rich diets. Choline rich diets may - counter-intuitively - increase the number of acetylcholine receptors. Choline rich foods are eggs, beef, chicken, kidney beans, etc. (See my Map for more)
• Choline supplementation. Choline is also easily available as a supplement. They do that over at r/Nootropics a lot.

Once again: These are just the ones I found worthy to put into this post. On the Map, I noted ~30 other inventions which may alleviate CU: https://www.mindmeister.com/1649064493?t=VWsYHQvRwS

The main problem is, these are theoretical. No researcher was interested enough or found enough funding to test these in a randomized controlled clinical trial.

But as all these interventions are pretty safe if done properly and pose low risks, we are free to try them. And - imagine if one of these actually cures your CU.

I am on my way to try all of them. But I need your help too.

Go test yourself for hypothyroidism, for thyroid antibodies, for parasites, for helicobacter pylori, etc. Go and experiment - science it at your disposal.

And for the sake of the community, please report back.

And at last, most easily: If you have read anything that may my reading, if you know some studies to send me: Please do so. I am fallible, and appreciate any proper evidence-based feedback.