14 March, 2018

Rosacea Bulletin Board; Latest news on rosacea treatments

March 15th 2018

New class of menopause drugs reduces severity of hot flushes in three days

A new class of experimental drugs reduces hot flushes in menopausal women by almost three-quarters in just three days. The treatment, tested by scientists at Imperial College London, also reduces the severity of hot flushes by over a third within three days of taking it. The research, funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR), is a new in-depth analysis of data collected from a clinical trial initially published last year.

This class of new drugs may provide women with a much-needed alternative to HRT, but it could also be an interesting new treatment on the horizon for people with vascular rosacea and facial flushing. Other medication aimed at reducing the severity of hot flashes (for instance clonidine, mirtazapine, other SSRI-antidepressants and certain beta blockers) all are prescribed by various dermatologists to try to curb facial flushing, a difficult to treat rosacea symptom.

The original drug trial, which was a randomised, double-blind, placebo-controlled trial, involved 37 menopausal women aged between 40 and 62 years old – and who experienced seven or more hot flushes a day. Participants were randomly chosen to first receive either an 80mg daily dose of the drug, called MLE4901 (which was previously developed as a drug for schizophrenia) or a placebo over the course of a four-week period. They then switched to receive the other tablet for an additional four weeks. This ensured the women acted as their own controls during the study, and the effects of the drug were clear. The researchers found that the compound MLE4901 significantly reduced the average total number of flushes during the four-week treatment period, as well as their severity, compared to when the patients received the placebo for four weeks.

The new experimental compounds are thought to work by blocking the action of a brain chemical called neurokinin B (NKB). Previous animal and human trials have shown increased levels of NKB may trigger hot flushes. The drug compound is thought to prevent NKB activating temperature control areas within the brain – which appears to halt hot flushes.

The new data also revealed that the drug was as effective at improving daytime flush symptoms as it was at improving night time symptoms. Furthermore, the women reported a 82 percent decrease in the amount their hot flushes interrupted their sleep, and a 77 percent reduction in interruption to their concentration.

Dr Julia Prague, first author of the study, explained: “As NKB has many targets of action within the brain the potential for this drug class to really improve many of the symptoms of the menopause, such as hot flushes, difficulty sleeping, weight gain, and poor concentration, is huge. To see the lives of our participants change so dramatically and so quickly was so exciting, and suggests great promise for the future of this new type of treatment.”

The new analysis shows the compound has a significant effect within just three days explains
Professor Waljit Dhillo, an NIHR Research Professor from the Department of Medicine at Imperial: “We already knew this compound could be a game-changer for menopausal women, and get rid of three-quarters of their hot flushes in four weeks. But this new analysis confirms the beneficial effect is obtained very quickly – within just three days.” Professor Dhillo explains this specific compound will not be taken further in trials, due to side effects that may affect liver function. However, two very similar drugs, which also block NKB but do not appear to carry these side effects have entered larger patient trials, with one such trial launched in the US last year.

The research was funded by the Medical Research Council and the National Institute for Health Research. The study was supported by the Imperial NIHR/Wellcome Trust Clinical Research Facility.

September 12th 2017

Stanford University has started clinical trials for Secukinumab, used to treat rosacea. It is an open label study to assess the effect of Secukinumab in moderate to severe papulopustular rosacea. However hopes are that it will also address rosacea redness and inflammation. Test participants receive injections of secukinumab. First impressions from one rosacea patient who is undergoing these tests were: "Redness was almost completely gone by Saturday afternoon. [one day post injection]. The doctor says full results are shown anywhere from 12 to 16 weeks."

Update from this rosacea patient, September 29th 2017: "Secukinumab update: So this thing has really worked immensely. My redness is gone and I'm going back to Stanford medical center to get my 5th dosage. I'd recommend everyone in this group if you can get there, to do so. So you can finally rid yourself of this disease."

Secukinumab is a "human IgG1κ monoclonal antibody" that binds to the protein interleukin (IL)-17A. It is injected once weekly for four weeks (or around 5 booster shots) and then once a month for 5 months. It works a bit like methotrexate; suppressing the immune response and inflammation. Secukinumab lowers the bodies immune response and is used to treat auto immune diseases like psoriasis and related inflammation in the joints (artritis psoriatica). In psoriasis the bodies immune system goes in overdrive, and multiplies the skin cells too quickly, causing plaques of skin, inflammation and scaling and ultimately a lot of skin cell shedding. By lowering the immune system response, the skin symptoms can be calmed down too. Rosacea does not have an issue usually with increased skin cell formation, but some scientists do think that rosacea can be an auto immune disease as well, having the bodies own immune system attacking normal tissue and as such creating inflammation and redness.

I know of some severe rosacea sufferers who were given methotrexate and who had their skin issues (redness, flushing) calm down significantly. Side effects can be significant however, increased risk of infections (viral infections, nose and throat infections, sinus infections and other infections) and it even raises the risk of certain cancers. That is generally the downside of methotrexate. Luckily Secukinumab does not seem to come with an increased risk of cancer. Several studies show that secukinumab demonstrates "a highly favorable safety profile, especially compared with commonly used psoriasis treatments such as methotrexate and TNF-α blockers. More specifically, secukinumab carries no increased risks for end-organ toxicities, serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and nonmelanoma skin cancer."

So despite of secukinumab being somewhat comparable to methotrexate, a drug that lowers (auto)immune response and inflammation as well, it comes with far less severe side effect risks. On January 21, 2015, the FDA announced that it had approved secukinumab to treat adults with moderate-to-severe plaque psoriasis, followed later with the approval for the treatment of ankylosing spondylitis, and psoriatic arthritis. A 2016 study also showed that secukinumab seems to be effective in the treatment of multiple sclerosis.

I am a bit hopeful for this new trial! I know that my dermatologist treated some very severe rosacea patients with methotrexate for a little while, and their skin really cleared up (also through suppressed immune response and inflammation), but that the increased risk of infections was too tricky. Since secukinumab does not have that side effect profile as much, it seems a great alternative.

Open Label Study to Assess the Effect of Secukinumab in Moderate to Severe 
Papulopustular Rosacea 
This study is currently recruiting participants.

Verified July 2017 by Anne Chang, Stanford University
Information provided by (Responsible Party):
Anne Chang, Stanford University
ClinicalTrials.gov Identifier:
First received: March 9, 2017
Last updated: July 11, 2017
Last verified: July 2017

This is a study to determine whether secukinumab is a potential therapy for those with papulopustular rosacea. We will observe whether this drug decreases the size and/or amount and severity of the pustules of those who suffer from rosacea.

Papulopustular RosaceaDrug: SecukinumabPhase 1Phase 2

Study Type:Interventional
Study Design:Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title:An Open Label Phase 1b Study of Secukinumab in Patients With Moderate to Severe Papulopustular Rosacea

Further study details as provided by Anne Chang, Stanford University:

Primary Outcome Measures:
  • number of papules/pustules on rosacea patients at week 16 vs 0 [ Time Frame: 16 weeks ]
    Comparison of number of papules/pustules at 16 weeks compared to 0 weeks

Secondary Outcome Measures:
  • reduction in the number of papules and/or pustules in moderate to severe papulopustular rosacea at week 12 vs 0 [ Time Frame: 12 weeks ]
    Compare number of papules/pustules at 12 weeks compared to 0 weeks
  • reduction of the overall severity of rosacea by global assessment [ Time Frame: 16 weeks ]
    comparing week 16 and 0, includes clinical and patient reported symptoms
  • reduction of erythema in patients with moderate to severe papulopustular rosacea [ Time Frame: 16 weeks ]
    comparing week 16 to 0
  • improved quality of life measures in patients with moderate to severe papulopustular rosacea [ Time Frame: 16 weeks ]
    by patient questionnaire
  • assess adverse events ≥ grade 3 in patients taking secukinumab for moderate to severe papulopustular rosacea [ Time Frame: 16 weeks ]
    frequency and severity of adverse events will be recorded throughout the study by CTCAE version 4.0
  • changes in immune infiltrate in papulopustular rosacea lesions after secukinumab use [ Time Frame: 16 weeks ]
    assess by immunohistochemistry at 16 weeks versus 0 weeks

Estimated Enrollment:24
Anticipated Study Start Date:July 14, 2017
Estimated Study Completion Date:January 1, 2019
Estimated Primary Completion Date:July 1, 2018 (Final data collection date for primary outcome measure)
ArmsAssigned Interventions
Experimental: secukinumab arm
This is an open label study without placebo and it is a single arm study
Drug: Secukinumab
We will be giving secukinumab to patients with papulopustular rosacea

Detailed Description:
Rosacea is a common inflammatory skin disease affecting up to 10% of adults. Despite this, the etiology of rosacea is unclear, although there may be a genetic predisposition (Chang et al., 2015). Currently, there is no cure. Rosacea can lead to scarring, itching, burning, and is associated with anxiety and depression (Moustafa et al., 2015), significantly affecting quality of life.
Secukinumab is an antibody that binds to a protein (interleukin (IL)-17A) that is involved in inflammation. When IL-17A is bound to secukinumab, it cannot bind to its receptor, thereby inhibiting its ability to feed the inflammatory response. In clinical trials, secukinumab has been effective for moderate to severe psoriasis (Blauvelt et al., 2015). Recently, human data from all types of rosacea have shown Th1/Th17 polarization profile of the T-cell response, suggesting that anti-IL-17 therapy may be beneficial for rosacea (Buhl et al., 2015). Hence, secukinumab could be effective against rosacea. This proposal is a proof-of-concept study to use secukinumab in open label design for moderate to severe papulopustular rosacea.

Ages Eligible for Study:  18 Years and older   (Adult, Senior)
Sexes Eligible for Study:  All
Accepts Healthy Volunteers:  No
Inclusion Criteria:
  • 1) moderate to severe papulopustular rosacea defined clinically using the grading system of Wilkin et al. (2004) as having at least ten lesions (either papules or pustules) on face at time of enrollment 2) age 18 years or greater willing and able to understand and sign informed consent form
Exclusion Criteria:
  • 1) known hypersensitivity to secukinumab 2) topical or oral anti-rosacea medication usage for 28 days prior to enrollment 3) active Crohn's disease, as secukinumab may exacerbate this disease 4) active infection including tuberculosis, hepatitis B or C, human immunodeficiency virus 5) participants with latent tuberculosis will need to have treatment initiated prior to starting study drug 6) pregnant or lactating 7) active and/or uncontrolled medical conditions that may interfere with study procedures or obscure rosacea assessment such as cutaneous lupus 8) use of retinoids within past 3 months of enrollment 9) use of antibiotics within 4 weeks of enrollment 10) use of light based or laser treatment to face within 8 weeks of enrollment 11) use of topical or systemic steroids within 4 weeks of enrollment 12) acne conglobate, acne fulminans, chloracne, severe acne requiring systemic treatment
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03079531

Contact: Anne S Chang, MD650 721-7151alschang@stanford.edu
Contact: Michaella Montana, BS650 721 7195mmontana@stanford.edu

United States, California
Stanford DermatologyRecruiting
Redwood City, CaliforniaUnited States, 94603
Contact: Anne Chang, MD    650-721-7151    alschang@stanford.edu   
Contact: Michaella Montana, BS    650 721 7159    mmontana@stanford.edu   
Sponsors and Collaborators
Anne Chang
Principal Investigator:Anne Chang, MDStanford University
Additional relevant MeSH terms:
Skin Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 11, 2017

Anti-CGRP migraine drugs for rosacea treatment 

I've read recently that several companies are busy with clinical trials for a new migraine treatment with anti CGRP drugs, with positive results. These drugs are geared for migraine, but the way in which they work (their aim is to constrict blood vessels), makes them also exciting and possible future treatment options for rosacea.

From Science magazine: "Four pharmaceutical companies are racing to complete advanced clinical trials of antibodies that either neutralize CGRP by binding to it, or block its receptor. So far, the data suggest the drugs work faster, for longer, and better than anything currently available. Most striking, is a subset of “superresponders,” whose attacks appear to cease entirely for 6 months after a single injection of a CGRP-blocking antibody."

CGRP is a 37–amino acid (neuro)peptide that is released by the nervous system and is a very potent blood vessel dilator. When released from the trigeminovascular nerves, CGRP is a powerful vasodilator of the blood vessels of the brain.

Medication that was designed to block CGRP’s receptor turned out to have too many side effects. Then researchers focused on antibodies to block CGRP, because they can last a long time in the body and can be exceptionally specific, reducing the frequency with which people need injections. many colleagues didn't think it was worth a shot, because antibodies are generally too large to pass through the blood-brain barrier, and it was thought to be necessary for migraine meds to target migraines actually in the brain. However, to their surprise, the CGRP peptide-blocking antibody "TEV-48125" managed to just do this; treating migraines from outside the brain, by blocking CGRP only in the peripheral nervous system. Trials show significant reductions in number of headache days over placebo, even for the most severe cases. This type of drug also lowers the risk of the side effects often provoked by drugs that act in the brain. Although there are still worries too, because of CGRP’s natural role in dilating arteries and maintaining blood supply to the heart and brain. “Theoretically, if you block CGRP you could translate a minor stroke or cardiac ischemia … into a full blown stroke or heart attack.” So far, the companies say they haven’t seen that or other significant side effects in the several thousand people who have completed phase I and II trials, but the drugs have only been administered for up to 6 months—not long enough to judge long-term effects.

CGRP-blocking drugs are also tested now for fibromyalgia, a condition that is somewhat overlapping in some symptoms with rosacea. And scientists have also discovered that CGRP plays a role in rosacea flushing and skin redness. Interestingly, migraine medication has so far been helping some people with rosacea. Drugs like propranolol, imitrex/sumatriptan and even botox have all been helpful for rosacea. Someone on the Rosacea Forum is successfully using the migraine med Maxalt/Rizatriptan for her severe type 1 rosacea/erythromelalgia.

Stress, rosacea flares and CGRP
CGRP is also part of the puzzle as to why stress can make rosacea flare so badly. Apart from stress raising blood pressure and inflammatory substances, experiments in rats now showed that corticotropin-releasing hormone, which the body releases in response to stress, also increases neuronal production of CGRP. More CGRP means much more blood vessel dilation, which causes our rosacea flares (for those with burning, flushing and redness). Strikingly, many migraine medications also boost CGRP in animal models, possibly explaining why people who use drugs like triptans too frequently end up with more severe migraines.

CGRP antagonistic treatment options for Rosacea

I hope that we can soon benefit from injections of this CGRP peptide-blocking antibody "TEV-48125". Those medications are in the making now, from what I read, so it might take a bit more time before they come on the market. In the meantime, scientists are also working on a topical cream that works in a similar way, blocking CGRP. patent is created for a special cream for rosacea patients to do just that. 'Therapeutic/cosmetic compositions comprising CGRP antagonists for treating skin redness/rosacea/discreet erythema.'

But they are not just focusing on a CGRP blocker: "Skin redness, rosacea and/or discreet erythema afflicting a mammalian, notably human patient, are therapeutically treated by administrating to such patient a therapeutically/cosmetically effective amount of at least one CGRP antagonist, advantageously in combinatory immixture with at least one antagonist of a neuropeptide other than CGRP, e.g., a substance P antagonist, and/or at least one inflammation mediator antagonist."

So this patent for a new cream will focus on three different things;
*blocking CGRP (and thus blocking one factor that leads to blood vessel dilation in our faces)
*blocking P antagonist
*blocking an inflammation mediator in the skin

CGRP is a polypeptide chemical species that is produced and released by nerve endings. CGRP dilates blood vessels and is involved in lung issues and inflammatory diseases, in allergic diseases and in certain skin diseases such as eczema and prurigo. It is a new concept to treat skin redness with a CGRP antagonist. But developers now think that CGRP blocking substances can not only treat skin redness, but also prevent it from occurring.

Blocking CGRP in the skin of our faces, through a cream, should help combat skin redness and flushing. This will be tested on test persons with rosacea, by first inducing a flush (with a substance called capsaicin), and then applying the cream and seeing if the redness can be toned down by it. They will test if the levels of CGRP that is released (and that cause blood vessel dilation), will be reduced upon measuring. Secondly, P antagonist will have to be another type of antagonist of a neuropeptide used, reinforcing the CGRP antagonist. A third ingredient will have to reduce inflammation in the skin (and they will select it from a group consisting of histamine antagonists, interleukin 1 antagonists, and tumor necrosis factor alpha antagonists, and the inflammation mediator antagonist is supposed to be a diethylenediamine, aminopropane or phenothiazine compound, selected from a group consisting of cinnarizine, cyclizine, dexchlorpheniramine, triprolidine, alimemazine, promethazine, auranofin, lisophyline, A802715, sulfasalazine, cetirizine hydrochloride, loratidine, esbatine, and setastine hydrochloride).

The patent described rosacea as follows:  
"Rosacea is a skin affliction characterized by erythema (redness) of the face, predominantly on the cheeks, the forehead and the nose, hyperseborrhoea (thickened skin) of the face on the forehead, the nose and the cheeks, and an infectious component manifesting acneiform pustules (skin outbreaks and bumps). Moreover, these indications are associated with a neurogenic component, namely, a cutaneous hyperreactivity of the skin of the face and of the neck (nerve burning), characterized by the appearance of redness and subjective sensations of the itching or pruritus type (skin itching), sensations of burning or of heating, sensations of stinging, tingling, discomfort, tightness, etc.

These signs of hyperreactivity may be triggered by very varied factors such as the intake of food or of hot or alcoholic drinks, by rapid temperature variations, by heat and in particular exposure to ultraviolet or to infrared irradiation, by a low relative humidity (dry air), by exposure of the skin to strong winds or to currents of air (conditioned air, fans and blowing machines), by the application of surfactants (soaps, washing detergents), irritant dermatological topical agents (retinoids, benzoyl peroxide, alpha-hydroxy acids, etc.), or the use of certain cosmetics, even when these are themselves not recognized as being particularly irritating.

Hitherto, the mechanism for triggering these indications was very poorly understood and rosacea was treated with active agents such as anti-seborrhoeic agents and anti-infection agents, for example benzoyl peroxide, retinoic acid, metronidazole or cyclins, which act on infection and hyperseborrhoea but do not permit the neurogenic component of this affliction, and in particular hyperreactivity of the skin and redness, to be treated.
Similarly, hitherto no treatment existed for the redness which develops in discreet erythema. This latter affliction occurs at times of emotion and is characterized by redness of the face and neckline, which possibly may be accompanied by pruritus (itching). This condition is very irritating for individuals suffering therefrom, and to date it could only be treated by beta-blockers, powerful drugs used for treating hypertension and exhibiting many contraindications.
Thus, serious need continues to exist in this art for an effective treatment of skin redness and of the state of hyperreactivity of skin affected by rosacea or discreet erythema."

The patent acknowledges that their invention does not necessarily have to be applied through a cream on top of the skin: it is also possible to inject the CGRP antagonist into the skin, or even to take pills to achieve the same effect. They aim for a acceptable cream carrier, but the problem with most creams is that they contain alcohols (they help the active ingredient to penetrate deeper into the skin) and preservatives (parabens for instance, which are skin irritants). And some companies even put propylene glycol and plastic elements into their creams, which make them pretty much unusable for those with hyper reactive, intolerant rosacea skin. In the examples for cream ingredients that are mentioned in the patent itself, the list seems fairly OK to be honest, the only ingredients I wouldn't tolerate myself (but my skin is sickly reactive) are sunflower oil (12%), stearic acid, fragrance (if they are smart they leave that one out!) and preservatives.

CGRP and Rosacea

Rosacea is a common skin disorder that is not yet fully understood. It has been suggested that it is linked to interactions between nerves and blood vessels, which release inflammatory substances, but also specific neuropeptides, which cause the blood vessels in our skin to dilate. This is probably especially the case in rosacea subtype 1, with flushing, redness of the skin and burning (and less in subtype 2 with pimples and skin outbreaks). These specific neurotransmitters are easily triggered to be released, for instance by stress, ultra-violet light or microbial antigens. And when they are released, they trigger flushing and redness for us.

When you flush from heat or temperature changes, it are primary sensory neurons that stimulate the blood vessels to dilate and to release inflammatory neuropeptides. These neuropeptides play a very important role in rosacea. For example, flushing has been suggested to be controlled by two vasodilatory mechanisms including humoral substances and neuronal stimuli (Wilkin, 1988), but the exact mechanism of action is unknown. Although scientists learn increasingly more over time about how sensory nerve endings are activated to release vasoactive neuropeptides during flushing, which also triggers the inflammatory process in different stages of rosacea. Specific TRP Channels are involved in this.

Capsaicin receptor
This newly discovered TRP channel receptor family is currently composed of 28 channels with seven subfamilies. They sit on neuronal and non-neuronal tissues all over the body. One in particular is interesting for rosacea, as it is singe handedly capable to cause a lot of blood vessel dilation. It is called vanilloid 1 (TRPV1), also known as the “capsaicin receptor”. It has many functions, including as a censor in cells, signalling pain sensations and inflammation. This receptor responds to a lot of triggers, including heat, cold temperatures, touch and changes in the cell membrane.
The image left shows the structure and activators "capsaicin receptor" (TRPV1), as well as ankyrin 1 (TRPA1) receptors in primary sensory neurons with a link to rosacea. Both receptors have a similar structure and can be activated by temperature increases or for instance by spicy food. TRPA1 can be activated by reactive oxygen species (ROS; they are chemically reactive chemical species containing oxygen. They are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cells. But during times of environmental stress, for instance when exposed to UV radiation or heat, ROS levels can increase dramatically). And when activated, TRPA1 will signal for signal blood vessel widening. When this happens, mediators, such as proteases, are released, and they create inflammation. It is thought that these two, TRPV1 and TRPA1, have an interaction with each other, that regulates their activity.

TRP Channels as Thermosensors in Rosacea?
Both TRPA1 and TRPV1 channels are triggered by heat and temperature increase. It is no surprise probably that 53% of rosacea patients stated in polls that hot and cold weather are triggers for their rosacea. Very cold temperatures can also directly activate TRPA1 channels. Perhaps TRPA1 is a “cold sensor” channel. Another TRP channel (melastin) TRPM8 is also activated at temperatures below ∼23 °C. So when you are hypersensitive for the cold, it is most likely this TRPA1 channel deep in your body cells, that is responsible! (Just so you know how to blame haha). Anyway, the cold can also cause inflammation in rosacea skin.

But heat is just as much a trigger for rosacea. Heat, sun, hot baths; they all dilate out blood vessels as our body temperature rises. And rosacea skin already is a little bit warmer than 'normal' skin temperature. When the temperature rises quickly, even in healthy people, our cells produce TRPV1
Therefore TRPV1 channels have an essential role in temperature hypersensitivity when it comes to inflammation. And on top of all this, rosacea facial skin has shown to have a significantly lower heat pain threshold compared to the rest of our skin. Our faces notice heat quicker and develop painful skin much quicker (tingling, burning, prickling, blushing, pain) when we are in a warm surrounding than the rest of our bodies skin. I think everyone had detected that for him or herself already anyway :) And again, our little friend TRPV1 seems to be involved in this. The same goes for flushing after eating spices TRPV1 is dubbed the "capsaicin receptor", because it is directly activated when someone eats capsaicin, which is the chemical that makes chilli peppers so hot. The same happened in trials with mice; capsaicin also stimulates an increase in mouse skin blood flow, which shows that this blood flow increase is triggered ultimately by TRPA1 stimulation.
TRPA1 is triggered by cinnamaldehyde, the main ingredient of cinnamon, which also leads to intense and acute painful burning sensation. This is even the case by those who do not have rosacea, and the burning they can feel from this is probably similar to that observed in rosacea.
These findings highlight that TRPA1 and TRPV1 may be activated by the triggers of rosacea, such as cold or hot temperatures and spices, to mediate flushing or burning sensation episodes of rosacea.

Another aspect that makes rosacea skin burn and flush, is blood flow. Flushing longer than 10 minutes is indicative for rosacea (and therefore 'not normal' for normal skin). The smallest systems of blood vessels in our body are dilated in rosacea patients. TRPA1 is also here a factor. It sits in the basal layer of the epidermis, in the dermis, and in the epithelium of the hair follicle, so basically all throughout our skin. And when this TRPA1 is activated (for instance through heat, cold, stress, spices), a substance called "proinflammatory cytokine IL-1" is released, which is a key contributor to skin inflammation. Our skin actually recovers from such a TRPA1 triggered rosacea attack, by exposing our skin to cold air.

Apart from more blood flow in the skin, rosacea patients in studies also showed heightened sympathetic nerve activity compared to those without rosacea. The sympathetic nervous system is a part of the body’s autonomic nervous system that controls involuntary functions such as heart rate, digestion, breathing and perspiration. This portion of the autonomic nervous system functions largely below the level of consciousness and has been shown to respond to emotion.

Substance P and CGRP in Rosacea
So, studies have shown that activation of TRPV1 (by capsaicin) and TRPA1 (by mustard oil) caused the release of neuropeptides. Normal human skin that was rubbed in with a cream containing capsaicin, showed a big red flare. But, this flare could then controlled again by a specific TRPV1 antagonist, SB705498.

And there is also a new oral CGRP antagonist, telcagepant, which also managed to bring down a capsaicin-induced flushed skin reaction.
Ultimately, what makes our skin flare, is not TRPV1, but another chemical, that is triggered by TRPV1: called CGRP. CGRP is one of the strongest blood vessel dilators in the skin. And to make matters worse, it makes sure that your skin also has increased inflammatory substances as a result of all this extra blood flow going around. The neuropeptide SP is elevated in rosacea skin. They linger around the dilated blood vessels. Research showed that laser treatment reduced facial sensitivity, sensory nerve marker, and SP-positive nerve fibers in the skin of 31 rosacea patients. And there is also evidence that SP can also induce skin redness. When rosacea patients have an inflammatory flare, and biopsies are taken from their skin, scientists tend to find widely dilated blood vessels in the skin. SP might play a role in all this, as SP can stimulate mast cells to release histamine and 5-hydroxytryptamine. These mediators bind to histamine H1 receptors and serotonin 5-hydroxytryptamine-1 receptors, and as such they cause blood vessel dilation through the nerves of the skin. CGRP can make matters worse then, by forming skin redness. It is therefore a whole cluster of substances that work together to fire up a flare for us: CGRP creates blood vessel dilation and SP triggers skin redness, histamine release and inflammation, and they even strengthen each others powers by blocking degradation of each other by the body.

Proteases in Rosacea
It is also known that protease activity is higher in the facial skin of rosacea patients, and that antibiotics such as tetracyclines can indirectly inhibit (control) these proteases. Proteases also degrade elastin and collagen, which means your skin becomes less firm and strong and is not beneficial for the lymphatic system in your skin. They also indirectly increase inflammation in the skin, by stimulating the release of SP and CGRP.

And then in the last place, there is Reactive Oxygen Species (ROS), which also seems to play a role in rosacea. Substance P can cause their release. There is evidence in the literature suggesting that inflammation in the early stage of rosacea may be linked with ROS such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, which are released by inflammatory cells such as neutrophils. The level of ROS was significantly higher in the facial skin of patients with rosacea compared with healthy control subjects, OR of the same rosacea patients after being treated with the antibiotic azithromycin. ROS is involved in microbicidal activity. Studies have shown that cathelicidin, a potent inflammatory peptide, is upregulated in rosacea. Cathelicidin can stimulate ROS, which plays a role in inflammation. And ROS is in turn again linked to TRPV1 receptor activation, which dilates our blood vessels and increases blood flow in the skin. It is a rosacea avalanche, in other words, when all working and activating each other together. And this is another reason why rosacea should be treated as soon as possible and controlled.

So in summary, TRPV1 and TRPA1 may contribute to the development of rosacea. The high skin reactivity of rosacea skin can be blamed on TRPA1 and TRPV1 receptors. When they are activated, they create blood vessel dilating substances such as CGRP and SP, as well as inflammation, which may further aggravate the symptoms of rosacea. They work together and strengthen each others actions.
All the more reason to be very excited about this new treatment option; blocking of the neuropeptide-driven inflammatory processes resulting from activation of TRPV1 and TRPA1 receptors. This could become a completely new therapeutic approach to treating rosacea.

 August 2017

My dermatologist told about a cream that really seems promising for rosacea skin. Some patients reported very good success with a mix of 0,5% ketamine with 1% amitriptyline in a cream base.. You use it topically and it apparently pales the skin. It also helps (more officially) with erythromelalgia, a health condition that also involves a deep red flushing and burned red skin of the legs, arms, chest etc. The cream has to be made by a compounding pharmacist. My doctor is looking for one right now, willing to make it, as it's not a commercial cream yet.

Here is some more information on this cream:

Deansm wrote on December 2nd, 2016: "Cleared up my type 1 Rosacea (flushing red nose).
I have had flushing and swelling (caused by the flushing) on my nose for around 7 years (no pustules or pastules). Tried antibiotics, Soolantra, metrogel etc, nothing worked, every treatment has had absolutely zero effect. Two months ago the GP I am seeing prescribed me an ointment containing Ketamine 0.5% and Amitriptyline 1%. Withing 3 days of using it twice a day the flushing disappeared and my skin is white, the same as it was before Rosacea. It has been the same ever since for the last two months. I can eat, exercise, go out in the sun and nothing will bring on a flush. If anyone has this subtype and nothing has worked have a look into this, I have no side affects(the GP said it is very safe as the amount of active ingredients is too low and it's not absorbed systemically). I am not sure which or if both of the ingredients are working. I have since learned that topical Ketamine behaves as an anti-inflammatory by acting on Toll-like receptor (TLRs), which leads to down regulation of pro-inflammatory gene expression."


"The packaging has no branding, it was made in a compounding pharmacy. He said he has found it helpful going back years for patients with Erythromelalgia and it was worth trying for my Rosacea as nothing else worked."

Hg24 wrote on December 3rd, 2016: "This is really interesting, Dean. I googled and found reference to a study about this topical for erythromelalgia. The ointment seems to be for the pain (versus redness). I have type 1 rosacea, too. Flushing and permanent redness. Dean, you mentioned that your skin color is back to normal (pre-rosacea). So did you also have permanent redness? Or just the redness that comes on temporarily when you flushed?  I guess I'm wondering if the ointment returned your vessels to normal - constricted them back. I wonder if the ingredients work because they address nerve pain. Nerves can stimulate our flushing. Eg, nerves release acetylcholine, a chemical that tells our vessels to dialate."

Deansm wrote on December 3rd, 2016: "I'm from Wales, I don't see any reason why it could not be prescribed in the other UK countries (The only problem I can think of is Scotland/Wales/England having separate devolved NHS bodies and rules etc). It probably is completely up to the GP, how many treatments you have already tried etc. He told me the ointment reduced redness and flushing on patients with Erythromelalgia(no idea what this was). I never expected this to work as every other treatment he presvribed (Soolantra, Antibiotics, Metrogel) has either done nothing or even made my Rosacea worse.
My Rosacea started (I was 24) as a sudden huge flareup (huge flushing episode) on my nose when I went to bed one night. I had never blushed or flushed on my nose before that first flareup.
Ever since every night without fail I would have a flareup when I went to bed. Through the day I had one or two flareups and my nose was sensitive to flushing but not as bad as in the night. After each flare up it would take around 2-3 hours for my skin to return normalish in colour but there was always a slight pink hue on my nose. The worse symptom of all is the nose swelling for around 7 hours when I sleep and waking up every morning with a swollen nose. The flushing has stopped now and that stopped the swelling. My nose still looks a bit swollen but it's slowly going down now(2 months so far)."

Fiugs wrote on December 4th, 2016: "There is a topical with the brand name Epicept, although I think the compund's percentages are different than you describe, Deansm. 
https://www3.rcsb.org/ligand/NP1. Did your GP indicate if s/he thought this would be a short or long term solution? Just wondering because I got the impression that some topical analgesics lose their effectiveness after a while.... I say that only based on what my local pharmacist told me in relation to a lidocaine based gel I was inquiring about; he said it would stop working after a while. I will certainly ask my GP about this! Thanks Deansm and all the best. I also found this article, referring to a compound using the same percentages as Deansm has been given http://jamanetwork.com/journals/jamadermatology/fullarticle/403191

Deansm wrote on December 4th, 2016: "From looking at the link EpiCept Cream is much stronger (2% ketamine / 4% amitriptyline), The cream I am on is 1%ami and 0.5%ket and it stops the flushing (the lower dose it works the better). Since my doctor said he had success with the ointement on patients with Erythromelalgia I have been reading a lot on Erythromelalgia forums about the safety of this cream (it seems very safe at low dose). I am not sure which ingredient (or a combination of both) is stopping the flushing, but this is something I found about topical ketamine.
Also from reading various Erythromelalgia forum posts, the vasodilation, flushing, redness are very similar to Rosacea, only it happens on the feet and hands and sometimes the face in Erythromelalgia. The only real difference over type 1 Rosacea as far as symptoms is the addition of more pain, stinging. It is interesting hearing about the other treatments they use on those forums to stop flushing that might also work for flushing on people with Rosacea."

Brady Barrows wrote on December 4th, 2016: "What a wonderful find to substantiate this thread. Note what the article says: "Erythromelalgia is a clinical syndrome characterized by attacks in which the affected limbs become bright red, hot, and excruciatingly painful. The common trigger is heat exposure induced by exercise or increased ambient temperature. As the condition progresses, the limbs become permanently red, hot, and painful. The pain of erythromelalgia, commonly described as hot and burning in quality, is frequently disabling, and patients obtain relief by lowering skin temperature, for example, by applying cold objects to the affected area, exposing the affected extremities to cold surfaces, immersing the limb in ice water, or by elevating the affected extremity. Frequently, these measures damage the skin, further exacerbating the pain, and occasionally cause maceration.
Pain associated with erythromelalgia may be difficult to treat. Because erythromelalgia is not a single disease but a syndrome, the response to various treatments may differ depending on the underlying condition and pathophysiology. Furthermore, treatment of the pain symptoms may have little if any effect on the other manifestations (ie, the redness and increased temperature of the affected limbs). According to various theories, erythromelalgia is a vascular disorder or neuropathic condition. In previous studies, we have shown that both systems are involved, but we do not know which one is affected first. It is plausible that the vascular and neuropathic components differ in each subject depending on the underlying cause."
Hopefully in the future we will know more if this treatment for erythromelalgia will be a standard treatment for rosacea."

arsenalista wrote on December 5th, 2016: "Looks like another guy has also great results with this stuff.. https://www.reddit.com/r/SkincareAddiction/comments/5ggpha/beforeafter_dealing_with_rosaceaerythromelalgia/ I was read about Erythromelalgia (first time hear about it) and it looks like something very similar to rosacea but more painful. One of my worst symptoms is a chronic burning feeling at all my face. Damn, have to get the prescription."

wrote on December 6th, 2016: "A very interesting find! I'm very curious if more people with facial (rosacea) flushing and burning will find relief from this cream. It's also a big bonus if your pharmacist can just add the powdered medication to your regular moisturizer. It's a fascinating distinction between facial erythromelalgia and rosacea. I'm not completely sure how you can detect one from the other, (apart from EM typically at the least affecting the hands and feet - but people with rosacea can get Raynauds (me too), which mimic these symptoms a lot), as these cases mentioned here look and sound pretty much like rosacea.

"A 53-year-old man presented to an outside dermatologist with an erythematous
facial eruption of 4 years' duration. The eruption was associated with burning and swelling,
which the patient reported worsened with sun exposure. These symptoms were debilitating,
preventing the patient from working and maintaining daily activities. Initially, the eruption was
thought to be rosacea and actinic damage; however, it was unresponsive to standard therapies."

"Upon further questioning, the patient reported skin burning not only with sun exposure, but also 
with heat exposure. Furthermore, he reported attempting cooling measures, such as the frequent 
use of ice packs, to relieve his symptoms. With these additional details, a clinical diagnosis of facial 
and auricular erythromelalgia was established. Further workup excluded potential causes of secondary erythromelalgia. Given that erythromelalgia is thought to involve both small fiber neuropathy as well as vasculopathy, we initiated therapy with aspirin, pentoxifylline, and
gabapentin.1 Subsequently, nifedipine was added to this treatment regimen. At 5 months' follow-
up, the patient reported 80% improvement (Fig 2, B) and was able to return to work and enjoy
normal daily activities

With a picture:

Curious if aspirin, pentoxifylline and gabapentin together could help some of us too.  And this woman seems to have serious rosacea, and she wonders whether or not she has erythromelalgia or rosacea;

With pictures:

Someone with fybro emailed me that her rosacea disappeared once she started to take guaifenesin tablets (a decongestant). Anyway, shows how complex these skin conditions are, there might be a lot of overlap and different factors at play. So curious to hear who else here might have benefit from this cream that is suggested." 

RaymondS wrote on April 18th, 2017: "Didn't harm me but didn't help either. And it was a hell of a process to get the stuff. Just proves what works for one doesn't always work for another. 
I will keep it and just use in one area to make sure that over time it works or doesn't. 
But unfortunately it did not cure me."

Fiugs replied on April 18th, 2017: "Sorry to hear it didn't work for you either. I gave up on mine quite some time ago as it really aggravated my skin. It seems that only one person on our forum - the original poster - got marked results with this. It's truly weird, isn't it, that our skins are all so different! Every day I grow more of the opinion that there is no such single condition as Rosacea, but rather it's a blanket term for a red, irritated and sensitive flushy face, that may or may not include P&Ps, the unique cure of which is probably only going to be determined by the cause(s)."

Vice wrote on February 23rd, 2017: "Nobody should be worried about ketmamine having an effect. I take ketamine in powedered form recreationally and in my eyes 'medicinally'. It has an anti depressant effect and is currently being reviewed and researched as a breakthrough anti depressant for treatment resistant patients. It's a wonder drug really. The hallucinations are more distortions and only occur with high doses. - I personally love them myself. I am also trying to get the cream ointment and am in the middle of the process to getting it in uk now but it's difficult. Obviously I know it won't have any effect on my mind but it's still crazy that a drug I used systemically to get high might also be a good treatment for Rosacea! Who'd have thought!"