17 September, 2017

Montelukast (Singulair) for rosacea flushing and redness

My dermatologist suggested lately that I could try out an asthma/allergy med called Montelukast (brand name Singulair). I was already given it last year coincidentally by my GP for my bronchitis at the time, but never took it very long. My dermatologist said that singulair is helping some of his rosacea patients, especially flushers, as it is supposed to lower inflammation and interferes with mast cell issues, which can play a role in allergies and flushing.
Singulair (this is the brand name, the generic active ingredient MONTELUKAST is just as good and what makes it work) is designed to treat asthma inflammation in the lungs. It also prevents the narrowing of airways triggered by exercise. Singulair is a leukotriene receptor antagonists. It works by blocking substances in your lungs called leukotrienes that cause narrowing and swelling of airways. Blocking leukotrienes improves asthma symptoms and helps prevent asthma attacks.

Leukotrienes are also involved in rosacea flushing and skin inflammation however. Leukotrienes are a family of certain inflammatory mediators produced in leukocytes in the body. They play a role in the regulation of the immune responses in the body. But when leukotrienes are produced, they also stimulate the production of histamine (which is a blood vessel dilator and also involved in allergic reactions), as well as the production of prostaglandins. There are 'good' and 'bad' prostaglandins and the body. The BAD ones create inflammation and pain. They also play a role for instance in the painful inflammatory response in the uterus when women menstruate. This is why NSAID's, which control the prostaglandin production, can really help with menstruation pain; they make sure there are less of these bad prostaglandins produced by the body and this lowers inflammation and pain.

Bad prostaglandins are bad news for rosacea, as they cause inflammation of the skin. They can cause facial flushing. Increased levels of prostaglandin D2 make the skin look red and inflamed. (By the way, certain foods, especially sugar and white flours, also raise the levels of prostaglandin D2 in the body and skin). Unfortunately, research tests showed that taking a prostaglandin D2 (PGD2) receptor subtype 1 antagonist (laropiprant) (to counteract the levels of prostaglandin D2) did not improve rosacea subtype 1 symptoms. Still, inhibiting even some of the leukotrienes is beneficial, and many rosaeans have reported that leukotriene blockers help decrease the inflammation associated with their rosacea. 
As illustration: Doctors have used an antibiotic called azithromycin effectively in the treatment of occular and regular rosacea, and one of the ways in which it helps rosacea, is in the way azithromycin lessens certain pro-inflammatory cytokines in the body (including IL-1, IL-6, IL-8, IL-10, and TNF-α), and because it down-regulates the production of nuclear factor (NF) kappaB and of leukotriene B4.

One of the roles of leukotrienes (specifically of leukotriene D4) in asthma is to contract the smooth muscles lining the smaller parts of the lungs. Of too many leukotrienes are produced by the body, they cause a lot of inflammation in asthma and allergic rhinitis. Leukotriene antagonists like singulair/montelukast are used to treat these disorders, by lowering the production or activity of leukotrienes. Cysteinyl leukotriene receptors are present on mast cells, eosinophil, and endothelial cells. They can stimulate pro-inflammatory activities by mast cells. They can create inflammation, induce asthma and other inflammatory disorders, thereby reducing the airflow to the lungs. Cysteinyl leukotrienes seem to also play a role in adverse drug reactions in general.

So, despite singulair/ montelukast being developed to treat asthma symptoms, the way in which it lowers specific chemicals (leukotrienes, prostaglandins, histamine) that also play a role in rosacea inflammation, it might help some people with rosacea with their general skin redness and flushing. 

I am glad to try it out and have already taken it for a few weeks, but too soon to tell if it improves matters. Some days I think it does, others I am not so sure. Hopefully better effects in weeks to come. One of the known side effects is increase anxiety or jitteryness. I have not felt as calm as normal lately, but these things can be hard to pinpoint to one specific cause. I know of two other rosacea patients who currently try singulair out, and both of them are in the same boat, not being sure whether or not it helps or not. Ginaisred for instance, and she wrote about it on The Rosacea Forum: "Hi all, thought I would start a new thread to discuss Montelukast. I know some people on this forum are patients of Professor Anthony Chu at Hammersmith, and he has recently advised us flushers to start using Montelukast. I thought I would create a post to keep you updated and anyone else who is trialing it please add in your thoughts.. So far: I have been on it for a week - sadly no improvements yet. I assume it may take a while if it was to work?  Fingers crossed for me."

Singulair has been used by rosacea patients in the past already too
and some wrote reviews. let's have a look what they thought about it.

YankeesRtheBest wrote on May 11th, 2007:  "Singulair is amazing..I have been on singulair for about 2 months now and it has been excellent at keeping my Rosacea under control. My flushing has been non-existent. Even the terrible night flushes and exercise-induced flushing has subsided. I started singulair because I tested positive for allergies (tree pollen, dust mites) I started getting allergy shots and my allergist also prescribed me the Singulair. What is even more amazing is that my broken blood vessels are much less noticeable than they were and my chronic redness is at least 50 percent better. I strongly recommend this, however I'm not sure how you can get it prescribed for you if you don't have allergies or asthma. he only thing that hasn't been helped much is my ocular rosacea. Hope this info helps. [..] I am on 10 mg. I noticed that my Rosacea was significantly better after about 4 or 5 weeks. Now, after 2 months of being on it, my flushing has been diminished to almost non-existent. And yes, even my emotional/social nervousness flushes and indoor heat flushing has been helped tremendously. I don't know if this would be the case for everyone, but Singulair def seems like a wonderful option for people to try. Good luck. -Chris"

Froggirl replied: "Thanks for this info, it's so interesting, at first I assumed singulair was a type of antihistamine (which I'm already on) but it's completely different...as far as I can tell from googling it's usually used for asthma, not for skin reactions, although I found one reference that said it possibly could help skin allergies. So I'm really curious to know if your doctor prescribe it for asthma or skin allergies? I did some more googling and it is used for mastocytosis, which is a disease where the mast cells degranulate too easily, and so causes extreme allergy type reactions, including flushing and wheezing. I'm being checked out for this at the moment because everyday now I'm flushing all over and having wheezing attacks (but have no allergies). [..] Despite it being unclear what triggers rosacea in the first place it's pretty clear that the symptoms are related to inflammation, and leukotriene's are one of the inflammatory mediators that contribute to inflammation, along with histamine and prostaglandins etc. So potentially blocking any of these inflammatory substances could reduce the inflammation and improve rosacea. In allergies the release of these chemicals is due to the immune system overacting to common substances, but the end result is that the same chemicals get released, causing redness, swelling and warmth. And then the inflammation caused by these chemicals trigger the release of more chemicals and things can just get worse and worse. So even though the initial trigger for the inflammation may differ between rosacea and allergies the same treatments can potentially help both."

Froggirl updated on June 1st 2007: "I'm up to 9 days and the last few days my asthma has been much better and my flushings has maybe been a bit less but nothing dramatic. Saw my doctor today and he said it does start to kick in for asthma after 7 days and gets to the full effect at about 2 months so i assume it will be a similar story for flushing."

Melissa W wrote on May 12th, 2007: "In Nov (2006) I asked my derm to put me on singulair because I had read (I think in Nase's book) that it may help with rosacea. I also happen to have asthma. I developed it 7 years ago along with all my other allergies which appeared all of a sudden but then my asthma mysteriously disappeared about 2 and 1/2 years ago. Anyway, I have noticed no change in my rosacea due to singulair but I am currently still on it because my derm said there are no negative side effects from it (a safe drug) and also because I still have so many allergies."

YankeesRtheBest updated on June 8th 2007: "I would defenitively give the singulair a while to work. I noticed that my flushing was 95 percent gone after about 2 months. It all has to do with the inflammatory leukotrienes. I spoke to my allergist about this. I told him how my rosacea was so much better after being on the singulair for a couple months and he explained to me that inflammatory leukotrienes are the reason for different types of inflammation such as in the reaction to allergies or asthma. He said inflammatory leukotrienes are also in the blood vessels. Singulair helps release these leukotrienes from the vessels. This could be why it helps the flushing of rosacea and also why my broken blood vessels appear to be less visible. But yea...def give it a couple months. Don't give up on it too soon. Good luck. -Chris"

Barbara wrote on June 10th 2007: "I’m 3 weeks on Singulair now. Still no results for flushing. I really hope I will see some first results in the next 2 weeks. After stopping my antidepressant some time ago my flushing slowly has come back to the same distressing strength than before taking the antidepressant, so I’m so desperately hoping that Singulair will help! The last 2 weeks I had some minor belly ache. Could be from Singulair as it is listed as one of the most possible side effects. But it is only minor, so no reason to stop taking it. Take care all, Barbara"

She updated on July 25th 2007: "Update: So I stopped taking Singulair last week on wednesday. On Sunday evening and the whole Monday a was quite flushy and my face got redder again and still is. The last weeks while taking Singulair I was much "cooler" and pale. I really thougt that this was because of summer, when I don't flush so often. But after stopping Singulair I have the feeling that it acctually may have helped me. HHMMMM...it's always so difficult to tell if this flushy time would have also happened if I would still be on Singulair."

And she updated on September 26th 2007: "I started my second Singulair trial 4 weeks ago. And this time I not only can say for sure that it is really helping, moreover it started helping already the next day after taking the first tablet. I took the first tablet in the morning. When I got up the next morning and looked into the mirror I thought: “Wow, I look so pale, but that can’t be because of Singulair, I just took the first tablet yesterday!?”. But it’s true, I am really paler since taking Singulair and the threshold for flushing is noticeable higher than it would be at this time of the year. Two colleges at work already asked me if I would feel sick because I look so pale!
Don’t get me wrong. I still suffer from frequent mild up to strong flushes depending on the trigger. It is just in compare to not taking Singulair that I feel better. Singulair just puts the threshold higher before a flush starts. I would say it saves me from a lot of mild flushes and helps my face to stay a little bit “cooler”. But the most noticeable result from Singulair is my paler face. It is not a cure though but every little relief is highly welcome. And because Singulair works against inflammation I assume it may slow down the progression of rosacea in general, or at least I hope so. However I feel far from being able to live my life in a fairly “normal” way. This flushing/blushing thing is draining so much joy and energy out of me. I feel sooo tired. Just to think how happy I am that I have perhaps one flush less a day because of taking Singulair shows me how desperate I am.   Sorry for whining. I really started that post with another intention.
Best wishes,

Barbara further updated on December 1st 2007: "I just want to give an update on my treatment with Singulair. I take it daily since August now and it is still helping me to paler and cooler face. In autumn/winter I normally have a lot of mild or strong flushes during the day depending on the trigger and often nose flushes during the night. This time Singulair helps keep away many of the mild flushes and the nose flushing during the night. And it definitely helps reducing the flush when I come from the cold outside into a warm room. However; it is only helping to some degree…if the trigger is strong enough I still have my strong flushes. Especially the ones that come from anxiety, embarrassment and warm indoor heating. But I’m thankful for every flush that I don’t have, even if it would have been “only” a mild one. So far I don’t have any negative side effects from Singulair that I’m aware of. It is just soo expensive!!"

iVAN wrote on June 17th 2007: "Been on Singulair for 5 weeks and have no improvements in
any rosacea or flushing symptoms. Actually I don't notice it doing anything at all so far."

Twickle Purple wrote on June 20th 2007: "Within days of starting Singulaire my face was cooler, and now I flush much less. My face is almost always cool to the touch. My triggers are mostly allergy related and the Singulaire has worked great. I take it with a reactine and a zantac in the morning."

She updated on September 27th 2007: "I urge anyone taking this to be aware of the side effects.
This drug helped me SO MUCH but I had to stop taking it because of the horrible side effects I was experiencing. Check this out: http://www.medications.com/singulair/browse
I have been off the Singulair for over 3 weeks now and am finally feeling better. The deep pain and ache side effects slowly went away within the first week and by the second week I was left with just generalized weakness but no more pain. In my third week my strength was coming back, I could hold a full teapot, but I had no stamina even for a short walk. Now I am starting my 4th week post-Singulair and I am getting some vigor back. I went for my first walk yesterday and was able to walk at a gentle pace for about 20 minutes -- no hills or inclines though, I'm not up to that just yet. I am saddened that such a helpful medication could rob me of my life-force like Singulair did."

Froggirl updated on June 21st 2007: "I wonder then if it works best taken with antihistamines? Because as far I as know leukotrienes are unlikely to be released in the body on their own but in tandem with histamine (and the other mast cell contents), meaning that if you take just singulair the histamine may still effects the blood vessels anyway..Similair to how H1 antihistamine didn't make much of difference to my flushing but taking a combination of H1 and H2 did. I've been on sigulair over a month now and my facial flushing is improved, not gone by any means but it is noticeably better and i'm hopeful them it might improve even more over the next month.

Max wrote on June 21st 2007: "No noticeable results for me after 3 weeks on singulair..."

Liz wrote on July 16th 2007: "Been taking singulair for 3 weeks now... face is still covered in hives, red and swollen... with some nice deep sores added for extra misery. All singulair has done was take about $100 out of my wallet for copays. Should i give it another month? what do you think? - liz"

Kathy S. wrote on July 25th 2007: "Singulair wasn't amazing for me. I only took it for a little over a week but it made me irritable and shaky, some little panic attacks, it was really weird. I took it with zyrtec. Also it didn't help with my flushing, I believe it got worse. I hope that others are really seeing help from it. I just didn't get the results and couldn't take something that made me stress more as that is my biggest cuprit and wind."

Alba wrote on January 29th 2008: "I just started singulair 2 days ago, i think its already working have been flushing less often."

dwit392 wrote on February 15th 2008: "When I combined Singulair and Zyrtec I seemed to get amazing results. I don't believe I got the results with Singulair alone (I took my prescription in two parts of 15 days each) I didn't really realize until I stopped taking Singulair how much it was helping me. I need a new prescription now. It seemed to greatly reduce my internal heat. My redness was down 25%, flushing threshold was about 20% higher, and I stopped getting those annoying evening flushes, due to dry air or internal heat or whatever. Only thing strange about singulair is that I had to take it right before I went to bed because if I took it in the afternoon it seemed to induce a flush. I take 10 mg once per day before bed. I usually take it without food. I dont think it really matters."

Mutantfrog wrote on February 18th 2010: "I've been taking Singulair for about 10 days now, and I'm starting to see some improvements already. My flushing response has been WAY down. The 2 times I have really flushed in the last 5 days (which is amazing in of itself) the flushes were significantly shorter in duration. I was told singulair typically takes about 2 weeks to start working well, so I was surprised to see this difference already. I keep a photo journal of my progress, so that I can tell when rx/ipl and such change one way or the other - hopefully making things a little less suggestive. I haven't experienced any real side effects yet. Though I'm on the lookout, thanks to the other posts in this thread. I was prescribed it for allergies/mild persistent asthma, but it will be a really nice side effect if it helps the rosacea too. [..]  My skin...still flushes. I still have the a few P&P. But the flushes haven't been quite as intense, or as frequent. I've even been able to drop the topical for my skin (Klaron) about 2 wks ago - skin hasn't looked significantly better/worse but the point is it didn't FLARE like it usually does after stopping the topical. Nice to be able to drop something more from my routine.
[..] The burning/easy irritation of my skin is SIGNIFICANTLY better than 3 or 4 months ago. I just don't flush as easily in the last 3 weeks or so. I've even been able to add in some foods I normally can't eat due to flushing - and have had little to no reaction. Heat (dry heat especially) still gets me pretty red but the flushes go away pretty quickly (about 1hr vs all day), hurt less and spawn fewer bumps (I always get bumps after being really red - and they show up only in the "rosacea red" areas of my face). "

Queta wrote on July 17th 2010: "Hi- I tried Singulair quite awhile ago for nasal/cheek swelling related to allergies. I took it for about a month. It didn't seem to make a radical difference, but it made me angry. I was very short-tempered and angry after about a week of taking it. Finally after a few weeks of being unusually angry I looked it up and a small number of people report the same experience. One guy even told about how he and his wife divorced because her attitude completely changed after taking it. I'm sure that's only a portion of that story but I will say it affected my mood a lot. No one else on here has reported that effect, as far as I can tell. Regards Queta"

Mrsmoof wrote on october 11th 2010: "6 1/2 weeks on Singulair.. Haven't noticed much of a difference. I have noticed though my neck and face seem a little cooler. Redness, flushing still about the same. Will give it 3 months."

Snuffleupagus wrote on October 11th 2012: "Is it possible for Singulair to make flushing WORSE? I took it for two nights and I had horrible "centre flushes" causing me to wake up in the middle of the night. (not like a regular whole cheek flush, but focused more in one area and VERY red/purple!) Wondering if this is just a coincidence (I have been getting these on and off constantly over the last 6 months)."

Cricket0117 wrote on April 30th 2013: "I started taking Singulair last week Friday, sat morning when I got up my face turned a little pink instead of the red and burning I've had for the last 4 months. I have not had any major flares or burning since then. My face is far from perfect but it's improved from what I've been dealing with.Has anyone had similar results and has taken it long term with good results."

lm4727 wrote on May 26th 2014: "Hi all, Both Singulair and anti-histamines made a dramatic difference for my skin (flushing, redness, hives), but I had to stop both because they made me tired and sluggish. I would recommend Singulair to anyone who doesn't have side effects from it. Two zyrtec per day did the trick for me as well, but I can't take these drugs for any extended period of time."

Montelukast has also been tested on acne patients, with good results. 52 patients with moderate acne were evaluated and divided in test groups. One group received doxycycline 100 mg/day plus 1% Clindamycin solution (Group 1), the other group was given Montelukast 5 mg daily plus 1% clindamycin solution (Group 2). Montelukast turned out to be as effective as the antibiotic doxycycline in the treatment of acne after a three month trial, although the effects of the clindamycin solution might have also added to the success perhaps. 

Singulair is not the only mast cell related medication I have used so far. In the past I had some success with a trio of medications that are used for mastocytosis.

You can read about the background info on it, and my experience at the time in this blog post. I took 2 different antihistamine medications on top for a month: Inorial and zaditine. They initially really helped me quite a lot to cut down on the facial flushing and redness. I literally looked pale some weeks, and thought I found the holy grail. But after a month or so, I felt I became more red and more easily flushed, possibly because they made my skin more dry. More than normal, at some point! I am wondering if my body maybe compensated and started producing more histamine than normal perhaps. I remember an old forum member called Dan warning for this phenomenon when taking high doses of antihistamines for rosacea...
I therefore no longer use Inorial and zaditine (but still use Xyzal daily), only when I can't get out of some dinner party invite and know I will have to eat foods high in histamine. For occasional use I get relief from them therefore. However, for those who have mastocytosis, these drugs can really help. I also am eager to restart them and just see if the same thing happens second time round. I see my local dermatologist soon from now and will ask for a new trial with these meds.

Then in 2016 I used Tilade, which is also a mast cell, anti inflammatory substance for the lungs. 

Tilade inhaler 2mg (CFC-Free) contains nedocromil sodium which is a non-steroidal agent, with anti-inflammatory properties, that reduces inflammation by a mechanism that is different to asthma medications containing corticosteroids (not to be taken when you have rosacea!). Tilade inhaler works directly on the airway walls to reduce inflammatory reactions, by inhibiting the activation of several inflammatory cells (such as macrophages and mast cells) at the site of inflammation in the lungs and preventing them releasing chemicals (like histamine, prostaglandin and leukotrienes) that mediate the inflammatory process. Tilade stabilizes mast cells (linked to allergies) and reduces the release of histamine and inflammation (by reducing the total number of eosinophils). The overall effect is to dampen down the inflammatory process in the airways, reducing irritation and swelling to improve airflow into the lungs. This helps to prevent symptoms of asthma caused by swollen and inflamed airways, like wheezing, cough, tightness of the chest and shortness of breath. It does not relieve bronchospasm which happens during an asthma attack and needs a “reliever” medication to open the airways. 

So I used it for a month or more and it helped me calm down the bronchitis and also made my skin very calm and pale-ish for a while. Until it made me more red and flushed as well, after the one month mark. Just like the mastocytotis medication!

After a while of using it twice daily, I felt I needed more and more of it, or else I'd turn very red once the half life was exceeded too much and it stopped working. I assume it was some sort of rebound. I am a severe flusher and even a sneeze attack makes me all red, so as I write often, this isn't how everybody with rosacea will/would respond to Tilade most likely. Besides, it's not aimed at rosacea, I just noticed a pale skin while taking it for lung inflammation. So.. I used it a full month. And within the 3rd week I started noticing that about 6 or so hours after using the inhaler, I had what felt like a weird rebound flaring, flushing and burning?? All red! I stopped the inhaler, had 4 days of all round terrible burned up skin, cancelled all my going out plans and grumped it out. Then it subsided a bit, and I restarted that Tilade puffer, just to see if it really was the inhaler in my case. And the same thing happened. Pale that afternoon (yesss!), then super red after not snorting the next dose.  Pictures were while using Tilade and when it still made my skin calm, then last one when it stopped doing that: 

12 September, 2017

Rosacea Bulletin Board; Latest news on rosacea treatments

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."

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: