The Allergist

Demystifying Hives: Autoimmunity, Treatment, and the Journey Forward

April 02, 2024 CSACI
Demystifying Hives: Autoimmunity, Treatment, and the Journey Forward
The Allergist
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The Allergist
Demystifying Hives: Autoimmunity, Treatment, and the Journey Forward
Apr 02, 2024
CSACI

“(Urticaria) is not an allergic condition, it's an autoimmune condition, one. Two, it's not dangerous, but it can last long. Three, we have very good strategies to control it.”                                                                                                                         
                                                                                                                           
    - Dr. Moshe Ben-shoshan


Hives are probably one of the most misunderstood rashes by the general public. Hives are not life-threatening, but they're debilitating. They're not an allergy, but they're often blamed for being one. They're a marker of autoimmunity with little to do with one particular disease and their course and triggers in one particular person is at best challenging to predict.


Dr. Moshe Ben-shoshan tackles the intriguing world of chronic urticaria; cutting through common misconceptions, and walking us through the latest in diagnostic strategies and management options for hives. From the targeted effectiveness of second-generation antihistamines to the advanced treatment possibilities offered by biologics like omalizumab, and even the role of immunosuppressants such as cyclosporine. Special attention is given to the nuances of chronic urticaria in children versus adults.


Emphasizing the critical role of disease scoring systems, Dr. Ben-shoshan explains how these tools are vital for assessing severity and guiding treatment decisions. The conversation also sheds light on the diagnostic value of blood tests, showcasing the multifaceted approach required to effectively manage hives.


Dr. Ben-shoshan tip-toes into the delicate territory of how to handle the increasing requests for testing and dietary modifications. We also take a quick glimpse into the future of urticaria management including targeted pediatric guidance and new biologics on the horizon. 


This episode offers an indispensable resource for allergists and healthcare professionals seeking to enhance their understanding of chronic urticaria. It’s packed with practical insights and a look towards promising advancements in the field.



Visit the Canadian Society of Allergy and Clinical Immunology

Find an allergist using our helpful tool

Find Dr. Hanna on X, previously Twitter, @PedsAllergyDoc or CSACI @CSACI_ca

The Allergist is produced for CSACI by PodCraft Productions

Show Notes Transcript

“(Urticaria) is not an allergic condition, it's an autoimmune condition, one. Two, it's not dangerous, but it can last long. Three, we have very good strategies to control it.”                                                                                                                         
                                                                                                                           
    - Dr. Moshe Ben-shoshan


Hives are probably one of the most misunderstood rashes by the general public. Hives are not life-threatening, but they're debilitating. They're not an allergy, but they're often blamed for being one. They're a marker of autoimmunity with little to do with one particular disease and their course and triggers in one particular person is at best challenging to predict.


Dr. Moshe Ben-shoshan tackles the intriguing world of chronic urticaria; cutting through common misconceptions, and walking us through the latest in diagnostic strategies and management options for hives. From the targeted effectiveness of second-generation antihistamines to the advanced treatment possibilities offered by biologics like omalizumab, and even the role of immunosuppressants such as cyclosporine. Special attention is given to the nuances of chronic urticaria in children versus adults.


Emphasizing the critical role of disease scoring systems, Dr. Ben-shoshan explains how these tools are vital for assessing severity and guiding treatment decisions. The conversation also sheds light on the diagnostic value of blood tests, showcasing the multifaceted approach required to effectively manage hives.


Dr. Ben-shoshan tip-toes into the delicate territory of how to handle the increasing requests for testing and dietary modifications. We also take a quick glimpse into the future of urticaria management including targeted pediatric guidance and new biologics on the horizon. 


This episode offers an indispensable resource for allergists and healthcare professionals seeking to enhance their understanding of chronic urticaria. It’s packed with practical insights and a look towards promising advancements in the field.



Visit the Canadian Society of Allergy and Clinical Immunology

Find an allergist using our helpful tool

Find Dr. Hanna on X, previously Twitter, @PedsAllergyDoc or CSACI @CSACI_ca

The Allergist is produced for CSACI by PodCraft Productions

Dr. Mariam Hanna:

Hello, I'm Dr. Mariam Hanna and this is The Allergist, a show that separates myth from medicine, deciphering allergies and understanding the immune system.

Hives are probably one of the most misunderstood rashes by the general public. Hives are not life-threatening, but they're debilitating. They're not an allergy, but they're often blamed for being one. They're a marker of autoimmunity with little to do with one particular disease and their course and triggers in one particular person is at best challenging to predict. Case in point, a dear colleague's child developed an autoimmune condition recently and they struggled to manage it for years. This child had many complications, but when they developed hives, that was the one thing they pointed to that had the biggest impact on this child's quality of life, the biggest impact that was really hard for me to grapple with, as I often find myself lulled into believing the benign nature of hives. And for a moment I often forget the impact that this has on a patient's daily life.

From the practicing allergist perspective, we come across referrals with a common statement, hives, please rule out allergy. It sends shivers at my spine. What are physicians and patients expecting from our consultation? In fact, it's the minority of physicians that tell me hives, please provide assistance in management. And this is despite the fact that allergists actually have a lot to say about this disease and its management and very little specifically to tell you about a particular allergy in this instance. Dr. Ben-shoshan is going to provide insight into this condition and help us tackle this issue. Allow me to introduce him. Dr. Moshe Ben-shoshan is a pediatric allergist and clinical immunologist with a master's in epidemiology at the Montreal Children's Hospital in Quebec. He has received numerous awards including the Emerging Clinician Scientist Fellowship Award, the Estelle Simons Research Award by the CSACI, amongst many others. His research has resulted in more than 200 published manuscripts and he's still working on more.

His work on the diagnostic approach of antibiotic allergy in children has led to a fundamental shift in clinical practice for the diagnosis and management of amoxicillin allergies in children. He has established the largest cross Canada registries that collect data on important diseases in allergy and immunodeficiency, a testament to his broad areas of interest in research within our specialty. And for today, he's also one of the Canadian researchers selected to participate in the 2021 International Galen Guidelines for the definition classification, diagnosis and management of urticaria, which is our selected topic of today. Dr. Ben-shoshan, thank you so much for taking time out of your hugely busy schedule to join us and welcome to the podcast.


Dr. Moshe Ben-shoshan:

Thank you so much for having me.


Dr. Mariam Hanna:

I want to start with how you just counsel patients once you've made this diagnosis. We always want to hear what's your spiel? How do you explain this to families?


Dr. Moshe Ben-shoshan:

So one of the most problematic thing is that patients come with expectations because as you said, when people see hives they think automatically about allergies. And the main thing is to explain to them, "Okay, first of all, you need to realize this is not an allergy, this is not an allergic condition. This is more like an autoimmune condition or auto allergic condition. You are not reacting to something at the outside, you're reacting to something in the inside, so complicated your life by avoiding external triggers, elimination diet, detergent, soaps and so on," which are what patients come with regularly or often is useless. Basically you need to understand that the origin of the disease is inside. It's not dangerous, but it'll take long to resolve. But we have very good management strategies.


Dr. Mariam Hanna:

So do you provide them with counseling around disease duration or things to avoid in particular when you see them?


Dr. Moshe Ben-shoshan:

So I tell them... So that's one of the first thing. It's not dangerous, but 10% resolve each year, so it can take 10 years until it goes away. I hope for you that you'll be one of those that are lucky and resolve within the first years, but I don't want you to get discouraged if it lasts longer. And there's nothing specific that you need to avoid. But there are some co-factors that can flare the hives and these co-factors are not the cause of your hive, but they can make it worse. For example, a nonsteroidal anti-inflammatory drugs, use of alcohol for adults, stress, any infection can basically flare the hives and we had people that had some flares following vaccines or even getting better after vaccine. So it's very hard to predict which will be the factor that will flare the specific person's hive, but it needs to not get discouraged if it happens because we have good means to control it once it happens.


Dr. Mariam Hanna:

Speaking of vaccines, because you've said it, after COVID-19 vaccination, we saw a spike in the number of referrals that we received for chronic urticaria or urticaria in general. Can you comment a little bit about that for us?


Dr. Moshe Ben-shoshan:

Yeah, so there are studies showing that among patients with chronic urticaria is 10% increase in or flares, following the vaccine. It makes sense because like any immune system that autoimmunity probably is activated but by other factors that activate the immune system. And we have specifically published a paper on children with chronic urticaria and for us, we didn't see any exacerbation in chronic urticaria or any flares, but there are some studies in adults that show that about 10% can flare following the vaccine. And again, that I think points to the fact that the disease is probably not exactly the same in children as it is in adults.


Dr. Mariam Hanna:

How do you think or in what ways do we think that chronic urticaria differs between pediatrics and adults?


Dr. Moshe Ben-shoshan:

First, let's speak about the epidemiology. In the past it was thought that chronic urticaria is much as common in children, today, we know it's wrong. In a recent meta-analysis and systematic review by [inaudible 00:06:18] 2020, they showed that the prevalence of chronic urticaria in adult is about 1% and in children it's 1.4%. So it's certainly not less common in children. That's one thing, so regarding the epidemiology. But there are still differences regarding the epidemiology of chronic urticaria in adults. For example, in adults it is more common in women, but in children the sex distribution is equal. So that's one difference. It was thought that regarding again the epidemiology that chronic urticaria in adults resolve much more slowly. But we've published a study in 2017 in JAMA Derm showing that the resolution rate in children is 10% per year just like in adults. Inducible urticaria which are urticarias induced by a specific trigger are less likely to resolve and resolve much more slowly, but that's a different thing.

But we didn't find any substantial difference regarding resolution rate. So there's clearly a difference in the epidemiology. Regarding the pathogenesis, we are not sure what is the pathogenesis, though we assume it is also autoallergy, but unlike in adults, we don't have these big studies showing that you have in the majority of cases an IgE against an internal substance like interleukin 24 or antithyroid peroxidase. So these studies are certainly lacking in children. This is one of the aim of the registry we've put forward to try and identify what is exactly the pathogenesis of chronic urticaria in children. Regarding the clinical presentation, there's also difference, for example, in adults we see much more often angioedema, so about 40% of cases of chronic urticaria in adults are associated with angioedema as well. While in children it's usually less than 10 to 5%. I just want to go back again to the definition of a chronic urticaria.

So we remember its hives on and off for at least six weeks or just angioedema or both, okay? And then the third component that is a bit different is the management. So in adults, we say that about 50% do not respond to a second generation antihistamines, even in high doses. We and also the group in Turkey have shown that in children, the percentage is much lower, only 10% will require a more aggressive treatment than second generation antihistamine even in the standard dose. Question is whether it's because children are more compliant because the parents supervise them or because it's really a different disease. So that's something else. That's another knowledge gap to address.


Dr. Mariam Hanna:

Many knowledge gaps. If I can ask you, do you think the epidemiology is similar or different between acute and chronic urticaria? Are there differences?


Dr. Moshe Ben-shoshan:

I'm pretty sure it's different. Completely different because acute care less than six weeks usually in about 90% of cases, especially in children, is related to viral infections and it just resolved, doesn't come back, when he's sick again with viral infection it can happen again and they warn the patient. But it's certainly a different than chronic urticaria which can be triggered maybe like 10 days after a viral infection, but it lasts longer because the mechanism are beyond the viral infection. It had triggered probably an autoimmune mechanism. Just in the past we called chronic urticaria CIU and what we call it CSU, chronic spontaneous and ITP was idiopathic, but now it's immune. Probably in CIU should go to immune and maybe like in ITP, the viral infection is an initial trigger, but the immune system had been activated beyond that initial viral trigger.


Dr. Mariam Hanna:

Excellent answer. Okay. Disease scoring and disease severity, this is often used for qualifying for medications and in clinical trials. How do you address this or incorporate this into daily clinical practice or do you even use it?


Dr. Moshe Ben-shoshan:

I do that and the reason that I do that is that because I have experience, because when you ask patient and they did not record their symptoms, they'll always remember the most severe reaction and you would assume that the treatment that you've given was useless. Well, when you have a log of the exact scoring that most of the time it was fine, there was one episode, yes, that episode was very debilitating for the patient, but that's not how you decide how to manage the patient. Just like in asthma, in other chronic conditions and we have good scoring system, that's because we don't have good biomarkers. So we don't have blood markers that can say this will resolve in two months. This will resolve in a year. But we do have a good scoring system that can show us how well the treatment has controlled the symptoms.

And our group has recently validated the same scoring system in children. So we know that it can be used in children effectively as well. And we have two main scoring system, the US7 and the UCT. The US7 is basically scoring the hive and an itchiness and it's a score of a sum of both and it goes between zero and six. So each one of the cons that itchiness and the hives gets zero to three, because it's a sum it will get between zero minimum, zero plus zero and the maximum will be six, three plus three. It looks a little bit bothersome when you see the first time the patient, you explain to them how to do that, half of them do not understand. Initially you need to explain to them repeatedly, but it's worthwhile. So I always do that and then when I see them again, I know exactly what caught them out of control, what this balance their urticaria and how well they were managed.

And I think also it's important for the patient because it says okay, through the month, there are two days when I had a score of five, but most of the month I had one and two. So this is not really a reason to stop the medication that I'm using right now. And there's UCT is a bit different. It's more useful for inducible forms because inducible forms are types of urticaria that are induced by an external trigger like cold or heat. Unfortunately we have one of the most common inducible form in Canada is related to cold. And this is I think... Well, probably one of the entity that we really need to be aware of because this can eminent to anaphylaxis sometimes when you're exposed to cold abruptly.

And if you do the US7, if you're not exposed to cold, it'll be perfect. So the UCT is capturing better these inducible form because it consists of four question ranked between zero and four, how well were your hive control in the last month? So even if you had one episode of cold induced symptoms, the patient will answer that they were not well controlled and it'll capture better what happens throughout the month. Unlike the US7 for these inducible forms that can rarely induce hives depending on the exposure.


Dr. Mariam Hanna:

With inducible urticarias, do you use standardized testing in clinical practice or is this something that you would just use in research only settings? Do you do attempt test on them? Do you scratch them and figure out how much pressure it took? What do you to use clinically?


Dr. Moshe Ben-shoshan:

I'm very practical and it's very fun to deal with the inducible forms because the patient will come to you, usually the classical thing, he's allergic to chlorine and you hear the story and this is nonsense, nobody can be allergic to chlorine. And you hear the story and you see, oh, whenever he goes to the pool and he goes out, he gets hive, it must be the chlorine. And the problem is that the family doctor sends him with a referral to test for chlorine allergy. And then you put the ice cube, which is simple. You don't need the temp test, you don't need to be that accurate. It's a very crude test and it's a very simple one. You put the ice cube for five minutes and you remove it and boom, a huge hive and you know got your answer and parents are convinced, the child understands what's happening.

I think these are very useful tests. And I try to be as practical as possible. And again, I mean yeah, I may be giving a little bit for your accuracy by using more practical tests, but this is very effective. So I do the ice cube test, I do the dermatographism with the tip of a pen or I do cholinergic. Sometimes I just make them run up and down the stairs in the hospital. That's very fun until they sweat. So I try to be as resourceful as possible in order to make both myself understand the diagnosis and the patient realize what's going on and you'll be surprised how easier it is to manage it afterwards once you identify the culprit. So I do them, you don't need to be that sophisticated to do them.


Dr. Mariam Hanna:

All right. And I like your no-nonsense type approach. That's just very practical. Okay, how do you counsel your families on titrating up or down their medications according to their disease course? What's your secret way of doing that or inspiring way of doing that?


Dr. Moshe Ben-shoshan:

Well, we have UCT, the US7 that I use. And in the guidelines, the European guidelines, it's clear that we have an algorithm that we use often for adults, second generation antihistamine going up to four times the dose. If it doesn't help after two to four weeks or if it's intolerable, you go to omalizumab and then if that doesn't work up to six months you go to cyclosporine. Hopefully that algorithm will be updated soon. So we extrapolate that for children. And then I look at the US7 when I get in and I see when it's more than 16 per week. So the US7 is more than 16, I know it's not well controlled. I know that patient needs something more and I also ensure that they're compliant and they're taking their antihistamines up to four times the dose. And that's basically my thing.

So the first time I am going to see them after two to four weeks because they're very miserable when they come the first time. In children, 90% of cases they'll be much better because I understand the meaning of chronic urticaria. They understand that they need to take it every day to control the symptoms. And there was a recent study showing the daily taking antihistamine is better than just taking them during flares. And if they're not controlled then I offer them the omalizumab and it's a very safe drug and we have good experience with omalizumab. And then I have a few patients also on cyclosporine. Hopefully we'll have other biologic coming into play and we'll offer more options, dupilumab and remibrutinib. So there are other new things that are exciting and seems to be very effective in chronic urticaria. And it's very easy when you show the patients the US7 that you put a little bit of effort because you filled it and you'll be surprised how often they fill, especially with the parents, the mother, it's very clear what you need to do.


Dr. Mariam Hanna:

How do you wean down medications, like as they're doing better or resolving, at what point do you decide we're going to stop or we're going to reduce the doses?


Dr. Moshe Ben-shoshan:

So it's a gray zone. There's no clear answer here. What I do specifically practically, I tell them you have a US7 of zero now for three months, because I follow them every three months. Almost three months you have 7, zero, so don't stop cold turkey. Go one day yes, one day no for two to four weeks. If it goes well, you can stop it. That's what I do. If they were on four times the dose, we go gradually to two times a dose or three times a dose depending how hard it is. So I try not to stop cold turkey and go down more gradually.


Dr. Mariam Hanna:

At what point would you consider doing blood work for patients with urticaria in your practice?


Dr. Moshe Ben-shoshan:

So that's a great question. When I started fellowship, we had a panel for chronic urticaria with anti-nuclear, antibody and ANCA and liver enzymes and whatever you can think about. We're basically a rheumatologist pretending to be allergist. But right now with the guidelines, there are four basic blood tests to take, but I usually take for my patients and even then they're not very well established that this is what we have and it's better to have something that has some kind of reasoning. And the blood that I usually take is CBC, CRP, anti-TPO/total IgE. And the reason is CBC and CRP to make sure we're not missing some kind of vasculitis. Because some rare cases of vasculitis can manifest as chronic Urticaria. I had it mainly with adults but also with children that had chronic hives but also one of the main symptom was extreme fatigue.

And when you ask an investigator, there's also articulation problem and many times swollen fingers. So this is why we take CBC and CRP. The other two are related to the management. So because we have studies especially again in adults showing that those with high IgE are more likely to react to omalizumab, we look at the level of IgE because we know that those that have low IgE are less likely to benefit from omalizumab. It doesn't mean that we won't try it, but you are more likely to succeed if omalizumab is higher than 43, for example, at units per liter. So that's the cutoff in adults. Again, we don't know in children. And why we take anti-TPO because that's a marker of a different type of autoimmunity in chronic urticaria. So most cases of chronic urticaria are thought to be due to an IgE against a cell antigen.

So for example, IgE that binds thyroid peroxidase or interleukin 24. But there's the minority about 20% to 10% due to IgG against the constant region of the IgE or IgG against the IgE receptor. And these cases are associated with high levels of antithyroid peroxidase antibodies. So that's why we take them because these are what we call slow responders. So if we give omalizumab, they're not likely to react in one or two days like the case that I described or cases that have IgE. They can react after a month or more. That's why we give that interval of six months for omalizumab. So these are the four markers that we take. To tell you that these are the optimal markers, probably not, but there are practical markers. All lab are doing them and I find them useful.


Dr. Mariam Hanna:

How do you address patient demands for testing or dietary modification? What's your polite way of saying no?


Dr. Moshe Ben-shoshan:

Yeah, so anything... I'll be going to be very politically correct now. Like anything in medicine, it's a shared decision. So I just give you an example of a patient that came to my clinic yesterday. The mother was extremely frustrated. The child probably was on the spectrum with hives for more than a year and the mother was complaining that it's probably because of the food and she was waiting eight months to see us and she's not going to leave without a skin test. Despite the fact that I explained what the pathogenesis and it's not a food and had it been a food allergy, the presentation would've been different, it wouldn't be hives every day. So some families are more receptive to that and they understand and they will cooperate. Some, it's like anything in life, you try to blame something external, it's easier than something internal in the problem.

Sometimes it helps because it's a placebo effect. So in these cases, when I have no option to convince the parents and it seems that... And I can tell you most times if I do not do that and I insist, they'll go to another allergist and we'll do that at the end, sometimes it's better to be wise than rather than right. So I'll do the test and hope to guide, and most of the time I'm right. The test will be negative. The minority might have a positive one and then I need to convince them that's a false positive one.

And it's easy to do it usually afterwards. But first of all, I need to have the patience on my team. I need to have the parents on my team, on my side, and we need to work together. So confronting them, even if you're right, will not lead me too far. So most of the time I'm successful in explaining and applying to the reason, but sometimes when it doesn't work, I'm being a coward and doing skin tests, but at the end of the day, it's rarely positive. So we are on the right way afterwards.


Dr. Mariam Hanna:

Nice to know that you have these frustrating encounters like the rest of us in allergy. You mentioned some biologics in our toolbox. There's currently only one that is indicated and in the guidelines with more hopefully on the way, is there still a role for immunosuppression in chronic urticaria? You talked about in the early days of your practice that this was more common. Do you still use it sometimes?


Dr. Moshe Ben-shoshan:

Well, cyclosporine is like an immunosuppressant in a way. So I still use cyclosporine sometimes. I don't use any more methotrexate or an MMF. I mean, I just didn't need it. So again, because we think that there are two main mechanisms for chronic urticaria, one of them is involving IgE and omalizumab will help, and the other one is involving IgE, but in less direct way. Most, I would say that 100% of my cases will be well controlled with either omalizumab or cyclosporine, the severe cases even in adults. The problem is that cyclosporine has substantial side effects. So again, if you asking everybody, each one of us has a different practice, like dermatologists usually start with very high dose of cyclosporine. I start with very small doses below the therapeutic window. You need to take blood tests and electrolytes and liver enzymes and take blood pressure and creatinine to make sure there's a known side effects.

But that's the only obstacle basically to use cyclosporine because when you use cyclosporine, even in small doses in patients with chronic urticaria that did not respond to omalizumab, my experience is that it's very helpful. And then I follow the level of cyclosporine and in most cases it's below the therapeutic window, but the patient is ecstatic with happiness because suddenly it works. And so I don't think there's much room nowadays for methotrexate and more aggressive treatment in the pathway even use plasmapheresis. I don't think there's much place for that. We have much better strategies now to treat it, but that's my personal experience.


Dr. Mariam Hanna:

Okay. Speaking of more room in the future, where are urticaria guidelines moving in the future? What do you think is going to happen with the next iteration of these guidelines?


Dr. Moshe Ben-shoshan:

So first of all, I think we'll start to have more data on children. So it might change the algorithm for children might differ a little bit from the one for adults. I'm pretty sure we'll have new biologics like Dupi is already approved in Japan for chronic urticaria. I'm pretty sure we'll have in the near horizon the BTK inhibitor of remibrutinib. So I think that's where it's going. I know that I can tell you that I'm part of a North American group to establish North American guidance for clinical care. And again, my approach is to make things as simple as post possible. So both allergist and patient can follow guidelines that are evidence-based and not some pure imaginations or assumptions that we have. Like the initial days of food introduction, oh, yeah, let's wait for the immune system to mature and then [inaudible 00:24:00]. No, that's wrong thing to do. We need to give it before it matures so it matures and become tolerant, right? So I think that's where it's going. Like evidence-based more and we'll have North American guidelines and I hope we'll have more options in these guidelines.


Dr. Mariam Hanna:

You heard it here first directly from Dr. Ben-shoshan. All right. Time to wrap up and ask today's allergist, Dr. Moshe Ben-shoshan for his top three key messages to impart to patients and physicians on today's topic, chronic urticaria. Dr. Ben-shoshan, over to you.


Dr. Moshe Ben-shoshan:

Okay, so my first message, as you might guess, it's not an allergic condition, it's an autoimmune condition, one. Two, it's not dangerous, but it can last long. Three, we have very good strategies to control it.


Dr. Mariam Hanna:

You are so succinct, no one does it as well as you. All right, thank you, Dr. Ben-shoshan for joining us on today's episode of The Allergist.


Dr. Moshe Ben-shoshan:

Thank you.


Dr. Mariam Hanna:

This podcast is produced by the Canadian Society of Allergy and Clinical Immunology. The allergist is produced for CSACI by PodCraft Productions. The views expressed by our guests are theirs alone and do not necessarily reflect the views of the Canadian society. This podcast is not intended to provide any individual medical advice to our listeners. Please visit www.csaci.ca for show notes and any pertinent links from today's conversation. To find an allergist app on the website is a useful tool to locate an allergist in your area. If you like the show, please give us a five star rating and leave a comment wherever you download your podcast, because we're all about passion, persistence, and practicality in urticaria guidelines. Thank you for listening. Sincerely, be out.