Patients With CSU Need New Therapies, Says Dr Jonathan Bernstein

Jonathan Bernstein, MD

Currently, there are not a lot of treatments for chronic spontaneous urticaria (CSU), and they aren’t totally effective in all patients, leaving a need for newer options and options for patients who are refractory to treatment, said Jonathan Bernstein, MD, an allergy specialist at Bernstein Allergy Group Inc. However, he’s optimistic that we’re on the cusp of having new options.

In the second part of his interview with The American Journal of Managed Care^® (AJMC^®), Bernstein discussed diagnosing CSU, the specialists involved in care, comorbidities, and more.

In part 1 of the interview, he described the pathophysiology of CSU and the impact the fluctuations of the disease have on patients.

AJMC: When you're considering a patient with CSU, what's in your differential diagnosis, and how do you definitively diagnose CSU?

Bernstein: The nature of the hives is that they are wheals with itching. They're evanescent and they come and go. Some people say they have itchy lesions, but they don't go away. They're persistent. Also, they have serpiginous borders, and they travel to different parts of the body. They don't leave scars, even after scratching. Unlike other chronic itching skin disease diseases, they don't blister. And some people don't recognize the difference between a blister and a wheal. So, we try to show pictures to patients and show them, “This is what hives look like. Is this what you're having?” Because it makes it easier for them to help discuss it: “That's not what I'm having, doc, that's just something different.”

Hives are very polymorphic and they're very heterogeneous, and they look different. Some can be coalescent—we call those giant hives. There's also scattered small papules, and those look quite different. Other chronic diseases can be associated with urticaria. Mast cell disorders and certain other conditions can present like urticaria, like cold autoinflammatory disorders, which are rare, but complex diseases. There’s Schnitzler syndrome, which can be associated with hives. Many people think that if the hives are persistent, then it's more likely vasculitis, but there have been pathology studies showing that even urticaria vasculitis can be evanescent and last less than 24 hours, and patients can still have vasculitis. So, that makes a case for patients who aren't responsive to high dose antihistamines, which is step 1 therapy of the international guidelines, they should be considered for a skin biopsy if there's atypical lesions to make sure that these are hives. Depending on what the infiltrates are—eosinophilic or neutrophilic or a mixture—that can help us determine the condition quite a bit. So, I think that those are the major the things we think about when we think about differential diagnosis or urticaria.

AJMC: Which specialties are involved in managing patients with CSU, and how can multidisciplinary care be optimized for these patients?

Bernstein: Primary care doctors will see these patients often. These patients might also be seen in the emergency room or in urgent care centers. It's important for all physicians to recognize what hives are and determine whether they're acute or chronic. And if they're acute, obviously you want to treat them symptomatically and take a history to see if there's anything that could be contributing to it: food, a stinging insect, a drug, or something of that nature. But we have to be careful not to make associations and that these are direct cause and effects. If it's a food, they eat it, they get hives within 15 to 30 minutes. And if they don't eat it, the hives don't come back. But if the hives are persistent, then it's less likely the food that they suspect.

Many patients do come in thinking that it's something they're doing, and many times they don't know what it is, and they try to do things like they eliminate all these foods and stop their medications. They need to treat their other underlying medical problems. So, that can be potentially dangerous, and that's why they need to work with someone knowledgeable in the treatment of hives. So, if the primary care doctor is able to at least evaluate that from initial get go and even treat with antihistamines, if they respond, that's good, but if not, they really should be seen by a specialist. The people who are taking care of urticaria are allergists, immunologists, and dermatologists predominantly. So, I think that this is where you would get more advanced care if the hives are persistent despite antihistamines dosing up to 4 times the recommended dose.

AJMC: What comorbidities that are commonly seen with CSU, and how do these affect your management plan for patients?

Bernstein: A lot of patients with hives might come in with fatigue. They might come in with muscle aches and pains. They're itching significantly. So, they might have some of these non-specific low-grade symptoms—even low-grade fever sometimes—but that may make you suspect something more systemic. When we think about the initial workout, we don't advocate a lot of treatment and diagnostic testing, the studies have shown that it doesn't really contribute much to the overall management. But there is consensus to get a complete blood count with differential and maybe a C-reactive protein, and, if not done recently, a thyroid test.

Now that there's a paradigm shift, especially in patients who come in and they're not responsive antihistamines, that perhaps getting a total IgE, a thyroid peroxidase enzyme level, and maybe even a Chronic Urticaria Index panel, which is a surrogate marker for autoantibodies against Ig receptors on mast cells, might be useful at the specialist level to determine the prognosis in terms of response to medicines like omalizumab (Xolair) versus other therapies like cyclosporine, which are steps 2 and 3 in international guidelines. So, when we see these patients coming in and they have low-grade fevers and they have joint pain but they're having diffuse hives, we do think about other systemic conditions, and I think getting some of these limited tests will help us rule those things out. If there's clinical suspicion for other things, then by all means, additional testing should be done, but we shouldn't just close our eyes and order a bunch of tests unless there's some justification. Many times those tests don't really alter the management of the disease. So, but it is common that these patients can present with mild systemic symptoms, and that shouldn't distract or drive the clinician to think this is something much more serious because this is something commonly seen in chronic spontaneous urticaria as well.

AJMC: Do you see any common triggers for CSU, and what are your methods for counseling patients to avoid or mitigate these?

Bernstein: By definition, chronic spontaneous urticaria is spontaneous, and there aren't any real well-known triggers for chronic spontaneous urticaria. People often say, “Oh, it happens when I'm stressed out.” It certainly could be a contributing factor, because we do know that when people are stressed, certain neurogenic pathways are activated and nerves can be depolarized and release neuropeptides that can activate mast cells. But, in terms of chronic spontaneous urticaria, we don't advocate getting panels of food testing or testing for aeroallergens because those are not common triggers for chronic spontaneous urticaria unless the history dictates otherwise. I mean patients might roll on the grass and get hives, that's more contact urticaria. But foods are typically not a common cause of chronic urticaria, even though patients are frustrated and try to implicate them. But that comes out in the history.

Where we see triggers are patients who have chronic inducible urticaria. So patients may notice that when they scratch their skin, they welt up, as in dermatographia, or they may note that when they're in cold temperatures or when they jump into a cold pool, that they'll break out in hives. Or when they get very anxious or angry or their whole body temperature heats up and starts to cool down, they get hives called cholinergic urticaria. These are inducible hives that we should be querying all of our patients about, and some validated patient-reported outcome measures for some of these inducible hives are starting to emerge.

That being said, most of the time we don't find the cause for chronic spontaneous urticaria. We are understanding that autoimmune mechanisms and possibly autoallergic mechanisms are involved but probably don't explain everything about mast cell activation and mediator release. Most of the time, there is no identifiable trigger for chronic spontaneous urticaria.

The only way to mitigate it is to avoid the triggers, and for inducible hives, treat the patient and get them well controlled with medications.

AJMC: What do you see as the biggest unmet need for patients living with CSU?

Bernstein: I think it's important that doctors and primary care doctors alike understand how to at least diagnose chronic spontaneous urticaria and how to evaluate these patients. That doesn't mean they need to be involved in advanced treatment, but they need to make sure that these patients are diagnosed, that they go through initial treatments, and if they aren't responsive, then they should be referred to an experienced specialist who is knowledgeable about the management of these patients.

After high-dose antihistamines, which is up to 4 times the recommended FDA dose of second-generation antihistamines, there really aren't a lot of available treatments. There is omalizumab, which is a repurposed drug that was initially developed for asthma and now has been approved for urticaria since 2014. It has been shown to cause complete control of urticaria in up to 40, maybe 45%, of patients. There is a partial response in a number of patients, but that's not adequate because patients are still miserable when they went from 50% of their body to 25% of their body with hives, they're still breaking out daily. There's a lot of social stigma with that. People say, “What's wrong with you? Are you contagious?” And things of that nature. And it's uncomfortable.

We need newer therapies and to understand the mechanisms of action of urticaria, and understanding the pathophysiology of urticaria that allows us to develop drugs that target different pathways is extremely important. I think we're on the cusp. Right now, we have several novel therapies that are targeting different regulatory pathways in mast cells that can potentially turn off mast cells and basophils and stop hives. Basophils are involved and they do release histamine, but mast cells are the primary cell.

I think that the biggest unmet need is advanced therapeutics to treat the patients who are refractory to the current treatments that we have available and to identify ways of inducing remission early. Patients can take these medicines to resolve the hives but don't have to be on them for the rest of their lives necessarily. Hives do go into remission. Every time we start drugs and get good control, over time it is important to step down to see if they still need the therapy, like we do with any chronic disease.