CSU Can Affect All Aspects of Patients’ Lives, Explained Dr Jonathan Bernstein

Jonathan Bernstein, MD

Patients with chronic spontaneous urticaria (CSU) experience chronic hives that can make them feel miserable and greatly affect all aspects of their lives, explained Jonathan Bernstein, MD, an allergy specialist at Bernstein Allergy Group Inc.

During his interview with The American Journal of Managed Care^® (AJMC^®), Bernstein also described the pathophysiology of CSU and the impact the fluctuations of the disease have on patients.

AJMC: Could you please describe the pathophysiology of CSU, and how it's both an autoallergic and autoimmune disease?

Bernstein: Well, urticaria is a mast cell–driven condition. Mast cells are ubiquitous in our body in different organ systems, and they are increased in patients with chronic spontaneous urticaria in the skin. They are reactive. They become activated and release bioactive mediators and cytokines that lead to vascular changes that result in urticaria and, in more severe circumstances, angioedema or soft tissue swelling. There are many ways to activate a mast cell, not just through IgE receptors or through autoantibodies; there are many different receptors on mast cells that can be targets for activation. Most patients seem to respond clinically to H1 antihistamines, which are simply medications that block histamine receptors. They're not really having a direct effect on mast cell activation or what happens at the mast cell level. They're just blocking the effects of histamine.

However, we see over 50% of patients are not responsive to H1 antihistamines, and that indicates that there are other pathways involved. Then these pathways have shown that autoantibodies produced in response to the Ig receptor—the high affinity Ig receptor—or to antibodies—Ig antibodies—attached to those receptors or to self-antigens or receptors or cytokines. These are what have been referred to as autoallergic and autoimmune disease. These are 2 pathways that have been proposed to explain why patients are not responsive to classical treatments, and that's why more advanced therapeutics are needed. But there are probably many other pathways and many other ways to regulate mast cell activation that is probably more relevant. I think autoantibodies are definitely increased in patients with chronic spontaneous urticaria, and we see a much greater prevalence of autoantibodies to different organ systems, whether it's antinuclear antibodies or thyroid peroxidase or thyroid autoantibodies. But how that equates to the pathogenesis is still a little questionable.

Needless to say, the treatments that are being developed are targeting mast cell activation in many novel ways that are very encouraging in really look very promising for helping some of these patients who are much more resistant to the traditional care.

AJMC: How is the IgG pathway and how that is also involved in the pathophysiology?

Bernstein: I mentioned the fact that [it has been] known for many years that there are IgG antibodies that can activate mast cells through binding to high affinity Ig receptors on the mast cell. These are autoantibodies targeting these receptors. Or through Ig, they could be IgG or anti-IgE antibodies because they're binding to Ig molecules that attach to these receptors. And then there can be IgE antibodies targeting other self-antigens like thyroid peroxidase. And other thyroid antibodies have IgE antibodies proposed against certain cytokines like IL-24. This is what I mean by when I talk about autoimmune and autoallergic disease. This is what I was referring to.

AJMC: What are the dermatologic symptoms most associated with CSU and how do they fluctuate over time making this a serious disease?

Bernstein: Patients can have chronic hives—meaning they have hives that are persistent over 6 or more week. If the hives are just acute, they can occur suddenly and they can resolve and not come back, but they don't last. They're not chronic, and they don't last more than 6 weeks. The hives are associated with wheals and itching. This is what hives are. The critical thing about hives is that they come and go. They travel to different parts of the body, and they don't last typically longer than 24 hours. That’s the effect on the epidermis. The other part of this process is they're extremely pruritic. They're very itchy and they're very annoying. If you have over 50% of your body covered in hives and they're not resolving, you can imagine how miserable people can be. It can affect all aspects of life—work, leisure activities, sleep, interpersonal relationships.

The other part is that when these inflammatory responses extend in the deeper dermis, then people might start showing angioedema as well. And up to 40% of patients with chronic spontaneous urticaria also have angioedema, typically affecting the face, the lips, the tongue, things of that nature. So, it is a common problem. But these hives are very distinct. They have irregular borders, serpiginous border. They're erythematous but they're raised and they travel.

Now, there are other types of hives that are inducible hives, which we used to refer to as physical hives. They can be triggered by physical triggers like heat, cold, exercise, pressure, sunlight, and also scratching, which is referred to as dermatographia. Those also can be seen in patients with chronic spontaneous urticaria. And 30% to 40% of cases may actually have associated chronic inducible hives.

These are important characteristics to ask patients, because if you have angioedema, it's associated with more severe disease. If you have chronic inducible hives, then that's associated with more protracted course the natural courses last up to 3 to 5 years or 1 to 5 years in patients, depending on the study quoted. But typically, when patients with inducible hives, they may have more protracted courses that may last longer. When patients present, we try to quantify the number of hives and the severity of itch. This is what we use the Urticaria Activity Score (UAS) for. This can be done over 24 hours, or it can be done over a 7-week period. Basically, it quantifies the number of hives, and also the severity of itch. Of course, the higher the number on a scale from zero to 42, the more severe. When you have a very high UAS7 [the sum of UAS scores over 7 consecutive days] score at baseline, that also correlates with severity and more severe disease.

AJMC: Could you please discuss the epidemiology that's associated with CSU and why this disease might be underdiagnosed?

Bernstein: Anywhere from 1% to 3% of the general population has hives. The difficulty is that there aren't great epidemiologic studies on hives, and hives can come and go. It may not always be reported. For that reason, the epidemiology is lacking. That being said, we do know that it affects a significant percentage of the population. The other thing is that it may not be recognized. Hives may not be recognized as being chronic spontaneous urticaria. They might be diagnosed as part of other conditions like mast cell activation syndromes or other comorbid conditions, and they are not recognized as a standalone condition: chronic spontaneous urticaria. But so it could be underdiagnosed and certainly it's not always reported. So, we don't have good systems for looking at epidemiology.

There are now apps that are being developed. One is called the Cruse app, which is in 16 countries, including the United States, which uses a lot of these validated patient-reported outcome measures that can be easily downloaded onto people's cell phones, and they can record their symptoms. This will allow us to capture better real-world data about the prevalence and the natural course of urticaria, and hopefully, could be used to look at response to treatments as well, and help us develop understandings of mechanisms as well as other potential pathways for targeting hives. This is a real-world app that is being done for a number of chronic diseases, not just hives. It's being done for rhinitis and asthma, currently, and now being adapted for urticaria. I think this will help us with epidemiology in the future.

AJMC: Does this disease have a female or male predilection? What's the age of patients?

Bernstein: Demographically, women are much more likely to be affected by urticaria over 2-to-1 ratio. It's much more common in women, but it does affect men. The average ages are of onset is about 20 to 40 years of age, but in some countries, the average age of onset is 12 to 13 to 14 years. It depends on the study, and it depends on the population, but it affects the spectrum from young to old. Again, it is more common in women than men, but there is no ethnic predilection, per se. So that's what we know about the demographics of this condition.

AJMC: What are some of the common psychological symptoms or effects in patients with CSU, and how do you manage them?

Bernstein: As I've alluded to, hives could be quite serious and severe, and they can impact people's daily lives. They can impact sleep, interpersonal relationships, leisure activities, and work. There's a lot of presenteeism or work impairment, and that’s been demonstrated using validated work impairment questionnaires surveys. We know it affects quality of life because there are disease specific as well as general non-specific quality-of-life measures, such as the 36-Item Short Form or 12-Item Short Form surveys. And there is the Chronic Urticaria Quality of Life Questionnaire, which demonstrates significant burden of disease. And so how do you do that? I think it's important to really quantify how much impact the disease is having. What is the burden of illness for patients? I think it's important to have shared decision making and to really involve the patient in their care. I think it's important to understand the algorithmic approach to treatment of hives, and get these patients managed.

Once they're better controlled, their psychological symptoms significantly improve. Stress is reduced, their sleep patterns improve, their activities improve, and their lives are normalized. So, it's a matter of understanding how to diagnose, how to evaluate, and how to manage these cases. I think that will address the psychological symptoms. Now, many patients have underlying primary anxiety or effective disorders. They always think that this might be causing their symptoms. We do know that neurogenic responses and neurogenic pathways play a role, but I don't think this is what's causing hives. But I think when you reduce stress, you do improve patients’ overall well-being, including their ability to deal with urticaria and other chronic disorders.

AJMC: Can you talk more about how this disease impacts sleep and work productivity?

Bernstein: Sleep is extremely important, we know that patients are itching and they're scratching all the time, and they're just miserable, and they can't sleep. If you can't sleep, then other problems occur. You just aren't able to function during the day. You aren't able to interact well with other people. So, it has almost like a chain reaction response. And so sleep is significantly impacted. And there are sleep impairment questionnaires that have been used in many studies to show that, at baseline, patients have significant impact on sleep. There have been many national health surveys looking at the impact of urticaria on sleep. This has been well documented.

The same is true of work productivity. These are all validated indexes that have been used in clinical trials, but also in real-world health surveys, and we know that chronic urticaria does impact work productivity. This leads to an economic burden, because when we think about the cost of treating urticaria, it's not just direct cost, which is the cost of medication and office visits and whatever else, but also the indirect cost, which is the loss of work productivity and so forth. So, these all have to be factored in. When we think about the overall cost of hives, it approaches the same cost to treat hypertension and diabetes and other severe chronic skin diseases like psoriasis.