Exploration in CSU

Today, we will explore chronic spontaneous urticaria.

I am Jonathan Rodrigues, a Medical Director in Dermatology and Allergy with Novartis Pharmaceuticals.

And I am Merin Kalangara, also a Medical Director of Dermatology and Allergy with Novartis Pharmaceuticals.

The objectives of this presentation are:

To discuss the patient burden associated with chronic spontaneous urticaria or CSU and the importance of early diagnosis.

As well as to review the role that Bruton’s tyrosine kinase or BTK plays in the pathophysiology of CSU.

We will be reviewing the mechanism of disease, as well as the management, highlighting the role of BTK in CSU.

Chronic urticaria is classified as either being spontaneous or inducible.

Chronic spontaneous urticaria is defined by the spontaneous appearance of hives, swelling, or both for greater than 6 weeks due to known or unknown causes.

An accurate and thorough symptom assessment is very important in the workup for chronic spontaneous urticaria as this would remove the need for the costly investigations that do not necessarily contribute to diagnosis or improved clinical outcomes but rather further cause delay in the diagnosis of CSU.

This chart represents the diagnostic algorithm of patients presenting with wheals and or angioedema greater than 6 weeks.

In patients presenting with hives with or without swelling in the absence of prominent systemic symptoms, average hive duration of longer than 24 hours and primarily inducible symptoms and in patients who present with isolated angioedema, the absence of concomitant ACE-inhibitor therapy, as well as negative workup for hereditary or acquired angioedema a diagnosis of chronic spontaneous urticaria may be established in a straightforward fashion.

Let’s take a look at the clinical features of CSU.

CSU is defined by itch, hives, and/or angioedema for more than 6 weeks.

While individual hives usually resolve within 30 minutes to 24 hours, individual instances of angioedema may even take up to 72 hours for resolution.

The prevalence of CSU is increasing globally and is approximately 1% in the United States with an overall lifetime prevalence of 4.4%.

Onset of symptoms is typically between ages of 30 and 50 years.

Women are affected twice as often as men.

Diagnostic delays are common for patients with CSU and are likely driven by:

- Inadequate knowledge of CSU among patients and providers

- Unnecessary allergy or laboratory investigations

- Incorrect treatment patterns

- And poor compliance with guidelines and best practices

With the low rates of associated clinical improvements from multiple tests, testing may not be a cost-effective strategy in the management of CSU patients, considering an average screening cost of $573 per patient.

This slide depicts different patients’ emotions and experiences as symptoms begin to manifest.

Some CSU patients could have significant delays in diagnosis, averaging 2 years from symptom onset to diagnosis.

Some CSU patients may also continue to have ongoing symptoms with no response to standard antihistamine therapy and these patients are referred to as refractory CSU patients.

The rate of traditional practitioner visits by CSU patients was approximately twice that of matched controls.

The mean number of hospitalization of CSU patients was 3 times that of matched controls.

More patients treated for chronic hives reported work impairment than matched nontreated controls. There were increased prevalence of depression, anxiety and sleep disturbances amongst patients treated for chronic hives compared to matched controls.

Overall, CSU has impact on quality of life similar to other chronic dermatological diseases, such as psoriasis, atopic dermatitis, or psoriatic arthritis.

This chart shows the impact on a patient’s quality of life due to refractory CSU.

The significant impact of refractory CSU on patients quality of life highlights the need for urgent diagnosis and treatment.

The pathogenesis of chronic spontaneous urticaria involves antibody-mediated mast cell and basophil activation.

This mast cell activation occurs through crosslinking of IgE by autoallergens or IgG, or crosslinking of high-affinity IgE receptors by IgG.

Activated mast cells release proinflammatory mediators, primarily histamine, via specific pathways.

And with the release of these mediators, there could be increased vascular permeability which leads to symptoms of hives and swelling, and stimulation of irritant receptors that causes pruritus.

The pathogenesis of chronic spontaneous urticaria involves antibody-mediated mast cell and basophil activation, occurring via IgE (in “auto allergic” or type I CSU) or IgG (in “auto immune” or type IIb CSU) generated by differentiated B cells.

Type I CSU involves crosslinking of the high-affinity IgE receptor via autoreactive IgE molecules against self-antigens promoting mast cell and basophil degranulation and type IIb CSU involves IgG molecules directed against the Fc portion of IgE or the high-affinity IgE receptor promotes spontaneous cellular degranulation.

Bruton’s tyrosine kinase or BTK belongs to the Tec family of kinases and plays an important role in the development and function of leucocytes.

BTK regulates the high-affinity IgE receptor signaling in mast cells, and this function could position it as an attractive molecule in IgE-mediated diseases.

IgE antibodies bind the high-affinity IgE receptor on mast cells and basophils to trigger degranulation and acute inflammation.

BTK also integrates B-cell receptor signaling to regulate B-cell development and function and acts downstream of the high-affinity IgG receptor or Fc gamma receptors on various innate as well as adaptive immune cells.

This figure depicts the central role played by BTK in mast cell activation, degranulation, and release of inflammatory mediators, which induce symptoms of CSU including itch, hives, and swelling.

This mast cell activation occurs through crosslinking of IgE by autoallergens or IgG, or crosslinking of the high-affinity IgE receptor by IgG.

This updated 2022 version of the international urticaria guidelines cover the definition of CSU and outline expert-guided and evidence-based diagnostic and therapeutic approaches for CSU.

The guidelines for chronic spontaneous urticaria endorsed an assess, act, and adjust paradigm that encourages the routine use of validated patient reported outcome measures to monitor disease activity and achieve optimal disease control.

The management of chronic spontaneous urticaria is often fraught with several challenges such as:x``

- Acute flares which are unpredictable and highly distressing; a short course of systemic steroids can be used in rescue cases for these acute exacerbations but not recommended for long-term use due to adverse effects.

- Diagnostic delays may impact identification of other comorbid or masking diseases, with attendant increases in health care utilization costs.

- And finally, a paucity of reliable biomarkers to assess disease severity and predict treatment response, again hinder optimal patient management.

To summarize, CSU is defined by itch, hives, and/or angioedema for more than 6 weeks.

Patients who do not respond to antihistamine therapy often report significantly decreased quality of life.

The international guidelines promote accurate diagnosis of CSU through thorough history without unnecessary investigations that may delay diagnosis and create a cost burden without improvement in outcomes.

Activated dermal mast cells and basophils play a major role in the pathophysiology of CSU.

BTK mediates mast cell degranulation downstream of Fc epsilon receptor I, and thus plays a role in pathophysiology of both known CSU endotypes.

Thank you for your time and attention.