Allergy & Immunology

Chronic Spontaneous Urticaria


Evaluating the Complex Differential Diagnosis of Chronic Spontaneous Urticaria

patient care perspectives by Jonathan A. Bernstein, MD

Diagnosing chronic spontaneous urticaria (CSU) can be challenging. Clinicians can work through the differential diagnosis by documenting the presence of hives, taking a thorough patient history, and excluding underlying conditions.

Expert Commentary
“. . . taking a thorough history to rule out other underlying causes, supplemented with a few tests that have been demonstrated to predict response to different therapies, will allow the clinician to successfully diagnose and treat CSU effectively.”
— Jonathan A. Bernstein, MD

Many different conditions can present with itching and/or rashes that can mimic chronic urticaria. So, when a patient presents with a pruritic rash, it is important to make sure that you are actually dealing with hives. It is always nice to see a picture of a patient’s hives because hives have distinguishing characteristics from other pruritic rashes with raised wheals and serpiginous erythematous borders. Most importantly, hives come and go over a 24-hour period and sometimes may not be actively present at the time of the patient’s office visit. If the pruritic rash is persistent, meaning that the lesions do not come and go or travel to different parts of the body, then it is likely not hives. Other types of rashes that mimic hives include urticarial vasculitis and maculopapular cutaneous mastocytosis lesions, which are both persistent. Rarely, spontaneous urticarial conditions can manifest as autoinflammatory diseases, such as Schnitzler syndrome. Thus, there are many conditions that can cause patients to have itching and lesions that look like hives but are not actually hives.


If patients have new-onset, recurrent hives that have been present for 6 weeks, they meet the criteria for chronic hives. These patients may have been on a routine dose of second-generation antihistamines but have not yet tried a higher dose of antihistamine. On initial presentation, we typically get a thorough history to rule out any underlying causes and avoidable triggers. If we find anything suspicious in a patient’s history, we perform additional testing; however, extensive testing is typically not recommended unless something in the history indicates that it is needed. Guidelines recommend obtaining a complete blood count with differential; erythrocyte sedimentation rate; C-reactive protein; and, if not previously done, a thyroid-stimulating hormone level.


In CSU, cases of isolated hives, hives associated with angioedema, and isolated angioedema occur about 50%, 40%, and 10% of the time, respectively. Usually, we cannot definitively tell patients what causes or triggers their hives, but up to 50% of individuals with CSU do have an autoimmune etiology. So, characterizing patients with CSU as having an autoimmune or autoallergic condition is appropriate, especially if they are not responsive to second-generation antihistamines. When there is an inducible component to the urticaria, we can confirm with provocation testing. However, there are many different receptors on mast cells that can be activated by different triggers associated with CSU, which are targets for novel therapeutic agents. In this regard, we are beginning to understand more about the mechanistic pathways related to CSU than we did previously.


Nonetheless, CSU can be alarming to patients when 70% of their body is covered in hives that are very itchy. Therefore, educating the patient about the nature of hives and how they manifest is essential to allay their concerns about their prognosis. It is also important to document the initial severity and control of hives so that the impact of treatment can be monitored over time. In summary, taking a thorough history to rule out other underlying causes, supplemented with a few tests that have been demonstrated to predict response to different therapies, will allow the clinician to successfully diagnose and treat CSU effectively.


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Lang DM. Chronic urticaria. N Engl J Med. 2022;387(9):824-831. doi:10.1056/NEJMra2120166


Metz M, Altrichter S, Buttgereit T, et al. The diagnostic workup in chronic spontaneous urticaria—what to test and why. J Allergy Clin Immunol Pract. 2021;9(6):2274-2283. doi:10.1016/j.jaip.2021.03.049


Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77(3):734-766. doi:10.1111/all.15090

Jonathan A. Bernstein, MD

    Adjunct Professor
    Division of Rheumatology, Allergy and Immunology
    Department of Internal Medicine
    University of Cincinnati College of Medicine
    Partner, Bernstein Allergy Group and Bernstein Clinical Research Center
    Cincinnati, OH