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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease."

Chronic spontaneous urticaria (CSU), a mast cell-driven disease that affects , makes up about 80% of all cases of chronic urticaria. Treatment is aimed at preventing or controlling the rapid onset of itchy, inflamed wheals and/or angioedema that recur on an almost daily basis without any identifiable cause. By definition, CSU symptoms continue for more than 6 weeks, but often last for years -- with a devastating impact on quality of life.

Many questions remain about the pathogenesis of CSU. Fortunately, new insight into the close correlation between CSU and autoimmune disease, and the mechanisms that control disease duration and treatment response, is offering hope. Recent research into the presumed autoimmune CSU endotypes is shining a bright light on the characteristic clinical and laboratory features, as well as the links to autoimmune disease. These findings have significant implications for clinical practice and for improving patients' lives.

Patients with CSU have an increased risk of comorbid autoimmune diseases -- primarily Hashimoto's thyroiditis, vitiligo, and rheumatoid arthritis. CSU is also seen in patients who already have autoimmune disease, and most frequently occurs in those with autoimmune thyroid disease (AITD), systemic lupus erythematosus, rheumatoid arthritis, celiac disease, Sjögren's syndrome, and type 1 diabetes.

Physicians seeing patients with CSU should consider investigating the possible presence of other immune pathologies. The most recent (2022) recommends that physicians assess CSU patients for thyroid hormones and autoantibodies when the patient history indicates that an extended diagnostic workup is required.

"Due to its immune-mediated nature, CSU has a wide range of associated comorbidities, in which autoimmune diseases are undoubtedly the most frequent," said Giuseppe Murdaca, MD, PhD, of the University of Genoa in Italy, and colleagues in a on autoimmune disease in chronic urticaria. "A multidisciplinary and multimorbid approach to the patient affected by CSU allows not only control of the natural course of the disease, but also any associated comorbidities," the team wrote.

An earlier literature noted that the prevalence of autoimmune disease in CSU has increased, and is now somewhat higher than in the general population (≥1% vs ≤1%). Most of the studies included in the review reported rates of the following autoimmune diseases:

• Comorbid insulin-dependent diabetes mellitus, rheumatoid arthritis, psoriasis, and celiac disease: ≥1%

• Graves' disease: ≥2%

• Vitiligo: ≥3%

• Pernicious anemia and Hashimoto's thyroiditis: ≥5%

In the last decade, the description of , classified as type I and type IIb autoimmune mechanisms, has provided a valuable research focus, with implications for clinical practice. Both CSU endotypes contain the same mast cell-activating autoantibodies found in atopic dermatitis, celiac disease, type 1 diabetes, and rheumatoid arthritis.

• Type 1 autoimmune CSU, also known as autoallergic CSU (aaCSU), accounts for more than half of all cases of CSU and is associated with immunoglobulin E (IgE) autoantibodies against an endogenous allergen such as thyroid peroxidase or interleukin-24.

• is mediated by IgG, IgM, and IgA autoantibodies against IgE or its high-affinity receptor, FcεRI. Only 8% of CSU patients are estimated to have this urticarial endotype. Type IIb aiCSU is characterized by increased disease severity and more concomitant autoimmune disease compared with type 1. Other features include low levels of total IgE, elevated levels of IgG-anti–thyroid peroxidase, basopenia, eosinopenia, poor response to antihistamines and omalizumab, and a good response to cyclosporine.

The current gold standard for the diagnosis of aiCSU, following results from the 2019 , is triple positivity on the following:

• Autologous serum skin test (ASST)

• Basophil histamine release assay (BHRA) and/or basophil activation test (BAT)

• Immunoassay for IgG autoantibodies against FcεRIα/IgE

Triple positivity is associated with elevated disease activity and usually presents with low levels of IgE and higher rates of eosinopenia and basopenia.

In 2021, results from a multicenter by Marcus Maurer, MD, of Charité Universitätsmedizin Berlin in Germany, and colleagues found a significant link between autoimmune comorbidity and aiCSU, as confirmed by triple positivity. The analysis of data from 1,199 CSU patients showed that the risk of autoimmune disease was 1.7, 2.9, and 3.3 times higher for patients with positive ASST, BHRA, and BAT, respectively.

The findings support the concept that aiCSU is a distinct endotype of CSU, the researchers said. "Therefore, we recommend that CSU patients be assessed for features of aiCSU and be investigated, at the onset of their urticaria and at regular intervals, for comorbid autoimmune diseases."

In the analysis, 28% of CSU patients had at least one autoimmune disease, most often AITD (usually Hashimoto's thyroiditis), and 2% had two or more autoimmune diseases, most frequently Hashimoto's thyroiditis plus vitiligo.

Comorbid autoimmune disease was associated with female gender, family history of autoimmune disease, and higher rates of hypothyroidism and hyperthyroidism. A total of 71% of patients with high normal/high or low thyroid-stimulating hormone (TSH) levels were diagnosed with Hashimoto's thyroiditis or had elevated IgG anti-TPO levels. One patient had Graves' disease and 7 had undefined AITD.

Based on this, along with earlier evidence, the investigators concluded that adults with CSU seen in clinical practice should undergo routine screening for elevated IgG anti-TPO. Maurer and co-authors said, "If thyroid function is not impaired and symptoms are absent, patients should be followed up periodically to monitor for symptoms of hypothyroidism and to detect any rise in their TSH and/or development of autoimmune diseases other than Hashimoto's thyroiditis."

Research into the role and relevance of autoimmune disease in CSU is important, the team emphasized: "First, the presence of autoimmune diseases in patients with CSU may predict the duration, activity, and course of CSU and the response to treatment. Secondly, various features of CSU may be associated with a higher risk of having comorbid autoimmune diseases. Knowledge of these features can help facilitate early diagnosis of comorbid autoimmune diseases in patients with CSU. Thirdly, therapeutic interventions in patients with CSU and concomitant autoimmune diseases need to be aligned to assure maximum efficacy as well as minimum drug interactions and adverse effects."

In 2023, three international studies provided new evidence about the features, frequency, and overlap of CSU endotypes and their association with autoimmune disease. The first, a by Maurer's team in 111 CSU patients, showed that most patients had either aaCSU, aiCSU, or both. Although all but one patient with autoimmune CSU also had autoallergic CSU, only 13% of patients with aaCSU also had aiCSU. About 41% of CSU patients had neither endotype.

The study also showed that patients with autoimmune CSU tended to be female with higher levels of thyroid peroxidase autoantibodies and a more severely impaired quality of life. By comparison, those with autoallergic CSU were often younger than those without that endotype.

"Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management," the investigators wrote.

The second study, a of data from 394 patients with CSU, identified aaCSU and/or aiCSU in 51% of the cohort using medical records and specific laboratory criteria. A total of 38% of patients were classified as having aaCSU, 9% as aiCSU, and 2% as non–aaCSU/aiCSU.

Eosinopenia was associated with aiCSU as well as both aaCSU/aiCSU, but not with aaCSU alone or non-aaCSU/aiCSU endotypes. The results suggest an important role for type IIb autoimmune responses in patients with CSU, but more study is needed to determine the usefulness of endotyping in clinical practice, the researchers said.

In the third , the clinical, laboratory, and therapeutic features of 377 CSU patients seen at a tertiary care center were prospectively collected, compared for the presence or absence of autoimmune disease, and classified according to IgE levels. Following aggression regression analysis, the team found that aiCSU occurred most frequently in middle-aged women who had a common pattern of blood test findings, including low baseline IgE/FcεRI.

"Total baseline IgE ≤43.8 IU/mL was both the optimal cutoff to predict autoimmune disease in the CSU cohort, and a significant risk factor for the presence of autoimmune disease," the team noted.

Read previous installments in this series:

Part 1: Urticaria/Hives: The Search Continues for Causes

Part 2: Keys to Diagnosis of Urticaria