Taking together all systemic autoimmune diseases, the most frequent correlation with urticaria has been seen in connective tissue diseases, with rheumatoid arthritis placed first [21]. The onset of a systemic autoimmune disease has been demonstrated with a higher incidence in female patients with urticaria, especially for rheumatoid arthritis (RA), Sjögren’s syndrome (SS), and systemic lupus erythematosus (SLE). Moreover, the presence of a positive rheumatoid factor and antinuclear antibodies were significantly more frequent in patients with chronic urticaria [27]. Ghazanfar et al. [70] have in fact highlighted how the increased general inflammatory state caused by CU correlates significantly with the increased prevalence of rheumatoid arthritis in women affected by CU (HR = 1.8), as a consequence of mast cell destabilization. In addition, UC has been shown to have a genetic association with the human leukocyte antigen (HLA)-DR4 and HLA-DQ8 alleles, of which the former is strongly associated with rheumatoid arthritis [71]. A cross-sectional study of 390 CSU patients reported a higher prevalence of connective tissue diseases (CTDs) such as RA, SS, and SLE in UC patients than in the normal population, with a prevalence of 1.8% for RA and of 0.3% for SLE [72]. Chiu et al. have deepened the biochemical correlation existing between CU and SLE, recognizing a fundamental role of autoantibodies, complement activation, and the coagulation cascade. CU and SLE were in fact both characterized by a higher prevalence of autoantibodies against FceRI and IgE. The appearance of urticaria in patients with active SLE is due to immune complex deposition and complement activation; this could indicate the key role of SLE in the etiopathogenesis of UC. Furthermore, an increased risk of SLE with UC was confirmed only in women, particularly in those aged between 20 and 59 years [73,74,75]. CSU can also be triggered by drugs routinely used to treat lupus, especially nonsteroidal anti-inflammatory drugs, with a predominance of constitutional, mucocutaneous, and musculoskeletal involvement, without a high frequency of manifestations of severe lupus [76].

A recent study by Magen et al. highlighted a high prevalence of UC in patients affected by alopecia areata (AA), recognizing in the IgG-anti-IgE autoantibodies and RI anti-Fc (high affinity IgE receptor) the possible physiopathological correlation factors [77]. The presence of such functional FceRIa-Ab anti-IgE antibodies in UC patients is responsible for the release of histamine by activating the complement system. The same immunological mechanism is also found in subjects affected by myasthenia gravis (MG), an autoimmune disease that causes weakness of striated muscles mediated by the AChR-Abs antibody, responsible for the degradation of the neuromuscular junction by activation of the complement system. Although the pathogenic link between these two autoimmune diseases remains unclear, complement activation plays an important pathophysiological role in both diseases, being able to represent their possible link [78,79].

The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria [28], published in March 2022, reports that it is well known that causes of CSU include autoimmunity type I (CSU)aiTI, or “autoallergic CSU”; with IgE autoantibodies against autoantigens and type IIb autoimmunity (CSU)aiTIIb; with activating autoantibodies directed by mast cells. In the diagnostic process, the patient’s history and a physical exam can provide clues to the underlying causes. For this purpose, the execution of basic tests, such as CRP (more often elevated) and the dosage of eosinophils and basophils (more often reduced in CSUaiTIIb), is of primary importance. Testing for TPO-IgG and total IgE should also be performed in CSU patients in specialist care, as they are useful for diagnostic purposes. CSUaiTIIb patients are more likely to have low or very low total IgE and elevated anti-TPO IgG levels, and a high ratio of anti-TPO IgG to total IgE is currently the best surrogate marker for CSUaiTIIb. Other underlying causes include active thyroid disease, infections, inflammatory processes, food and medications. In CSU, the most common comorbidities are CIndUs, autoimmune diseases, and allergies. Findings from the patient’s medical history, a physical exam, or baseline tests that indicate a comorbidity or consequence of CSU should prompt further investigation, such as screening for specific diseases by means of questionnaires, provocation tests, further laboratory tests, or referral to a specialist.

Autoinflammatory diseases (Cryopyrin-Associated Periodic Syndrome (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome (SchS), Adult Still’s Disease (AOSD)) represent a group of chronic disabling diseases characterized by a condition of direct self-inflammation, mediated by disturbances in innate immune signalling pathways [80]. Specifically, an excessive secretion of cytokines by innate immune cells (such as macrophages, monocytes) is observed, among which we mention the group of interleukin (IL)-1, which, accumulating at the level of different tissues and systems, lead to the clinical development of disease. The latter includes recurrent fever attacks, musculoskeletal, gastrointestinal, and neurological involvement. The integumentary system is also a frequent site of autoinflammatory disease, with typical symptoms including urticaria, pustular and ulcerative lesions [81].

The urticarial rash in patients with autoinflammatory syndromes is often grossly indistinguishable from that in patients with CSU. However, it is possible to observe, in these cases, a wider spectrum of lesions than true urticaria, i.e., flat wheals that can, at first sight, resemble erythematous patches, but also more solid and stable lesions. The distribution of this type of urticarial rash is also slightly different, being distributed rather symmetrically over the trunk and/or extremities, usually sparing the head [82].

Considering the great clinical similarity between these two diseases, the need arises, where an autoinflammatory disease is suspected, to perform specific tests, including dosage for elevated inflammatory markers; serum protein electrophoresis to rule out monoclonal gammopathy in adults; urinalysis to screen for proteinuria from secondary renal amyloidosis; and skin biopsy to look for neutrophil-rich infiltrates. If an inherited autoinflammatory disease is suspected, testing for mutations in the relevant genes should be performed [83].

Within the broad spectrum of autoinflammatory diseases, two are those that present most frequently clinically with urticarial lesions that enter into the differential diagnosis with CSU: urticarial vasculitis (UV) and Schnitzler Syndrome (SchS).

If a form of UV is suspected, the differential diagnosis with CSU [84] is based on testing for skin histopathology, as well as specific laboratory tests, such as complete blood count, serum creatinine, C-reactive protein (C-RP), rate of erythrocyte sedimentation (ESR), urinalysis, complement studies (C1q, C3, C4), and anti-C1q antibody analysis underlying connective tissue disease or viral infection [84,85].

As for SchS, a member of the family of autoinflammatory syndromes, this too often manifests itself with chronic recurrent, nonpruritic and confluent plaques. These urticarial plaques can persist for up to 24 h and then resolve without residual pigmentation. Characteristic of SchS is the presence of monoclonal paraproteinemia, typically IgM, with neutrophil-dominated cellular infiltrates and upregulation of cytokines and inflammasome components in lesional skin, supporting them as potential biomarkers to differentiate SchS from CSU [86]. IL-1-related cytokines and inflammasome components are upregulated in skin biopsy specimens from SchS patients, resulting in products from mast cells (IL-1β, IL-6) and neutrophils (IL-6, IL-18). In view of these immunohistochemical features, it is recommended to apply a panel of skin biomarkers, including MPO, IL-1β, IL-6, IL-18, as well as ASC and caspase-1, to differentiate SchS from CSU [85].