Unfortunately for many patients with CSU, the itchy hives and/or angioedema associated with the condition is not all they have to contend with. A substantial number of patients also experience comorbidities associated with the development of CSU.
The pathogenesis of CSU in a subset of patients is believed to be a consequence of an autoimmune response driven by IgE or IgG autoantibodies. Patients with CSU, therefore, are thought to be at an increased risk of developing other autoimmune disorders. In fact, while the global prevalence of autoimmune diseases is considered to be ≤1%, in patients with CSU it is thought to be ≥1% (Kolkhir et al., 2017a; Kolkhir et al., 2017b).
A population study exploring the links between CSU and other autoimmune conditions compared the health records of 12,778 Israeli patients with chronic urticaria (CU) to 10,714 patients without CU. A diagnosis of CU was associated with an increased risk of developing hypothyroidism (9.8% vs. 0.6%; p<0.0005) and hyperthyroidism (2.6% vs. 0.09%; p<0.0005). Interestingly, the presence of autoimmune disease was significantly higher in female patients than male patients. Female patients had an odds ratio (OR) of hypothyroidism versus control of 23.07 (95% CI, 17.80–29.91; p<0.0005) while male patients had an OR of 7.57 (95% CI, 3.33–17.21; p<0.0005). A similar effect was seen with hyperthyroidism (female patients OR, 34.98; 95% CI, 18.00–67.99; p<0.0005 vs. male patients OR, 19.73; 95% CI, 2.72–142.69; p<0.0005) and type 1 diabetes (female patients OR, 12.92; 95% CI, 6.53–25.53; p<0.0005 vs. male patients OR, 2.34; 95% CI, 1.15–4.73; p=0.01). Importantly, the onset of type 1 diabetes was observed in the majority (84.8%) of patients in the years after receiving a diagnosis of CU. Meanwhile, a number of autoimmune conditions were only significantly increased in female patients. These included rheumatoid arthritis (OR, 19.88; 95% CI, 10.15–38.92; p<0.0005), Sjögen syndrome (OR, 23.30; 95% CI, 7.31–74.20; p<0.0005), coeliac disease (OR, 57.83; 95% CI, 7.99–418.29; p<0.0005) and systemic lupus erythematosus (OR, 26.71; 95% CI, 6.49–109.90; p<0.0005) (Confino-Cohen et al., 2012). More recently, a Korean study utilised their national database to explore the presence of various conditions in patients with CU, patients with CSU and patients without CU/CSU. Similar to Confino-Cohen et al., Korean patients with CU (12.34%) or CSU (11.34%) had a significantly increased rate of autoimmune thyroid diseases (AITD) compared to controls (5.49%) (Kim et al., 2018).
Alopecia areata (AA) is another autoimmune disease with a global prevalence of 0.1–0.2%. However, this differs between populations and studies with an observed prevalence of ~0.7–3% in the USA, and ~2% in the UK. An Israeli study matched 1,751 patients with AA to 3,502 control patients and assessed their respective comorbidities. Interestingly, patients with AA had a significantly increased risk of having comorbid CSU (OR, 6.15; 95% CI, 4.06–9.32; p<0.001) than the control group. Furthermore, patients with both AA and CSU were more likely to also have comorbid allergic rhinitis and atopic dermatitis than patients with CSU but not AA in the control group (Magen et al., 2018).
To gain greater clarity on the association of AITD and CSU, a systematic literature review compared data from 169 identified publications. A strong correlation was seen between CSU and elevated IgG antithyroid autoantibodies, in particular IgG-anti-TPO antibodies. Furthermore, some evidence suggests that patients with CSU typically have higher levels of IgE-anti-TPO autoantibodies than controls. As expected, these changes in autoantibody levels are also associated with elevated rates of AITD. It was identified that patients with CSU are more likely to experience hypothyroidism and Hashimoto’s thyroiditis than hyperthyroidism and Grave’s disease. In addition, and supporting the Israeli population study, thyroid dysfunction was more commonly observed in female than male patients with CSU (Confino-Cohen et al., 2012; Kolkhir et al, 2017a).
A separate systematic literature review looked at the published rates of a broader spectrum of autoimmune diseases in patients with CSU. The rates of comorbidity in the majority of studies were ≥1% for insulin-dependent diabetes mellitus, rheumatoid arthritis, psoriasis and coeliac disease, ≥2% for Grave’s disease, ≥3% for vitiligo and ≥5% for pernicious anaemia and Hashimoto’s thyroiditis (Kolkhir et al., 2017b).
While a link between chronic urticaria and atopic diseases has been suggested, until recently the epidemiological data was lacking (Shalom et al., 2017), but some data is starting to clarify the situation. Among a Korean population of patients with CU or CSU, the likelihood or having comorbid allergic rhinitis, drug or other allergies, or asthma was approximately 4.68 times higher than in the control group (Table 4) (Kim et al., 2018).
Table 4: Mean percentage of patients diagnosed with comorbidity between 2010 and 2013 in Korea (Kim et al., 2018).
In an Israeli population study, 11,271 patients with CU were compared to 67,216 age- and sex-matched controls. Interestingly, while fewer people experienced allergic comorbidities than observed in the Korean study they were still significantly more common in patients with CU than in the control group. In this setting, 10.8%, 9.8% and 19.9% of patients with CU had been diagnosed with asthma, atopic dermatitis or allergic rhinitis, respectively compared to 6.5%, 3.7% and 10.1% of patients in the control group. A multivariate analysis that adjusted for age, sex, body mass index, smoking status and ethnicity revealed that CU was significantly associated allergic rhinitis (OR, 2.03; p<0.001), atopic dermatitis (OR, 2.77; p<0.001) and asthma (OR, 1.62; p<0.001) (Shalom et al., 2017). Meanwhile, a comparison of elderly (>60 years of age) and non-elderly patients with CU in Korea revealed that elderly patients with CU were significantly more likely to have comorbid atopic dermatitis than non-elderly patients (37.8% vs. 21.7%, p=0.022). However, no difference was seen in the prevalence of asthma or allergic rhinitis (Ban et al., 2014).
The role of allergies and mast cells in irritable bowel syndrome (IBS) has gained increased attention recently. With this possible pathophysiological similarity between IBS and CU, Shalom et al. produced a follow-up study addressing the epidemiological links between the two conditions in Israel. A total of 1.7% of patients with CU had concomitant IBS versus 0.8% of controls (p<0.001) giving an OR of 1.86 (95% CI, 1.57–2.19; p<0.001). While a pathophysiological explanation remains hypothetical, this study does suggest an association between IBS and CU, warranting further investigation (Shalom et al., 2018).
Dermatological conditions can have a substantial impact on the mental wellbeing of patients. A UK study reported that 17% of dermatology patients required psychological support while 85% reported that the psychosocial aspects of their skin condition are a major component of their illness (Bewley et al., 2012).
The psychological burden of CSU is significant. In a survey of 369 patients with CSU, the prevalence of psychological issues was roughly twice as high as reported by matched controls (Figure 10) (Balp et al., 2015).
Similar results were reported in a German study of 100 patients with CSU who were screened for mental health comorbidities. Among this group of patients, 48% had one or more mental health disorder with the most common being anxiety (30%) and depressive and somatoform disorders (17% each) (Staubach et al., 2011).
The psychological comorbidities associated with CSU have been shown to extend beyond anxiety and depression. Patients with CSU also have higher levels of alexithymia (the inability to identify and communicate emotions) than healthy controls and may be related to a link between pruritus severity and state anger as assessed by the State-Trait Anger Inventory (STAXI) (Conrad et al., 2008). Furthermore, post-traumatic stress disorder (PTSD) has been associated with CSU with 34% of patients with CSU in one study meeting the diagnostic criteria for PTSD vs. 18% of allergy control patients (Chung et al., 2010; Gupta & Gupta, 2012; Gupta et al., 2017).
Furthermore, the impact of these associated comorbidities should not be underestimated. In a study of 746 patients with CU and 5,107 patients with psoriasis, patients with CU had a comparable impairment of mental/physical health to those patients with moderate-to-severe psoriasis (Figure 11) (Mendelson et al., 2017).