In chronic urticaria, patient-reported outcome measures (PROMs) are important for assessing disease status and the impact of symptoms on patients’ lives [16]. However, to our knowledge, there is no validated tool to measure such outcomes in UV patients. Although UAS7 and CU-Q2oL were not designed for UV assessment, we used these tools to measure how successful or unsuccessful the first-line therapy was in managing the disease. A modest control of disease severity was considered the major criteria for prescribing omalizumab. Both questionnaires were used to observe their fluctuations over the course of the disease, serving as guides for the management and indication of omalizumab.
Understanding the role of omalizumab in UV remains controversial. Theoretically, omalizumab should improve any IgE-mediated condition, such as type I hypersensitivity reactions [17]. UV is mediated by a type III hypersensitivity reaction, with antigen-antibody complexes depositing at the vascular lamina. Omalizumab might not work in UV because its pharmacodynamics are incompatible with the pathogenesis of this disease [18].
Few publications have reported the use of omalizumab in UV. For instance, in a publication by Fueyo-Casado et al., omalizumab was initiated in a female patient with a baseline UAS7 of 32 at 300 mg monthly for 12 months. The patient achieved remission (UAS of 0) by the fifth dose. In contrast, at a baseline UAS7 of 19, we administered half the dose monthly for the first 3 months, and UAS7 improved after this time (UAS7 = 6). As the benefits of omalizumab are considered to be dose-dependent, there was some efficacy in using half of the recommended dose. Unfortunately, the omalizumab treatment was suspended due to economic limitations, as is frequently seen with many low-income patients [19, 20]. It is interesting, however, to highlight that CU-Q2oL did not improve as well as UAS7, leading to a worse quality of life even in the presence of less severe disease after the three-week treatment.
Although the correlation between UAS7 and CU-Q2oL was fairly good in the domains previously described, continuous administration with omalizumab at the beginning of treatment might be recommended, because 150 mg dose improves severity but seems insufficient to improve quality of life.
In another publication by Diez et al., a regimen of 150 mg every 4 weeks achieved remission in two patients, and Sussman et al. reported successful results in a patient who also achieved remission [21, 22]. It is unclear whether 150 mg or 300 mg should be used and for how long, but certainly quality of life should be considered in the initial assessment of UV.
Although corticosteroids are the mainstay of UV treatment, we preferred omalizumab and hydroxychloroquine because corticosteroids traditionally need to be used over the long term to prevent disease relapse, leading to more adverse effects [23]. Omalizumab and hydroxychloroquine safety profiles are better than those of corticosteroids and result in fewer complications [23]. Corticosteroids were used only during periods of highly active disease. Our patient developed an exacerbation 5 months after the three-month course of omalizumab, with the highest UAS7 (28) and the greatest impairment in quality of life. The association between UAS7 and CU-Q2oL was evident during this crisis. Both greatly improved after the administration of corticosteroids and omalizumab. This combination proved useful during exacerbations.
PROMs assist physicians in making inferences about changes in disease activity, response to treatment, and changes in health-related quality of life (HRQoL) [24]. Either the Dermatology Life Quality Index (DLQI) or CU-Q2oL might be used for chronic spontaneous urticaria (CSU) [25, 26]. However, neither have been validated for UV management. In a publication by Stull D. et al., CSU latent growth curve trajectories showed correlations between slopes of change in UAS7 and CU-Q2oL in clinical trials of ASTERIA I (0.90), ASTERIA II (0.89), and GLACIAL (0.92) [24]. Although we cannot directly compare our results due to methodological discrepancies, we also found a strong correlation between UAS7 and CU-Q2oL mean scores (r = .74, p = .022). This contrasts with another publication in which UAS7 was shown to only moderately correlate with the CU-Q2oL total score (r = 0.40, p < 0.0001) and with the DLQI score (r = 0.37, p < 0.0001) in CSU patients [27]. A weak significant correlation (r = 0.31, p < 0.05) between urticaria activity score values and DLQI in CU patients has also been reported [28].
Interestingly, there seems to be a group of patients with relatively low UAS7 that nevertheless experience a remarkable impairment in their HRQoL [27]. This was replicated in our patient and is the reason why, in some scenarios, quality of life impairment was considered as a primary indication for omalizumab prescription independent of disease severity. Omalizumab was prescribed due to quality of life impairment on six occasions, once in the context of controlled disease and five times in mild disease assessed by UAS7. We believe that this phenomenon could be explained in part by the fact that such observation was made by analyzing quality of life as a total or average sum rather than addressing it by its axes separately as it was originally designed to be used. Certainly, discrepancy between different axes might be found. For instance, in a study of 51 CSU patients, significant correlations with UAS7 were reported for functioning (r = 0.31, p = .03), itching/embarrassment (r = 0.54, p = .001), and mental status (r = 0.28, p = .048), while those of sleep, swelling/eating, and limited appearance were not [26]. We found similar results in our patient, with stronger correlations between UAS7 and functioning (r = .84, p = .005), itching/embarrassment (r = .84, p = .005), mental status (r = .79, p = .011), and sleep (r = .72, p = .029) (Fig. 4). Correlations for swelling/eating (r = .04, p = .922) and limited appearance (r = .51, p = .165) were not statistically significant, since they did not improve as expected with treatment.
We would not recommend evaluating CU-C2oL as a single score since axis-per-axis evaluation might lead to a more thorough understanding of quality of life impairment. Under some circumstances, disruption in a single axis might be a sufficient indication to initiate omalizumab therapy even if the remainder axes have progressed favorably within a less active disease. Impairment in quality of life by itself might lead to significant morbidity. Patients with CSU often experience depression and anxiety, with studies showing a positive correlation between itch intensity and severity of depression [29]. Patients complain of recurrent pain syndromes, including tension headaches and fibromyalgia, while the prevalence of psychiatric disorders such as depression, hysteria, hypochondria, and post-traumatic stress disorder is high in these individuals [30,31,32].
Of note, to prevent such comorbidities, it is essential that every prescribed therapeutic regimen be evaluated objectively with parameters of disease control. Although it is not validated for urticarial vasculitis, the Spanish version of UCT was discretely used since month 13 [33]. UCT is a validated instrument designed to assess the level of disease control in CU patients, in which a score ≥ 12 indicates well-controlled urticaria, while a score of ≤11 indicates poor disease control [34]. UCT has been shown to correlate slightly better with the total CU-Q2oL score than with UAS7 [34]. The mean score of the five UCT questionnaires answered by our patient revealed poor control. In general, UCT scores did not correlate with either UAS7 or each of the CU-Q2oL domains. However, UCT correlated strongly with the total CU-Q2oL score (r = −.95, p = .023). Although we have very limited data from this test, it was the least useful method for managing the disease.
Little is known about the role of omalizumab in UV and how treatment should be followed-up in terms of disease activity and PROMs improvement. Based on our observations, we believe omalizumab 150 mg might be a feasible therapeutic alternative when first-line treatment is unsuccessful. Omalizumab in UV has shown improvement in quality of life and disease severity without the significant adverse effects caused by first-line regimens. UAS7 and CU-Q2oL might be useful in the clinical setting as objective measures to determine treatment efficacy. However, some domains in the CU-Q2oL questionnaires do not correlate well with UAS7, which might serve as a relative indication to continue treatment despite disease severity improvement. Further studies are needed to confirm our findings.
