Chronic spontaneous urticaria (CSU) is a common disease characterized by the spontaneous occurrence of itchy wheals, angioedema, or both, for a period of more than 6 weeks. The condition usually lasts approximately one year in 70% of patients, but it can persist for more than 5 years in up to 15%,1 with a detrimental effect on patient's quality of life.

Two drugs are currently approved for the treatment of CSU in Europe and North America: non-sedating H1-antihistamines (anti-H1) and the monoclonal antibody omalizumab. Anti-H1 are safe and cheap and are recommended in the current American and European guidelines for the initial treatment of patients with CSU.2,3 However, with standard doses, up to 50% of patients1 are unable to achieve a good control of the disease.

Omalizumab, a recombinant humanized monoclonal antibody, has shown high efficacy in phase III clinical trials, and is currently approved for the treatment of moderate-to-severe CSU unresponsive to anti-H1. However, there is limited information on the use of omalizumab in real life using the same doses, response evaluation parameters and endpoints that were used in phase III clinical trials.2,4,5

Disease activity in CSU can be assessed in real practice and in clinical trials with the weekly Urticaria Activity Score (UAS7), a simple scoring system that was proposed in the 2017 version6 of the EAACI/ GA2LEN/ EDF/ WAO guidelines. The patient quantifies the daily number of wheals (range: 0-none to 3-severe) and daily severity of pruritus (range: 0-none to 3-severe) for 7 consecutive days, with a maximum sum score of 42. UAS7 allows comparison of the results from different studies and centers, and is a useful tool for both clinical trials and real life practice.7

Few studies have assessed UAS7 response at weeks 12 and 24 in real life using omalizumab 300mg every 4 weeks.7–18 Real world and randomized clinical trials outcomes need to be compared because patient populations in both settings may differ; for instance, patients with inducible urticaria or CSU with severe comorbidities (history of cancer, parasitic infection, history of anaphylaxis, pregnancy, previous treatment last 30 days of cyclosporine, etc.) were excluded from clinical trials.2,4,5

The aim of this study was to assess the effectiveness and safety of omalizumab in real life and compare them with the efficacy and safety reported in clinical trials. We also wanted to identify possible predictors of response to omalizumab.

We conducted a retrospective review of all patients with moderate- to-severe CSU (UAS≥16) treated with omalizumab from February 2014 to September 2017 at the Department of Dermatology of the Hospital de la Santa Creu i Sant Pau, a University-affiliated referral hospital in Barcelona, Spain. Data were retrieved from the medical records and from a prospective registry started in 2009, which received the approval of our local Ethics Committee (16/049 (OBS)), enrolling all patients starting omalizumab for CSU in our center. Patients’ informed consent was obtained prior to inclusion in the study.

In agreement with the summary of product characteristics (SmPC), and the European Guidelines,6 only patients with CSU who did not respond to high doses of anti-H1 (up to 4-fold licensed dose) and received the approved dose of omalizumab (300mg every four weeks) for at least 12 weeks (three doses) were included in this study. Omalizumab was administered by experienced medical and nursing personnel at the day-care hospital facilities.

Collected data included patients’ demographics (age, weight, height and body mass index [BMI]), duration of CSU prior to the start of omalizumab treatment, UAS7 value at baseline, week 12 and week 24, use of previous or concomitant immunosuppressants (cyclosporine A, azathioprine, mycophenolate mofetil and/or methotrexate) and other treatments (montelukast), adverse events, concomitant angioedema, concomitant inducible urticaria, and use of corticosteroids. Analytical parameters studied included blood counts and leukocyte counts, standard serum biochemistry determinations, serum C-reactive protein (CRP), total immunoglobulin E and complement (C3 and C4) levels, plasma D dimer levels, antinuclear antibody titres, and anti-thyroid antibody titres. Long-term urticaria was arbitrarily defined at 18 months after statistical analysis and consistent with the median duration of disease in a recently published cohort from Barcelona.19

UAS7 values were recorded twice daily during a week for every patient at baseline, before the start of treatment, and prior to visits corresponding to week 12 and week 24 of treatment. The outcome of treatment was defined according to UAS7 values as “clinical response” (UAS7 ≤6) and “complete response” (UAS7=0), as in published clinical trials.2,4,5

All adverse events (AEs) were recorded and classified into mild, moderate and severe. All cutaneous reactions that occurred on the injection site without systemic symptoms were considered to be mild AEs; anaphylaxis or death were considered as severe AEs, and all the other AEs related to omalizumab administration were considered to be moderate in severity.

Omalizumab is a monoclonal antibody approved for the treatment of moderate-to-severe CSU. Licensed dosage according to the European Medicines Agency-approved SmPC is 300mg every 4 weeks and 150 and 300mg every 4 weeks according to the Food and Drug Administration label. Patients treated with 300mg show better responses compared to those treated with 75mg and 150mg, and the higher dose is associated with better control of angioedema.5

Previously published real-life studies show marked heterogeneity in comparing the percentage of omalizumab responders. Differences in dosage, definition of response and time point of evaluation are seen compared to clinical trials, as shown in Table 3. Many real-life studies define response as clinical improvement, a subjective criterion that makes comparisons difficult. UAS7 was first used in real-life clinical practice by Metz et al.,20 and other authors8,13–15,17,20 have subsequently used UAS7=0 (complete response) or UAS7≤6 (response). We agree with the EAACI/GA2LEN/EDF/WAO urticaria guideline6 recommendation that UAS7 should be the standard method of measurement and UAS7=0/UAS7≤6 the criteria of efficacy, as in clinical trials.

Moreover, the evaluation time points in real-life studies have not been specified8,9,11,12,14,15,18,20 or have differed (i.e. week 4)8 with respect to those used in the main clinical trials,2,4,5 namely week 12 and week 24. Late response can only be assessed by reporting results at week 24, as in the ASTERIA I and GLACIAL clinical trials4,5,8 and the real-life study by Büyüköztürk et al..8 However, in none of these studies was any information provided in terms of complete or clinical response, and Büyüköztürk et al. only reported the absolute reduction in UAS7.

The response to omalizumab treatment in real-life studies has been shown to be better than in clinical trials,2,4,5,7–18,20 as detailed in Table 3. The clinical response (UAS7 ≤6) and complete response (UAS7=0) rates at week 12 in our cohort were also numerically higher than in the ASTERIA I and II and the GLACIAL clinical trials, but the ‘response’ rates in earlier real-life studies are higher than in our cohort, probably due to the choice of clinical judgement, not UAS7, as outcome measure.8,13,15 Comparison of response rates at week 24 cannot be made, since both GLACIAL and ASTERIA I only include safety and Itch Severity Scale (ISS) data and ASTERIA II did not include an evaluation at week 24.

The mean duration of CSU was much longer in pivotal trials (approximately 7 years (range 6.1 to 7.4) compared to approximately 2 years in our series. This might provide an explanation for differences in response, as suggested by lower response rates at week 12 in patients with longer duration of symptoms in our series.

Mean age, baseline UAS7, presence of angioedema, and prior use of corticosteroids do not differ in our cohort with respect to pivotal studies. Patients’ mean body mass index in our cohort was 25.1 (IC 95% 24, 2-26), compared to 29.4, 29.3 and 29.5 in GLACIAL and ASTERIA I and II, respectively. Curto-Barredo et al21 recently identified high BMI as a predictor of partial response to 300mg dose, but good response with updosing. However, we did not find any statistically significant association in our series.

According to Maurer et al.,1 inducible urticaria is a negative predictor of response, and it was an exclusion criteria in pivotal trials. Seventeen (35.4%) of our patients had inducible urticaria at some point during the course of their disease, but this was not found to be a prognostic factor regarding response to omalizumab at any time point in our cohort. High baseline UAS7 values were not a negative prognostic factor regarding response to omalizumab, again in contrast with the findings of Maurer et al..1

In our cohort, complete response rates increased with time whereas clinical response rates decreased from week 12 to week 24. Some patients with clinical response at week 12 lost this status by week 24. On the other hand, complete response status tended to be consistent over time; 25 out of 48 patients maintained their complete response status from week 12 to week 24, including 5 patients who stopped treatment at week 12 because of complete response.

Presence of angioedema has also been associated with a decreased therapeutic response to omalizumab.1 In our real-life cohort, a history of angioedema was associated with a higher probability of complete response at week 24; no significant associations were found at other time points and with clinical response. However, the limitations of UAS7 to assess angioedema may influence this result. Otherwise, our data are consistent with those of Tonacci et al,22 who found clinical response to omalizumab treatment in patients with CSU to be independent of disease severity or IgE levels at baseline.

Regarding prior treatment of CSU, ASTERIA studies included only approved doses of anti-H1 as background therapy, whereas the GLACIAL study permitted higher doses of anti-H1 as well as other types of background therapy. In a post-hoc analysis, the intensity of prior treatment has not been found to influence the response to omalizumab,22 in agreement with our cohort data. On the other hand, the odds of achieving complete response at week 12 were close to 4:1 for patients who had not been previously treated with immunosuppressive agents. Previous treatment with immunosuppressive agents was common in our population (31.3% versus 9.5% in the GLACIAL study), and a trend has been previously reported for immunosuppressant-naïve patients to present a better response to omalizumab,14 which is consistent with our results.

Limitations of this study are its observational nature, without a control group, measurement scale limitations and the small sample size compared to pivotal trials.

In conclusion, this retrospective review of a cohort of 48 consecutive patients treated with omalizumab 300mg every 4 weeks for at least 12 weeks in real life practice shows numerically better response rates than randomized clinical trials at week 12.2,4,5 At week 24, more than 50% of patients had complete response as defined by UAS 7. Long term (≥18 months) duration of CSU was associated with a lower probability of response to omalizumab at different time points. A similar tendency was observed for previous immunosuppressive treatment. The safety profile of omalizumab in our cohort was consistent with randomized clinical trials, with minimal, tolerable and infrequent side effects.

Further studies will be needed to confirm our results and their applicability to other patient populations.

X. Cubiró and E. Rozas-Muñoz declare no conflicts of interest. L. Puig, E. Serra-Baldrich and J Spertino have received speaker's honoraria and have participated in clinical trials sponsored by Novartis