Retrospective case note review of chronic spontaneous urticaria outcomes and adverse effects in patients treated with omalizumab or ciclosporin in UK secondary care

Patients

The baseline characteristics of the patients included in the omalizumab and ciclosporin
studies are presented in Table 1. In the omalizumab study, of the 46 patients with CSU (mean age 43.3 years; SD 13.1),
36 (78%) were female. Thirty-six (78%) patients had CSU and 10 (22%) had CSU concurrent
with chronic inducible urticaria (CIndU; 7 pressure urticaria, 3 dermographism); four
also had documented features of urticarial vasculitis (UV). Angioedema was recorded
for 38 (83%) patients; 31 (86%) of those with CSU only and 7 (70%) of those with CSU + CIndU
(see Table 1). The ciclosporin study included 72 patients with CSU (mean age 40.5 years; SD 12.8),
of whom 61 (85%) were female. Among these, 66 (92%) had a diagnosis of CSU only, while
6 (8%) had CSU + CIndU (three dermographism, two delayed pressure urticaria, one symptomatic
dermographism/delayed pressure urticaria and aquagenic pruritus). Fifty patients (69%)
had a recorded history of angioedema (see Table 1).

Table 1. Baseline patient and disease characteristics

Dosing

Twenty-four (52%) omalizumab-treated patients were initiated on 150 mg and 20 (43%)
on 300 mg omalizumab. Eight (17%) patients increased the dose from 150 mg to a maximum
of 300 mg and 4 (9%) patients reduced the dose from 300 mg. Dosing frequency was 4
weekly in 32 patients, 3 weekly in one patient, 2 weekly in six patients and 4 weekly
in six patients (one patient received only one dose). Omalizumab treatment had been
discontinued in 20 patients (43%) at the time of data collection; the reasons for
withdrawal were not documented.

The median (range) duration of ciclosporin treatment was 4.8 (0.2–67.1) months overall,
4.4 (0.2–67.1) months for complete courses and 28.1 (17.3–38.6) months for ongoing
courses at data collection. The mean daily dose of ciclosporin was 174 mg (SD 85.6).
The dose in mg/kg could be calculated for 37 patients; 3 mg/kg was the most common
starting dose [8/37 patients (22%)] and 4 mg/kg was the most common maximum dose [10/37
patients (27%)]. During ciclosporin therapy, 27 (38%) patients remained on a constant
dose, 15 (21%) increased dose, 13 (18%) decreased dose, 7 (10%) increased then decreased
dose, 4 (6%) decreased then increased dose and 6 (8%) had other patterns of dose changes.
Ciclosporin had been discontinued in 67 (93%) patients at the time of data collection,
with 25 (35%) stopping within 3 months of initiation. Reasons for ciclosporin withdrawal
were given for 49/67 (73%) patients, indicating lack of benefit in 23/49 patients
(46%), intolerance in 13/49 (26%), successful treatment in 11/49 (22%) and other reasons
in 3 (6%).

Treatment response

Omalizumab study

Clinician-documented comments on the best response to omalizumab treatment were available
for 36 (78%) patients, of whom 15 (42%) were clear of symptoms, 12 (33%) had some
improvement and 9 (25%) had not responded.

The UAS7 score was available for 27 patients at baseline [mean weekly UAS7 27.5 (SD
10.4)]. UAS7 was available for 28 patients at some time following omalizumab initiation
[mean UAS7 3.1 (SD 6.3)], and of these 19 (68%) achieved a score of 0 (itch/hives
free). The mean weekly UAS7 score for 19 patients with UAS7 recorded at 3 months (±1 month)
following omalizumab initiation was 5.8 (SD 9.8). In the 22 patients with paired UAS7
scores, the mean weekly score decreased by 25.4 (SD 12.5) points (P  0.0001, paired
t test) following omalizumab initiation, as shown in Figure 1. The mean of the patients’ percentage improvements was 85%. A reduction in UAS7 score
of at least 75% from baseline was observed in 17/22 (77%) patients and a reduction
of at least 90% in 15/22 (68%), see Figure 2.

Figure 1. Omalizumab response: within-patient paired UAS7 scores at baseline and lowest recorded
on treatment.

Figure 2. Proportions of patients with 75 and 90% improvement in UAS7 and DLQI from baseline.

The impact of CSU on QoL was measured using the DLQI in 32 patients at baseline [mean
score 19.5 (SD 5.2)]. DLQI was available in 31 patients at some time during omalizumab
treatment [mean score 3.2 (SD 5.2)], and of these 20 (65%) achieved a DLQI score of
0–1 (no impact of disease on QoL). In the 28 patients with paired scores, the mean
DLQI score decreased by 16.4 (SD 9.1) points (P  0.0001, paired t test) following
omalizumab initiation, as shown in Figure 3. The mean of the patients’ percentage improvements was 80%. An improvement of at
least 75% in DLQI was observed in 22/28 (79%) patients and an improvement of at least
90% in 18/28 (64%; see Figure 2).

Figure 3. Omalizumab response: within-patient paired DLQI scores at baseline and lowest recorded
on treatment.

Ciclosporin study

The best response to ciclosporin according to clinician-documented comments [available
for 60 (83%) patients] was clear of symptoms in 10 (17%), improved in 33 (55%) and
no response in 17 (28%) patients. The UAS7 score was not used to assess response to
ciclosporin.

DLQI was measured in 20 patients at baseline [mean score 17.4 (SD 6.6)]. DLQI score
was available at some time during ciclosporin treatment in 19 patients [mean score
8.5 (SD 7.3)], and of these 4 (21%) achieved a DLQI score of 0–1. In the 17 patients
with paired DLQI scores, mean score decreased by 8.9 (SD 9.2) points (P = 0.0005,
paired t test), as shown in Figure 4. The mean of the patients’ percentage improvements was 45%. An improvement in DLQI
of at least 75% was observed in 7/17 (41%) patients and an improvement of at least
90% in 3/17 (18%; see Figure 2).

Figure 4. Ciclosporin response: within-patient paired DLQI scores at baseline and lowest recorded
on treatment.

Adverse events

Omalizumab study

Potential adverse events were documented during omalizumab treatment for 17 (37%)
patients, with a total of 36 events (Table 2). The most common adverse events recorded were skin reactions (eight reports from
four patients), angioedema (six reports from three patients), and ‘anaphylaxis’ (three
reports from two patients). Overall 35 events were clinician-assessed for severity
and causal relationship with omalizumab and judged to be mild in 10 (29%), moderate
in 19 (54%) severe in 4 (11%) or not applicable (pregnancy) in 2 (6%). A possible
causal relationship with omalizumab was recorded in 20 (57%), with 6 (17%) unrelated
and 9 (26%) unknown. Episodes of anaphylaxis were reviewed in detail. One episode
of ‘anaphylaxis’ was clinician-rated as ‘moderate’ in severity, and ‘possibly related’
to omalizumab. The episode occurred 2.5 h after omalizumab administration and involved
shortness of breath, tongue angioedema and urticaria (blood pressure and pulse were
normal, tryptase was not measured), which responded to oxygen, antihistamine, hydrocortisone
and self-administered adrenaline in 15 min and the patient was not admitted to hospital.
A second episode in the same patient also occurred on the day of omalizumab dosing
and was clinician-rated as ‘severe’ and ‘possibly related’ to omalizumab. On this
occasion the patient was admitted to hospital overnight; tryptase was slightly raised
at 15.5 ng/ml acutely (normal  11.4 ng/ml) and 13.4 ng/ml the next day. Although
both episodes in this patient were documented as ‘possibly related’ to omalizumab,
the patient had a history of complex and severe CSU, including recurrent ‘anaphylaxis’
prior to omalizumab, which was incompletely controlled by the therapy. In our opinion
the two episodes of ‘anaphylaxis’ in this patient were most likely to have been an
exacerbation of the underlying CSU. The third episode of reported anaphylaxis, in
a different patient, also occurred on the day of omalizumab injection, and was clinician-rated
as ‘severe’. However, we consider this episode not to be consistent with anaphylaxis,
although possibly related to omalizumab, based on reviewing the case in detail (symptoms:
sharp joint pains and nausea, without severe shortness of breath, hypotension, hives
or angioedema; treated by hospital admission for fluids and hydrocortisone). Omalizumab
treatment was continued in all three cases.

Table 2. Adverse events

Ciclosporin study

Potential adverse events were documented during ciclosporin treatment for 28 (39%)
patients, with 49 episodes (Table 2). The most commonly reported adverse events were hypertension (eight reports), fatigue/tiredness
(six reports), gastrointestinal problems (four reports) and headache (four reports).
Of the 49 events, 45 were clinician-assessed for severity, with 24 (53%) rated mild,
16 (36%) moderate, 3 (7%) severe and 2 (4%) not applicable (pregnancy). Thirty (61%)
were judged ‘possibly related’ to ciclosporin, 4 (8%) unrelated and 15 (31%) unknown.