- Email: [email protected]
Omalizumab is effective in symptomatic dermographism—results of a randomized placebo-controlled trial
Accepted Manuscript Omalizumab is Effective in Symptomatic Dermographism - results of a Randomized, Placebo Controlled Trial Marcus Maurer, M.D., Andrea Schütz, M.D., Karsten Weller, M.D., Nicole Schoepke, M.D., Adriane Peveling-Oberhag, M.D., Petra Staubach, M.D., Sabine Müller, M.D., Thilo Jakob, M.D., Martin Metz, M.D. PII:
S0091-6749(17)30514-6
DOI:
10.1016/j.jaci.2017.01.042
Reference:
YMAI 12723
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 3 August 2016 Revised Date:
8 December 2016
Accepted Date: 5 January 2017
Please cite this article as: Maurer M, Schütz A, Weller K, Schoepke N, Peveling-Oberhag A, Staubach P, Müller S, Jakob T, Metz M, Omalizumab is Effective in Symptomatic Dermographism - results of a Randomized, Placebo Controlled Trial, Journal of Allergy and Clinical Immunology (2017), doi: 10.1016/ j.jaci.2017.01.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Omalizumab is effective in symptomatic dermographism - results of a
2
randomized, placebo controlled trial
3 Marcus Maurer, M.D.1, Andrea Schütz, M.D.1, Karsten Weller, M.D.1, Nicole
5
Schoepke, M.D.1, Adriane Peveling-Oberhag, M.D.2, Petra Staubach, M.D.2, Sabine
6
Müller, M.D.3, Thilo Jakob, M.D.3,4, Martin Metz, M.D.1
7
RI PT
4
8
1
9
2
10
3
11
4
12
Marburg, Campus Giessen, Justus-Liebig University, Giessen, Germany
SC
Dept. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany Dept. of Dermatology, University Medical Center Mainz, Mainz, Germany
M AN U
Dept. of Dermatology, University Medical Center Freiburg, Freiburg, Germany Dept. of Dermatology and Allergology, University Medical Center Giessen and
13
TE D
14 Corresponding author:
16
Martin Metz, MD
17
Dept. of Dermatology and Allergy
18
Charité – Universitätsmedizin Berlin
19
Charitéplatz 1
20
D-10117 Berlin, Germany
21
Phone: +49-30-450-518 159
22
Fax:
23
Email: [email protected]
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+49-30-450-518 972
1
ACCEPTED MANUSCRIPT 24
Short summary
25
We report the results of a randomized controlled multicenter trial in patients with
26
symptomatic dermographism. Treatment with omalizumab 150 mg and 300 mg was
27
effective and well tolerated, as compared to placebo.
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M AN U
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2
ACCEPTED MANUSCRIPT To the editor:
30
Symptomatic dermographism (SDerm) is the most common form of physical urticaria
31
with a prevalence of up to 5%.1 SDerm is characterized by itchy wheals that occur in
32
response to friction, for example after rubbing or scratching of the skin, and usually
33
last for one to two hours.2 SDerm commonly lasts for years and significantly impairs
34
quality of life.2 The underlying cause of SDerm is unknown, and the trigger is difficult
35
if not impossible to avoid. Therefore, symptomatic treatment with antihistamines is
36
the first choice treatment. However, higher than standard doses are usually required
37
to achieve symptom control, and some patients do not respond to updosing of
38
antihistamines.2
SC
Omalizumab,
M AN U
39
RI PT
29
a
humanized
anti-IgE
antibody,
is
highly
effective
in
antihistamine-refractory patients with chronic spontaneous urticaria (CSU), also
41
known as chronic idiopathic urticaria (CIU), and the drug was licensed for the use in
42
CSU/CIU in 2014. Case reports suggest that patients with physical urticaria including
43
SDerm can also benefit from omalizumab treatment.3, 4 Here, we report the results of
44
a phase 2 trial with SDerm patients, in which we evaluated the efficacy and safety of
45
two different doses of omalizumab as compared to placebo.
EP
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40
Overall, 61 SDerm patients were randomized, received at least one treatment,
47
and were included in the safety analyses, and 55 were included in the primary
48
endpoint analysis (For details on study procedures see Suppl. material and Fig E1).
49
The baseline, demographic and clinical characteristics were comparable in all groups
50
(Table E1). Most notably, the mean DLQI score at baseline was 11.1 (Table E1), i.e.
51
a score that indicates a very large effect on quality of life. 5
AC C
46
52
Critical friction thresholds (CFT, the strongest trigger strength, at which a
53
patient developed symptoms) at week 10 (primary readout) were significantly
54
improved in the omalizumab 150 mg (-1.8 ± 0.4, p=0.014) and 300 mg group (-2.0 ± 3
ACCEPTED MANUSCRIPT 0.4, p=0.004), as compared to the placebo group (-0.6 ± 0.3, Fig 1A). Both,
56
omalizumab 150 mg and 300 mg resulted in a rapid improvement of friction
57
thresholds, as early as in week four after the start of treatment (Fig 1B). After the last
58
injection, during the follow up period, provocation trigger thresholds in the
59
omalizumab groups increased and did not show differences to those in the placebo
60
group six weeks after the last treatment. No significant differences between 150 mg
61
and 300 mg omalizumab were observed at any time during the study (Fig 1A, B).
RI PT
55
To test if SDerm patients with low and high trigger thresholds and disease
63
activity show differences in their responses to omalizumab, we assessed threshold
64
values in every patient at baseline and ten weeks later. As shown in figure 1C,
65
SDerm patients with low and high baseline thresholds showed similar responses to
66
omalizumab treatment. The rates of SDerm patients who showed complete response
67
at week 10 after placebo treatment were 2/18 (11%), whereas 8/18 (44%) showed
68
complete response to 150 mg omalizumab. With omalizumab 300 mg, 10/19 (53%)
69
showed complete response (Fig 1C). No response at all was observed in 15 of 18
70
(83%) patients treated with placebo, 6 of 18 (33%) patients treated with omalizumab
71
150mg, and 8 of 19 (42%) patients treated with omalizumab 300 mg (Fig 1C).
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62
The frequency of adverse events was similar across all groups. The frequency
73
of serious adverse events was low with one event in the 150 mg omalizumab group,
74
one in the 300 mg omalizumab group, and one in the placebo group (Table E2), none
75
of them were considered related to the study medication.
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72
76
SDerm patients refractory to antihistamine treatment were considerably
77
impaired in their quality of life (QoL, Table E1). Treatment with both, 150 mg and 300
78
mg omalizumab improved of QoL as assessed by mean Dermatology Life Quality
79
Index (DLQI) scores at week ten compared to baseline (Fig 2A,B). Overall, 13 of 18
80
(72%) patients treated with 150 mg omalizumab and 11 of 19 (58%) patients treated 4
ACCEPTED MANUSCRIPT 81
with 300 mg omalizumab improved at least four points in the DLQI scale, the minimal
82
clinically important difference.6 In contrast, only 6 of 19 (32%) of placebo treated
83
patients improved by four or more points. Taken together, we found pronounced, statistically significant and clinically
85
meaningful reductions in disease activity and impact in SDerm patients treated with
86
omalizumab 150 mg or 300 mg. The risk/benefit profile for omalizumab was good
87
(Table E2) and did not show any new safety aspects as compared to previously
88
published trials.
SC
RI PT
84
Interestingly, both doses of omalizumab, 150 mg and 300 mg, were effective,
90
with no statistical differences between them. This is in contrast to CSU, where both
91
doses are also effective, but 300 mg omalizumab is more effective than 150 mg.7, 8
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It is, as of yet, unclear, why omalizumab has these strong effects on disease
93
activity in SDerm. A comparison of baseline characteristics in responders and partial
94
or non-responders (Table E3), revealed no statistically significant differences
95
between the two groups. Passive serum transfer experiments have suggested that a
96
soluble transferable factor, presumably IgE, is involved in the pathogenesis of
97
physical urticaria forms such as SDerm, cold urticaria, or solar urticaria.9 But as of
98
now, no relevant role of IgE in any of these diseases has been proven.10 Future
99
clinical trials with more patients will have to be performed to identify potential
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subgroups that can predict a response to omalizumab treatment in SDerm.
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Future studies are needed to characterize the role of IgE in the pathogenesis of
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SDerm and the mechanisms of action of omalizumab in SDerm and other physical
103
urticarias. Also, additional controlled trials are needed to test if omalizumab is
104
similarly effective in other physical urticaria types such as solar, heat or pressure
105
urticaria - all of which have been described in case reports to respond to
106
omalizumab. Furthermore, future trials with larger numbers of patients need to 5
ACCEPTED MANUSCRIPT 107
provide more detailed information on the time to response after omalizumab
108
treatment and the optimal doses used in the treatment of physical urticaria patients. In conclusion, omalizumab in doses of 150 mg and 300 mg resulted in a high
110
rate of complete and partial responders in SDerm patients and a pronounced overall
111
reduction of disease activity and QoL impairment in these patients. The results of our
112
study show that SDerm patients unresponsive to antihistamine treatment can benefit
113
from well-tolerated and effective treatment with omalizumab.
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Dept. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany Dept. of Dermatology, University Medical Center Mainz, Mainz, Germany 3 Dept. of Dermatology, University Medical Center Freiburg, Freiburg, Germany 4 Dept. of Dermatology and Allergology, University Medical Center Giessen and Marburg, Campus Giessen, Justus-Liebig University, Giessen, Germany 2
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Marcus Maurer, M.D.1 Andrea Schütz, M.D.1 Karsten Weller, M.D.1 Nicole Schoepke, M.D.1 Adriane Peveling-Oberhag, M.D.2 Petra Staubach, M.D. 2 Sabine Müller, M.D.3 Thilo Jakob, M.D.3,4 Martin Metz, M.D. 1
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ACCEPTED MANUSCRIPT Acknowledgements
134
The authors thank Hesna Gözlükaya and Nikki Rooks for excellent technical
135
assistance and the physicians of the Charité urticaria clinic, a GA2LEN Urticaria
136
Center of Reference and Excellence (UCARE, www.ga2len.net/ucare), for their
137
support and helpful discussions. The trial was an investigator-initiated trial funded, in
138
part, by Novartis and by intramural grants. MaMe is supported by the Else Kröner-
139
Fresenius-Stiftung.
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140 Keywords
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Inducible urticaria, omalizumab, symptomatic urticaria, urticaria factitia, IgE
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143 144
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Figure legends
147 Figure 1. Omalizumab markedly reduces trigger thresholds in symptomatic
149
dermographism.
150
Omalizumab 150mg, omalizumab 300mg, or placebo were injected subcutaneously
151
three times every four weeks and critical friction thresholds (CFT) were assessed
152
using FricTest®. Data is presented as (A) mean reduction of CTT from baseline at the
153
primary endpoint at week ten and (B) mean absolute values at every investigated
154
time point with error bars indicating SEMs. The arrow indicates time of injection, the
155
star indicates the primary endpoint readout two weeks after the last injection.
156
Individual provocation thresholds before and after treatment are shown in C.
157
*=p<0.05, **=p<0.01, ***=p<0.005, n.s.=not significant.
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158
Figure 2. Omalizumab treatment improves quality of life in patients with
160
antihistamine refractory symptomatic dermographism.
161
A. Mean change in DLQI scores assessed at week ten (primary endpoint) to
162
baseline, with error bars indicating SEMs. B. DLQI scores assessed at baseline and
163
at ten weeks after start of treatment, presented as box-and-whiskers showing
164
median, upper and lower quartile in the box and whiskers indicating 1.5 times the
165
interquartile range (Tukey).
166
*=p<0.05, **=p<0.01, ***=p<0.005, n.s.=not significant; DLQI=dermatology quality of
167
life index.
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6.
7.
8.
9. 10.
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3.
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2.
Abajian M, Schoepke N, Altrichter S, Zuberbier T, Maurer M. Physical urticarias and cholinergic urticaria. Immunol Allergy Clin North Am 2014; 34:73-88. Schoepke N, Mlynek A, Weller K, Church MK, Maurer M. Symptomatic dermographism: an inadequately described disease. J Eur Acad Dermatol Venereol 2015; 29:708-12. Krause K, Ardelean E, Kessler B, Magerl M, Metz M, Siebenhaar F, et al. Antihistamine-resistant urticaria factitia successfully treated with antiimmunoglobulin E therapy. Allergy 2010; 65:1494-5. Metz M, Altrichter S, Ardelean E, Kessler B, Krause K, Magerl M, et al. Antiimmunoglobulin E treatment of patients with recalcitrant physical urticaria. Int Arch Allergy Immunol 2011; 154:177-80. Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 1994-2007: a comprehensive review of validation data and clinical results. Br J Dermatol 2008; 159:997-1035. Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology 2015; 230:27-33. Maurer M, Rosen K, Hsieh HJ, Saini S, Grattan C, Gimenez-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013; 368:924-35. Zhao ZT, Ji CM, Yu WJ, Meng L, Hawro T, Wei JF, et al. Omalizumab for the treatment of chronic spontaneous urticaria: A meta-analysis of randomized clinical trials. J Allergy Clin Immunol 2016; 137:1742-50 e4. Grabbe J. Pathomechanisms in physical urticaria. J Investig Dermatol Symp Proc 2001; 6:135-6. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2015; 135:337-42.
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References
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0 -1 -2
*
**
-3
4 3
* 2 1 0
**
* *** ***
**
RI PT
Change of CFT (in FricTest grades)
Placebo
B
Omalizumab 150 mg 300 mg
CFT (FricTest grade)
A
Placebo 150 mg Omalizumab 300 mg Omalizumab
0
2
4
6
8 10 12 14 16
150 mg Omalizumab
M AN U
Placebo 4
4
3
3
3
2
2
2
0
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4
Baseline Week 10
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Critical friction thresholds (FricTest® grade)
C
SC
Week
Complete response
1
1
0
0 Baseline Week 10
Partial response
Figure 1
300 mg Omalizumab
Baseline Week 10
No response
ACCEPTED MANUSCRIPT
0
Placebo
150 mg
300 mg
-4 -6
150 mg
20 15 10
**
Placebo
300 mg
25
-2
-8
Omalizumab 30
DLQI
Change in DLQI
B
Omalizumab
p = 0.07
5
-10
0
n.s.
RI PT
A
***
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Baseline
Figure 2
After treatment
*
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ACCEPTED MANUSCRIPT
Randomized n = 61
Allocated (21) Received (21)
Omalizumab 300 mg Allocated (21) Received (21)
Discontinued n=1
Discontinued n=1
Completed (19)
Completed (18)
Completed (20)
Analyzed Safety (21) Efficacy (18)
Analyzed Safety (19) Efficacy (18)
Analyzed Safety (21) Efficacy (19)
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Discontinued n=2
Omalizumab 150 mg Allocated (19) Received (19)
M AN U
Placebo
SC
Symptomatic dermographism patients
Figure E1
ACCEPTED MANUSCRIPT Symptomatic dermographism patients All patients (n=61)
Placebo (n=21)
Omalizumab 150mg (n=19)
Omalizumab 300mg (n=21)
Male Female Age (years)
27 (44%) 34 (56%) 40 (30-50)
9 (43%) 12 (57%) 37 (26-46)
6 (32%) 13 (68%) 45 (34-52)
12 (57%) 9 (43%) 40 (31-51)
BMI (kg/m2) CFT at Baseline (FricTest grade) Duration of SDerm (months) DLQI at Baseline
25.8 (4.7)
25.1 (4.8)
26.6 (5.5)
25.6 (3.7)
3.5 (0.8)
3.6 (0.6)
3.4 (1.0)
3.5 (0.8)
55.7 (64.7)
51.3 (46.9)
63.3 (74.3)
53.1 (72.3)
11.1 (6.1)
11.3 (5.5)
10.6 (5.7)
11.4 (7.3)
SC
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Sex
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Supplementary Table E1
ACCEPTED MANUSCRIPT Symptomatic dermographism patients Omalizumab 150mg; n=19
Omalizumab 300mg; n=21
Total number of adverse events
54
100
57
Total number of serious adverse events
1
1
1
Patients with any adverse event
19 (90%)
17 (89%)
17 (81%)
Patients with any serious adverse event
1*1 (5%)
1*2 (5%)
1*3 (5%)
0
0
0
Discontinuation due to adverse event
RI PT
Placebo n=21
SC
*1 renal colic due to calculus of ureter with hospital admission *2 surgery because of an inguinal hernia *3 acute cystitis with hospital admission
AEs observed in two or more patients per treatment group:
Other infections Headache
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Supplementary Table E2
8 (39%)
12 (63%)
6 (29%)
2 (10%)
6 (32%)
2 (10%)
10 (48%)
6 (32%)
9 (43%)
M AN U
Upper respiratory tract infection
ACCEPTED MANUSCRIPT Complete responder (n=18)
Atopy
8 (42%)
7 (39%)
Food allergy
1 (5%)
1 (6%)
CSU comorbidity
1 (5%)
4 (22%)
Presence of other types of CINDU
0 (0%)
2.9 (0.7)
Table E3.
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Duration of SDerm (years, mean ± SEM)
SC
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Non or partial responder (n=19)
1 (6%)
6.8 (1.8)
S0091-6749(17)30514-6
DOI:
10.1016/j.jaci.2017.01.042
Reference:
YMAI 12723
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 3 August 2016 Revised Date:
8 December 2016
Accepted Date: 5 January 2017
Please cite this article as: Maurer M, Schütz A, Weller K, Schoepke N, Peveling-Oberhag A, Staubach P, Müller S, Jakob T, Metz M, Omalizumab is Effective in Symptomatic Dermographism - results of a Randomized, Placebo Controlled Trial, Journal of Allergy and Clinical Immunology (2017), doi: 10.1016/ j.jaci.2017.01.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Omalizumab is effective in symptomatic dermographism - results of a
2
randomized, placebo controlled trial
3 Marcus Maurer, M.D.1, Andrea Schütz, M.D.1, Karsten Weller, M.D.1, Nicole
5
Schoepke, M.D.1, Adriane Peveling-Oberhag, M.D.2, Petra Staubach, M.D.2, Sabine
6
Müller, M.D.3, Thilo Jakob, M.D.3,4, Martin Metz, M.D.1
7
RI PT
4
8
1
9
2
10
3
11
4
12
Marburg, Campus Giessen, Justus-Liebig University, Giessen, Germany
SC
Dept. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany Dept. of Dermatology, University Medical Center Mainz, Mainz, Germany
M AN U
Dept. of Dermatology, University Medical Center Freiburg, Freiburg, Germany Dept. of Dermatology and Allergology, University Medical Center Giessen and
13
TE D
14 Corresponding author:
16
Martin Metz, MD
17
Dept. of Dermatology and Allergy
18
Charité – Universitätsmedizin Berlin
19
Charitéplatz 1
20
D-10117 Berlin, Germany
21
Phone: +49-30-450-518 159
22
Fax:
23
Email: [email protected]
AC C
EP
15
+49-30-450-518 972
1
ACCEPTED MANUSCRIPT 24
Short summary
25
We report the results of a randomized controlled multicenter trial in patients with
26
symptomatic dermographism. Treatment with omalizumab 150 mg and 300 mg was
27
effective and well tolerated, as compared to placebo.
AC C
EP
TE D
M AN U
SC
RI PT
28
2
ACCEPTED MANUSCRIPT To the editor:
30
Symptomatic dermographism (SDerm) is the most common form of physical urticaria
31
with a prevalence of up to 5%.1 SDerm is characterized by itchy wheals that occur in
32
response to friction, for example after rubbing or scratching of the skin, and usually
33
last for one to two hours.2 SDerm commonly lasts for years and significantly impairs
34
quality of life.2 The underlying cause of SDerm is unknown, and the trigger is difficult
35
if not impossible to avoid. Therefore, symptomatic treatment with antihistamines is
36
the first choice treatment. However, higher than standard doses are usually required
37
to achieve symptom control, and some patients do not respond to updosing of
38
antihistamines.2
SC
Omalizumab,
M AN U
39
RI PT
29
a
humanized
anti-IgE
antibody,
is
highly
effective
in
antihistamine-refractory patients with chronic spontaneous urticaria (CSU), also
41
known as chronic idiopathic urticaria (CIU), and the drug was licensed for the use in
42
CSU/CIU in 2014. Case reports suggest that patients with physical urticaria including
43
SDerm can also benefit from omalizumab treatment.3, 4 Here, we report the results of
44
a phase 2 trial with SDerm patients, in which we evaluated the efficacy and safety of
45
two different doses of omalizumab as compared to placebo.
EP
TE D
40
Overall, 61 SDerm patients were randomized, received at least one treatment,
47
and were included in the safety analyses, and 55 were included in the primary
48
endpoint analysis (For details on study procedures see Suppl. material and Fig E1).
49
The baseline, demographic and clinical characteristics were comparable in all groups
50
(Table E1). Most notably, the mean DLQI score at baseline was 11.1 (Table E1), i.e.
51
a score that indicates a very large effect on quality of life. 5
AC C
46
52
Critical friction thresholds (CFT, the strongest trigger strength, at which a
53
patient developed symptoms) at week 10 (primary readout) were significantly
54
improved in the omalizumab 150 mg (-1.8 ± 0.4, p=0.014) and 300 mg group (-2.0 ± 3
ACCEPTED MANUSCRIPT 0.4, p=0.004), as compared to the placebo group (-0.6 ± 0.3, Fig 1A). Both,
56
omalizumab 150 mg and 300 mg resulted in a rapid improvement of friction
57
thresholds, as early as in week four after the start of treatment (Fig 1B). After the last
58
injection, during the follow up period, provocation trigger thresholds in the
59
omalizumab groups increased and did not show differences to those in the placebo
60
group six weeks after the last treatment. No significant differences between 150 mg
61
and 300 mg omalizumab were observed at any time during the study (Fig 1A, B).
RI PT
55
To test if SDerm patients with low and high trigger thresholds and disease
63
activity show differences in their responses to omalizumab, we assessed threshold
64
values in every patient at baseline and ten weeks later. As shown in figure 1C,
65
SDerm patients with low and high baseline thresholds showed similar responses to
66
omalizumab treatment. The rates of SDerm patients who showed complete response
67
at week 10 after placebo treatment were 2/18 (11%), whereas 8/18 (44%) showed
68
complete response to 150 mg omalizumab. With omalizumab 300 mg, 10/19 (53%)
69
showed complete response (Fig 1C). No response at all was observed in 15 of 18
70
(83%) patients treated with placebo, 6 of 18 (33%) patients treated with omalizumab
71
150mg, and 8 of 19 (42%) patients treated with omalizumab 300 mg (Fig 1C).
EP
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SC
62
The frequency of adverse events was similar across all groups. The frequency
73
of serious adverse events was low with one event in the 150 mg omalizumab group,
74
one in the 300 mg omalizumab group, and one in the placebo group (Table E2), none
75
of them were considered related to the study medication.
AC C
72
76
SDerm patients refractory to antihistamine treatment were considerably
77
impaired in their quality of life (QoL, Table E1). Treatment with both, 150 mg and 300
78
mg omalizumab improved of QoL as assessed by mean Dermatology Life Quality
79
Index (DLQI) scores at week ten compared to baseline (Fig 2A,B). Overall, 13 of 18
80
(72%) patients treated with 150 mg omalizumab and 11 of 19 (58%) patients treated 4
ACCEPTED MANUSCRIPT 81
with 300 mg omalizumab improved at least four points in the DLQI scale, the minimal
82
clinically important difference.6 In contrast, only 6 of 19 (32%) of placebo treated
83
patients improved by four or more points. Taken together, we found pronounced, statistically significant and clinically
85
meaningful reductions in disease activity and impact in SDerm patients treated with
86
omalizumab 150 mg or 300 mg. The risk/benefit profile for omalizumab was good
87
(Table E2) and did not show any new safety aspects as compared to previously
88
published trials.
SC
RI PT
84
Interestingly, both doses of omalizumab, 150 mg and 300 mg, were effective,
90
with no statistical differences between them. This is in contrast to CSU, where both
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doses are also effective, but 300 mg omalizumab is more effective than 150 mg.7, 8
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It is, as of yet, unclear, why omalizumab has these strong effects on disease
93
activity in SDerm. A comparison of baseline characteristics in responders and partial
94
or non-responders (Table E3), revealed no statistically significant differences
95
between the two groups. Passive serum transfer experiments have suggested that a
96
soluble transferable factor, presumably IgE, is involved in the pathogenesis of
97
physical urticaria forms such as SDerm, cold urticaria, or solar urticaria.9 But as of
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now, no relevant role of IgE in any of these diseases has been proven.10 Future
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clinical trials with more patients will have to be performed to identify potential
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subgroups that can predict a response to omalizumab treatment in SDerm.
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Future studies are needed to characterize the role of IgE in the pathogenesis of
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SDerm and the mechanisms of action of omalizumab in SDerm and other physical
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urticarias. Also, additional controlled trials are needed to test if omalizumab is
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similarly effective in other physical urticaria types such as solar, heat or pressure
105
urticaria - all of which have been described in case reports to respond to
106
omalizumab. Furthermore, future trials with larger numbers of patients need to 5
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provide more detailed information on the time to response after omalizumab
108
treatment and the optimal doses used in the treatment of physical urticaria patients. In conclusion, omalizumab in doses of 150 mg and 300 mg resulted in a high
110
rate of complete and partial responders in SDerm patients and a pronounced overall
111
reduction of disease activity and QoL impairment in these patients. The results of our
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study show that SDerm patients unresponsive to antihistamine treatment can benefit
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from well-tolerated and effective treatment with omalizumab.
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Dept. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany Dept. of Dermatology, University Medical Center Mainz, Mainz, Germany 3 Dept. of Dermatology, University Medical Center Freiburg, Freiburg, Germany 4 Dept. of Dermatology and Allergology, University Medical Center Giessen and Marburg, Campus Giessen, Justus-Liebig University, Giessen, Germany 2
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Marcus Maurer, M.D.1 Andrea Schütz, M.D.1 Karsten Weller, M.D.1 Nicole Schoepke, M.D.1 Adriane Peveling-Oberhag, M.D.2 Petra Staubach, M.D. 2 Sabine Müller, M.D.3 Thilo Jakob, M.D.3,4 Martin Metz, M.D. 1
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The authors thank Hesna Gözlükaya and Nikki Rooks for excellent technical
135
assistance and the physicians of the Charité urticaria clinic, a GA2LEN Urticaria
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Center of Reference and Excellence (UCARE, www.ga2len.net/ucare), for their
137
support and helpful discussions. The trial was an investigator-initiated trial funded, in
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part, by Novartis and by intramural grants. MaMe is supported by the Else Kröner-
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Fresenius-Stiftung.
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140 Keywords
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Inducible urticaria, omalizumab, symptomatic urticaria, urticaria factitia, IgE
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143 144
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Figure legends
147 Figure 1. Omalizumab markedly reduces trigger thresholds in symptomatic
149
dermographism.
150
Omalizumab 150mg, omalizumab 300mg, or placebo were injected subcutaneously
151
three times every four weeks and critical friction thresholds (CFT) were assessed
152
using FricTest®. Data is presented as (A) mean reduction of CTT from baseline at the
153
primary endpoint at week ten and (B) mean absolute values at every investigated
154
time point with error bars indicating SEMs. The arrow indicates time of injection, the
155
star indicates the primary endpoint readout two weeks after the last injection.
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Individual provocation thresholds before and after treatment are shown in C.
157
*=p<0.05, **=p<0.01, ***=p<0.005, n.s.=not significant.
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158
Figure 2. Omalizumab treatment improves quality of life in patients with
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antihistamine refractory symptomatic dermographism.
161
A. Mean change in DLQI scores assessed at week ten (primary endpoint) to
162
baseline, with error bars indicating SEMs. B. DLQI scores assessed at baseline and
163
at ten weeks after start of treatment, presented as box-and-whiskers showing
164
median, upper and lower quartile in the box and whiskers indicating 1.5 times the
165
interquartile range (Tukey).
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*=p<0.05, **=p<0.01, ***=p<0.005, n.s.=not significant; DLQI=dermatology quality of
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life index.
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6.
7.
8.
9. 10.
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Abajian M, Schoepke N, Altrichter S, Zuberbier T, Maurer M. Physical urticarias and cholinergic urticaria. Immunol Allergy Clin North Am 2014; 34:73-88. Schoepke N, Mlynek A, Weller K, Church MK, Maurer M. Symptomatic dermographism: an inadequately described disease. J Eur Acad Dermatol Venereol 2015; 29:708-12. Krause K, Ardelean E, Kessler B, Magerl M, Metz M, Siebenhaar F, et al. Antihistamine-resistant urticaria factitia successfully treated with antiimmunoglobulin E therapy. Allergy 2010; 65:1494-5. Metz M, Altrichter S, Ardelean E, Kessler B, Krause K, Magerl M, et al. Antiimmunoglobulin E treatment of patients with recalcitrant physical urticaria. Int Arch Allergy Immunol 2011; 154:177-80. Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 1994-2007: a comprehensive review of validation data and clinical results. Br J Dermatol 2008; 159:997-1035. Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology 2015; 230:27-33. Maurer M, Rosen K, Hsieh HJ, Saini S, Grattan C, Gimenez-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013; 368:924-35. Zhao ZT, Ji CM, Yu WJ, Meng L, Hawro T, Wei JF, et al. Omalizumab for the treatment of chronic spontaneous urticaria: A meta-analysis of randomized clinical trials. J Allergy Clin Immunol 2016; 137:1742-50 e4. Grabbe J. Pathomechanisms in physical urticaria. J Investig Dermatol Symp Proc 2001; 6:135-6. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2015; 135:337-42.
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References
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0 -1 -2
*
**
-3
4 3
* 2 1 0
**
* *** ***
**
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Change of CFT (in FricTest grades)
Placebo
B
Omalizumab 150 mg 300 mg
CFT (FricTest grade)
A
Placebo 150 mg Omalizumab 300 mg Omalizumab
0
2
4
6
8 10 12 14 16
150 mg Omalizumab
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4
3
3
3
2
2
2
0
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Baseline Week 10
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Critical friction thresholds (FricTest® grade)
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Week
Complete response
1
1
0
0 Baseline Week 10
Partial response
Figure 1
300 mg Omalizumab
Baseline Week 10
No response
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0
Placebo
150 mg
300 mg
-4 -6
150 mg
20 15 10
**
Placebo
300 mg
25
-2
-8
Omalizumab 30
DLQI
Change in DLQI
B
Omalizumab
p = 0.07
5
-10
0
n.s.
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A
***
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Baseline
Figure 2
After treatment
*
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Randomized n = 61
Allocated (21) Received (21)
Omalizumab 300 mg Allocated (21) Received (21)
Discontinued n=1
Discontinued n=1
Completed (19)
Completed (18)
Completed (20)
Analyzed Safety (21) Efficacy (18)
Analyzed Safety (19) Efficacy (18)
Analyzed Safety (21) Efficacy (19)
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Discontinued n=2
Omalizumab 150 mg Allocated (19) Received (19)
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Symptomatic dermographism patients
Figure E1
ACCEPTED MANUSCRIPT Symptomatic dermographism patients All patients (n=61)
Placebo (n=21)
Omalizumab 150mg (n=19)
Omalizumab 300mg (n=21)
Male Female Age (years)
27 (44%) 34 (56%) 40 (30-50)
9 (43%) 12 (57%) 37 (26-46)
6 (32%) 13 (68%) 45 (34-52)
12 (57%) 9 (43%) 40 (31-51)
BMI (kg/m2) CFT at Baseline (FricTest grade) Duration of SDerm (months) DLQI at Baseline
25.8 (4.7)
25.1 (4.8)
26.6 (5.5)
25.6 (3.7)
3.5 (0.8)
3.6 (0.6)
3.4 (1.0)
3.5 (0.8)
55.7 (64.7)
51.3 (46.9)
63.3 (74.3)
53.1 (72.3)
11.1 (6.1)
11.3 (5.5)
10.6 (5.7)
11.4 (7.3)
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Sex
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Supplementary Table E1
ACCEPTED MANUSCRIPT Symptomatic dermographism patients Omalizumab 150mg; n=19
Omalizumab 300mg; n=21
Total number of adverse events
54
100
57
Total number of serious adverse events
1
1
1
Patients with any adverse event
19 (90%)
17 (89%)
17 (81%)
Patients with any serious adverse event
1*1 (5%)
1*2 (5%)
1*3 (5%)
0
0
0
Discontinuation due to adverse event
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Placebo n=21
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*1 renal colic due to calculus of ureter with hospital admission *2 surgery because of an inguinal hernia *3 acute cystitis with hospital admission
AEs observed in two or more patients per treatment group:
Other infections Headache
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Supplementary Table E2
8 (39%)
12 (63%)
6 (29%)
2 (10%)
6 (32%)
2 (10%)
10 (48%)
6 (32%)
9 (43%)
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Upper respiratory tract infection
ACCEPTED MANUSCRIPT Complete responder (n=18)
Atopy
8 (42%)
7 (39%)
Food allergy
1 (5%)
1 (6%)
CSU comorbidity
1 (5%)
4 (22%)
Presence of other types of CINDU
0 (0%)
2.9 (0.7)
Table E3.
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Duration of SDerm (years, mean ± SEM)
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Non or partial responder (n=19)
1 (6%)
6.8 (1.8)