Sesión Académica del CRAIC "Alergia a nueces y otras semillas"
Targeting Grossly Elevated IgE. Prof. Dr. Markus Ollert
1. Targeting grossly elevated IgE: a novel
therapeutic option in severe patients
Markus Ollert, MD
Professor of Molecular Dermatology and Immunology
Department of Dermatology and Allergy
Clinical Research Group of Molecular Dermatology and Immunology/ZAUM
Klinikum rechts der Isar, Technische Universität München (TUM) and Helmholtz Center
Munich for Environmental Health, Munich, Germany
Session „Dermatitis Atopica“, XVII Congreso SLaai, Cartagena, Colombia, 25 October 2012
2. • Inflammatory, chronically
relapsing, non-contagious and
pruritic skin disorder
• Known since ancient times
Robert Willan, Delineations of
Cutaneous Diseases. 1817
Bieber T. N Engl J Med 2008; 358:1483-1494
Atopic Eczema / Dermatitis
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
3. • Inflammatory, chronically
relapsing, non-contagious and
pruritic skin disorder
• Known since ancient times
• Up to 10 % of adults in
industrialized countries are
affected
• Especially for severe cases, no
satisfactory treatment option
is available until today
Bieber T. N Engl J Med 2008; 358:1483-1494
Atopic Eczema / Dermatitis
Technische
Universität
München
0
5
10
15
20
25
30
1946
1958
1964
1968
1970
1971
1974
1979
1981
1985
1986
1989
1991
1992
1993
1994
1997
1999
2000
%
Taylor, UK
Ninan, UK
Schultz-L, DK
Varonier, CH
Aberg, S
Eaton, UK
Austin, UK
Butland, UK
Yura, J
Heinrich, J
Schäfer, D
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
5. House dust mite
(Encasing, SIT)
Food allergens
(Elimination: cow´s milk,
hen´s egg, wheat, nuts)
Inhalant allergens
(SIT with pollen extract)
S. aureus antigens
(SEA, SEB, FN-BP)
Malassezia sympodialis
(Mala s 1-6)
Autoallergy
(Hom s 1-4)
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
6. Targeting IgE antibodies –
A universal therapeutic solution for
allergic atopic disorders with “high IgE
phenotypes” such as atopic dermatitis?
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
7. The pathogenetic role of IgE in atopic
dermatitis: a highly controversial issue
Off-label use of anti-IgE antibody
omalizumab in atopic dermatitis: very
ambivalent results
Belloni B et al. JACI 2007; 120: 1223-1225
Bieber T. N Engl J Med 2008; 358: 1483-1494
Heil PM et al. JDDG 2010; 8: 990-998
Patient A: IgE = 12,534 kU/L
IgE and Atopic Dermatitis
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
8. Patient A: IgE = 12,534 kU/L
Omalizumab
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
9. Table 2: Pharmacotherapy on first presentation in our outpatient clinic
Agent Daily dose
Fluticasone / salmeterol 500 µg / 50 µg bid per DPI (Diskus®)
Formoterol 12 µg per pMDI
Prednisolone 50 mg p.o.
Omeprazole 20 mg p.o.
Montelukast 10 mg p.o.
Ipratropiumbromide / fenoterol 20 µg / 50 µg p.r.n per pMDI
(was actually used 10 – 12 times a day)
Cetirizine 10 mg p.o.
NaCl 0.9% 2 ml tid per nebulizer
DPI: dry powder inhaler; pMDI: pressurized metered dose inhaler.
Case Report: 15-Year-Old Patient with
Severe Asthma
Kerzel et al., Klin Padiatr. 2011;223:356-359
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
Technische
Universität
München
10. Table 1: Relevant laboratory findings before plasmapheresis
Actual value Reference range
total IgE 4,170 kU/l [< 100 kU/l]
specific IgE against
phleum pratense
35 kU/l [< 0.35 kU/l]
rye pollen 25 kU/l [< 0.35 kU/l]
cat 209 kU/l [< 0.35 kU/l]
dog 186 kU/l [< 0.35 kU/l]
leukocytes 11.4 G/l [4.5 – 10 G/l]
eosinophils 22% [1 – 4%]
High IgE Asthma Phenotype: Therapy with
Plasmapheresis and Anti-IgE
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
Kerzel et al., Klin Padiatr. 2011;223:356-359
11. 0 24 48
0
1000
2000
3000
4000
5000
200 700
IgE
80 kU/l
2.300 kU/l free IgE
start omalizumab
plasma-
pheresis
plasma-
pheresis
plasma-
pheresis
hour
kU/l
0 24 48
0
1000
2000
3000
4000
5000
200 700
IgE
80 kU/l
2.300 kU/l free IgE
start omalizumab
plasma-
pheresis
plasma-
pheresis
plasma-
pheresis
hour
kU/l
Figure 1: Dynamics of serum IgE during and after plasma exchange
High IgE Asthma Phenotype: Therapy with
Plasmapheresis and Anti-IgE
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
Kerzel et al., Klin Padiatr. 2011;223:356-359
12. 0 100 200 300
0
100
200
300
400
2000
3000
4000
5000
total IgE
free IgE
start omalizumab
day
kU/l
Figure 2: Dynamics of total IgE and free IgE during omalizumab therapy
High IgE Asthma Phenotype: Therapy with
Plasmapheresis and Anti-IgE
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
Kerzel et al., Klin Padiatr. 2011;223:356-359
13. -50 0 50 100 150
40
60
80
100
100
150
200
250
300
SR
FEV1
days
%predicted
plasmapheresis
omalizumab
Figure 3: Lung function before and after plasmapheresis
High IgE Asthma Phenotype: Therapy with
Plasmapheresis and Anti-IgE
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
Kerzel et al., Klin Padiatr. 2011;223:356-359
14. Targeting IgE antibodies –
Can we apply an IgE-directed treatment
regimen to atopic dermatitis with “high
IgE phenotype”?
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
15. Investigator-initiated pilot study
Investigator-initiated open-label clinical pilot trial, approved by ethics committee,
government agencies and European Medicines Agency (EMA) (EudraCT #2009-
014582-51)
10 patients with severe therapy refractory atopic dermatitis and grossly elevated
total IgE-levels ranging from 3,728 kU/L to 69,972 kU/L
Initial immunoadsorption prior to administration of anti-IgE-antibody
omalizumab for 6 months and a 6 months follow-up
Ig-Apheresis
2-4 days
Tx with Anti-IgE (Omalizumab)
450 mg s.c. bi-weekly
24 weeks
Control period/Follow-up
24 weeks
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
16. Ig-Apheresis
2-4 days
Tx with Anti-IgE (Omalizumab)
450 mg s.c. bi-weekly
24 weeks
Control period/Follow-up
24 weeks
Primary endpoint: long-term control of free IgE levels (<150 / <1000 kU/L)
Secondary endpoints:
- severity of AD (rated by SCORAD)
- TARC (CCL 17) levels in serum
- patient’s personal evaluation on severity and pruritus scale
- standardized photography
Sponsor: Klinikum rechts der Isar/TUM
Support: Miltenyi Biotec (supply and materials for Therasorb Ig-apheresis)
Investigator-initiated pilot study
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
17. Conventional plasmapheresis Immune apheresis (Immune adsorption)
Technische
Universität
München
Ig-binding specificity/capacity of the
TheraSorb system: IgG > IgM > IgE
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
Ig-binding specificity/capacity of other
available systems: IgG > IgM >>> IgE
18. Immunoadsorption with TheraSorb™
Tolerated very well by all patients without
any noteworthy side effects.
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
19. IgE during immunoadsorption
0%
20%
40%
60%
80%
100%
120%
beofore IA1 IA1 IA2 IA3 IA4
IgE
IgE during immunoadsorption
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Paitent 9
Patient 10
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
20. IgE during omalizumab – first 12 weeks
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
1
= nach IA
3 5 7 9 11 13
freeIgEinIU/ml
week
Free IgE in the course of study
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Patient 9
Patient 10
Free IgE levels
continued to drop
during OMZ therapy
reaching free IgE-
levels of
<150 kU/L in 5/10
and
<1,000 kU/L in 9/10
patients during the
entire treatment
period of 24 weeks
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
21. IgE during omalizumab – first 12 weeks
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
22. Control of pruritus and visual
analogue scale
(subjective patient score)
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
25. SCORAD – first 12-25 weeks of IIT
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
26. SCORAD – first 12 weeks of IIT
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
27. SCORAD / IgE / TARC
(entire study period)
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
28. 0
2000
4000
6000
8000
10000
12000
14000
free IgE in kU/L
free IgE in kU/L
SCORAD
SCORAD and IgE
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
fIgE
End of OMZ Tx
Immune
apheresis
30. 1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
week 1 week 3 week 13 week 25 week 49
TARC (CCL 17)pg/ml
TARC Levels
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein End of OMZ Tx
Immune
apheresis
31. week 1 week 3 week 13 week 25 week 49
Clinical Phenotype
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
End of OMZ Tx
Immune
apheresis
33. Consumption of topical medication (up to week 12)
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein
34. • Immunoadsorption prior to omalizumab is suitable to
reduce highly elevated serum IgE levels and may
improve clinical symptoms of atopic dermatitis
• Further studies regarding IgE control in atopic dermatitis
are justified and needed due to the given limitations of
our pilot study
• Targeting IgE by apheresis: a promising treatment option
in severely diseased patients with „high IgE phenotype“
Conclusion
Technische
Universität
München
Klinik und Poliklinik für Dermatologie
und Allergologie
am Biederstein