of atopic dermatitis remained highest in children with
early, persistent atopic (25%) compared with the other 2
groups (16.2% and 8.7%, respectively).
This study shows that our intervention measures were
highly effective in preventing asthma in children in this
high-risk cohort who had not developed atopy by age
wheeze and not through an allergic/atopic mechanism.
Another striking finding of this study is the very high
prevalence of asthma at age 7 years in children with early,
persistent atopy. This subgroup of children was at high
risk of developing asthma and atopic dermatitis as part of
the ‘‘atopic march’’ regardless of our intervention pro-
gram. Therefore, being atopic by age 1 year appears to be
an extremely important marker for subsequent develop-
ment of asthma.5-7
We have not been able to identify which environmental
exposure could explain the results. Because our study was
designed to determine the effectiveness of a multifaceted
intervention program, the sample size based on such a
study design does not permit us to determine which
component of the intervention program was useful. As
well, it is possible that prenatal exposures may affect on
the immune system and lung development and influence
expression of disease postnatally. Our finding of the
differential effect of intervention measures on asthma
and atopy suggests that the pathogenesis of asthma is
different from that of other atopic disorders. However,
because of the relatively small sample of high-risk chil-
dren studied, these observations should be confirmed in a
larger population-based cohort. Genetic studies may help
define better the factors critical to this process among
of asthma and atopy.
Moira Chan-Yeung, MBa
Helen Dimich-Ward, PhDa
Allan Becker, MDb
Fromathe University of British Columbia, Vancouver; andbthe University of
Manitoba, Winnipeg, Canada. E-mail: email@example.com.
Supported by the Canadian Institutes of Health Research,the British Columbia
Lung Association, and the Manitoba Medical Service Foundation.
Disclosure of potential conflict of interest: The authors have declared that they
have no conflict of interest.
1. Schiessl B, Zenmann B, Hodgin-Pickart LA, de Weck AL, Griot-Wenk M,
Mayor P, et al. Importance of early allergen contact for the development of
a sustained immunoglobulin E response in a dog model. Int Arch Allergy
2. Chan-Yeung M, Manfreda J, Dimich-Ward H, Ferguson A, Watson W,
Becker A. A randomized controlled study on the effectiveness of a multi-
faceted intervention program in the primary prevention of asthma in high-
risk infants. Arch Pediatr Adolesc Med 2000;154:657-63.
3. Becker A, Watson W, Ferguson A, Dimich-Ward H, Chan-Yeung M. The
Canadian Primary Prevention of Asthma study: outcomes at 2 years of
age. J Allergy Clin Immunol 2004;113:650-6.
4. Chan-Yeung M, Ferguson F, Watson W, Dimich-Ward H, Rousseau R,
Lilley M, et al. The Canadian Childhood Asthma Prevention Study: out-
comes at 7 years of age. J Allergy Clin Immunol 2005;116:49-55.
5. Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and
atopy during childhood by allergen avoidance in infancy: a randomized
controlled study. Thorax 2003;58:489-93.
6. Peat JK, Mihrshahi S, Kemp A, Marks GB, Tovey ER, Webb K, et al, for
the CAPS Team. Three year outcomes of dietary fatty acid modification
and house dust mite avoidance in the Childhood Asthma Prevention Study
(CAPS). J Allergy Clin Immunol 2004;114:807-13.
7. Illi S, von Mutius E, Lau S, Niggermann B, Gruber C, Wahn U, et al. Pe-
rennial allergen sensitization early in life and chronic asthma in children: a
birth cohort study. Lancet 2006;368:763-70.
Available online October 8, 2007.
Low-dose anti-IgE therapy in patients with
atopic eczema with high serum IgE levels
To the Editor:
In a preliminary experience with a limited patient
number, we observed surprising success with low-dose
tic improvement was paralleled by a decrease in the
mRNA ratio for IgE/IgG in the patients’ PBMCs. We
patients with severe generalized atopic eczema (3 of these
patients have been reported previously).
All patients displayed total serum IgE values far above
Repository at www.jacionline.org). All patients had un-
dergone at least 1 standard therapy (systemic corticoste-
roids, cyclosporine A, UV treatment) before enrollment
fore inclusion. All patients, regardless of their IgE values,
were treated with a fixed schedule of 10 cycles of 150
mg omalizumab (Xolair; Novartis, Nu ¨rnberg, Germany)
subcutaneously in 2-week intervals. Before each visit,
Scoring Atopic Dermatitis (SCORAD)2and a detailed
photo documentation were taken. Patients were allowed
to use prednicarbat creme as concomitant treatment but
ment. All patients agreed to the withdrawal of 10 mL of
blood for serum sampling at every visit and to withdrawal
end of treatment. Serum immunoglobulins, isolation of
mRNA, and quantitative PCR to target immunoglobulin-
specific transcripts were carried out as documented previ-
ously.1To use a second investigator-independent parame-
activation-regulated chemokine (TARC/CCL17) levels3,4
in the serum during therapy as recommended by the man-
Low-doseomalizumab waswelltoleratedinall patients
without signs of adverse reactions.
clinical response (SCORAD reduction of more than 50%),
4 patients showed satisfying results (SCORAD reduction
between 25% and 50%), 3 patients showed clinically no
than 25%), and 2 patients showed a deterioration of their
eczema (SCORAD increase of more than 25%) (Fig 1, A).
J ALLERGY CLIN IMMUNOL
VOLUME 120, NUMBER 5
Letters to the Editor 1223
Letters to the Editor
well),norelevant changes(below 25%) in 5 patients, anda
showed either a clinical deterioration or no changes in
SCORAD (Fig 1, C). The ratio of IgE-specific to IgG-spe-
cific transcripts decreased in 8 patients, of whom 6 patients
also showed good clinical improvement (accounting for
showed noclinicalchange,and 1patient showeda relevant
increase in SCORAD level. The IgE/IgG mRNA ratio in-
under therapy (Fig 1, B). As observed previously, total IgE
(bound and free IgE) slightly increased during therapy,
whereas free IgE remained basically stable over the treat-
ment period. Total serum IgM and total serum IgG showed
Of note, the changes observed in our limited number
of analyzed patients have to be evaluated in the
contextofknown percentages of placebo-induced clinical
improvement in atopic eczema patients undergoing
clinical trials. This percentage has been described to be
as high at 40%. Therefore, the observed outcome in our
omalizumab trial might not entirely reflect drug-associ-
ated clinical changes. In line with this observation, the
cases showing deterioration of their skin conditions
under anti-IgE, in our eyes, most probably experienced
spontaneous flare-ups, which were not controlled/cured
by omalizumab, rather than presenting a true drug-
induced negative effect.
Our current study extends the previously published
reports on omalizumab in atopic eczema by integrating
laboratory data in the follow-up of treated patients. The
clinical improvements during the 20-week treatment pe-
riod in 6 of 11 patients support data showing good clinical
response in selected patients.5Similar to these patients,
we have used omalizumab in a much lower dosage than
required for the complete removal of IgE from the cir-
culation. In fact, only a very small proportion (probably
between 1% and 5 % of all serum IgE molecules) in our
likely that the reduction in free serum IgE accounted for
the clinical response. Alternatively, molecular changes
such as the observed switch to reduced IgE mRNA pro-
duction could mirror a clinical outcome.
The parameter used to identify responders in our previ-
ous publication,1namely the changes in IgE/IgG mRNA,
showed association with a positive clinical course but
Of note, the reported number of 11 patients can only be
considered as a pilot investigation without the power to
IgG mRNA turned out to identify better patients with a
good or satisfying clinical response as compared to serum
by researchers as being suitable in the follow-up of
generalized atopic eczema patients.4
One of the most striking findings of our current study
and our previous work is the fact that despite dramatic
changes in the mRNA level for the different immunoglob-
ulins (see Table E1), the amount of serum immunoglobu-
lins did not change substantially during the treatment
period. One explanation for this discrepancy could be
that most immunoglobulins are not produced in PBMC
plasma cells but by long-living plasma cells residing in
the bone marrow.6In addition, the thorough analysis of
the transcriptional changes revealed that besides the
mRNA for secreted form of the immunoglobulins, the
increase playsmost likelyarole forIgG(which wasfound
increased in most patients) rather than for IgE, which is an
immunoglobulin in which the membrane-type encoding
mRNA is not processed properly.7From our data, de-
creases in the mRNA ratio for IgE/IgG more than for IgE
alone would be a promising marker to identify individuals
responding to omalizumab treatment. However, this
marker will have to be confirmed in larger cohorts.
FIG 1. Patient-specificchangesinSCORAD(A),ratioofIgE/IgGmRNA
(B), and TARC level (C). The calculation of mRNA ratios is based on
the totality of transcripts for IgM, IgG, and IgE and is expressed as
a percentage ratio of the respective immunoglobulin transcripts.9
Positive clinical findings (reduction in SCORAD, TARC levels, and
IgE/IgG mRNA) are presented in the upper part of the y-axis.
J ALLERGY CLIN IMMUNOL
1224 Letters to the Editor
Letters to the Editor
As a summary of our clinical observations and in Download full-text
response to the good safety data8being reported for this
antibody, we think that our pilot data might warrant the
exploration of omalizumab in patients with generalized
atopic eczema under controlled study conditions. In our
eyes, this antibody does not have to be dosed to com-
pletely remove IgE from serum.
We greatly appreciate the excellent technical assistance of Kerstin
Holtz, Beate Heuser, and Johanna Grosch.
Benedetta Belloni, MDa
Mahzad Ziai, MDa
Annick Lim, MSb,c
Brigitte Lemercier, BSb,c
Martin Sbornik, MDa
Stephan Weidinger, MDa
Christian Andres, MDa
Christina Schnopp, MDa
Johannes Ring, MDa
Ru ¨diger Hein, MDa
Markus Ollert, MDa,d
Martin Mempel, MDa,d,e
Fromathe Department of Dermatology and Allergy, Biederstein, Technical
University Munich, Germany;
Immunite ´ anti-virale, Biothe ´rapie et Vaccins, andcINSERM U668, Institut
Pasteur, Paris, France; anddthe Clinical Research Division of Molecular
and Clinical Allergotoxicology and
Dermatology and Allergy, GSF National Research Center for Environ-
ment and Health, Technical University Munich, Germany. E-mail:
Disclosure of potential conflict of interest: M. Mempel has consulting arrange-
ments with Novartis. The rest of the authors have declared that they have no
conflict of interest.
Supported by the Deutsche Forschungsgemeinschaft (Me 1798/2-1 to M.M.),
the Bundesministerium fu ¨r Bildung und Forschung (01GC0104 (subproject
bUnite ´ de Recherche et d’Expertise
ethe Division of Environmental
4 to M.M. and M.O.), the Wilhelm-Vaillant Foundation (to M.M. and
S.W.), and the Kommission fu ¨r Klinische Forschung University Hospital
‘‘Rechts der Isar,’’ Technical University Munich.
1. Lim A, Luderschmidt S, Weidinger A, Schnopp C, Ring J, Hein R, et al.
The IgE repertoire in PBMCs of atopic patients is characterized by indi-
vidual rearrangements without VH bias. J Allergy Clin Immunol 2007;
2. Kunz B, Oranje AP, Labreze L, Stalder JF, Ring J, Taieb A. Clinical val-
idation and guidelines for the SCORAD index: consensus report of the
European Task Force on Atopic Dermatitis. Dermatology 1997;195:10-9.
3. Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H,
et al. Thymus and activation-regulated chemokine in atopic dermatitis:
Serum thymus and activation-regulated chemokine level is closely related
with disease activity. J Allergy Clin Immunol 2001;107:535-41.
4. Hijnen D, De Bruin-Weller M, Oosting B, Lebre C, De Jong E, Bruijn-
zeel-Koomen C, et al. Serum thymus and activation-regulated chemokine
(TARC) and cutaneous T cell- attracting chemokine (CTACK) levels in
allergic diseases: TARC and CTACK are disease-specific markers for
atopic dermatitis. J Allergy Clin Immunol 2004;113:334-40.
atopic dermatitis with omalizumab. J Am Acad Dermatol 2006;54:68-72.
6. Manz RA, Hauser AE, Hiepe F, Radbruch A. Maintenance of serum an-
tibody levels. Annu Rev Immunol 2005;23:367-86.
7. Karnowski A, Achatz-Straussberger G, Klockenbusch C, Achatz G,
Lamers MC. Inefficient processing of mRNA for the membrane form of
IgE is a genetic mechanism to limit recruitment of IgE-secreting cells.
Eur J Immunol 2006;36:1917-25.
8. Deniz YM, Gupta N. Safety and tolerability of omalizumab (Xolair), a
recombinant humanized monoclonal anti-IgE antibody. Clin Rev Allergy
9. Lim A, Baron V, Ferradini L, Bonneville M, Kourilsky P, Pannetier C.
Combination of MHC-peptide multimer-based T cell sorting with the Im-
munoscope permits sensitive ex vivo quantitation and follow-up of human
CD81 T cell immune responses. J Immunol Meth 2002;261:177-94.
Available online October 15, 2007.
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Letters to the Editor