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Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabruck, Osnabruck, Germany
Coronel Institute of Occupational Health, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
Summary
Correspondence
Lilla Landeck.
E-mail: llandeck@uos.de
Funding sources
None.
Conicts of interest
None to declare.
S.K. and S.M.J. contributed equally to this
manuscript.
DOI 10.1111/bjd.12035
Background Filaggrin loss-of-function mutations and atopy may alter the clinical
course of irritant contact dermatitis (ICD).
Objective To investigate the clinical course of patients with occupational ICD
according to loss-of-function mutations in the filaggrin gene (FLG) and atopy.
Methods In a prospective cohort study, the clinical course, use of topical corticosteroids, sick leave, recovery rate and job continuation were investigated in 459
inpatients treated for occupational ICD of the hands. Patients were genotyped for
four FLG mutations, examined for atopy and followed for up to 3 years after
discharge.
Results Our study included 327 (712%) atopic individuals and 132 nonatopic
individuals. Overall, 68 patients showed a mutation in the FLG alleles R501X,
R2447X, S3247X and 2282del4 (60 atopic and eight nonatopic). Nonatopic
patients with ICD responded well to therapeutic approaches, while atopy status
made subjects more resistant to therapy, resulting in lower rates of recovery and
job continuation and higher use of topical corticosteroids. Carriage of FLG lossof-function mutations in combination with atopy worsened the course. The risk
of abandoning ones profession in this group was significantly increased when
compared with pure ICD (odds ratio 31) after 3 years.
Conclusions Patients with atopy are a special risk population for ICD. In the presence of atopy, FLG mutations seem to be a modifier of the severity of the clinical course in ICD. Early-stage identification of this subgroup may result in
additional emphasis to these patients regarding the importance of adherence to
specific therapeutic interventions.
1302
Methods
Study population
After obtaining approval by the ethics committee of the University of Osnabruck, a cohort of 712 patients who were hospitalized at our clinic for treatment of long-lasting chronic
occupational hand eczema were asked to participate in the
study conducted in accordance with the Declaration of Helsinki. Forty-seven patients (66%) chose not to enrol. After
obtaining informed consent, patients genotype was determined for mutations in genes coding for FLG, 2282del4,
R501X, R2447X and S3247X, between November 2005 and
March 2011. Patients were consecutively included into this
study if they met the following inclusion criteria: Caucasian,
2012 The Authors
BJD 2012 British Association of Dermatologists 2012 167, pp13021309
Timepoint 2
After
hospitalization
Timepoint 1
Start of the study
3-week inpatient
treatment
Timepoint 4
After being back
to work
Timepoint 6
3-years after
hospitalization
Timepoint 3
After
hospitalization &
sick leave
3-week
sick leave
Timepoint 5
1-year after
hospitalization
Back to work
for 4 weeks
using the KASP genotyping system, a homogeneous fluorescent resonance energy transfer-based system, coupled with
competitive allele specific polymerase chain reaction. Blind
duplicates and HardyWeinberg equilibrium tests were used
as quality control tests. R501X was genotyped using the primer pair GAATGCCTGGAGCTGTCTCG (C-allele) and
CTGAATGCCTGGAGCTGTCTCA (T-allele) with the common
allele primer GCACTGGAGGAAGACAAGGATCG. R2447X was
genotyped using the primer pair GAGTGCCTGGAGCTGTCTCG
(C-allele) and GAGTGCCTGGAGCTGTCTCA (T-allele) with the
common allele primer GAGGAAGACAAGGATCCCACCACA.
S3247X was genotyped using the primer pair GTGTCT
GGAGCCGTGCCTTG (C-allele) and GGTGTCTGGAGCCGTG
CCTTT (A-allele) with the common primer CTTCCAGAAAC
CATCGTGGATCTGT. Genotyping for 2282del4 was performed
as described previously.17
Data analyses and statistics
For additional analysis, the total study population was further
classified according to FLG and atopy status into: (i) pure
ICD (no atopy or FLG loss-of-function mutations); (ii) ICD
and FLG loss-of-function mutation(s) (combined loss-of-function genotype, grouping together individuals with one or
more of any of the filaggrin mutations); (iii) ICD and atopy;
Results
A total number of 432 patients completed the 1-year evaluation, and 204 of these were also evaluated at the 3-year follow-up, at the time of drafting this manuscript. The remaining
255 patients are still under observation and will finish the 3year follow-up within the next 2 years. More than half of our
study population originated from the subgroup of ICD and
atopy (582%), representing therefore the largest of the four
subgroups, followed by ICD (27%) as shown in Table 1.
Female (%)
377
46 (1966)
41 (1658)
729
P < 005
42 (1867)
P < 005
28 (1560)
P < 005
14 (053)
P < 005
48 (5480)
n.s.
429
n.s.
49 (3359)
n.s.
43 (2952)
n.s.
17 (942)
n.s.
24 (8180)
n.s.
550
P < 005
40 (1962)
P < 005
29 (1657)
P < 005
11 (144)
P < 005
60 (6370)
n.s.
16 (152)
48 (5360)
General characteristics
Table 1 shows a summary of the general epidemiological data
of the subgroups.
Atopy and FLG carriers
Our study included 327 (712%) atopic individuals and 132
nonatopic individuals. Overall, 63 patients showed a heterozygous mutation, and five individuals a compound heterozygous
mutation, in the FLG alleles R501X, R2447X, S3247X and
2282del4. No homozygote carriers were detected. Among the
atopic individuals, 60 out of the 327 (183%, 95% CI 144
228) were carriers of a FLG loss-of-function mutation and in
nonatopic individuals eight of the 132 (6.1%, 95% CI 29
112) were carriers. Atopic patients (with and without FLG
loss-of-function mutations) were not only the youngest in our
study but were also the patients who were youngest at the
onset of hand eczema. This finding was significant when compared with the group with ICD (P < 005). At the same time,
they displayed a significantly lower number of years of exposure to irritants when developing hand eczema compared with
the subjects with pure ICD.
Discussion
Our study investigated the clinical course of a large cohort
of a well-defined patient population with occupational ICD
of the hands with respect to the clinical course in relation
ICD (n = 124)
5 (014)
124
2 (011)
124
2 (014)
124
2 (012)
112
2 (016)
122
2 (013)
56
15
6 (018)
267
3 (011)
267
2 (014)
260
3 (017)
243
3 (015)
248
2 (015)
124
19
5 (311)
8
3 (16)
8
25 (09)
8
3 (08)
8
4 (112)
8
6 (27)
3
235
7
60
3
60
3
57
3
54
3
54
2
21
21
(113)
(07)
(011)
(016)
(016)
(07)
ICD (reference)
101 (815)
124
15 (134)
112
44 (361)
122
17 (309)
55
232 (869)
267
n.s.
46 (189)
243
115 (464)
248
n.s.
61 (50)
122
P < 005, OR 22
(95% CI 1144)
6 (75)
8
n.s.
1 (125)
8
2 (25)
8
n.s.
1 (50)
2
n.s.
50 (833)
60
n.s.
12 (222)
54
24 (444)
54
n.s.
8 (40)
20
n.s.
ICD, irritant contact dermatitis; n.s. not significant; OR, odds ratio; CI, confidence interval.
ICD
ICD and
atopy
30 (242)
124
8 (66)
122
1 (18)
56
56 (21)
267
17 (69)
248
6 (48)
124
0 (0)
8
0 (0)
8
0 (0)
3
ICD
(reference)
ICD and
atopy
16 (131)
122
46 (185)
248
n.s.
0 (0)
8
n.s.
11 (196)
56
36 (290)
124
n.s.
1 (333)
3
n.s.
14 (259)
54
P < 005, OR 23
(95% CI 1152)
9 (429)
21
P < 005, OR 31
(95% CI 1191)
Acknowledgement
We acknowledge the support of the EU COST Action BM
0903 (Skin Barrier in Atopic Diseases, SKINBAD).
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