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Use of sunscreens to protect against ultraviolet-induced lupus erythematosus.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 9, September 2004, pp 3045–3048
© 2004, American College of Rheumatology
CONCISE COMMUNICATIONS
the last decade, high-potency sunscreens that protect against
UV-induced sunburn have become widely available. However,
the degree to which these sunscreens protect against other
unwanted effects of UV irradiation has been called into
question (4,5). Therefore, we have routinely included sunscreens in our diagnostic testing protocol for LE.
A recent study involving 11 patients suggested that
sunscreens protect against UV-induced LE lesions (6). In
order to obtain a more general assessment of the protective
capacity of sunscreens in LE in a larger cohort of patients, we
performed a retrospective evaluation of 66 patients who underwent photoprovocation testing between 1999 and 2002.
After informed written consent had been obtained, testing was
done (according to a standard protocol) on the upper back,
with a field size of 8 ⫻ 5 cm (7). The doses applied were 100
mJ/cm2 of UVA (from a Dermalight UltrA1 source; Hoenle
Medizintechnik, Munich, Germany) or the 1.5-fold minimal
erythema dose of UVB (from a Waldmann UVB 800 unit;
Munich, Germany), or a combination of both, on 3 consecutive
days. An additional field was irradiated with combined UVA/
UVB 15 minutes after the application of a commercial sunscreen that efficiently filters UVA (Anthelios W30; La RochePosay, La Roche-Posay, France). This sunscreen contained a
DOI 10.1002/art.20426
Use of sunscreens to protect against ultravioletinduced lupus erythematosus
Photosensitivity is the leading symptom of cutaneous
and systemic lupus erythematosus (LE). The role of sunlight in
the induction of LE lesions has long been recognized, based on
the observation that lesions are predominantly localized to
sun-exposed areas of the body, especially the face, but also the
head and neck area. Moreover, LE worsens during the summer
period or in the weeks following increased sun exposure (1,2).
Definite proof for a causative role of ultraviolet (UV) irradiation in the induction of LE came from experimental photoprovocation testing in the early 1990s (3). Those studies
unraveled the fact that the UV action spectrum that provokes
LE in sensitive individuals includes both the ultraviolet B
(UVB; 290–320 nm) and the UVA (320–400 nm) range.
Moreover, the studies showed that LE does not develop
immediately after UV exposure, but after a delay of 2–3 weeks.
In view of the central role of sunlight in provoking LE,
it is important for patients to establish efficient UV protection
throughout the year. This is a particular challenge for areas of
the skin that cannot effectively be covered by clothing. Over
Figure 1. Patient with chronic discoid lupus erythematosus, showing a positive reaction to ultraviolet B (UVB) and UVA/UVB
2 weeks after photoprovocation, but no reaction to UVA alone (top). No reaction to UVA/UBV was observed in the area to
which sunscreen was applied (bottom).
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3046
CONCISE COMMUNICATIONS
Table 1. Action spectra for the induction of LE lesions*
Patient group
UVA
UVB
UVA ⫹ UVB
Chronic discoid LE (n ⫽ 33)
Systemic LE (n ⫽ 4)
Subacute cutaneous LE (n ⫽ 2)
Tumidus-type LE (n ⫽ 12)
Profound LE (n ⫽ 1)
9 (27)
3 (75)
1 (50)
4 (33)
0 (0)
16 (48)
3 (75)
1 (50)
4 (33)
1 (100)
32 (97)
4 (100)
2 (100)
12 (100)
1 (100)
* Values are the number (%) of patients. The ability of different
wavelength spectra to induce lupus erythematosus (LE) on the upper
back is described in ref. 3. Only erythematosus infiltrates at week 2 or
3 were considered positive. UV ⫽ ultraviolet.
formulation of different active ingredients shielding predominantly against UVA (parsol 1789), UVB (uvinul N539, uvinul
T150), or against UVA and UVB (mexoryl XL, titanium
dioxide).
According to the recommendations of the US Food
and Drug Administration and the European Cosmetic Toiletry
and Perfumery Association, 2 mg/cm2 of sunscreen was applied. Readings were performed on days 2, 3, and 4 and again
1, 2, and 3 weeks after photoprovocation. Late readings are
particularly important, because cutaneous LE tends to develop
primarily 2–3 weeks after irradiation (1). Criteria for a positive
reaction were a palpable erythematous infiltrate clinically
resembling LE that developed with a crescendo time course,
becoming most pronounced 2–3 weeks after photoprovocation.
Approximately 75% of our LE patients showed a
positive reaction to the UV challenge (Figure 1). Only those
patients who showed photosensitivity (n ⫽ 52) were analyzed
further. Most of these patients had discoid or tumidus-type
LE. As described previously (2,3), we found the combined
irradiation with UVA and UVB to be most effective in
triggering cutaneous LE (98%). In fact, 30% of subjects
reacted to the combined irradiation only and to neither UVA
nor UVB when applied alone, suggesting a synergistic effect of
the combination in some patients. In 19% of the patients, both
UVA and UVB induced LE lesions. UVA alone induced LE in
only 17 patients (33%). UVB induced LE in 48% of the
patients. One patient showed a positive reaction exclusively to
UVB and was excluded from further analysis (Table 1). In
selected patients, histologic examination was performed to
confirm the clinical diagnosis.
Of 51 patients who had developed LE in the UVA/
UVB field, 49 (96%) were entirely protected by the sunscreen
against the development of LE or LE-like lesions. Protected
patients showed either no reaction or pigmentation only
(Table 2). Thus, the capacity of the sunscreen to prevent UVinduced LE was higher than the protective action against
UV-induced pigmentation. In a small number of patients, we
investigated in a third area a high- potency sunscreen based
primarily on physical protection (TiO2) and obtained similar
results.
Our data show that modern sunscreens that efficiently
protect against both UVA and UVB are very effective in
protecting against UV-induced LE. Preliminary data suggest
that daily application of high-potency sunscreens also protects
patients against UV-induced LE by natural sunlight. Our
personal experience is mainly limited to only 2 sunscreens, but
other high-potency sunscreens that protect against UVA and
Table 2. Protective effect of sunscreen in patients who developed LE
lesions at the site of combined UVA/UVB irradiation*
Patient group
LE
lesion
No
reaction
Pigmentation
only
Chronic discoid LE (n ⫽ 33)
Systemic LE (n ⫽ 4)
Subacute cutaneous LE (n ⫽ 2)
Tumidus-type LE (n ⫽ 12)
Profound LE (n ⫽ 1)
Total
2 (6)
0 (0)
0 (0)
0 (0)
0 (0)
2 (4)
15 (47)
2 (50)
1 (50)
6 (50)
0 (0)
26 (47)
15 (47)
2 (50)
1 (50)
6 (50)
1 (100)
25 (49)
* Values are the number (%) of patients. Sunscreen (2 mg/cm2) was
applied to a closely adjacent test site 15 minutes before irradiation with
ultraviolet A (UVA) and UVB. LE ⫽ lupus erythematosus.
UVB might be similarly effective. However, a study comparing
3 different sunscreen formulations in a set of 11 patients found
these sunscreens to vary in their protective capacity against LE
provocation, though all of the formulations used contained
various compounds that filter UVA and UVB (6). The best
protection was achieved by the only formulation that contained
Mexoryl XL, a rather novel compound filtering in both the
UVA and UVB range. Interestingly, this compound was also
contained in the sunscreen used in our present study. The fact
that our sunscreen protected against LE in 98% of patients but
still allowed for pigmentation in 49% suggests that the effectiveness of a compound to shield against LE cannot necessarily
be extrapolated from its capacity to prevent other biologic
responses elicited by sunlight.
Dr. Röcken’s work was supported in part by grant RO764/8-1
from the Deutsche Forschungsgemeinschaft.
Thomas Herzinger, MD
Gerd Plewig, MD
Ludwig-Maximillian-University
Munich, Germany
Martin Röcken, MD
Eberhard-Karl-University
Tübingen, Germany
1. Millard TP, Hawk JL, McGregor JM. Photosensitivity in lupus.
Lupus 2000;9:3–10.
2. Kuhn A, Sonntag M, Ruzicka T, Lehmann P, Megahed M. Histopathologic findings in lupus erythematosus tumidus: review of 80
patients. J Am Acad Dermatol 2003;48:901–8.
3. Lehmann P, Holzle E, Kind P, Goerz G, Plewig G. Experimental
reproduction of skin lesions in lupus erythematosus by UVA and
UVB radiation. J Am Acad Dermatol 1990;22:181–7.
4. Haywood R, Wardman P, Sanders R, Linge C. Sunscreens inadequately protect against ultraviolet-A-induced free radicals in skin:
implications for skin aging and melanoma? J Invest Dermatol
2003;121:862–8.
5. Poon TS, Barnetson RS, Halliday GM. Prevention of immunosuppression by sunscreens in humans is unrelated to protection from
erythema and dependent on protection from ultraviolet A in the
face of constant ultraviolet B protection. Invest Dermatol 2003;121:
184–90.
6. Stege H, Budde MA, Grether-Beck S, Krutmann J. Evaluation of
the capacity of sunscreens to photoprotect lupus erythematosus
patients by employing the photoprovocation test. Photodermatol
Photoimmunol Photomed 2000;16:256–9.
7. Walchner M, Messer G, Kind P. Phototesting and photoprotection
in LE. Lupus 1997;6:167–74.
CONCISE COMMUNICATIONS
DOI 10.1002/art.20475
Lack of linkage of IL1RN genotypes with ankylosing
spondylitis susceptibility
The interleukin-1 receptor antagonist gene (IL1RN), a
natural modulator existing in the body, can bind IL-1R and
block its effects. Recently, a variable-number tandem repeat
polymorphism in intron 2 of IL1RN was associated with
ankylosing spondylitis (AS) in 2 European population groups
(1,2). Here, we investigated the role of IL1RN genes in AS
susceptibility in North American families with 2 or more
siblings meeting the 1984 modified New York criteria for AS (3).
Informed consent was obtained from each family member. This study was approved by the Committee for the Protection
of Human Subjects at the University of Texas Health Science
Center at Houston. In total, 229 pedigrees with at least 1 affected
individual were included for family-based association analyses,
and 244 affected sibpairs derived from 180 pedigrees were
included for linkage analyses after removing the pedigrees in
which the self-reported relationship was not consistent with the
genetic data. Of these families, 94% were Caucasian, and 97% of
the probands were HLA–B27 positive.
The genetic variation of IL1RN was ascertained by
sequencing its complete coding sequence, all intron/exon junction regions, 3⬘- and 5⬘-untranslated regions, and the promoter
region in 102 patients and 48 ethnically matched controls. In
total, 25 single-nucleotide polymorphisms (SNPs) were identified (data not shown). The 5 most informative SNPs
(rs1794065, rs419598, rs315952, rs315951, and rs895495) were
selected for further association and linkage studies, along with
6 microsatellite markers (D2S2216, D2S373, D2S340, D2S160,
D2S121, and D2S347) that are mapped to this region (see
Table 1 for the location of the markers). Family-based association analyses were performed using the pedigree disequilibrium test (PDT) (4) and the transmission disequilibrium test
(TDT) (5). Neither the TDT nor the PDT approach showed
significant association for individual markers (Table 1) and for
the haplotypes based on 5 SNPs (data not shown).
We further examined the linkage of the region containing IL1RN using the 11 markers. Nonparametric linkage
(NPL) analyses were performed with all 5 SNPs and 3 microsatellite markers (D2S2216, D2S160, and D2S347) using 244
affected sibpairs derived from 180 pedigrees. Both parametric
(LOD; logarithm of odds) and nonparametric (NPL and ASM)
analyses were conducted for linkage analyses, using
GeneHunter-Plus software (6) for LOD, and NPL and ASM
for an allele-sharing–based approach (7) (see Table 1). Three
other markers, including D2S373, D2S340, and D2S121, in the
same region were also typed in a subset of the pedigrees (171
affected sibpairs derived from 119 pedigrees). No linkage was
observed with any of the 11 markers studied.
In a recent collaborative study of a large cohort of
Canadian patients with AS, using 3 SNPs of IL1RN identified
in this study (rs419598, rs315952, and rs315951), we found an
association of AS with the SNPs of IL1RN and their haplotypes
(8). TDT analysis of a limited sample of AS families from
western Canada demonstrated significant differences in transmission of an IL1RN SNP haplotype that was diseaseassociated in the case–control evaluation. In this study, we
were not able to validate the association in our cohort,
although our sample size for the TDT and PDT analyses was
much larger. The discrepancy may reflect clinical differences in
the patient populations studied, i.e., differences in disease
3047
severity or disease phenotypes (such as uveitis or peripheral
arthritis, the frequencies of which were not specified in other
series) (1,8) due to differing referral patterns between the
North American Ankylosing Spondylitis Gene Consortium
centers and other centers where associations have been described. Variable patterns of association across populations
may also be attributable to population-specific mechanisms of
genetic susceptibility. Finally, these data do not exclude a
minor role for IL1RN genes. The number of sibpairs that
would be necessary to detect a gene with a small genetic effect
(␭s ⱕ1.5) would be ⬎1,000. If such a small effect were present,
our study would lack power to determine this.
Thus, we present evidence that may lead to the exclusion of this region on chromosome 2q and, more specifically,
IL1RN as having a significant impact on AS susceptibility.
However, an impact on disease severity cannot be ruled out by
this study. This is currently under further investigation.
Li Jin, PhD
Ge Zhang, MS
Joshua M. Akey, PhD
Jingchun Luo, MM
Juwon Lee, PhD
University of Cincinnati
Cincinnati, OH
Michael H. Weisman, MD
Cedars–Sinai Medical Center
Los Angeles, CA
Jane Bruckel, BSN
Spondylitis Association of America
Sherman Oaks, CA
Robert D. Inman, MD
Millicent A. Stone, MD
University of Toronto
Toronto, Ontario, Canada
Muhammad A. Khan, MD
Case Western Reserve University
Cleveland, OH
H. Ralph Schumacher, MD
University of Pennsylvania
Philadelphia, PA
Walter P. Maksymowych, MD
University of Alberta
Edmonton, Alberta, Canada
Maren L. Mahowald, MD
University of Minnesota
Minneapolis, MN
Allen D. Sawitzke, MD
University of Utah
Salt Lake City, UT
Frank B. Vasey, MD
University of South Florida
Tampa, FL
David T. Y. Yu, MD
University of California, Los Angeles
John D. Reveille, MD
University of Texas Health Science Center at Houston
1. McGarry F, Neilly J, Anderson N, Sturrock R, Field M. A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra)
gene is associated with ankylosing spondylitis. Rheumatology (Oxford) 2001;40:1359–64.
3048
CONCISE COMMUNICATIONS
Table 1. Linkage and family-based linkage disequilibrium analyses of markers near and within IL1RN*
Marker
Position
NPL
P for
NPL
ASM LOD
P for
TDT
P for
PDT
D2S2216
D2S373*
D2S340*
D2S160
rs1794065
rs419598
rs315952
rs315951
rs895495
D2S121*
D2S347
111.21
114.21
120.29
122.96
123.26
123.27
123.27
123.27
123.27
123.49
131.51
⫺0.422
0.149
0.629
0.790
0.019
⫺0.001
0.675
0.574
1.252
⫺0.457
0.341
0.668
0.438
0.260
0.205
0.491
0.499
0.242
0.275
0.097
0.678
0.360
0.000
0.012
0.230
0.254
0.208
0.214
0.210
0.202
0.221
0.000
0.041
0.763
0.287
0.412
0.343
0.384
0.439
0.347
0.333
0.674
0.148
0.568
0.722
0.622
0.522
0.924
0.294
0.370
0.409
0.377
0.469
0.878
0.569
* D2S373, D2S340, and D2S121 were typed only in a subset of pedigrees. The genetic distances of the single-nucleotide
polymorphisms from 2pter were inferred from their genomic coordinates, based on National Center for Biotechnology
Information Human Genome Build 33. LOD ⫽ logarithm of odds. NPL ⫽ nonparametric linkage; TDT ⫽ transmission
disequilibrium test; PDT ⫽ pedigree disequilibrium test.
2. Van der Paardt M, Crusius JB, Garcia-Gonzalez MA, Baudoin P,
Kostense PJ, Alizadeh BZ, et al. Interleukin-1␤ and interleukin-1
receptor antagonist gene polymorphisms in ankylosing spondylitis.
Rheumatology (Oxford) 2002;41:1419–23.
3. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of
the New York criteria. Arthritis Rheum 1984;27:361–8.
4. Martin ER, Monks SA, Warren LL, Kaplan NL. A test for linkage
and association in general pedigrees: the pedigree disequilibrium
test. Am J Hum Genet 2000;68:146–54.
5. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for
linkage disequilibrium: the insulin gene region and insulin-
dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;
52:506–16.
6. Markianos K, Daly MJ, Kruglyak L. Efficient multipoint linkage
analysis through reduction of inheritance space. Am J Hum Genet
2001;68:963–77.
7. Kong A, Cox NJ. Allele-sharing models: LOD scores and accurate
linkage tests. Am J Hum Genet 1997;61:1179–88.
8. Maksymowych WP, Reeve JP, Reveille JD, Akey JM, Buenviaje H,
O’Brien L, et al. High-throughput single-nucleotide polymorphism
analysis of the IL1RN locus in patients with ankylosing spondylitis
by matrix-assisted laser desorption ionization–time-of-flight mass
spectroscopy. Arthritis Rheum 2003;48:2011–8.
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