Contact allergy to oxidised geraniol may be over‐represented in individuals with photocontact allergy to ketoprofen

Simultaneous overrepresentations of contact allergies and photocontact allergies are common in individuals with photocontact allergy to ketoprofen.


| INTRODUCTION
An overrepresentation of simultaneous contact allergies including balsam of Peru, fragrance mix I and cinnamic alcohol have been known since many years in patients with photocontact allergy to the non-steroidal anti-inflammatory drug (NSAID) ketoprofen. 1 For the eight fragrance materials in fragrance mix I, the overrepresentation of contact allergy was not only expectedly noted for cinnamic alcohol but also for cinnamal, eugenol and isoeugenol. 2 Furthermore, the fragrance-related sensitisers oxidised (ox.) linalool and ox.limonene have been added to the list of overrepresented contact allergies in patients with photocontact allergy to ketoprofen. 3 Recently, contact allergy to non-fragrance contact sensitisers in the baseline patch Magnus Bruze is a member of the expert panel for fragrance safetyhttp://fragrancesafetypanel.org/test series was reported to be overrepresented in ketoprofenphotoallergic patients. 4][7][8][9][10] A secondary aim was to explore whether there is any association between photocontact allergy to ketoprofen and/or contact allergy to ox. geraniol on the one hand and ox.limonene and/or ox.linalool on the other.

| Patients
In 2012, 672 patients (males and females, mean age 43.8 years, range 14-88 years) were patch tested because of a suspected allergic contact dermatitis with the Swedish baseline patch test series to which ox. geraniol, geraniol, geranial, neral, and citral were provisionally inserted. 9,10In the same period (2012), 11 (2 males, 9 females, mean age 47.3 years, range 26-64 years) of the 672 patients were because of a suspected photocontact dermatitis in addition photopatch tested with the European photopatch test series in which ketoprofen is included. 11Four patients had positive photopatch test reactions to ketoprofen.
A total of 315 of the 672 patients patch tested in 2012 were also simultaneously tested with ox.limonene and ox.linalool.Two of these patients had a positive photopatch test reaction to ketoprofen.

| Photopatch testing
The European baseline photopatch test series with ketoprofen 1% in petrolatum 11 was purchased from Chemotechnique Diagnostics.
The Finn chamber technique with the chambers (Ø 8 mm) mounted on Scanpor tape was used; 20 mg of the petrolatum preparations were applied onto the chambers, 12 which were applied on the upper back 15 in duplicate as parallel columns.The patches remained under occlusion for 24 h.They were then removed with a minimum of light exposure and with one side covered immediately with black cloth.
The other side was irradiated with 5 J/cm 2 of broadband UVA (PUVA4000, Photochemotherapy, Herbert Waldmann, Werk für Lichttechnik, Germany).Reading was performed on D3 and D7 according to the ICDRG classification. 14

| Statistical calculations
The frequency of contact allergy to each of the two preparations with ox.geraniol, geraniol, geranial, neral and citral was compared using Fisher's exact test, two-sided, between routinely patch tested dermatitis patients without a diagnosed photocontact allergy to ketoprofen (dermatitis group) and patients being photoallergic to ketoprofen (ketoprofen group).Fisher's exact test, two-sided, was also used to compare allergy rates pair-wise between ox.geraniol and ox.limonene and/or ox.linalool in the dermatitis patients and patients being photoallergic to ketoprofen.The same statistical method was used to compare the rates of simultaneous contact allergy to all three sensitisers (ox.geraniol 11%, ox.limonene and ox.linalool) between patch-tested dermatitis patients and patients being photoallergic to ketoprofen.
T A B L E 1 Reactions to preparations of oxidised geraniol, geraniol, geranial, neral and citral in ketoprofen-photoallergic patients (K) and in dermatitis patients without a diagnosed photocontact allergy to ketoprofen (D).

| Ethics
This study was approved by the Regional Ethical Review Board, Lund, Sweden, Dnr 2020/02190.

| RESULTS
The contact allergy rates to ox. geraniol 11% and 6%, geraniol 6%, geranial 3.5%, neral 3.5% and citral 3.5% have been included in two publications with the Swedish Contact Dermatitis Research Group. 9,10 this paper, the contact allergy rates for these fragrance materials are presented for those 672 dermatitis patients tested in Malmö with the Swedish baseline series in which the fragrance materials were provisionally inserted.

| DISCUSSION
The overrepresentation of contact allergy to ox. geraniol in patients with photocontact allergy to ketoprofen was statistically significant ( p = 0.020) although only four patients were diagnosed with photocontact allergy to ketoprofen in the investigative period.There was on the other hand, no overrepresentation of contact allergy to neither geraniol, geranial, neral and citral.The lack of overrepresentation for these fragrance materials may reflect the truth but may also be due to a too low power in this study.It would be desirable to test substantially more patients to get a better power, but it is virtually impossible at our department mainly due to two factors: (i) lack of test preparations and (ii) fewer patients photopatch testing positively to ketoprofen.However, except for ox.geraniol, it seems likely that there in reality is no overrepresentation of contact allergy to the abovementioned fragrance materials, at least concerning geraniol and citral.
Investigations with higher power based on 30 patients with photocontact allergy to ketoprofen and more than 6700 dermatitis patients tested with the ingredients of fragrance mix I containing geraniol and fragrance mix II in which citral is included did not show any overrepresentation (unpublished data).
geraniol in this study, contains besides geraniol-7-hydroperoxide geraniol, geranial and neral. 12Geranial and neral are also besides geraniol epoxides generated metabolically from geraniol in the skin. 16Citral consists of the two isomers, geranial and neral.With this background, it is not surprising that there are many concomitant patch test reactions to ox. geraniol, geraniol, geranial, neral and citral. 8 far, overrepresentation of contact allergy to discrete fragrance materials has been demonstrated for cinnamic alcohol, cinnamal, eugenol and isoeugenol in individuals with photocontact allergy to ketoprofen compared to both dermatitis patients and individuals from the general population in the Malmö area. 2 There was like the present study, no overrepresentation to geraniol in the referred study. 2 Previously, an overrepresentation of contact allergy to ox. linalool and ox.limonene was reported in individuals with photocontact allergy to ketoprofen compared to dermatitis patients. 3This overrepresentation is also seen in this study (p = 0.0018 for ox.linalool and p = 0.0016 for ox.limonene, Table 2).The actual sensitisers in ox.linalool and ox.limonene being responsible for the overrepresentation are not identified but are most likely the hydroperoxides.Similarly, the hydroperoxide in the preparations of ox.geraniol, geraniol-7-hydroperoxide, is most likely the sensitiser responsible for the simultaneous contact allergy to ox. geraniol in ketoprofen-photoallergic individuals.This hypothesis is supported by two facts.(i) Sensitisation experiments have shown that geraniol hydroperoxide gave the most important contribution to the allergenic activity of air-exposed geraniol together with geranial and neral. 5,6i) However, there was no over-representation of contact allergy to geranial and neral among the ketoprofen-photoallergic individuals in this study (Table 1).
Obviously, simultaneous contact allergy to ox. geraniol and the ox.terpenes limonene and linalool 3 is significantly overrepresented in ketoprofen-photoallergic individuals.The results of this study also show that individuals with photocontact allergy to ketoprofen are more likely to be contact allergic to the combination ox.geraniol, ox.limonene and/or ox.linalool (Table 2).
It may look like the overrepresentation of simultaneous contact allergy in ketoprofen-photoallergic individuals only concerns fragrance materials.However, a recent publication presents data on overrepresentation of contact allergy to non-fragrance materials in individuals with photocontact allergy to ketoprofen compared to dermatitis patients and the general population. 4Black rubber mix, budesonide, para-tertiary butyl phenol-formaldehyde resin (PTBP-F-R) and PFR-2, a resol resin based on phenol and formaldehyde, 17 were overrepresented with the highest odds ratios for PTBP-F-R and PFR-2. 4sed on the results of this study with a low statistical power,
ox. geraniol adds to the list of contact sensitisers for which simultaneous contact allergy is overrepresented in ketoprofen-photoallergic individuals.These sensitisers represent chemically a diversity of structures including aliphatic and aromatic compounds.The mechanism for the concomitant allergies is not known.Albeit the simultaneous contact allergies cannot be explained presently, clinically the knowledge on their existence means that these strongly overrepresented contact allergies can represent markers of photocontact allergy to ketoprofen and bensophenone-substituted sunscreen agents.A photopatch test with the European photopatch test series or any other photopatch test series containing ketoprofen and bensophenone-based sunscreen agents should therefore be considered, particularly when no clinical relevance can be associated with diagnosed contact allergy to the overrepresented ox.terpenes in this study.