Tixocortol-21-pivalate (TIX), a lipophilic ester and anti-inflammatory corticosteroid, is considered a Coopman Group A (hydrocortisone-type) corticosteroid.
It is one of the least potent steroids, but it is a strong sensitizer in terms of elicitation. Depending on the region, TIX is found in both prescription and nonprescription creams, lotions, ointments, and powders for eczema and other local inflammations; in ear, nose, and eye drops; and in rectal suspensions. It is also present in nasal sprays used to treat rhinitis, pharyngitis, and ulcerative colitis. In occupational settings, TIX may be encountered in medicaments, creams, lotions, ointments, and powders.
In the United States, TIX is unavailable; hence, its relevance as an allergen is almost nonexistent. In Europe it has limited use as an inhalant although it can be found in both over-the-counter and prescription topical medicaments. In Australia TIX is found in topical medicaments. Scant data are available from other countries. The results of patch testing with TIX, especially in the United States, must be interpreted with these points in mind. Why, then, is patch testing with TIX important?
TIX is included on patch test series because it serves as a marker for sensitization to Coopman Group A corticosteroids. That is, patch testing with TIX can be used to help diagnose allergic contact dermatitis caused by Group A corticosteroids. Some researchers have found its performance to be adequate for this task while others have found it to be the best marker for hydrocortisone. (The two corticosteroids differ only in the side chain (a thioester) attached at the C21 position.) A study from the Mayo Clinic compared detection rates across 17 corticosteroid allergens. Had TIX alone been used to screen for a corticosteroid allergy, fewer than 50% of cases would have been identified. The finding underscores why testing with more than one corticosteroid is recommended.
Based on patch test data from the North American Contact Dermatitis Group (NACDG) from 2001 to 2014, the prevalence of positive reactions to TIX has ranged from about 2 to 3%. Based on NACDG data, TIX also has ranked as a highly relevant allergen as well as an occupational allergen. In particular, healthcare workers are significantly more likely to develop contact allergy to TIX than nonhealthcare workers. Despite the regional difference in the availability of TIX, the prevalence of positive patch test reactions to TIX has been lower in Europe than in North America. The frequency of reported positive reactions to TIX has ranged from a low of 0.1% in southern clinics (mostly Italian) to a high of 1.7% in northeastern clinics (Finland, Lithuania). In Europe, the frequency of positive patch test reactions in children has been reported to be about 0.5%— regardless of age or the presence of atopy. A recent report from the United States, however, placed TIX at 29th among the 40 most common pediatric allergens with a prevalence of 1.84%.
Patients’ corticosteroid allergies may be unrecognized before patch testing. Their dermatitis may be subacute, or it may be chronic and unresponsive to treatment. They often have atopic, stasis, or hand or leg dermatitis. As with any corticosteroid, sensitization should be suspected in patients who fail to respond to treatment or whose condition is worsened by exposure to TIX or one of its related compounds.
Concurrent allergy to other topical preparations is common. Indeed, patients who react to TIX also may react to hydrocortisone (acetate), prednisolone, diflucortolone, methylprednisolone, hydrocortisone-17-butyrate, methylprednisolone aceponate, and prednicarbate. TIX has also been reported as an excellent complementary detector of sensitivity to budesonide, which itself serves as a marker for detecting sensitization to Coopman Group B corticosteroids. Furthermore, reactions to TIX have been associated with reactions to hydrocortisone-17-butyrate, which is in the Coopman D2 group of corticosteroids.
Both the most appropriate vehicle and optimum concentration for patch testing with TIX have been debated, but petrolatum is used in many baseline series. The preferred concentration varies across baseline series. The European Baseline and the Minimum International Baseline series adopted TIX at 0.1% while 1% is used in the Core Allergen Series of the American Contact Dermatitis Society, the North American Standard Series, the Australian Baseline Series, and the British Baseline Series. A multicenter trial found no difference in the number of individuals who reacted to 0.1% and 1.0% TIX.
Timing of readings is important with TIX. In one study about 19% of positive reactions would have been missed by early readings. Therefore, a late reading should be conducted on day 6 or 7 to avoid a false-negative outcome. Edge effects (a reaction confined to the ring of a round patch test chamber) have also been associated with TIX. Some clinicians may consider such a reaction to be a doubtful reaction. Performing a reading at day 7 or another patch test at a lower concentration of TIX can help clarify the interpretation of the finding. Once patients have had a positive patch test reaction to TIX, testing with an appropriate extended steroid series should be considered.
Because TIX readily cross-reacts with other corticosteroids, patients who test positive to this allergen must be informed that they also may react to many related substances. To avoid exposure, patients should be educated about checking ingredient labels or package inserts of all topical, anti-inflammatory preparations (prescription and over-the-counter). If no information is available, patients should verify that preparations are free of TIX (or related corticosteroids) with their pharmacist. Patients also need to inform their healthcare providers that they are allergic to TIX to ensure that their caregivers only use or prescribe products that are free from this allergen. Patients need to be particularly careful about avoiding preparations and nasal sprays that contain TIX and cross-reacting corticosteroids. Patients may encounter TIX listed as an ingredient under alternative names such as tixocortol 21-pivalate; tixocortol pivalate; 11ß,17-dihydroxy- 21-mercaptopregn-4-ene-3,20-dione 21-pivalate; pregn-4-ene- 3,20-dione, 21-((2,2-dimethyl-1-oxopropyl)thio)-11,17-dihydroxy-, (11beta); JO 1016; Pivalone; Procolon; Rectovalone; Tivalon-NT; and Tiprederm.
As one of the important markers for steroid allergy, TIX was developed for the third T.R.U.E. TEST® panel based on interest from the NACDG, International Contact Dermatitis Research Group, and European Environmental and Contact Dermatitis Research Group. TIX is also available in 0.1% (CS498) and 1% (NA61) concentrations in petrolatum from allergEAZE®. If you have questions about the best formulation for your patch testing needs, why not give us a call at 1-800-878-3838?
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