In 1997 the Food and Drug Administration approved the Thin-layer Rapid Use Epicutaneous (T.R.U.E.) Test for use as a valuable, first-line screening tool to assess for allergic contact dermatitis. Many dermatologists utilize this standard tool in their practice and refer to Contact Dermatitis Referral Centers when the T.R.U.E test fails to identify a relevant allergen. Specifically, the T.R.U.E. test screens for 46 distinct allergens and the Balsam of Peru mixture. The test is thought to adequately identify an allergen in approximately 24.5% of patients with allergic contact dermatitis.1 This being said, many relevant allergens are not detected by use of this screening tool alone. For this reason, “Allergen Focus” has been expanded this month to cover one of the notorious allergens that has been designated by the American Contact Dermatitis Society as the 2005 Allergen of the Year — corticosteroids. As always in this column, we will answer some of the most frequent questions relating to the origin of this allergen and how it is most commonly used. We’ll also highlight appropriate products that affected patients should avoid, along with tips to avoid cross-reactions and exposures.The Contact DermatitidesAllergic contact dermatitis is an important disease with high impact both in terms of patient morbidity and economics. The contact dermatitides include allergic contact dermatitis, irritant contact dermatitis and contact urticaria. Irritant contact dermatitis, the most common form, accounts for approximately 80% of environmental-occupational based dermatoses. Contact urticaria (wheal and flare reaction) represents an IgE and mast cell-mediated immediate-type hypersensitivity reaction that can lead to anaphylaxis, the foremost example of this being latex hypersensitivity. While beyond the scope of this section, we acknowledge this form of hypersensitivity due to the severity of the potential reactions and direct the reader to key sources.2,3The primary focus of this section is to highlight the educational component of allergic contact dermatitis.Case IllustrationA patient presented to the University of Miami Allergic Contact Dermatitis Clinic for evaluation of a generalized dermatitis. She had been evaluated by the T.R.U.E. Test, and no positive allergic reactions were found. She had tried numerous over-the-counter and prescription cortisone creams. The patient stated that she “needed to be on 60 mg of prednisone to remain rash free.” On “Internal Secretions”In 1855, Claude Bernard shocked the world with his outlandish hypothesis that glucose was released from the liver, which he touted as internal secretion. Furthermore, Bernard believed that this process was controlled by the central nervous system. His theory was later proved to be wrong, but his discovery sparked a question that would take almost 100 years to answer. Scientists began to hunt for the factors that dictated carbohydrate metabolism, and they debated whether internal secretion was real and what its role was in metabolism.4,5Addison’s “Blood-Glands” disorder Taking this work further, physician Thomas Addison, a contemporary of Bernard, described a “blood-glands disorder”. He hypothesized it was the insufficient release of “a substance” from internal glands was responsible for a constellation of distinct clinical findings.4Addison described these patients as having generalized weakness, vomiting, increased skin pigmentation and, on autopsy, diseased adrenal glands.6,7 Unfortunately, the disease that bears his name (Addison’s Disease) was also the last he was to describe. Spurned by the London Medico-Chirurugical Society’s rejection of his articles and findings on adrenal insufficiency, Addison, suffering from major depressive disorder, jumped from the window at his home. Although he only fell 9 feet, he suffered a fatal head trauma and on June 29, 1860, he died at the age of 72.8Gland EnhancementCharles Brown-Séquard, fueled by Addison’s enthusiasm for his work, performed numerous experiments to prove the function of the “blood-gland system”. Most famously, he proved that animals couldn’t survive without their adrenal glands.4 He was also the first to attempt ‘gland enhancement’ techniques. In the 1890s, he injected himself with an elution of crushed canine and guinea pig testicles to “increase the physical stamina of youth.”4 His method had many male followers, but with repeated failure to improve stamina, the Séquardian theory and his practice died out.9Discovering AdrenalineIn 1893, physician George Oliver, convinced that the adrenals held potent bioactive compounds, attempted to prove that adrenal extracts could raise blood pressure. Oliver injected his son with an extract that he had made from the adrenal glands obtained from the local butcher. Then using an arteriometer that he invented, he demonstrated an increase in his son’s brachial artery pressure.4Because his makeshift experiments were performed at home, Oliver doubted his findings would be believed. Thus, he presented his extract and findings to Edward Schafer, a physiologist in London. Schafer doubted Oliver’s findings at first but decided to let him inject one of his dogs with the extract. When the dog’s blood pressure elevated suddenly, they both celebrated the discovery. Schafer agreed to work with Oliver in order to describe the pressor effects on the circulation of these “suprarenal extracts”.10 When Oliver and Schafer presented this research at the Physiological Society in March 1894, there were two new scientists in the audience, Ernest Starling and William Bayliss. The discovery of adrenaline in 1895 by Napoleon Cybulski, a Polish physiologist, quickly followed on the heels of Oliver and Schafer’s demonstration of the pressor effects of the adrenals. John Jacob Abel and Jokichi Takamine independently also made this discovery in 1897 and 1900 respectively, not knowing of Cybulski’s work. Much hope was ascribed to adrenaline, but when it failed to improve the symptoms of adrenal insufficiency, scientists and physicians were baffled and disappointed. That was until Artur Biedl demonstrated that there were distinct differences between the adrenal cortex and medulla, with the medulla being necessary to sustain life.11 Thus, the search for The adrenal hormone that controlled glucose metabolism, which would also cure Addison’s disease, was focused on the adrenal medulla. Back when Oliver and Schafer presented their research at the Physiological Society in March 1894, two budding scientists had been in the audience, Earnest Starling and William Bayliss. These young scientists went on to make major contributions to endocrinology of their own. Starling, a professor at the University College, London, and notable elected member of the Royal Society, is best known for describing the opposing forces between outward hydrostatic force and the inward osmotic force in capillaries (Starling’s Principle). But in 1900, he partnered with his now brother-in-law, William Bayliss, to explore the peristaltic aspect of Ivan Pavlov’s experiments. On Pavlov’s ContributionPavlov had hypothesized that pancreatic secretion was under the sole control of the vagus nerve; however, Starling and Bayliss believed a product of the gut had activated this process.12 In order to build upon Pavlov’s original theory, Starling and Bayliss ground up mucosa of the duodenum with acid and sand and injected this concoction into an anesthetized dog. A few minutes after the injection, the pancreas began to produce secretions, suggesting that it was the food entering the duodenum that stimulated the pancreas.12 They dubbed their newly discovered internal secretion, “secretin”. Pavlov congratulated the scientists for their discovery, but 2 years later chose not to mention either of them in his 1904 Nobel Prize acceptance speech.4The Word “Hormone” is CoinedIn 1905, Starling was asked to give the Croonian Lectures at the Royal College of Physicians on the new field of endocrinology. While in preparation for his lectures, Starling dined with academicians from Cambridge University and posed to them an important question: How could a word be used to describe internal secretions that traveled to different parts of the body to produce effects? One poetry professor suggested the Greek verb for excite or arouse, hormau.4 Subsequently, on June 20, 1905, Starling’s lecture titled The Chemical Control of the Functions of the Body, describing Bernard’s theory of internally secreted substances poignantly announced the presence of chemical messengers, which he coined “hormones”.13 With this brave notion, Ernest Starling disproved that electrophysiology in the brain controlled metabolism. Unfortunately, he was not commemorated for his findings in his lifetime, but was awarded knighthood in 1974 posthumously. Searching for “Substance X”On the other side of the Atlantic, American physician and entrepreneur, Philip Hench, noted that regardless of gender, rheumatism improved if the patient simultaneously suffered an attack of jaundice.14 He speculated that jaundiced patients had an increased level of a hormone, which he named Substance X, that was accountable for the positive clinical effects. At this time there were few clues to its origin. Hench had administered human bile, ox bile and jaundiced blood to patients suffering from rheumatoid arthritis (RA) in a series of unsuccessful attempts to re-enact the actions of Substance X.15 Because he noted that the fatigue in Addison’s disease was similar to that in RA, he focused his efforts to searching the adrenals for Substance X.15Pinpointing the Adrenal HormoneAround this same time, Edward Calvin Kendall (who had debuted on the hormone scene with his discovery of the thyroxine hormone in 1914) was visited in his Mayo Laboratory by an intriguing Hungarian physiologist Albert Szent-Gyorgyi. The physiologist shared his ideas that adrenal gland research was the unexplored frontier. Enthused by Szent-Gyorgyi, Kendall joined the search for The adrenal hormone.Kendall met with a commercial producer of adrenaline to orchestrate a trade. Kendall agreed to provide the company, Parke-Davis, with large quantities of their patented Adrenalin in exchange for 500 pounds of fresh frozen adrenal glands per week.16 Parke-Davis saw the mutual benefit of Kendall’s proposal, as the medical demand for Adrenalin was substantial. It was now being used to treat asthma, allergic reactions, goiter, and hemorrhage control in surgery and elsewhere.17 In fact, Gene Tunney, a famous boxer of the time, carried Adrenalin with him to use in the “ring for extra vitality”.17 It is notable that with Parke-Davis’s support, Kendall was able to continuously run his Mayo laboratory 24 hours a day, processing 2 tons of adrenal glands per month, making him the pre-eminent scientist in The search.18While scientists around the globe were competing to identify The adrenal hormone, Kendall and Reichstein (at Basel University in Switzerland) were both determined to be the first. By the late 1930s, Kendall isolated several hormones from the adrenals, six of which were biologically active. He named these compounds A, B, C, D, E (aka cortisone), and F (aka hydrocortisone).19 Intuition told him that The hormone and his compound E and Substance X were one and the same.With growing rumors about German pilots using adrenal extracts to combat altitude sickness, the military turned its focus toward Kendall and his work was deemed “classified”.14 At a top-secret endocrinology meeting (held in 1941) to discuss the future of adrenal research, it was determined to designate Kendall’s patent applications confidential “in the interest of national defense.”16 Once Kendall was partnered with the military, he recruited researchers from across the country to work on synthetically producing his compound E. It was a Merck pharmaceuticals researcher who finally achieved this goal, for in 1948, Lewis Sarett synthesized cortisone from ox bile using a 36-step process (costing $200/gram).Treating Rheumatoid ArthritisStill believing that RA was an adrenal problem, Dr. Philip Hench, who had done the bile salt experimentations for RA, purchased a supply of synthetic cortisone from Kendall to treat the first RA patient.20 On Christmas Day 1948, Hench’s despondent patient began walking again. The patient’s dramatic recovery was broadcast internationally. On the BBC radio, it was reported that Hench had “opened the way to a real cure” for rheumatism.14 Cortisone offered such promise of a cure that the British treasury imported the drug from America (between 1950 and 1953), while they feverishly worked on producing their own.14 Commercializing Cortisone At the end of 3 decades of racing to find, synthesize and prove the efficacy of cortisone, Reichstein, Kendall, and Hench were co-awarded the Nobel Prize for Physiology and Medicine (c. 1950). And with this a new era began the dawn of the cortisone pharmaceutical industry.Topical hydrocortisone, acquired from Merck, made its triumphant debut in 1950, when two dermatologists from Alabama, Drs. Spies and Stone, used it to successfully treat a patient with chronic hand dermatitis, a case they published in the Southern Medical Journal.19,21 In response, Marion Sulzberger and Rudolf Baer, two prominent dermatologists and contact dermatitis specialists, issued a comment in the Yearbook of Dermatology on the unusual success of the cream, as previous clinical responses to date had been overwhelmingly disappointing.19 Sulzberger and Witten went on to further establish the effectiveness of topical cortisones when they performed one of the first controlled clinical trials with topical hydrocortisone (Compound F) as the active arm.22 As hydrocortisone became a proven treatment time and again, the demand for it rose and many dermatologists “seriously wondered if their specialty had come to its end.”16With this growing demand, massive efforts were underway to discover both a more efficient and less expensive method for synthesizing cortisone. By 1951, the Syntex Company discovered a way to synthesize cortisone using Russell Marker’s degradation protocol, which he designed to produce progesterone (c. 1935). Building on the advances of Marker Degradation MD (which notably dropped the price to $6 per gram), Syntex used sarsasapogenin, a plant steroid from Mexican yams, and by removing side chains from the parent compound were able to end with the degradation product, cortisone.23 By the 1950s, almost every pharmaceutical company synthesized its own cortisone.14 Allergy to CorticosteroidsIn 1959, the first two cases of corticosteroid allergy were published.24,25 In the British Journal of Dermatology, Kooij described a case of sensitization to topical hydrocortisone in which a 19-year-old garage worker presented to his doctor with a face and hand dermatitis. Assuming his reaction represented an ACD to a garage chemical, the physician prescribed Neo-cortef, a topical cream containing hydrocortisone and neomycin. The patient returned a few days later after his dermatitis worsened with the cream.24 He was patch tested to several different brands of hydrocortisone (to eliminate the chance of his sensitization being from a vehicle component) and to several antibiotic ointments. At the 72-hour evaluation, the patient was noted to be reactive to almost all the hydrocortisone creams, prednisolone, and neomycin, but not triamcinolone.24 This case provided the first insight into corticosteroid allergy and corticosteroid cross-reactivities.Despite growing reports of sensitizations, corticosteroid allergies were considered quite rare until the 1990s, when the North American Contact Dermatitis Group (NACDG) added structural class A and B corticosteroids to the North American Standard Series. Further-more, it should be noted that the corticosteroids are now divided into five different structural classes based on molecular structure and/or clinical observation of cross-reactivity. The molecular configuration of the steroids (specifically, the substitutions on C16 and at the ester of C17 and C21) has led to four different classes: A, B, C, and D as defined by Coopman et al in 1989.26 Matura et al then further subdivided class D into D1 and D2. The subdivision of class D was important clinically as the D2 group is far more likely to cross-react with group A and budesonide.27,28In the 2001-2002 study, the NACDG reported the prevalence of contact sensitization to tixocortol-21-pivalate (class A) as 3%, budesonide (class B) as 1.1%, and hydrocortisone-17-butyrate (class D2) as 0.5%.29 These data were confirmed by Davis and Farmer (The Mayo Group) who found an overall corticosteroid reactivity rate of up to 5.24%.30 To heighten awareness of this group of potential allergens, corticosteroids were designated the Allergen of the Year in 2005.31-36The Value of this CaseCorticosteroid allergies often present as unresponsive dermatoses or with a worsening of the patient’s dermatitis when a corticosteroid cream or an agent of higher potency in the same structural class is used. Our patient was found to be allergic to Class A corticosteroids, which were present in her over-the-counter topical steroid creams, prescription creams and notably the systemic steroid (prednisone). With higher doses of prednisone, the allergy was masked, but with a reduction of the dose (tapering), the underlying allergy she had to this class of medications became apparent.   Topical Corticosteriod Pocket GuideAccompanying this month’s issue is a useful pocket-sized drug guide titled, Topical Corticosteroids: A Quick Guide to Potency, Structural Class and Cross-Reactivity. This Connetics Corporation sponsored guide is meant to highlight the five core structural classes of corticosteroids, organized from low potency to high potency, as would be prescribed in practice. The chart also includes information about cross-reactivities between the substances within each class and between classes. Patch test substances are also noted. We hope you’ll find this guide, which is packaged in front of October issue, useful and practical.