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Corticosteroid Allergy

Vincent St Aubyn Crump, FRCP (UK)

Corticosteroids are the most widely used class of drugs in dermatology and in the emergency management of several allergic diseases, including asthma and anaphylaxis.

People with chronic eczema who require multiple prescriptions of topical steroids are at increased risk of becoming sensitized to topical steroids. This condition is increasing due to widespread use, but also heightened awareness that "the most useful anti-inflammatory preparation for treating dermatitis could itself be a cause of inflammation", and improved testing techniques. However, it is still under diagnosed, not only because of lack of awareness, but also because the manifestation is usually very subtle. Some of these subtle presentations include:

  • Patient with chronic eczema getting worse over the years, & requiring more and more steroids despite avoiding all the known triggers and complying with the prescribed treatment.
  • Frequent, recurrent secondarily infected eczema, improving on antibiotics and then relapsing as soon as the antibiotics is stopped. This might be due to the fact that some antibiotics also have anti-inflammatory properties.
  • Some patients might notice that their eczema is actually worsened by some steroid preparations, and will "only improve on specific brands of steroids".
  • Patients with eczema, on treatment with topical steroids might start developing hives, and increased itching, due to contact urticaria from the steroid. These patients might notice a significant improvement when they are put on oral antihistamines (even the non-sedating ones, which classically are of little benefit in eczema)
  • Patients with eczema that can only be controlled on oral steroids, and always relapse when weaned onto topical steroids, even when this is done slowly.
  • Increased redness and itching after applying their steroid creams
  • Diagnosis picked on Patch Test, without any previous suspicion by the patient or their doctors. This group should be hopefully decreasing, as awareness increases.

Other presentations of corticosteroid allergy include:

  • Occupational contact sensitization to topical corticosteroids may rarely occur in pharmacists (1)
  • Acute eczematous reaction, with marked erythema and oedema, sometimes with even erythema multiforme-like symptoms.
  • Eczematous lesions, particularly of the face, sometimes with spreading to the trunk and flexures or generalized erythema and urticaria from using inhaled steroids (2)
  • Local adverse effects of nasal corticosteroids have ranged from nasal congestion, pruritus, burning, and soreness to perforation of the nasal septum (2)
  • Inhalation of steroids into the lung has been reported to cause pruritus, dryness, erythema and swelling of the mouth (angioedema), a dry cough and painful swallowing from inhaled or nasal steroids (2)
  • Allergic contact dermatitis to nasal spray may masquerade as infectious rhinosinusitis (3)
  • Worsening of asthma despite adequate treatment. When asthma fails to improve, or frankly deteriorate with systemic cordicosteroid therapy, cordicosteroid allergy should be considered.

How common is allergy to topical steroids?

The incidence of contact allergy to corticosteroids has increased dramatically since the late 1980's. The North American Contact Dermatitis group (4) found a prevalence rate of 3.1% in patch test clinic patients. A large study in England (5) revealed a sensitization rate of 4.9% among 528 patch test clinic patients. The incidence reported in the literature varies between 0.5% to 6%.

The reasons for the wide variation in prevalence between centers and between countries include:

  • Patient selection / preceding skin diseases
  • Awareness
  • Prescribing habits in the area
  • Types of corticosteroids available in that country
  • Testing and reading methods used

Clinical Manifestations of steroids allergy

There are 3 manifestations of steroid allergy:

  • Immediate or Type 1 reaction, involving IgE antibodies. This reaction occurs within minutes of applying, ingesting or being injected with the steroid. It can manifest as local hives at the site of contact with topical steroids, contact urticaria. This usually occurs within 20 minutes of the cream being applied. With oral or parenteral steroids the reaction ranges from urticaria to full-blown anaphylactic shock. The Swiss Drug Monitoring Centre SANZ reported 14 cases of Immediate Hypersensitivity due to parenteral glucocorticosteroids between 1981 and 1995. Nine of these reactions were life-threatening:
      • 3 patients experience an acute asthma attack
      • 6 had serious anaphylactic reaction including shock
  • Delayed, Type 4 or Allergic Contact Dermatitis, involving lymphocytes and other immune cells. These reactions manifest as eczema / dermatitis hours to days after application of the steroid. It is identical in appearance to atopic eczema, and usually can only be diagnosed with a patch test.
  • A generalized Delayed Systemic reaction to oral or parenteral steroids in patients with Delayed Type 4 allergy to steroids is very rare. There are less than 30 cases of generalized delayed systemic reactions to steroids reported in the literature. Oral administration of hydrocortisone in topically sensitized patients may produce a systemic contact dermatitis. The risk of an immediate type reaction in these patients is low.

What is the cause of Immediate Hypersensitivity (Type 1 Reaction) to corticosteroids?

Some people may be allergic to a component of the steroid base, preservative or vehicle.

In one study (6), of the 7 patients with immediate allergic to corticosteroids, the reaction was caused by the steroid molecule (triamcinolone or methylprednisolone succinate) in four patients, by the excipient, carboxymethylcellulose in another two, and the sensitized molecule could not be identified in one patient.

Components of topical steroids known to cause Delayed Hypersensitivity (contact dermatitis) include:

  • The Steroid molecule (active ingredient) – In one study (5) 90.8% of the cases were allergic to tixocortol pivolate. The others reacted to hydrocortisone, budesonide, and hydrocortisone 17 butyrate ( locoid).   54% of the subjects reacted to more than one steroids simultaneously.
  • Propylene glycol
  • Parabens
  • Benzyl alcohol
  • Benzalkonium chloride

It is therefore important to do patch tests with these individual components, when the patch test to the steroid molecule is negative.

Risk factors for immediate corticosteroids allergy

  • Patients requiring repeated doses of steroids e.g., renal transplant patients, severe asthmatics
  • Aspirin sensitivity
  • Female sex

Risk factors for allergic contact dermatitis (delayed hypersensitivity) to corticosteroids

  • Chronic nonhealing dermatitis / eczema
  • Stasis dermatitis
  • Chronic hand eczema
  • Having allergic contact dermatitis to other chemicals

How is contact allergy to steroids diagnosed?

Immediate, Type 1 – Skin Prick test is probably the best test. The steroid is applied to the forearm and pricked with a lancette and read at 15 minutes, looking for a wheal and flare at the site.

Allergic Contact Dermatitis to corticosteroids

This is best done through a Patch Test. The standard Patch test is applied onto the back with tapes and first read at 48 hours and again at 72 hours. In Patch Testing for corticosteroids the 48 and 72- hour reading may be negative, which may be due to the initial vasoconstrictor and anti-inflammatory effect of the steroids, therefore a delayed reading at 5 days is recommended. Without a late reading on day 5 or day 7, up to 30% of contact allergy to corticosteroids markers are missed.

The most commonly used screening agent is tixocortol pivilate 1% in petrolatum. This compound has a very similar steroid conformation to hydrocortisone and is preferred because of its enhanced penetration. It is not in clinical use in New Zealand, but is used as a nasal spray in some countries. This agent does not detect all cases of sensitivity, so the other screening agents are added:

  • Budesonide 1% in ethanol along with tixocortical pivalate detected 91% of 127 steroid allergy subjects in a patch test clinic population of 2123. Therefore, Tixocortol pivalate and budesonide behave as two good markers of corticosteroids allergy, and should therefore be included in the standard panel of patch tests. Further, more extensive testing should be carried out when these two markers are positive.
  • The steroid product that the patient is using. An Australian study (7) demonstrated that patch testing with the patient's own steroid in the commercial cream base was positive in 15 of 19 steroid allergy patients, and gave a higher percentage of positive results than either testing with the commercial steroid ointment base or with the pure steroid in either petrolatum or alcohol.

A very simple useful test for contact allergy to topical steroids is the repeat open application test (ROAT), using the steroid cream applied twice daily to an area of skin unaffected by eczema, usually the anterior forearm for seven days. If the patient develops a reaction at seven days, the cream is considered unsafe.

Cross-reactions patterns of corticosteroids

Most steroid allergic patients react to several different steroids demonstrating that concomitant sensitization and / or cross-reactions occur. It is hypothesized that cross-reactions occur in certain groups of steroids. It is found that molecules of the same group have similar spatial structures to explain the cross-reaction observed (8).

Classification of corticosteroids by the function of their allergenicity (8)

  • Group A: Hydrocortisone and tixocortol Type
    • Prednisone,
    • Prednisolone acetate (Pred mild & Pred forte eye drops)
    • Methylprednisolone aceponate   (Advantan) ,
    • Meprednisone
    • Cortisone, Cortisone acetate
    • Hydrocortisone* (-HC, Egocort, Cortaid, Skincalm)
    • Tixocortol pivalate*
  • Group B: Triamcinalone acetonide Type
    • Triamcinalone alcohol
    • Triamcinalone acetonide* ( Aristocort)
    • Budesonide* (Pulmicort, Butacort & Entocort),
    • Amcinonide, desonide,
    • Halcinonide,
    • Fluocinonide (Metosyn) ,
    • Fluocinolone acetonide (Synalar) .
  • Group C: Betamethasone Type
    • Betamethasone sodium phosphate,
    • Dexamethasone, dexamethasone sodium phosphate
    • Fluocortolone
  • Group D: Hydrocortisone-17-butyrate & Clobetasone 17 butyrate Type
    • Hydrocortisone butyrate)* (Locoid)
    • Hydrocortisone-17-valerate,
    • Clobetasol propionate (Dermol, Dermovate)
    • Aclometasone dipropionate,
    • Betamethasone 17 valerate (Betnovate, Beta)
    • Betamethasone dipropionate ( Diprosone)
    • Clobetasone 17   butyrate (Eumovate)
    • Fluocortolone pivalate (Ultraproct)
    • Mometasone Furorate (Elocon)
    • Fluticasone propionate (cutivate)

*Suggested screening agents

Corticosteroids with lower risk of sensitization

  • Group C,
  • The metylated and halogenated members of Group D,
  • Newer synthetic steroids like Fluticasone propionate (cutivate) and mometasone furorate (Elocon) have a lower risk of sensitization (9)

Molecules from one group differ sufficiently from other groups to explain the lack of cross-reactions among groups A, B & D. However, Budesonide which belongs to Group B is well known to cross-react with Group D steroids . Therefore, Budesonide is a marker for Group B and some of Group D steroids, like hydrocortisone butyrate (locoid). Molecular structure is not the whole story since cross-reaction patterns differ from patient to patient. Also, because of metabolism and degradation, several different molecules can be formed, resulting from reactions from the degradation product and not the parent compound. Because of the difficulty of predicting cross reactions, when hypersensitivity to one steroid is demonstrated all the steroids available in New Zealand should be tested, in order to recommend a valid alternative.

References

  1. Lauerma AI. Occupational contact sensitization to corticosteroids. contact Dermatitis 1998;39:328-329
  2. Isaksson M. Skin Reactions to inhaled corticosteroids: Incidence, Avoidance and Management. Drug Safety, Volume 24, Number 5, 2001, pp. 369-373(5)
  3. Bircher AJ, Hirsbrunner P, et al. Allergic contact dermatitis from tixocortol pivalate in a nasal spray masquerading as infectious complication of sinusitis. ORL J Otholaryngol Relat Spec. 1995 Jan-Feb;57(1):54-6
  4. Marks JG, Belsito DV, et al. North America Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Am Acad Dermatol. 1998 Jun;38(6 Pt 1):911-8
  5. Burden AD, Beck MH. Contact Hypersensitivity to topical steroids. Br J Dermatol. 1992 Nov;127(5):497-500
  6. Venturini M, Lobera T et al. Immediate hypersensitivity to corticosteroids. J Investig Allergol Clin Immunol. 2006;16(1):51-6
  7. Freeman s. Contact & Occupational Dermatitis, Skin & Cancer Foundation, Sydney. Contact Dermatitis 1995 Oct,33(4):240-2
  8. Lepoittevin JP, Driegh J, Dooms-Goossens A. Studies in patients with corticosteroids contact allergy: understanding cross-reactivity among different steroids . Arch Dermatol 1995; 131(1):91-2
  9. Wilkinson SM, Beck MH. Skin Hospital, Manchester. Contact Dermatitis. 1996 May;34(5):182-91
  10. Contact and Occupational Dermatology, James G. Marks & Vincent A. DeLeo, Second Edition,

 

 

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