Corticosteroid allergy

I asked the advice of Dr. David Khan, program director for allergy/immunology at the University of Texas Southwestern Medical Center and a member of the practice parameter task force. He has published on the topic of drug allergy. His response is below.

“Over 100 cases of immediate reactions to corticosteroids have been published.(1) The largest series of patients evaluated thus far included 64 patients with immediate reactions.(2) The corticosteroids tested were dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. Prick tests were performed with stock solutions and intradermal tests were performed with 1:10 dilution. In addition, they also performed testing with excipients commonly found in corticosteroids including carboxymethylcelluose (CMC) and polyethylene glycol (PEG). Testing was performed using artificial tears as a source of CMC and a common laxative as a source of PEG. Drug challenges were performed after negative tests and “were tailored to the individual. Only 9/64 patients had confirmed corticosteroid allergy, most through drug challenge (confirming the importance of drug challenge in excluding and confirming a diagnosis). Interestingly 5/9 were allergic to the excipient, while the remaining 4 did not complete the testing to exclude excipient allergy. This study confirms the importance of testing for excipients, especially in patients with confirmed corticosteroid allergy.”

I have copied a question and answer from the archives of Ask the Expert. The concentrations in this question for skin testing with methylprednisolone is 20mg/ml and 2 mg/ml for percutaneous testing and 0.2 mg/ml and 2 mg/ml for intradermal testing. The predictive value of this testing is not validated. Also, there is an increased occurrence of corticosteroid allergy in subjects with aspirin exacerbated respiratory disease (AERD).

In summary, without a challenge there is no confirmation of allergy. Skin testing may be of help but excipients are a concern.

1. Baker A, Empson M, The R, Fitzharris P. Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature review. Clin Exp Allergy. 2015;45(3):669-76.
2. Li PH, Wagner A, Thomas I, Watts TJ, Rutkowski R, Rutkowski K. Steroid Allergy: Clinical Features and the Importance of Excipient Testing in a Diagnostic Algorithm. J Allergy Clin Immunol Pract. 2018;6(5):1655-61.

11/26/2018: Methylprednisolone injection reaction
Question: A 74 year-old old female with polymyalgia rheumatica on depo medrol 80 mg every 3 weeks (oral avoided due to abdominal issues). Second dose caused local pain at the site radiating into the whole extremity which got worse in 8-10 hours persisted for 10 days. The third reaction again pain at the site and involving the whole extremity but started within one hour - moderate severe pain requiring pain killers, no redness, rash, fever warmth, or noticeable swelling. My fear is further reaction might be more severe. Am I correct in assuming this is a delayed hypersensitive reaction. Question is whether this reaction is to steroid or one of the ingredients? Can I try another form of injectable steroid? If yes, which one or simply go to oral form? She has had a dramatic response to low dose steroid.

Answer: The symptoms and time course suggest that the adverse event associated with the intramuscular methylprednisolone is not IgE dependent. Corticosteroids, including methylprednisolone, are associated with a variety of adverse, immunologic reactions including IgE mediated responses. The summary statement from the practice parameter for drug allergy is (1):

“Corticosteroids Summary Statement Immediate-type reactions to corticosteroids are rare and may be either anaphylactic or anaphylactoid in nature. (C) Summary Statement

Most reported reactions to corticosteroids involved intravenous methylprednisolone and hydrocortisone, and preservatives and diluents have also been implicated. (C) Allergic contact dermatitis (Gell-Coombs type IV reaction) due to topical application of corticosteroids is the most common type of allergic reaction induced by this class of drugs. Rarely, immediate-type allergic reactions to corticosteroids have been described. Most such reported reactions are due to intravenous administration of methylprednisolone and hydrocortisone.(53,106-111) Patients with AERD or renal transplants may be at increased risk of reacting to corticosteroids, but this could be due to increased use of corticosteroids in these patients. In most cases, drug specific IgE has not been detected (either via skin testing or in vitro tests). Hence, it is unclear whether these reactions are anaphylactoid or represent true IgE-mediated allergy. Some of the reactions are believed to be secondary to the diluent or preservative, rather than the active drug.(107,296) Although corticosteroid-induced reactions are rare, the possibility should be entertained in patients who experience immediate symptoms (urticaria, angioedema, bronchospasm) in the context of receiving the drug, with no other ascertained cause. Evaluation should include skin testing with the corticosteroid in question, although its predictive value is uncertain. Skin testing with the diluent itself may also be helpful. Because most (but not all) patients appear to be able to tolerate other corticosteroids, management should focus on finding an alternate agent for future use. If a patient with suspected allergy to a corticosteroid requires treatment with it, rapid induction of drug tolerance should be performed.”

I have attached an Ask the Expert archive question about methylprednisolone anaphylaxis that contains some information about corticosteroid testing (see below). Many of the immediate reactions to corticosteroids have occurred in aspirin sensitive individuals.

In light of the delayed nature of the initial response, patch testing with corticosteroids and preservatives could be considered. The injectable formulation is likely to vary with manufacturers but the FDA package label specifies polyethylene glycol, polysorbate 80 and benzyl alcohol in the product (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/011757s104lbl.pdf). Cutaneous and systemic reactions to polyethylene glycol are described (see Ask the Expert question below). Patch and prick testing has been reported.

In summary, I would recommend the utilization of an alternative corticosteroid, ideally with a single dose vial and no preservatives. If that is not possible, then I would administer a graded challenge over several days or divide the dose of the methylprednisolone into more than one location. The other option would be to perform patch testing with different products to see if delayed reactions occur with one more than another. The corticosteroid with the least number of reports of reactions in general is dexamethasone. Finally, for added safety an oral challenge could be considered with an oral formulation of the corticosteroid chosen. If no systemic response to the oral challenge after several days then the parenteral approach could be used. Of course, all of this must be preceded by a shared decision making discussion with the patient and the other treating physician, recognizing there is little hard evidence to direct your decision.

1. Solensky R, Khan D. Drug allergy: An updated practice parameter. Ann Allergy Asthma Immunol 2010;106: 273e1-78.

8/14/2013: Potential anaphylaxis to methylprednisolone
Question: Recently evaluated a 22 year-old female with a history of developing a local reaction (red, itchy, softball size) within a few hours after receiving a intra-articular steroid injection several years ago (no records available regarding which steroid). No other symptoms (systemic or otherwise) with this reaction. The reaction resolved fairly promptly with diphenhydramine. This was the first time the patient received a steroid injection. She has subsequently tolerated several courses of oral steroids (prednisone and methylprednisolone) as well as OTC topical steroids. The patient is now going to require another steroid injection. Since the patient has tolerated oral methylprednisone several times, would it be safe to assume that the risk of reacting to intra-articular methlyprednisolone would be very low?

Answer: Based upon the history, I would think that a reaction to intraarticular injection of methylprednisolone would be very rare, and that your patient is at very little risk. However, unfortunately, as you can see from the abstracts copied below, such reactions have occurred, and they have been attributed both to the methylprednisolone molecule per se as well as to the succinate moiety used as a carrier vehicle for intravenous injection. I do not know the preparation that is planned to be used, but I assume it is a succinate.

Because such reactions have occurred, you cannot give a carte blanche assurance that she will not experience an adverse event. However, as noted, she is at very little, if any, increased risk because of her previous local. Nonetheless, because the issue has been raised, you could consider performing a skin test to methylprednisolone. The studies that I have copied below have utilized skin tests, and there is a recent document published by the Drug Allergy Interest Group (a position paper) of the ENDA/EAACI in Allergy, Volume 68 (6), pages 702-712, June 2013.

In this article, they recommend skin testing with methylprednisolone using a concentration of 2 mg/ml followed by 20 mg/ml via epicutaneous testing, and then intradermal testing with 0.2 mg/ml and 2 mg/ml. Although this concentration has not been validated in large numbers of individuals, a negative test would certainly give you more reassurance that the administration of methylprednisolone would be safe in your patient.

In summary:
1. As you know, anaphylactic reactions to corticosteroids are extremely rare, and this is certainly the case for methylprednisolone.
2. Nonetheless, such reactions have been reported to both the molecule itself as well as the succinate carrier.
3. Therefore, if you are concerned about the possibility of a reaction, however rare, you could perform skin testing using the above concentrations. If negative, this would give you considerable reassurance that the administration of methylprednisolone would be safe. If the test was positive, you might consider suggesting another steroid preparation.

Therapie. 1990 Nov-Dec;45(6):505-8.
[Severe anaphylactoid reactions after intravenous corticosteroids. Report of a case and review of the literature]. [Article in French]
Laine-Cessac P, Moshinaly H, Gouello JP, Geslin P, Allain P.
Source
Laboratoire de Pharmacologie, Centre Hospitalier Universitaire, Angers.
Abstract
We report a case of fatal anaphylactic reaction to intravenous methylprednisolone succinate therapy developed in a 51 year old asthmatic man with aspirin intolerance and undetermined myocarditis. 14 similar cases were found in literature and analysed: asthma and aspirin intolerance seem to be risk factors; the organism reacts against either unconjugated corticoid or esterified corticoid principally its succinate salt; the mechanism of these reactions remains not clear; it may be either a true allergic reaction or a nonspecific reaction

Document title: Anaphylactic shock induced by intraarticular injection of methylprednisolone acetate
Author(s)
MACE S. (1) ; VADAS P. (1) ; PRUZANSKI W. (1) ;
Affiliation(s) (1) Division of Immunology, The Wellesley Central Hospital, University of Toronto, Toronto, CANADA
Abstract
There are numerous reports of hypersensitivity reactions to corticosteroids. However, cases of anaphylactic shock after intraarticular injection of corticosteroids are exceedingly rare. We describe a case of anaphylaxis in a 31-year-old woman after intraarticular injection of synthetic methylprednisolone acetate. Immediately after injection she developed sneezing, angioedema, tachycardia, and marked hypotension. She responded promptly to treatment with subcutaneous epinephrine. She had received uneventfully one intraarticular injection of the same compound 4 years earlier. Intradermal skin testing showed strong reactivity to methylprednisolone acetate suspension, moderate reactivity to hydrocortisone and weak reactivity to betamethasone. Tests with dexamethasone. triamcinolone, lidocaine, latex and nonsteroid constituents of the injected suspension including polyethylene glycol, polysorbate 80, mono and dibasic sodium phosphate, and myristyl-gamma-picolinium chloride were negative. This patient had developed anaphylaxis due to methylprednisolone acetate alone. Although such events are very rare, it is advisable to keep injectable epinephrine in the offices of rheumatologists.

Journal of Rheumatology ISSN 0315-162X CODEN JRHUA9 Source.
Anaphylaxis Caused by the Sodium Succinate Ester of Hydrocortisone and Methylprednisolone

J Asthma 1986, Vol. 23, No. 2 , Pages 81-83 (doi:10.3109/027709086

Read More:
Anaphylaxis Caused by the Sodium Succinate Ester of Hydrocortisone and Methylprednisolone

Skin test with methylprednisolone (SPT 2 mg/ml and 20 mg/ml, IDT 0.2 mg/ml and 2 mg/ml)

Sincerely,
Phil Lieberman, M.D

I hope this information is of help to you and your practice.

All our best.

Dennis K. Ledford, MD, FAAAAI
David Khan, MD, FAAAAI