To the Editor:
Etanercept has been an effective, well tolerated medication with uncommon and usually acceptable adverse effects. We are aware of only 4 reports describing possible/probable etanercept allergy/anaphylaxis1,2,3,4,5. We describe 2 patients with allergic/anaphylactoid reactions to etanercept, review the literature, and comment on pertinent management issues.
A 49-year-old woman with a history of atopy and anaphylactoid/angioedematous symptoms to soy milk developed rheumatoid arthritis (RA) in 2009. She was started on prednisone, minocycline, sulfasalazine, ibuprofen, and hydroxychloroquine, with a poor response. She was then prescribed etanercept 50 mg weekly subcutaneously, which rendered her asymptomatic. However, after several months she reported increasingly frequent and severe episodes characterized by urticaria and swelling of the periorbital regions and her tongue within hours following administration of etanercept, requiring diphenhydramine, epinephrine, and corticosteroids. Etanercept was discontinued and there has been no recurrence of these events.
A 27-year-old woman presented in 2005 with persistent rash, fevers, arthritis, and elevated inflammatory markers; no other disorder was evident. Adult-onset Still’s disease was diagnosed, and she began taking oral steroids. She did not respond to or developed adverse reactions to anakinra, methotrexate, and azathioprine, and began taking subcutaneous etanercept 25 mg twice weekly. She reported episodes of facial swelling with periorbital edema, diffuse pruritic rash, and difficulty swallowing within hours after injection, requiring epinephrine and corticosteroids. Etanercept was discontinued and there has been no recurrence of these events.
We believe that our patients’ allergic reactions were caused by etanercept. While we did not carry out blinded, controlled provocation challenges (and did not want to), both patients responded stereotypically, repeatedly, and specifically to prescribed doses of medication; reactions did not recur following cessation of etanercept and did not occur with other medications. We could not investigate immunologic sensitivity to medication. We interpret our patients’ clinical stories as consistent with etanercept-induced anaphylactoid reactions. There is precedent, albeit uncommon, for this in the literature. Injection site reactions (pruritis, edema, and erythema) have been etanercept’s most common side effects6. Systemic/allergic reactions have not commonly been reported7,8. Discontinuation of treatment for systemic allergic reactions (dermatologic, infection) was more frequent for other anti-tumor necrosis factor-α (TNF-α) antagonists than for etanercept9; acute systemic allergic reactions were more frequent with infliximab than with adalimumab or etanercept. The manufacturer reported < 2% of patients experiencing allergic reactions in clinical trials (when the drug was administered with solvent-containing L-arginine hydrochloride, itself potentially allergenic); angioedema occurred in postmarketing reports but without details1. Immediate adverse reactions in a large cohort of patients receiving anti-TNF agents reported no cases of anaphylaxis or angioedema associated with etanercept9. And colleagues had not encountered patients with this response to a TNF-α antagonist.
However, there have been reports of adverse effects (Table 1). A patient taking methotrexate and etanercept manifested urticaria, macular rash, periorbital and general facial edema, and a 30 mm Hg fall in blood pressure on 2 occasions associated with subcutaneous methotrexate (but not etanercept), and had intracutaneous hypersensitivity to methotrexate2. Angioedema was reported in a patient 2 days after her third injection of etanercept3. Angioedema occurred in another patient 4 months after starting etanercept4. A letter reported hypersensitivity reactions among 671 patients with RA, spondyloarthropathy, ankylosing spondylitis, psoriatic arthritis, Behçet disease, and Crohn disease who were treated with anti-TNF agents. It appeared that 13 who received etanercept had atopic reactions: 5 urticaria/angioedema, 2 anaphylaxis, 4 local, and 2 other (pruritis, rash, eosinophilia). The authors said that 31 patients taking infliximab and 3 taking adalimumab reported anaphylaxis, urticaria, or angioedema5. We were able to identify only 2 reports of similar reactions to other biologic agents (anakinra and rituximab) for patients with rheumatic diseases10,11 (Table 1).
We can only speculate about the source of the allergic response to etanercept. Antichimeric antibodies (infliximab) may lead to more acute allergic reactions9. Fusion proteins (etanercept) induce a weaker immune response4,12. We do not know whether our patients’ responses were mediated by IgE or IgG or whether antibodies had developed against the “hinge/fusion” region of the molecule13,14,15.
Etanercept allergy presents some management implications. Attempting desensitization was not feasible for our patients. Lyophilized medication could have been administered in other diluents, and/or administered in escalating and divided dosages. It might have been of interest to see if administration of other TNF-α antagonists was tolerated5. We preferred to avoid the potential risks of these challenges and to consider other, nonbiological treatments. Certainly the simplest and most practical approach was to use other (non-TNF-α antagonist) disease-modifying antirheumatic agents for our patients, which is what we did.
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