An algorithm for the diagnosis and treatment of nonsteroidal antiinflammatory drugs hypersensitivity, 2024 update

Patient-reported allergy to non-steroidal anti-inflammatory drugs (NSAIDs) implies the avoidance of this group of drugs and a higher risk of developing opiod use disorder.¹ Therefore, evaluation by an allergist is crucial for potential delabelling and for an accurate management. This algorithm, updated from 2020,² provides guidance to help patient-reporting NSAID-induced hypersensitivity reactions (NSAID-HRs) management.

The major changes since the last algorithm concern the classification of NSAID-HRs,³ with the inclusion of blended reactions (simultaneous involvement of skin, respiratory, and/or gastrointestinal systems⁴ in cross-reactive patients (CRs)), as part of a multisystemic reaction in the new NSAIDs-induced urticaria/angiodema/anaphylaxis category (NIUAA) proposed recently by the EAACI/ENDA.⁵ Additionally, this update considers NSAID-exacerbated/induced food allergy (NEFA/NIFA) in the diagnostic work-up of NSAID-HRs; therefore, allergy evaluations should include the detection of sensitization to targeted food allergens in patients who have experienced urticaria/angioedema and/or anaphylactic reactions to NSAIDs taken after a meal^{6, 7} (Table 1). The appropriate classification of both entities is crucial taking into account their high frequencies (up to 28% of CRs⁴ and up to 18% of patients reporting acute NSAID-HRs,⁶ respectively).

As first approach in NSAID-HRs, it is important to interrogate about the number of episodes induced by different NSAIDs. If ≥3 episodes induced by different NSAIDs, including a strong COX-1 inhibitor, patients may be diagnosed as CRs,¹⁰ and the phenotype may be considered according to the symptomatology experienced after NSAIDs intake and the underlying diseases (Table 1 and Figure 1). CRs must avoid all strong COX-1 inhibitors, and a DPT to find alternative may be required, including weakly selective COX-1 inhibitors, and if patients react, preferential/selective COX-2 inhibitors.¹¹

If <3 episodes to <3 different NSAIDs, oral DPT with aspirin (ASA) (or with indomethacine if ASA is the culprit) is recommended to confirm/exclude CR.¹² Although there is not a single standardized protocol, recently it has been confirmed that an accumulated dose of 500 mg of ASA is sufficient to achieve an accurate diagnosis.¹³ If reactions involve the airways with or without skin symptoms, nasal/bronchial provocation test may be considered firstly if available,⁴ and if negative, oral graded DPT with ASA must be conducted cautiously as there is a risk of severe bronchospasm.⁹ If ASA is tolerated in oral DPT, DPT with the culprit is required in order to confirm selective response (SRs) or tolerance to NSAIDs. In acute reactions, previously to DPT with the culprit, skin testing may be useful only if pyrazolones are involved but not with other NSAIDs, although sensitivity is not optimal. For delayed reactions, intradermal skin test with delayed reading is more sensitive than patch tests, particularly for metamizole. Although patch tests have not been sufficiently standardized, they can be useful in cases of contact dermatitis and fixed drug eruption.³ In vitro basophil activation test (BAT) has also shown to be useful as a complementary tool for diagnosing acute SRs to pyrazolones, but not for other NSAIDs.¹⁴ As skin tests and BAT sensitivities decrease over time, an early assessment is required.^{3, 14}

Another novelty from the previous algorithm is the delabelling of patients reporting exclusively mild cutaneous reactions (urticaria and/or angioedema, or non-urticarial delayed reactions) by a direct oral two-step DPT with the culprit: 1/10–1/4 of the target dose with 60-min observation, followed by the remainder of the dose with a 120-min observation.¹⁵ If the involved NSAID is tolerated, NEFA/NIFA should be excluded by performing allergy evaluation to any food ingested 4 h before or after the reaction.^{6, 7}

Six years after diagnosis confirmation, NSAIDs-induced urticaria/angioedema patients must be re-evaluated as more than 50% tolerate NSAIDs over time, especially non-atopics, if reactions appear >1 h after NSAIDs intake, and if the reaction was manifested as urticaria.¹⁶ In NSAIDs-exacerbated respiratory disease, desensitization followed by aspirin treatment or biological agent therapy may be indicated when they do not respond to standard therapy. Biological agents such as anti-IgE (omalizumab) and anti-IL4/13 (dupilumab) may induce NSAID tolerance after 6 months of therapy in up to 60% and in up to 40% of patients, respectively.¹⁷ In NSAIDs-exacerbated cutaneous disease, clinical control of chronic urticaria by using antihistamines may allow for temporary tolerance of NSAIDs in up to 75% of patients.⁸

It is important to note that differences in patterns of consumption of drugs may exist between regions, which can involve differences in phenotype predominance. Additionally, diagnostic test availability may differ depending on geographical areas. Both facts could make it difficult to extrapolate the management of patients reporting NSAID-HRs worldwide.

The authors declare no conflicts of interest.