**4. Diagnostic strategy in skin reactions to NSAID**

The main tools that allow us to deal with cutaneous reactions to NSAIDs are the clinical history and controlled re-exposure to NSAIDs in a hospital setting [3]. The careful and complete review of clinical reactions to NSAID is essential before any challenge procedure and allows us to provisionally classify the patient with NH, while the latter, the SBPCOC, definitively assigns the patient to a specific phenotype. Our objective is to offer the best analgesic, anti-inflammatory or antiplatelet alternatives in the event that the patient tolerates the NSAID without reaction.

#### **4.1 To classify, to classify, to classify…always**

The clinical history is the basic method of temporarily assigning the patient to a specific clinical phenotype. The phenotypic classification of any patient with a possible NH (**Table 1**) will be the first (and the most important) diagnostic step in the investigation of these types of reactions. Properly classifying NH will help us to choose safest diagnostic approach for each patient [1, 3–5, 8].

The first key element to classify these patients will be the time elapsed between the administration of NSAID and the beginning of the reaction. The so-called latency time allow us to differentiate the reactions in: immediate (less than 24 hours, usually between 1 and 2 hours) and delayed reactions (over 24 hours). Secondly, we will have to evaluate the clinical manifestations of the reaction (respiratory, cutaneous or systemic), the NSAID involved, the route of administration and the reason why the drug was prescribed, as well as the coexistence of associated concomitant diseases (chronic rhinosinusitis with nasosinusal polyposis, bronchial asthma, spontaneous chronic urticaria or allergic respiratory disease). Thirdly, we will have to determine the NSAID tolerated previously and after the reaction. This will allow us to make a first historical approach to NSAID reactivity status: multiple

#### *Clinical Phenotypes in NSAID-Induced Urticaria/Angioedema DOI: http://dx.doi.org/10.5772/intechopen.96718*

reactor with reactivity among non-chemically related NSAIDs (**Table 3**) or selective reactor with sensitivity to a single NSAID with tolerance to at least one potent COX-1 inhibitor NSAID (**Table 4**).

Therefore, the classification of patients based on clinical phenotypes is critical in addressing diagnostic and therapeutic strategies in these patients. The identification of comorbidities such as chronic spontaneous urticaria, allergic respiratory disease or reactions to mite-contaminated cereal flour-based foods are key clinical elements that might define a phenotype and predict in most cases multiple reactivity to different groups of NSAIDs. The worsening of spontaneous chronic urticaria after NSAID administration and the development of the reaction within 1 to 6 hours of NSAID administration are common clinical features that can be referred up in most patients with skin-type reactions.

In a percentage of cases, clinical information on reactivity status is limited, either because the patient has had only a single reaction with a single NSAID or because of the impossibility of determining each of the NSAIDs involved in the patient's lifetime reactions. In these cases, determining this status is essential to approach a therapeutic plan. The only way to determine the reactivity status is through SBPCDC with NSAIDs that have differential inhibition against each of isoforms COX-1 and COX-2. However, we could collect in the clinical history some findings that may allow us to identify a multiple or selective reactor status (**Tables 3** and **4**). In general, a NSAID highly selective for COX-2 inhibition, such as a COXIb, will be better tolerated than a potent COX 1–2 inhibitor in patients who are multiple reactors. The degree of COX inhibition is directly proportional to the probability of reaction and the intensity of its clinical manifestations [1, 3–5, 8]. In the case of a selective reactor, all COX-1 inhibitor NSAIDs will be tolerated, except the one involved in the historical reaction (or those which are chemically related).


#### **Table 3.**

*Clinical findings suggesting a NSAID multiple reactor.*


#### **Table 4.**

*Clinical findings suggesting a selective reactor status.*

## **4.2 Principles to design the best controlled oral challenge for each clinical phenotype**

The fundamental objectives of SBPCOC is threefold: **first**, to determine the clinical syndrome associated with the reaction after administration of the NSAID. In the case of systemic anaphylaxis due to an NSAID, the use of the NSAID involved during the clinical reaction is completely contraindicated. **Second**, determine the tolerance pattern to NSAIDs in an individual patient. A negative SBPCOC will determine the NSAID reintroduction of the treatment in the patient with NH. The stratification of NSAID according to their inhibitory potency of each of the COX1 and COX2 isoenzymes determines the likelihood of reaction and therefore the order of administration of NSAIDs during SBPCOC [15]. Thus, for example, in a patient with diclofenac and ibuprofen-induced NIUA, a SBPCOC with celecoxib or etoricoxib is highly likely to be tolerated (and therefore included in the self-care plan for patient management) while an SBPCOC with another strong COX-1 inhibitor NSAID is highly likely to induce a reaction, diagnose the patient, and determine a multiple pattern of reactivity. And **third** and finally, it allows us to initiate a desensitization procedure in patients with immediate respiratory or cutaneous reactions requiring a desensitization procedure that determines the introduction of an NSAID for anti-inflammatory or antiaggregant treatment if necessary. Desensitization is a procedure which will be discussed later and which determines a temporary state of tolerance while the administration of the NSAID persists.

#### *4.2.1 SBPCOC with NSAID in patients with cross-reactive skin reactions*

The approach to patients with the various phenotypes of cross-reactive skin reactions (NECD, NIUA, IPA and NIRU) is very similar. We always have to bear in mind that these patients seek our advice because they lack analgesic and antiinflammatory alternative strategy, and their fundamental objective is to find an alternative that will solve their underlying disease without inducing a reaction. Therefore, the stratification of SBPCOC with NSAIDs plays an essential role in these cases, since it is directly related to a potential positive response during the challenge [15]. In virtually all cases these patients tolerate COXiB. Even in the rare cases where they do not tolerate a given COXiB, it is essential to expose them to another COXiB as it can be otherwise tolerated [16].

NSAIDs, which are COX2 inhibitors, but which inhibit COX-1 in a dose-dependent manner, such as meloxicam, would be the next alternative to propose in these patients. Paracetamol, a weak COX-1 and COX-2 inhibitor, is generally tolerated at the time of the clinical history by most patients. Its analgesic potential, but the absence of anti-inflammatory effects, is what finally decides the patient to go to the allergist looking for more appropriate alternatives. The use of potent COX1 and COX2 inhibitors, such as aspirin, ibuprofen, metamizole or diclofenac necessarily determine a reaction and therefore a diagnosis in this type of reaction [3, 8, 15].

#### *4.2.2 SBPCOC with NSAID in patients with selective urticaria and anaphylaxis*

The existence of an NSAID-induced anaphylaxis predicts the existence of a selective pattern that in many cases can already be detected in the clinical history, because the patient has tolerance to other non-chemically related NSAIDs. In a study of patients with NSAID anaphylaxis we have demonstrated that patients tolerated with impunity any NSAID, if we avoided the historically implicated NSAID or other chemically related NSAIDs during the SBPC [3]. In the group of patients with pyrazolone (metamizole, propyfenazone) anaphylaxis in Spain, skin tests (prick

test at 400 mg/mL and ID at 4 mg/mL) are extremely useful tools to detect an IgEmediated allergy to these drugs. A positive metamizole skin test will always determine a safe SBPCDC if another non-pyrazolone NSAID is used during challenge. With other NSAIDs, in my experience, skin tests have extremely low sensitivity.
