Safety of meloxicam in patients with aspirin/non-steroidal anti-inflammatory drug-induced urticaria and angioedema

It has been proposed that aspirin (ASA) and other non-steroidal anti-inflammatory drug (NSAID)-induced urticaria (UR)/angioedema (AE) are mediated through inhibition of cyclooxygenase-1 (COX-1) enzymes. Therefore, drugs with COX-2 selectivity may be well tolerated in such patients. We investigated the safety of preferential COX-2 inhibitor meloxicam in subjects with UR or AE type intolerance reaction to classical ASA/NSAIDs. Subjects with reliable or documented history of UR/AE due to classical ASA/NSAIDs underwent a single-blinded, placebo-controlled oral challenge with a cumulative dose of 7.5 mg meloxicam on 2 separate days. One-quarter and three-quarter divided doses of placebo and the active drug were given at 1-h intervals. A total of 116 patients (86 women and 30 men, mean age 39.6 ± 12.7 years) were enrolled to the study. The rate of atopy was 25.9%. Mean duration of drug reaction was 87.4 ± 110.8 (1-720) months. Almost half of the patients were multi-reactors. The most comorbid disease was asthma and the two most frequent NSAIDs inducing UR/AE were paracetamol (19. 6%) and ASA (19%). No reaction to placebo was observed. Ten out of 116 patients (8.6%) developed mild UR/AE, or only erythema and pruritus at a one-quarter or cumulative dose of 7.5 mg of meloxicam. The remaining subjects (91.4%) tolerated perfectly meloxicam challenge. This study indicates that 7.5 mg meloxicam is a safe alternative for ASA/NSAID-intolerant UR/AE patients. Intolerance reactions to meloxicam are much milder forms of the patients' historical ASA/NSAID-induced cutaneous reactions.     

Etoricoxib challenge in patients with chronic urticaria with NSAID intolerance

Patients with chronic urticaria frequently experience flares of hives following the ingestion of chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenic mechanism of these reactions is based on cyclooxygenase-1 (COX-1) enzyme inhibition. In most cases, nonselective NSAIDs, which inhibit both COX-1 and COX-2, are responsible for such adverse reactions; in contrast, analgesic and anti-inflammatory drugs exerting limited inhibition on COX-1 are generally better tolerated by these patients. This study aimed to detect tolerability of etoricoxib, a selective COX-2-inhibiting drug, in patients with chronic urticaria with a history of NSAID intolerance. Single-blind, placebo-controlled oral challenges with increasing doses of etoricoxib were carried out in 17 adult patients with chronic urticaria exacerbated by NSAID. All patients tolerated the drug at therapeutic doses. The study suggests that etoricoxib, with its favourable COX-1/COX-2 ratio, is well tolerated by patients with chronic urticaria exacerbated by NSAID intolerance.     

Nonsteroidal anti-inflammatory drug hypersensitivity: fable or reality?

In the medical community lectures and publications about nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity have led to an increasing awareness and diagnosis of this condition. Frequently, the diagnosis NSAID hypersensitivity is based only on history, which is a vague and unreliable indicator. A two-stage diagnostic procedure with skin tests (to exclude IgE-mediated allergy) followed by single-blinded, placebo-controlled oral challenges was carried out on patients attending our clinic from 1997 to 2003 with the diagnosis of a NSAID hypersensitivity. Out of 260 patients tested, 61.5% described their NSAID hypersensitivity as cutaneous (urticaria, angioedema), 24.2% had respiratory symptoms (asthma, rhinitis), 3.5% had anaphylactoid reactions, and 10.8% described uncertain signs. In fact 55.0% of all patients previously labelled as NSAID sensitive tolerated NSAID when assessed by oral challenge, whereas 13.8% were truly NSAID sensitive. In 31.2% of patients the challenge test with the suspicious drug was either not done or rejected by the patient; but all showed a proven tolerance of alternative NSAID. Our study demonstrates that oral challenge tests are safe, practical and useful in ruling out NSAID hypersensitivity in approximately 50% of the patients who have previously been labelled as such.     

Meloxicam in acute UV dermatitis — a pilot study

The non-steroidal anti-inflammatory drug (NSAID) meloxicam is a preferential cyclooxygenase-2 (COX-2) antagonist. The UV protective potential of this drug was studied to compare it with the reported beneficial effects of such preferentially COX-1 specific NSAIDs as indomethacin and acetylsalicylic acid in the literature. In a pilot study (open-label, non-randomized, non-controlled, unblinded), 10 patients received UV irradiation with the minimal erythema dose (MED), first with meloxicam (7.5 mg/die) to reduce post-operative pain and second without ingestion of meloxicam. The factor of UV protection was evaluated. In six of ten patients meloxicam showed no benefit, whereas four of ten patients had a 1.3- up to 3-fold UV protection. In this study, the benefit in UV protection of meloxicam as a prefential COX-2 antagonist was not above the reported benefit of the "old" COX-1 inhibiting NSAIDS.     

Drug‐induced angioedema without urticaria: prevalence and clinical features

Background Angioedema without urticaria can be caused by drugs. The purpose of our study was to assess the prevalence and clinical features of patients with drug‐induced angioedema without urticaria. Methods This study retrospectively reviewed case records at Siriraj Hospital, between January 2007 and December 2008. Patients aged at least 15 years were included. Results The prevalence of drug‐induced angioedema without urticaria among patients with adverse drug reactions was 2.3%/year. Non‐steroidal anti‐inflammatory drugs (NSAID) were the most common cause (50%), followed by antibiotics (20%). The commonest NSAID which induced angioedema were ibuprofen and diclofenac. The common sites were periorbital area (67.3%) and lips (27.6%). The median duration of suspected drug therapy before the development of angioedema was 1 day with the range of 10 min to 23 days. Conclusions Non‐steroidal anti‐inflammatory drugs and antibiotics were the most common drugs causing angioedema without urticaria. The duration of onset ranged from minutes to days. After stopping the suspected drugs, symptoms disappeared within 2–5 days in most patients.     

Intolerance reactions due to the selective cyclooxygenase type II inhibitors rofecoxib and celecoxib. Results of oral provocation tests in patients with NSAID hypersensitivity

Intolerance reactions due to the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) are frequent emergencies. It is thought that inhibition of the isoenzyme cyclooxygenase type I (COX-1) is responsible for the common NSAID-associated adverse effects, whereas inhibition of COX-2 is mainly responsible for the therapeutic effects. The goal of our study was to estimate the frequency of intolerance reactions due to ingestion of the two newly approved selective COX-2 inhibitors, rofecoxib or celecoxib. In a sample of 13 patients who had previously documented NSAID hypersensitivity reactions to non-selective COX inhibitors, 2 patients (15.3%) showed intolerance reactions (2 of 9 patients with rofecoxib, 1 of 5 patients with celecoxib). These drugs cannot therefore be administered uncritically to patients with known NSAID hypersensitivity. Selective COX-2 inhibitors can only be used as alternative drugs in these patients after assessing their specific tolerability in a properly performed provocation test.     

Correlation among skin prick test, total and specific IgE UniCAP tests in atopic patients from Zagreb, Croatia

The correlation of pollen allergens, Dermatophagoides pteronyssinus and animal dender was assessed during a two-year period. Results of skin prick test, total and specific IgE UniCAP tests were compared in atopic patients (AP) with the following diagnoses: atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic bronchitis or asthma, allergic urticaria and angioedema. The study included total and specific IgE (in vitro) tests to allergen mixtures (grass, tree, weed) or to single allergens of Dermatophagoides pteronyssinus (Der p), cat and dog fur, feather, etc. Comparison of skin prick test with total and specific IgE UniCAP immunoassay was done in 173 patients, i.e. 107 female and 66 male atopic patients aged 9-76 years. Allergies were most commonly recorded in the 25-35 age group. Total IgE ranged from 8.63 kU/l to >4000 kU/l, with specific IgE ranging from class 1 to class 5. Skin prick test showed high correlation with specific IgE for grass and weed pollen in patients with repiratory allergy (50.28%). Good correlation among all three tests was quite frequently observed. The results suggest that the study should be continued using these three tests in further cases of atopic dermatitis.     

Skin tests in the diagnosis of eruptions caused by betalactams

The aetiologic evaluation of adverse cutaneous reactions to penicillin's is still not an easy problem to solve. Skin testing is usually earned out intradermally with benzylpenicilloyl polylysine (BPO-PPL) and minor determinant mixture (MDM), but these are often unsuitable for the detection of sensitivity to betalactam antibiotics. 101 selected subjects, with different cutaneous reactions to betalactams and with a clinical history of positive challenge, were skin tested (patch lest, prick test, intradermal test) with a standard betalactam series (amoxycillin, sodium penicillin G, ampicillin, bacampicillin, aztreonam, ceftriazone, BPO-PPL, MDM). 1 or more positive reactions to skin tests, mainly to intradermal tests, were observed in 47.5% of the subjects studied, especially in those with maculopapular eruptions, urticaria/angioedema and drug reactions caused by ampicillin and amoxycillin. Cross-sensitivity was demonstrated in 22.8% of cases and was due almost solely to the semi synthetic penicillin. Finally, to increase the yield in detecting positive patients, it is necessary that ampicillin and amoxycillin be tested in addition to major and minor determinants.     

Acute phase inflammatory markers in patients with non‐steroidal anti‐inflammatory drugs (NSAIDs)‐induced acute urticaria/angioedema and after aspirin challenge

Background Active chronic urticaria, identified as a mast cell‐ and basophil‐dependent inflammatory disorder of the skin is able to elicit acute phase response (APR). However, systemic inflammatory response in different types of urticaria is poorly characterized. Aim To determine APR pattern in a clearly defined group of patients with acute urticaria and/or angioedema – induced by NSAIDs. Methods Plasma IL‐6 and serum C‐reactive protein (CRP) concentrations were studied in 17 patients with NSAIDs‐induced acute urticaria/angioedema (NSAIDsAU) and in 20 healthy controls. Eleven patients who used NSAIDs were presented at the emergency room with acute urticaria/angioedema while the remaining six manifested the symptoms during the aspirin challenge test. Patients were examined in a dynamic manner: during the acute phase, and next, after subsidence of the symptoms. Results CRP and IL‐6 concentrations increased significantly in patients with NSAIDsAU as compared with their asymptomatic period and the healthy subjects. In addition, NSAIDsAU patients showed elevated concentration of the biomarkers following aspirin provocation with the baseline values recovered in the asymptomatic period. Conclusion These results indicate that an acute systemic inflammatory response is activated in patients with NSAIDs‐induced urticaria and/or angioedema. The study supports the evidence proving that up‐regulation of CRP and IL‐6 in urticaria/angioedema does not necessarily reflect any concomitant infection or other inflammatory processes, but may be due to the disease itself.     

Drug skin tests in cutaneous adverse drug reactions to pristinamycin: 29 cases with a study of cross-reactions between synergistins

The present study was made to determine the value of drug skin tests in patients with cutaneous adverse drug reactions (CADRs) due to a synergistin (pristinamycin) and to determine the frequency of cross-reactions between synergistins. 29 patients were referred during the onset of the CADR due to pristinamycin: 18 with maculopapular rash, 9 erythrodermas, 1 angioedema and 1 Stevens–Johnson syndrome. They all had patch tests with pristinamycin and, in most cases, with other synergistins [virginiamycin and dalfopristin–quinupristin (DQ)], prick tests (10 cases) and intradermal tests (IDT) (5 cases). Skin tests with synergistins were positive in 27 cases, patch tests with pristinamycin in 20/29 cases (69%), prick tests with pristinamycin in 3/9 cases on immediate (1 case) or on delayed (2 cases) readings, and IDT with DQ in 4/5 cases. Cross-reactions between synergistins occurred in 9/22 with virginiamycin and in 7/8 cases with DQ. Skin tests with synergistins are useful in investigating CADR due to pristinamycin. Synergistins are composed of 2 chains (1 depsipeptide and 1 macrocyclic lactone) with many structural analogies between all synergistins. According to the chemical structures and our results, it seems advisable to avoid all synergistins in patients with CADR due to pristinamycin.     

慢性湿疹和慢性荨麻疹患者1145例过敏原检测结果分析

目的了解沿海地区慢性湿疹和慢性荨麻疹患者的过敏原分布情况,探讨预防过敏性疾病发生的有效措施。方法采用皮肤点刺试验,对沿海地区1145例慢性荨麻疹和慢性湿疹患者进行过敏原检测。结果慢性荨麻疹和慢性湿疹患者的主要致敏原分别为牛奶(54.61%)、鸡蛋(52.34%)和鸡蛋(60.04%)、粉尘螨(58.97%)。东港市本地父母辈和子女辈的过敏原皮肤反应强度指数差异无统计学意义(P>0.05);父母辈为内地居民,而子女辈出生于东港市的二代之间对鱼虾蟹贝等海产品皮肤反应强度指数差异有统计学意义(P<0.001)。复习国内几个代表地区的过敏原检测情况,发现与本研究结果有相同趋势。结论沿海地区慢性荨麻疹和慢性湿疹患者的过敏原中鱼虾等海产品呈低敏感性,提示早期接触过敏原对预防过敏反应发生有重要意义。     

Angioödem

Angioedema can be a symptom of anaphylaxis; it may be more hazardous that the circulatory collapse in otherwise healthy patients. Angioedema can be part of IgE- and histamine-mediated allergic reactions or part of NSAID-induced hypersensitivity with disturbances in arachidonic acid metabolism. If angioedema occurs without urticaria or other symptoms of anaphylaxis, it is usually mediated by increased bradykinin synthesis (HANE, EANE) or reduced metabolism (ACE inhibitors). These observations have led to new therapeutic approaches in HANE. Icatibant is a bradykinin-receptor-2 antagonist and blocks bradykinin-induced angioedema in HANE. How applicable this will be to ACE-inhibitor angioedema remains to be seen.     

In vitro release of interferon-gamma and macrophage migration inhibition factor in drug-induced urticaria and angioedema

T-cells are involved in the pathogenesis of cutaneous drug reactions. T-cell phenotype and cytokine release pattern in rivo and in vitro might correlate with the type of immune response involved in cutaneous drug reactions. In vitro release of interferon-gamma and macrophage migration inhibition factor (MIF) from peripheral blood lymphocytes, following in vitro challenge with the suspected unmodified drugs, was studied in 12 patients with drug-induced urticaria and/or angioedema and in two group-matched controls. The occurrence of positive interferon-gamma and MIF responses was significantly higher in patients with drug-induced urticaria and/or angioedema than in controls. The sensitivity and specificity of the interferon-gamma test (50% and 92%, respectively) were similar to that of the MIF test (58% and 96%, respectively). Percentage agreement between both tests was 80.9 (kappa = 0.76). In vitro release of interferon-gamma and MIF in drug-induced urticaria and/or angioedema suggests a drug-specific immune response, and may implicate the drug as a possible inducer of the reaction.     

Safety of cyclooxygenase 2 inhibitors and increased leukotriene synthesis in chronic idiopathic urticaria with sensitivity to nonsteroidal anti-inflammatory drugs

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate various forms of urticaria by a nonallergic mechanism involving inhibition of cyclooxygenases. OBJECTIVES: To assess safety of cyclooxygenase inhibitors in patients with chronic idiopathic urticaria (CIU) and NSAID sensitivity and to evaluate a role of cysteinyl leukotriene metabolism and mast cell activation in sensitivity to NSAIDs in CIU. DESIGN: Aspirin challenge test followed by randomized, prospective, double-blind, placebo-controlled crossover trial with cyclooxygenase 2 inhibitors. SETTING: Tertiary referral center of a university hospital. PATIENTS: Thirty-six patients with CIU. INTERVENTIONS: Aspirin challenge test (up to 500 mg); randomized trial with rofecoxib (up to 37.5 mg) and celecoxib (up to 300 mg) in aspirin-sensitive patients. After completion of the trial, 7 patients received naproxen sodium (500 mg) as a positive control. MAIN OUTCOME MEASURES: Standardized skin examination, skin biopsy with mast cell count, urinary levels of leukotriene E4 (LTE4), and serum levels of mast cell tryptase. RESULTS: Aspirin induced skin eruption in 18 patients. Rofecoxib or celecoxib did not elicit skin eruption in any of the aspirin-sensitive patients. Patients with CIU had higher urinary excretion of LTE4 than healthy control subjects. Basal urinary levels of LTE4 and serum mast cell tryptase were increased in aspirin-sensitive compared with aspirin-tolerant patients. Severity and duration of aspirin-induced urticaria showed a positive correlation with urinary LTE4 excretion. Naproxen precipitated urticaria in 5 of 7 aspirin-sensitive patients and caused further increase in urinary LTE4. CONCLUSIONS: Cyclooxygenase 2 inhibitors do not induce urticaria in patients with CIU sensitive to NSAIDs. Sensitivity to NSAIDs in CIU is associated with overproduction of cysteinyl leukotrienes and mast cell activation and most likely depends on inhibition of cyclooxygenase 1.     

The usefulness of skin tests to prove drug hypersensitivity

BACKGROUND: Suspected drug hypersensitivity is common. Only a minority of cutaneous adverse drug reactions (CADRs) are allergic in origin and will reappear after the next exposure. Methods to confirm suspected CADRs are needed and skin testing could serve as one possibility. OBJECTIVES: To analyse the usefulness of skin tests in revealing drug allergy. The relevance of skin test results was evaluated with drug provocation studies. METHODS: During 1989-2001, 947 patients with a history of suspected CADR were examined with skin tests including patch tests (PTs) (826 patients), skin prick tests (SPTs) (935 patients) and photopatch tests (12 patients). The occurrence of positive and negative test reactions to different drugs was correlated with clinical history. Drug provocation was carried out in 246 patients. RESULTS: Antimicrobial drugs were suspected and tested most often. A positive PT reaction to one or more drug was seen in 89 of 826 (10.8%), most often to beta-lactams, clindamycin and trimethoprim. A positive SPT reaction was seen in 10 of 935 (1.1%) patients. Challenge was carried out in 17 patients with positive skin test results. Thirteen of 16 (81.2%) PT positives developed exanthema, three remained negative and one SPT-positive patient developed urticaria. Among skin test negatives, 207 of 229 (90.4%) challenges were negative and 22 of 229 (9.6%) were positive, 12 with exanthema, three with fixed drug eruptions and seven with urticaria. CONCLUSIONS: Skin testing, especially the PT, was a useful screening method to find a cause of CADR if the reaction was exanthema and if antimicrobial, cardiovascular or antiepileptic drugs were suspected. The SPT detected occasional positives with antimicrobials. In cases of fixed drug eruption, PTs performed at the earlier reaction site were useful. When skin tests are negative or dubious, oral challenge should be carried out to confirm the association.     

Exercise-induced anaphylaxis after ingestion of sandwich with soy containing canned tuna: case report

We report a case of a 17-year-old female adolescent who experienced an episode of exercise-induced anaphylactic reaction following ingestion of tuna sandwich (from soy containing canned tuna). Her medical history revealed that she had previously had one episode of urticaria after ingestion of sulfamethoxazole with trimethoprim and anaphylactic reaction after ingestion of sunflower nuts. Skin prick tests and specific immunoglobulin E antibody to tuna were negative, and to soy were positive. Treadmill exercise induced test in fasting state and 1 hour after a fresh tuna meal and meal not containing soy were negative. However, an exercise challenge test one hour after soy ingestion resulted in pruritus of hands, shoulders and back, urticarial lesions of the face and neck with angioedema of the lips and eyelids, hoarseness, tachycardia and anxiety.     

Pine processionary caterpillar as a new cause of immunologic contact urticaria

Nowadays, caterpillars are included among the agents that elicit contact urticaria by a non‐immunologic mechanism. Our objective was to find the rôle that an IgE‐mediated mechanism could have among patients with suspected contact urticaria from pine processionary caterpillars. 16 patients with suspected contact urticaria from this caterpillar were studied by prick testing and specific IgE detection by immunoblotting. 87% of the patients had a positive prick test and immunoblotting for caterpillar extract. In these allergic patients, the symptoms associated with urticaria were: angioedema (79%), conjunctivitis (36%) and severe anaphylaxis (14%). The most frequent localizations of the wheals were the neck (100%) and forearms (93%). Angioedema was more frequent on the eyelids (79%). The IgE‐immunoblot detected in the caterpillar extract several reactive bands, with apparent MWs from to 45 to 4kDa. A total of 5 major allergens were identified, but a band around 14kDa proved to be the dominant allergen. Sensitization to Thaumetopoea pityocampa was found to be the most important mechanism of airborne contact urticaria from this caterpillar. Low‐MW proteins are the main IgE binding components of crude caterpillar extract.     

皮肤点刺试验检测慢性荨麻疹变应原的临床意义

目的探讨皮肤点刺试验检测慢性荨麻疹变应原的临床意义。方法用20种不同的变应原进行皮肤点刺试验,生理盐水为阴性对照,组胺为阳性对照。结果292例慢性荨麻疹患者中,有210例为阳性反应,阳性率为71.92%,单个变应原中,以吸入性粉尘螨的阳性率为最高,达63.69%。结论皮肤点刺试验特异性高,为慢性荨麻疹患者寻找可能的变应原提供依据,并力求避免接触,以提高患者的生活质量。     

Immediate patent blue-induced hypersensitivity during sentinel node detection: The value of cutaneous tests

BACKGROUND: Patent blue is a blue dye commonly used for sentinel node detection in the management of melanoma and breast cancer. Immediate hypersensitivity reactions to patent blue such as blue urticaria, bronchospasm or anaphylactic shock are not rare, being seen in 0.8 to 2.8% of patent blue-treated patients. PATIENTS AND METHODS: We report three cases of anaphylactic shock and two cases of urticaria developed after injection of patent blue in the context of sentinel node detection in breast cancer patients. Immediately after surgery, two patients developed generalized urticaria followed by circulatory collapse requiring resuscitation. The third patient presented massive anaphylactic shock without cutaneous or respiratory signs. Blue urticaria without haemodynamic disturbance was seen in the latter two patients. Prick tests using patent blue were positive for the three patients with positive intradermal reactions (1/10,000 dilution) in all patients. DISCUSSION: These observations underline the severity of patent blue-induced shocks with delayed onset, since they are often observed at the end of surgery. While the mode of sensitization is poorly understood, food and textile dyes are thought to play a role. Skin prick tests provide a simple and reliable method of diagnosing these events. There is a real risk of late anaphylactic shock during sentinel node detection using patent blue and discussion is needed concerning alternative methods of sentinel node detection.