Naproxen-Induced Leukocytoclastic Vasculitis

Cutaneous reactions to non-steroidal anti-inflammatory drugs (NSAIDs) are rare in spite of their wide use. Only a few cases of hypersensitivity angiitis related to naproxen have been described. We report the case of a 62-year-old woman in whom leukocytoclastic skin vasculitis, peripheral neuropathy and nephritis developed after a short naproxen treatment, and gradually regressed after discontinuation of the drug and under glucocorticoid therapy. In the light of the relevant literature, the clinical and laboratory features of this reversible condition are described. Received: 16 June 1999 / Accepted: 1 December 1999     

ANTIRHEUMATIC MEDICATION DURING LACTATION

All nonsteroidal anti-inflammatory drugs (NSAIDs) and antirheumaticdrugs are likely to be distributed into human milk to some extent;whether they are detected is a function of the assay sensitivity.For minimal infant exposure, the ideal drug for lactating womenis one which (a) has a short half-life, (b) is found in minimalquantities in human milk and (c) has inactive metabolites whichalso are present only in small amounts. In order to reduce thequantity of drug presented to the child, the drug should betaken by the mother at the time of breast-feeding with the nextfeed occurring after a time period equivalent to one half-lifeof the drug. Using the above-mentioned criteria, the choice of NSAIDs wouldbe between a short half-life propionic acid derivative, withlittle biotransformation, such as ibuprofen or flurbiprofen.Diclofenac is also suitable. Gold salts and corticosteroidswould seem safe to prescribe. However, the infant should beclosely monitored if antimalarials are being used by lactatingwomen. KEY WORDS: Anti-rheumatic drugs, Lactation     

Can NSAIDs cause acute biliary pain with cholestasis?

Two patients had many acute episodes of biliary pain with elevated liver function tests 12-48 h after the last ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) (including paracetamol) alone or in combination with codeine. One had known intolerance to NSAIDs, but paracetamol had not been previously incriminated in the pathogenesis of the attacks. In this patient the combined use of paracetamol and codeine probably also increased the severity of the episodes. We conclude that in some patients in whom endoscopic cholangiography is normal, biliary pain and abnormal liver function tests could be the result of NSAIDs. A thorough drug history is required in such cases.     

Oral drug challenges in non-steroidal anti-inflammatory drug-induced urticaria, angioedema and anaphylaxis

Background: Urticaria, angioedema and anaphylaxis are common adverse reactions to non‐steroidal anti‐inflammatory drugs (NSAIDs). Aim: To investigate the clinical characteristics of NSAID‐induced acute hypersensitivity reactions with structured oral drug challenges. Methods: Patients with NSAID‐induced urticaria, angioedema or anaphylaxis were challenged with either the homologous NSAID to confirm diagnosis or a heterologous NSAID to investigate cross‐reactivity. Data were analysed retrospectively and supplemented by a telephone questionnaire. Results: Sixty‐eight patients (mean age 48.3, 53 females) reported a total of 75 instances of NSAID‐induced reactions of which 64% were purely cutaneous and 36% were systemic anaphylaxis. Ibuprofen was the most frequent cause of reactions (35%), however, diclofenac was the most frequent cause of anaphylaxis (48%). Seventeen out of 40 (43%) homologous NSAID challenges were positive; presentation with anaphylaxis or reaction to diclofenac predicted a positive challenge. Only 7 of 28 (25%) of heterologous NSAID challenges were positive. Structured challenges enabled us to identify 23 (34%) patients with selective reactivity to a single NSAID, 19 (28%) patients with cross‐reactivity to multiple NSAIDs and 23 (34%) patients in whom NSAID hypersensitivity was not reproduced. Selective reactors presented most often with anaphylaxis and some had a background of beta‐lactam antibiotic allergy. Cross‐reactive patients often had a background of chronic urticaria and presented with milder reactions. Conclusion: In the absence of a reliable in vitro test, structured drug challenges allow identification of selective and cross‐reactive NSAID hypersensitivity syndromes. NSAID‐induced anaphylaxis is often associated with selective hypersensitivity and patients may not need to avoid other NSAIDs.     

Flurbiprofen Axetil,Nasal Polyps,and Status Asthmaticus: An Unusual Case Report

Introduction. Herein, we report a case of life-threatening status asthmaticus in a young male presented with nasal polyps but without any history of anaphylaxis or asthma. Discussion. The patient had normal results from preoperative respiratory systemic examinations. The postoperative asthma, which started after an infusion of nonsteroidal anti-inflammatory drugs (NSAIDs), was severe and difficult to manage. A relationship between the NSAID infusion and the asthma attack was indicated. Flurbiprofen axetil, a nonselective COX2 inhibitor, is most likely the causative agent in this case, although there are no prior reports of asthma caused by this agent. Conclusion. We concluded that flurbiprofen axetil evoked severe bronchospasm in this case. Patients who are sensitive to flurbiprofen axetil will usually react to other NSAIDs; therefore, other ordinary NSAIDs should be used with caution in hypersensitive patients. An intranasal ketorolac challenge in individuals with nasal polyps, which is a novel and safe alternative to aspirin challenge, may be recommended to rule out aspirin-exacerbated respiratory disease, prior to the systemic administration of NSAIDs.     

Delayed hypersensitivity to hydroxychloroquine manifested by two different types of cutaneous eruptions in the same patient

Hydroxychloroquine (HXQ) sulphate is a synthetic antimalaria drug that is widely used in rheumatology due to its immunosuppressive properties. Delayed-type sensitization to this drug is rare. A 47-year-old woman diagnosed with HLA B27 ankylosing spondylitis was treated with HXQ for 22 days and had to discontinue the drug due to gastric intolerance. Five days later the patient developed erythema multiforme (EM) with an extensive and unusual distribution. Patch test with 10% HXQ in DMSO were positive at 48 hours. Eight days later a generalized pruriginous erythematous papular exanthema developed, and a skin biopsy was obtained. The first reaction was EM. Patch-testing elicited systemic eczematous contact dermatitis. We report two different clinical patterns of delayed hypersensitivity in the same patient and with the same drug.     

Basophil activation test for the in vitro diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity.

There is need for an in vitro diagnostic test for hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). The purpose of this study was to assess the reliability of one such diagnostic, the basophil activation test. Forty-three drug hypersensitive patients referring several immediate reactions (anaphylaxis, urticaria, angioedema, asthma, and rhinoconjunctivitis) to one or more NSAIDs and 29 controls participated. Using the Basotest commercial kit, 63 determinations were performed with the drugs implicated in the adverse reactions (ASA, ibuprofen, metamizol, diclofenac, paracetamol, and ketorolac). In 16 patients additional determinations were made with other chemically unrelated NSAIDs. Forty-two determinations were made for controls. The analysis was performed by flow colorimetric cytometry and double staining with the monoclonal antibodies anti-IgE and anti-CD63. A Basophil Activation Index (percentage of activated basophils after allergen stimulation/percentage of basally activated basophils) of two or more was considered a positive result. Specificity of 100% and sensitivity of 42.85% were achieved. The positive predictive value was 100%, and the negative predictive value was 53.84%. In 35.29% of intolerant patients there was a positive reaction to at least two drugs implicated in adverse reactions, and in 27.27% of these patients there was a positive reaction to other chemically unrelated NSAIDs. The basophil activation test is useful for the in vitro diagnosis of NSAID hypersensitivity, providing good specificity and positive predictive value and diagnostic reliability in the assessment of NSAID intolerance.     

Anticonvulsant drug hypersensitivity.

BACKGROUND: Cutaneous adverse reactions are frequently described with anticonvulsant drugs, especially with aromatic drugs such as carbamazepine, phenytoin, and phenobarbital. Patch tests could be useful for diagnosing this clinical picture. Hypersensitivity to several anticonvulsant drugs is common but unpredictable. MATERIAL AND METHODS: 15 patients from our allergy section, suffering from anticonvulsant skin allergy, were included. We describe their analitic alterations, responsible drugs, and anticonvulsants tolerated, the results of patch tests with anticonvulsant drugs (5% pet. and aq.), and skin biopsies wherever carried out. RESULTS: 23 adverse skin reactions with different anticonvulsant drugs occurred in the 15 patients: 13 resulted in fever and generalized cutaneous rash, 7 patients suffered only from cutaneous rash. There was one case of palpable purpura, one of erythema multiforme (target lesions), and another one suffered only cutaneous pruritus. Eosinophilia was found in 5 cases. Liver enzymes were elevated in 9 (7 of whom suffered fever and cutaneous rash). The responsible drugs were carbamazepine (8 adverse reactions), phenytoin (5), lamotrigine (4), phenobarbital (4), sodium valproate (1), and felbamate (1). The drugs tolerated were sodium valproate (6 patients), topiramate (4), vigabatrin (2), lamotrigine (1), clonazepam (1), and gabapentin (1). We found 12 positive patch tests: 6 with carbamazepine, 3 with phenytoin and, 1 each with lamotrigine, sodium valproate and phenobarbital. Skin biopsies were carried out in 5 patients, 4 of whom showed some characteristic findings of erythema multiforme (lymphocytic exocytosis, dyskeratotic cells, vacuolation of basal cells and pigmentary incontinence) and the other one showed a typical leucocytoclastic angitis. CONCLUSIONS: The cutaneous adverse reactions more frequently seen in our allergy section because of anticonvulsant drugs are rashes with fever. Eosinophilia and elevated levels of liver enzymes are frequently associated. This clinical picture is called "anticonvulsant hypersensitivity syndrome." The drugs implicated most frequently are carbamazepine and phenytoin. Hypersensitivity to more than one drug was variable and unpredictable. The best-tolerated drug was sodium valproate, but it was not tolerated by a patient with phenytoin and carbamazepine hypersensitivity. Patch tests are useful for diagnosing anticonvulsant hypersensitivity. The most frequently findings in the skin biopsies were typical of erythema multiforme.     

Discrepancies in the diagnosis and classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions in children

Background

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently encountered in daily clinical practice. The aim of this study was to determine the confirmation rates, risk factors of NSAID hypersensitivity in children and to try to classify them with a standardized diagnostic protocol.

ANTIRHEUMATIC MEDICATION IN PREGNANCY

Drug effects on fetal physiology as well as possible teratogenesisneed to be considered before prescribing for women of child-bearingage. All nonsteroidal anti-inflammatory drugs (NSAIDs), becauseof their suppression of prostaglandin synthesis, may prolonggestation and labour. Aspirin is also associated with an increasedrisk of ante- and post-partum haemorrhage. Indomethacin maybe teratogenic in humans and like aspirin may induce pulmonaryhypertension in the neonate. To reduce the physiological alterationsinduced by NSAIDs, short-half-life drugs such as ibuprofen,flurbiprofen or ketoprofen should be used at the maximally tolerabledosage interval. Gold salts and corticosteroids show littlehuman evidence of teratogenicity although the largest possibledosage interval of gold should be used. D-Penicillamine maybe teratogenic thus it should not be commenced during pregnancyand if a patient becomes pregnant whilst receiving the drug,it should be slowly withdrawn or the dosage reduced. 4-Aminoquinolinecompounds are contra-indicated in pregnancy. KEY WORDS: Antirheumatic drugs, Pregnancy     

Safety of celecoxib in patients with adverse skin reactions to acetaminophen (paracetamol) and other non-steroidal anti-inflammatory drugs.

BACKGROUND: Acetaminophen (paracetamol-P) is a widely used analgesic-antipyretic drug with no anti inflammatory effects and its rate of adverse hypersensitivity reactions is very low. On the contrary non-steroidal anti-inflammatory drugs (NSAIDs) are commonly involved in side effects. Celecoxib (CE) is a novel drug, with high selectivity and affinity for COX-2 enzyme. OBJECTIVE: We evaluated the tolerability of CE in a group of patients with documented history of adverse cutaneous reactions to P and to classic NSAIDs. METHODS: We studied 29 patients with hypersensitivity to P and classic NSAIDs. The diagnosis of P-induced skin reactions was based on in vivo challenge. The placebo was blindly administered at the beginning of each challenge. After three days, a cumulative dosage of 200 mg of CE in refracted doses was given. After 2-3 days, a single dose of 200 mg was administered. All patients were observed for 6 hours after each challenge, and they were controlled again after 24 hours to exclude delayed reactions. The challenge was considered positive if one or more of the following appeared: erythema, rash or urticaria-angioedema. RESULTS: No reaction was observed with placebo and twenty eight patients (96.5 %) tolerated CE. Only one patient developed a moderate angioedema of the lips. CONCLUSION: Only one hypersensitivity reaction to CE was documented among 29 P-intolerant patients. Thus, we conclude that CE is a reasonably safe alternative which can be used in subjects who do not tolerate P.     

非甾体类抗炎药所致荨麻疹和血管性水肿

非甾体抗炎药(nonsteroidal anti-inflammatory drugs,NSAIDs)较易引起药物不良反应,其中大部分是由于个体对NSIADs高敏感所致,最常见表现为荨麻疹和(或)血管性水肿。本文将针对NSAIDs所致的荨麻疹和血管性水肿分类、表现、诊断及处理原则进行阐述。     

心血管手术术后三种静脉镇痛方法疗效与安全性研究

目的探讨氟比洛芬酯与曲马多分别复合芬太尼用于心血管手术围术期的镇痛效果及副作用,及对细胞因子的影响。方法150例择期行正中开胸心血管手术的患者,随机双盲对照法分为3组：氟比洛芬酯组（FF）,曲马多组（QF）,芬太尼组（F）。分别于深静脉通路建立后和缝心包时给予研究药物,FF组为氟比洛芬酯1mg／kg,QF组为曲马多2mg／kg,F组为空白脂肪乳5ml;手术结束时连接静脉恒速镇痛泵,内装研究药物与脂肪乳混合液100ml,流速2ml／h,FF组为氟比洛芬酯200mg和芬太尼1．0mg,QF组为曲马多700mg和芬太尼1．0mg,F组为芬太尼2．5mg。分别于围术期各观察点记录患者的VAS评分、恶心评分,镇静评分,胸液量,初醒时间,拔除气管插管时间,镇痛效果与副作用,是否追加镇痛药物,ICU停留时间,出院时间。其中每组随机抽取30例病例,分别于深静脉通路建立后（T0）,缝心包时（给与研究药物之前,T1）,术后4h（T2）,20h（T3）,24h（T4）抽取静脉血,检测细胞因子IL-1,IL-10,TNF-,PGE2。结果（1）VAS评分三组间相似,但术后追加镇痛药物F组明显高于其余两组（P〈0．05）;（2）F组恶心评分较高（P〈0．05）,镇静评分,呕吐、皮肤瘙痒、排尿困难等副作用的发生率三组患者无明显差异（P〉0．05）;（3）T1-T4,F组IL-1较哟升高明显,且明显高于FF,QF组（P〈0．05）;术后各组各时间点IL-10,PGE2较哟升高明显,F组升高持续时间较长（P〈0．05）;F组TNF-在T2,T4较T0明显升高（P〈0．05）,T2时明显高于FF,QF组;（4）初醒时间,拔出气管插管时间,ICU停留时间,24h胸液量,肝肾功能等三组患者无明显差异。结论静脉给予氟比洛芬酯或曲马多复合芬太尼的镇痛方法可安全、有效的应用于心血管手术术后镇痛,减少阿片类药物的用量,减轻术后炎症反应。     

Severe oral symptoms after the use of an oral solution containing ketoprofen in two NSAIDs-sensitive patients.

Cutaneous application of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen has been reported to induce contact dermatitis. However, there is no report of intraoral symptoms after the use of solutions containing this drug. In this report we describe two cases of severe intraoral symptoms after the use of a gargle containing ketoprofen in two patients with NSAIDs hypersensitivity. The patients underwent diagnostic procedures 6 months after the episodes of intraoral symptoms. Procedures included skin prick test for inhalant and food allergens, and total- and specific-IgE determinations to evaluate the presence of atopy. A single-blind, placebo-controlled challenge with different dilutions (1/1000, 1/100, 1/10, and 1/1) of ketoprofen oral solution was carried out by a modified version of a standardized protocol. We used the same commercial solution without the drug as placebo. Diagnostic procedures failed to demonstrate allergic sensitization to the common inhalant and food allergens. Both patients experienced a slight intraoral itching and edema of the lips a few minutes after the intraoral use of 1/100 dilution of active drug. Our cases suggest that the contact of an oral solution containing ketoprofen with oral mucosa may induce locally severe oral manifestations. Patients with NSAIDs sensitivity should be warned on the potential risk of using an oral solution containing this class of drugs.     

Inhibition of bone resorption in vitro and prevention of ovariectomy‐induced bone loss in vivo by flurbiprofen nitroxybutylester (HCT1026)

Objective

Inhibitors of prostaglandin production, such as nonsteroidal antiinflammatory drugs (NSAIDs), and pharmacologic nitric oxide (NO) donors, such as organic nitrates, have been suggested to protect against bone loss in both humans and experimental animals. Recently, a new class of nitrosylated NSAID (known as NO‐NSAIDs) has been developed, which combines the properties of a NO donor with those of a cyclooxygenase (COX) inhibitor. This study investigated the effects of one of these compounds, flurbiprofen nitroxybutylester (HCT1026), on bone metabolism in vitro and in vivo.

Methods

The effects of HCT1026 on osteoclast formation and resorption were determined in vitro using cocultures of primary mouse osteoblasts and osteoclasts. The effect of HCT1026 in vivo was assessed using a mouse model of ovariectomy‐induced bone loss.

Results

HCT1026 was significantly more efficacious than the parent compound, flurbiprofen, at inhibiting osteoclast formation and bone resorption in vitro, and these effects could not be reproduced by combinations of flurbiprofen with a variety of NO donors. Studies in vivo showed that HCT1026 protected against ovariectomy‐induced bone loss by inhibiting osteoclastic bone resorption, whereas flurbiprofen at similar concentrations was ineffective.

Conclusion

These data indicate that HCT1026 is a potent inhibitor of bone resorption in vitro and protects against ovariectomy‐induced bone loss in vivo by a novel mechanism that appears to be distinct from its NO donor properties and from its inhibitory effects on COX activity. We conclude that HCT1026 may be of clinical value in the prevention and treatment of inflammatory diseases such as rheumatoid arthritis, which are characterized by joint inflammation as well as periarticular and systemic bone loss.

     

Unilateral conjunctival chemosis as a unique symptom of nonsteroidal anti-inflammatory drug intolerance.

Patients with nonsteroidal anti-inflammatory drug (NSAID) intolerance usually have cutanous-mucosal or/and respiratory symptoms. We report the case of a patient who developed several episodes of left-eye conjunctivitis, manifested as conjunctival chemosis, with no other symptoms, after taking metamizole and other unidentified NSAIDs. We performed both a single blind placebo-controlled oral challenge test and conjunctival challenge test with different NSAIDs. The single blind placebo-controlled oral challenge was positive to ketoprofen and diclofenac. The conjunctival challenge with diclofenac and flurbiprofen was negative. The patient tolerated celecoxib and nabumetone. We believe this to be an exceptional case of NSAID intolerance as conjunctival chemosis has not hitherto been included in any of the classic types of pseudoallergic reactions.     

Urticaire aux AINS : une prise en charge similaire à celle de l’urticaire aiguë

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common providers of immediate hypersensitivity reactions. Among these reactions, isolated acute urticaria is the most common clinical feature with a non-allergic origin. It is a pharmacological side effect resulting from the alteration of arachidonic acid metabolism induced by NSAIDs. Diagnosis of this acute urticaria is clinical, requiring no allergy testing. Currently, the recommended therapeutic management of NSAID urticaria is the avoidance of all NSAID with COX-1 inhibitor activity (even if when reintroduced, they are most often well tolerated) and the use of selective COX-2 inhibitors. This review focuses on urticaria reactions to NSAIDs, which are simple to manage.     

Symptoms in patients with peptic ulcer and hematemesis and/or melena related to the use of non-steroid anti-inflammatory drugs

One hundred and seven consecutive patients with hematemesis and/or melena and a diagnosis of duodenal, gastric, or esophageal ulcers were interviewed immediately before or after endoscopy about the use of non-steroid anti-inflammatory drugs (NSAIDs) and symptoms before the hemorrhage. If the patients admitted no symptoms of abdominal pain or discomfort, nausea, vomiting, or heartburn, they were classified as having no ulcer symptoms before the hemorrhage. Patients who had not taken NSAIDs during the last 48 h before the hemorrhage were classified as not having taken NSAIDs. Significantly fewer patients had ulcer symptoms in the group that had used NSAIDs than in the other group (p less than 0.01). This may be interpreted as a possible masking effect by NSAIDs on ulcer symptoms. Physicians and patients should be aware of this possible effect of NSAIDs.     

Pathogenic importance of intestinal hypermotility in NSAID-induced small intestinal damage in rats

BACKGROUND/AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin produce damage in the small intestine as a major adverse reaction. We examined the effect of various NSAIDs on intestinal motility and investigated the pathogenic importance of motility changes in the intestinal ulcerogenic response to indomethacin in rats. METHODS: Animals without fasting were given various NSAIDs (indomethacin 10 mg/kg, diclofenac 40 mg/kg, flurbiprofen 20 mg/kg, naproxen 40 mg/kg) s.c., and in the case of indomethacin, the following parameters were examined in the small intestine 24 h later; the lesion score, the number of enterobacteria and myeloperoxidase (MPO) as well as inducible nitric oxide (iNOS) activity. Intestinal motility was monitored as intraluminal pressure recordings using a balloon under anesthesia. RESULTS: All NSAIDs tested decreased mucosal PGE(2) levels and produced hemorrhagic lesions in the small intestine, accompanied by intestinal hypermotility. As representative of NSAIDs, indomethacin also increased the extent of enterobacterial invasion and MPO as well as iNOS activity before the occurrence of intestinal damage, and the hypermotility response was observed earlier than the onset of any other event caused by this agent. The intestinal lesions induced by indomethacin were prevented by either supplementation with dmPGE(2), inhibition of bacterial invasion with ampicillin or inhibition of iNOS activity with aminoguanidine, while the hypermotility response was prevented by dmPGE(2) only. In addition, the observed effects of dmPGE(2) were all mimicked by atropine when the intestinal hypermotility was suppressed by this agent. CONCLUSION: These results suggest the pathogenic importance of intestinal hypermotility in the intestinal ulcerogenic response to NSAIDs in rats and show that this event is critical for the occurrence of enterobacterial invasion under PG deficiency, followed by various inflammatory changes and damage in the mucosa. This study also suggests that the antispasmodic drug is protective against NSAID-induced intestinal lesions.     

Pulmonary disease due to antirheumatic agents

Drug-induced lung disease presents several diagnostic and therapeutic problems to the clinician. This is especially true in the case of lung disease associated with antirheumatic agents in which pulmonary disease may be due to the underlying disorder. Unfortunately, no specific markers exist to differentiate drug-induced lung disease from other pathologic processes. In addition, the numerous drugs often used simultaneously or in close sequence in rheumatic disorders make assignment of toxicity to a specific agent difficult. Six groups of drugs used as anti-inflammatory/antirheumatic agents have been discussed in association with pulmonary damage penicillamine, gold, methotrexate, salicylates, NSAIDs, and colchicine. The major clinical syndromes ascribed to these drugs include hypersensitivity pneumonitis and chronic alveolitis/fibrosis (penicillamine, gold, methotrexate, NSAIDs), pulmonary-renal syndrome (penicillamine), bronchiolitis obliterans (penicillamine, gold), and noncardiogenic pulmonary edema (salicylates, colchicine). Unfortunately, treatment options remain limited. Withdrawal of the offending drug and supportive care are the mainstays of therapy. In cases in which active inflammation causes significant derangement of gas exchange, corticosteroids are warranted. More aggressive management using immunosuppressive drugs has been recommended in cases of refractory PABO and PAGS, but these recommendations are at present based only on isolated case reports.