Cutaneous drug eruption with two antihistaminic drugs of a same chemical family: cetirizine and hydroxyzine

BACKGROUND: H1-antihistamines are widely used to relieve symptoms of allergic disorders. A few skins reactions to H1-antihistamines have been described in the literature. We report the first case of cutaneous drug eruption as fixed drug eruption with 2 antihistamines of the same chemical family: cetirizine and hydroxyzine. CASE REPORT: A 73 year-old man was admitted because of a third cutaneous eruption with the same morphologic features of the same sites as before. The first and second eruption appeared after 4 hours of cetirizine intake, the third eruption appeared after 4 hours of hydroxyzine intake. Healing was obtained after stopping the medication. Histology showed induced drug reaction. Patch tests with cetirizine and hydroxyzine were negative, except false positivity with dimethylsulfoxide vehicles. DISCUSSION: The diagnosis of cutaneous drug eruption as non pigmenting fixed drug eruption related to cetirizine and hydroxyzine was retained. Allergy to both H1 antihistamines can be explained by the fact that they've got the same chemical node that is piperazine, and by the fact that cetirizine is the main metabolite of hydroxyzine. Oral test provocation was omitted because the patient had already reexposed himself to the drugs. To identify the drug responsible for fixed drug eruption, peroral provocation tests are the most valuable method, but carry the risk of a strong reaction. Some authors use patch tests, but their positivity is inconstant. Their interest in fixed drug eruption is undergoing assessment.     

Cutaneous drug eruption from cetirizine and hydroxyzine

Topical application of the antihistamines commonly leads to sensitization for patients, but skin reactions provoked by their systemic use are very rare. The antihistamines cetirizine and hydroxyzine are piperazine derivatives, on the structural basis of an ethylenediamine, but the cross-reactions between the 2 have rarely been reported. A 44-year-old man visited because of the generalized morbilliform eruptions with pruritus over his whole body, after intake of hydroxyzine (Ucerax) and azelastine (Azeptine), administered during a 2-day period for chronic urticaria. Previously, he had presented the same cutaneous reactions after oral administration of cetirizine (Lotec). Oral challenge tests performed with cetirizine and hydroxyzine led to the same cutaneous reactions. He was given the diagnosis of drug eruption from cetirizine and hydroxyzine, which suggests that there were cross-reactions among cetirizine, hydroxyzine, and ethylenediamine.     

Multiple H1-antihistamine-induced urticaria

H₁‐antihistamines are widely used in the treatment of various allergic diseases. Particularly, a cornerstone of the management of chronic idiopathic urticaria is treatment with H₁‐antihistamines. However, a few cases of H₁‐antihistamine‐induced urticaria have been reported. A 34‐year‐old woman presented with a 4‐month history of recurrent urticaria, which was prominently exacerbated by the administration of H₁‐antihistamines. The patient consented to a provocation test of fexofenadine among drugs including cetirizine and hydroxyzine, which were suspected of inducing severe symptoms in episodes. One hour after challenge with 12 mg fexofenadine (one‐fifth of the therapeutic dose), a urticarial reaction rapidly developed on nearly the entire body with remarkably increased levels of plasma histamine (190 nmol/L) and plasma leukotriene B4 (150 pg/mL). In challenge tests with other antihistamines, generalized urticaria occurred 5 and 1 h after intake of 10 mg loratadine and 10 mg bepotastine, respectively, whereas challenges with chlorpheniramine, mequitazine and azelastine were all negative. Skin prick tests with H₁‐antihistamines used in the challenges were all negative, indicating that the urticarial reactions after challenges with the causative drugs might not be immunoglobulin E‐mediated. Among the causative drugs in our case, cetirizine and hydroxyzine are the piperazine derivatives, whereas fexofenadine, bepotastine, ebastine and loratadine are the piperidine derivatives. The chemical structures of both derivatives are very similar. Therefore, in this case, H₁‐antihistamine‐induced urticaria may have been due to cross‐reactivity between metabolites of these drugs, but not to drugs before metabolization. Hypersensitivity to H₁‐antihistamines should be considered when urticarial lesions worsen after H₁‐antihistamine treatment.     

Adverse Reaction to Prednisone in a Patient with Systemic Lupus Erythematosus

Oral corticosteroids are the main therapeutic choice for systemic lupus erythematosus (SLE). Adverse reactions to systemic corticosteroids rarely occur and the etiology is unclear in most cases. A 14-year-old girl with newly diagnosed SLE developed a pruritic bullous eruption while on prednisone. The patient had been treated successfully in the hospital with intravenous methylprednisolone. In preparation for discharge, the steroid preparation was changed to prednisone to which the patient reacted with a development of new crops of bullous lesions. Skin biopsy specimens of lesional areas showed a bullous eruption consistent with erythema multiforme. The patient underwent immediate and delayed hypersensitivity tests. Intradermal and patch tests to liquid prednisone were positive. The patient was discharged on oral methylprednisolone and has not had recurrence of the skin lesions. In conclusion, a case of prednisone sensitivity in a patient with SLE is presented here. An alternative preparation, methylprednisolone, was used to successfully treat her underlying condition.     

Skin reactions to hydroxyzine

Sensitivity to histamine H1-antagonists has mainly been observed with phenothiazine and ethylenediamine, and is very rare with hydroxyzine. We report 3 cases of sensitization to hydroxyzine, which was prescribed to treat urticaria and atopic dermatitis. A generalized maculopapular eruption appeared shortly after taking the drug. Patch tests with Atarax® tablet were positive +++, and ++ or +++ with different dilutions of hydroxyzine. Patch tests with ethylenediamine, piperazrne and other antihistamines were negative: therefore, there is no cross-allergy. We believe these rapid systemic reactions to hydroxyzine after the initial dose may have been due to prior systemic sensitivity to this drug, which cannot be used topically. Allergy to antihistamines must be considered when cutaneous lesions worsen on such therapy.     

Fixed drug eruption to cetirizine with positive lesional patch tests to the three piperazine derivatives

BACKGROUND: The H1-antihistamine cetirizine, a piperazine derivative widely used in daily practice, is rarely the cause of cutaneous drug reaction. Nevertheless, four cases of fixed drug eruption (FDE) as a result of this drug have been described recently. We present the case of a 45-year-old woman with a multilocalized FDE following oral intake of cetirizine for allergic rhinitis. METHODS: Patch testing with hydroxyzine 1% and 10% in petrolatum (Chemotechnique), and with powdered Zyrtec (cetirizine) and Xyzal (levocetirizine) pills, prepared at 20% in water and at 20% in petrolatum, was performed in both residual lesions and healthy skin. RESULTS: Positive results (++) to these drugs (24 h occlusion and readings at days 2 and 3) were obtained in residual lesions only. These results allowed us to confirm the drug responsible for this FDE and to study cross-reactions between antihistamines of the same chemical family. CONCLUSIONS: To the best of our knowledge, this is the first report of FDE to cetirizine with positive patch testing to hydroxyzine, cetirizine, and levocetirizine. This case highlights the importance of patch testing in the study of cutaneous drug reactions, namely FDE.     

肿胀性红斑狼疮1例

患者女,33岁。面部出现肿胀性红斑3个月,发病前有牙龈肿痛。面部皮损组织病理检查示真皮浅层淋巴细胞浸润,网状层胶原束间有大量黏蛋白沉积。查抗核抗体、抗双链DNA、抗Sm、抗Ro/SSA、抗La/SSB抗体均为阴性。光敏试验显示皮肤对UVA和UVB有异常反应。诊断为肿胀性红斑狼疮。经外用17-α丁酸氢化可的松、硅油炉甘石霜(硅炉霜),口服泼尼松1mg/(kg·d)和羟氯喹8mg/(kg·d)治疗,皮损得到控制。     

Treatment of Urticaria

Urticaria is a cutaneous syndrome characterized by dermal edema (wheal) and erythema (flare) that blanches with pressure. The lesions typically last less than 24 hours and are usually pruritic. In 1983, Christensen and Maibach summarized the theory behind the use of histamine H₁ receptor antagonists (antihistamines) in clinical dermatology. These agents remain the mainstay of treatment for urticaria. This article reviews the medical literature on the effectiveness of antihistamines in urticarial syndromes, including acute, chronic idiopathic and the physical urticarias. Older antihistamines, such as chlorpheniramine and hydroxyzine, are effective in the treatment of urticarias, but they also have marked sedative and anticholinergic effects. Newer nonsedating antihistamines (second-generation antihistamines) have been developed that have reduced adverse effects because they do not cross the blood-brain barrier; these agents (acrivastine, cetirizine, loratadine, mizolastine, fexofenadine, ebastine, azelastine and epinastine) cause significantly less sedation and psychomotor impairment than their older counterparts. A review of the literature reveals that there are few studies which document the efficacy of second-generation antihistamines in the treatment of acute urticaria, a biologic entity that usually resolves within 3 weeks. We did not identify controlled studies that suggested superiority of any antihistamine in the treatment of acute urticaria. Loratadine or cetirizine, and possibly mizolastine, appear to be treatments of choice for chronic idiopathic urticaria. For symptomatic dermatographism, the combination of an antihistamine and an H₂ antagonist, e.g. chlorpheniramine and cimetidine, appears to be effective. Very few studies have been conducted on the use of antihistamines in the treatment of cold, cholinergic, and pressure urticaria. Antihistamines are the mainstay of urticarial therapy. This evidence-based review suggests that there are efficacy differences between newer, nonsedating antihistamines and older agents in some forms of the disorder. Clearly, further well-controlled clinical trials in larger numbers of patients are needed to clarify the role of these agents in the treatment of urticaria.     

Therapy of acute and chronic urticaria

Background The drug management of chronic urticaria can be divided into three approaches: (i) blockade of released histamine at the receptor sites; (ii) blockade of histamine release from mast cells; and (iii) blockade of other mediators and possible inflammatory and cellular components. The first approach is the most successful and widely used. It primarily involves the use of H₁-antihistamines, although tricyclic antidepressants and H₂-antihistamines also have a place. Treatments The usefulness of classic H₁-antihistamines, such as hydroxyzine, may be limited by side-effects (most notably, sedation). The four most widely used of the newer antihistamines are loratadine, terfenadine, astemizole and cetirizine. These antihistamines are significantly superior to placebo and have similar efficacies comparable with hydroxyzine. Novel agents and methods, including nifedipine, sulphasalazine and plasmapheresis have been tried with some success in refractory patients. Guidelines If acute cases are inadequately controlled, short-term oral corticosteroids may be added. Systemic corticosteroids are occasionally indicated for the management of severe acute urticaria, severe serum sickness, pressure urticaria or urticarial vasculitis, or to break the cycle of a resistant case, but have no place in regular therapy for chronic urticaria. For those with severe acute urticaria with signs of respiratory distress, possible treatments include subcutaneous epinephrine, systemic corticosteroids and intramuscular H₁-antihistamines. Patients with chronic urticaria inadequately controlled on H₁-antihistamines alone may benefit from the addition of a classic antihistamine, a tricyclic antidepressant or an H₂-antihistamine. A short course of systemic corticosteroids may help those with severe chronic refractory disease.     

Patch testing in fixed drug eruptions--a 20-year review

Background. The fixed drug eruption is a common adverse drug reaction. Clear identification of the culprit drug is not always possible in the clinical setting, and oral rechallenge may induce new lesions or severe reactions. Objectives. The main purpose of this study was to evaluate the diagnostic value of patch testing in establishing an aetiological diagnosis in fixed drug eruptions. Method. A retrospective analysis was conducted evaluating 52 patients (17M/35F, mean age 53±17 years) with clinical diagnoses of fixed drug eruptions submitted to patch tests in a 20‐year period in a Dermatology Department. Nonsteroidal anti‐inflammatory drugs (NSAID) were clinically suspected in 90.4% of the cases, followed by antibiotics (28.9%) and paracetamol (15.4%). Results. Patch tests on pigmented lesions were reactive in 21 patients (40.4%), 20 of those to NSAID (nimesulide, piroxicam and etoricoxib) and 1 to an antihistamine (cetirizine). All patch tests using other drugs were negative, even under conditions of high clinical suspicion. Oral rechallenge allowed confirmation of drug imputability in 5 of 31 test‐negative cases. Cross reactivity was frequently observed between piroxicam and other oxicams, and between different antihistamines. Conclusions. Patch testing was shown to be a simple and safe method to confirm drug imputabililty in fixed drug eruption, mainly when NSAID or multiple drugs are suspected. Persistent lack of reactivity to drug classes such as antibiotics and allopurinol represent an important limitation.     

Penile Involvement with Hand-Foot Syndrome

Hand-foot syndrome, or palmar plantar erythrodysesthesia, is a chemotherapy-induced cutaneous reaction typically characterized by painful erythema of the palms and soles followed by desquamation and exfoliation in those areas. This report represents the first case of hand-foot syndrome associated with penile erythema, pain, and desquamation in addition to the classic hand and sole findings.     

Scleroderma-like cutaneous lesions induced by paclitaxel: a case study

Paclitaxel is a recent antineoplastic agent that belongs to the taxane family. Its activity has been demonstrated in advanced and refractory ovarian, breast, lung, and head and neck cancer. Adverse cutaneous reactions to paclitaxel have been reported, namely bullous fixed drug eruption, onycholysis, acral erythema, erythema multiforme, and pustular eruption. We report the first case of scleroderma-like changes after paclitaxel administration. A 63-year-old patient presented with an edematous and infiltrated erythema of the head, neck, axillae, and left hand 10 days after administration of paclitaxel and paraplatin for primitive peritoneal cancer. Cutaneous lesions improved after a change from paclitaxel to cyclophosphamide. Cutaneous lesions recurred 3 months later, after reintroduction of paclitaxel, and progressively evolved to cutaneous sclerosis. Skin biopsy showed a dermal fibrosis. Biologic tests revealed no autoimmunity. Scleroderma-like lesions of this patient were reminiscent of previously reported cases that occurred after administration of docetaxel, which also belongs to the taxan family. Thus, scleroderma-like syndromes seem to represent a unique cutaneous adverse event caused by taxanes.     

Second- and third-generation antihistamines in the treatment of urticaria

ABSTRACT: Chronic urticaria is mainly idiopathic in nature and can be difficult to treat. While less responsive to antihistamine therapy than acute urticaria, antihistamines still play a key role in the management of symptomatology. While many of the antihistamines still commonly used to treat urticaria are first generation H₁ antagonists (e.g., diphenhydramine, hydroxyzine), the more recently developed second-generation agents (e.g., loratadine, cetirizine) and their metabolites—the third-generation antihistamines (e.g., fexofenadine, norastemizole, descarboxyloratadine)—possess many of the desirable clinical effects of the first-generation agents with a more tolerable side effect profile. This review discusses the advantages and disadvantages of each of the various second- and third-generation agents available, and presents some of the data showing the differences among these agents in the treatment of chronic urticaria.     

Differential diagnosis of severe cutaneous drug eruptions

Adverse cutaneous reactions to drugs are frequent, mostly secondary to antibacterials, however, serious adverse cutaneous reactions are infrequent. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of the same disease. They are the more severe drug eruptions, with a mortality around 30% for TEN. The confusion between erythema multiforme major and SJS means that erythema multiforme major is the main differential diagnosis. Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of TEN/SJS. Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is a severe cutaneous drug reaction with often a long duration of eruption and serious other organ involvement. Exfoliative dermatitis, whether caused by psoriasis, dermatitis or lymphoma, can be thought of as a differential diagnosis of DRESS/HSS. Angio-immunoblastic lymphadenopathy, viral eruption and vasculitis are other differential diagnoses of DRESS/HSS. Prompt recognition of a severe drug reaction and withdrawal of the culprit drug is often the most important therapeutic action. Alternatively, a delay in starting a specific treatment for a disease misdiagnosed as a drug eruption could be deleterious.     

Urticarial vasculitis: report of a case and review of the literature.

A woman with cutaneous vasculitis had a severe bullous eruption that was suggestive of erythema multiforme. The patient also had a history of recurrent urticaria that continued intermittently for over a year of follow-up examination. Skin biopsy specimens of both urticarial and erythema and multiforme lesions showed leukocytoclastic vasculitis. An illness resembling systemic lupus erythematosus (SLE) is suggested by transient, low-titer, positive antinuclear antibody tests, persistent deposits of immunoglobulin and complement in normal skin, arthralgias, circulating immune complexes, and chronic hypocomplementemia. This case is similar to cases previously reported as "hypocomplementemic vasculitis," an "unusual SLE-related syndrome," and "urticaria with vasculitis."     

Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil

Background:Several dermatoses are mediated by histamine, such as urticaria, angioedema, and papular urticaria. There are no Brazilian studies comparing the potency of antihistamines.Objectives:To evaluate the tolerability and efficacy of the main commercial brand and generic H1 antihistamines, regarding the suppression of the wheal and flare to the histamine test.Methods:A quasi-experimental, open study with 10 healthy adults submitted to the histamine test on the ventral aspect of the forearms. After 20 minutes, wheal and flares were measured. The tests were performed after two hours of intake of dexchlorpheniramine, hydroxyzine, levocetirizine, fexofenadine, cetirizine, loratadine, ebastine, desloratadine, epinastine and rupatadine, as well as generics of loratadine, cetirizine and fexofenadine.Results:All antihistamines presented a reduction in the wheal compared to the control (p <0.02), as well as in the flare, except for rupatadine (p = 0.70). In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1). As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1). The most common adverse effect was drowsiness, which was more prevalent among first-generation drugs (p < 0.01). Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p >0.03)..Study limitations:A single-center study evaluating only aspects related to histamine.Conclusions:Brazilian commercial antihistamines presented different profiles of inhibition of wheal and flares in the histamine test, as well as adverse effects. Generic loratadine, fexofenadine and cetirizine presented larger flares than brand drugs.     

Eosinophilic annular erythema: A late but complete response to hydroxychloroquine

A 69‐year‐old woman with a 12‐month history of asymptomatic erythematous, non‐scaly, annular and arciform plaques on her face, trunk and extremities is presented. The skin lesions had been unresponsive to treatment with systemic corticosteroids and antihistamines. Skin biopsy demonstrated superficial and deep dermal inflammatory infiltration consisting mainly of eosinophils and a few neutrophils. Dermal interstitial mucin deposition was also detected in the absence of vasculitis, flame figures or granulomatous reaction. The patient was diagnosed as having eosinophilic annular erythema and treated with hydroxychloroquine (2 × 200 mg/day, p.o.). Response to treatment was observed after 7 weeks and full recovery was achieved after 10 weeks. Eosinophilic annular erythema is rarely reported in the literature. Although hydroxychloroquine is a good choice for treatment, response time can vary between patients.     

Photoleukomelanodermatitis (Kobori) Induced by Afloqualone

We reported a case of photoleukomelanodermatitis (Kobori) type drug eruption due to afloqualone (Arofuto®). The patient was given afloqualone and imipramine hydrochloride (Chrytemin®) for cervical spondylosis from November of 1990. Edematous erythema with slight itching appeared on the sun-exposed areas in December of 1990. As drug eruption was suspected, drugs were ceased, and the cutaneous lesions almost disappeared but pigmentations and depigmentations developed in spots in sun-exposed areas in March of 1991. Photopatch and oral challenge tests were positive.