A study of persistent photosensitivity as a sequel of the prior administration of the drug benoxaprofen

Cutaneous photosensitivity is a recognized side-effect of a number of commonly used groups of drugs, among which are the non-steroidal anti-inflammatory agents (NSAIDs) one of which, benoxaprofen, was withdrawn from use in 1982. The abnormal reaction of the skin to light usually occurs during the period of the systemic administration of the drug, but may with some drugs persist for longer, even for months. Chronic photosensitivity, i.e. 'persistent light reaction' of some years duration, continuing after the withdrawal of the primary cause, has so far only been reliably reported when the initial exposure of the skin to the photoactive substance has been by external contact and not following ingestion. A suggestion that photosensitivity could persist for a period of years as a sequel of initial benoxaprofen-induced photosensitivity was studied in a group of 42 subjects said to be affected in this way. The results failed to confirm the presence of persistent photosensitivity. It appeared that the probable explanation for the episodic abnormal reactions to light over the years since 1982 was the systemic administration of other photoactive drugs including a series of NSAIDs.     

Drug‐induced photosensitivity: culprit drugs,potential mechanisms and clinical consequences

Drug‐induced photosensitivity, the development of phototoxic or photoallergic reactions due to pharmaceuticals and subsequent exposure to ultraviolet or visible light, is an adverse effect of growing interest. This is illustrated by the broad spectrum of recent investigations on the topic, ranging from molecular mechanisms and culprit drugs through epidemiological as well as public health related issues to long‐term photoaging and potential photocarcinogenic consequences. The present review summarizes the current state of knowledge on the topic while focusing on culprit drugs and long‐term effects. In total, 393 different drugs or drug compounds are reported to have a photosensitizing potential, although the level of evidence regarding their ability to induce photosensitive reactions varies markedly among these agents. The pharmaceuticals of interest belong to a wide variety of drug classes. The epidemiological risk associated with the use of photosensitizers is difficult to assess due to under‐reporting and geographical differences. However, the widespread use of photosensitizing drugs combined with the potential photocarcinogenic effects reported for several agents has major implications for health and safety and suggests a need for further research on the long‐term effects.     

Value of patch tests in clindamycin-related drug eruptions

Background. Patch tests help to confirm the aetiology of the cutaneous adverse drug reactions involving delayed hypersensitivity mechanisms, but the results vary with the pattern of skin reaction and the culprit drug. Objectives. To analyse the results of patch tests in patients with cutaneous adverse drug reactions imputable to clindamycin and assess their contribution to the diagnosis. Patients and methods. Between 2005 and 2009, we studied patients with delayed cutaneous adverse drug reactions following administration of clindamycin, usually associated with other drugs. After resolution of the cutaneous adverse drug reaction, patch tests were performed with a series of antibiotics, including pure clindamycin 10% in petrolatum. Results. We studied 30 patients (23 females and 7 males) aged 33–86 years (mean 59.97 years) with generalized maculopapular exanthema where clindamycin was among the highly suspected drugs. Two patients had a previous positive involuntary rechallenge. Patch tests with clindamycin were positive in 9 of 30 patients (30%). More than 50 control patients patch tested with clindamycin were negative. Discussion. We considered the positive patch tests results with clindamycin, in the 9 patients with maculopapular exantema, to be specific, versus the negative results observed in the control group. Although the sensitivity is low (30%), they confirmed the responsibility of this antibiotic in cutaneous adverse drug reactions in which, with only chronological criteria, it was not possible to conclude on the culprit drug.     

Drug-induced pemphigus

Pemphigus is an autoimmune bullous disease that may be influenced by genetic and exogenous factors. Drugs are a leading cause of pemphigus. There is a need for a thorough history taking so as to find the culprit medication. The diagnosis of drug-induced pemphigus is challenging. Patients have often been exposed to multiple drugs, and some drugs may have a prolonged latency period between exposure and onset of the disease. The in vitro interferon-gamma (IFN-gamma) release from lymphocytes test has been shown to be of diagnostic value in drug-induced skin reactions. Cessation of the offending drug may alleviate the clinical manifestations and reduce the need for medical treatment.     

Photosensitizing potential of certain nonsteroidal anti-inflammatory agents

The nonsteroidal anti-inflammatory drugs (NSAIDs) have been repeatedly associated with photosensitivity reactions. The underlying mechanism however is not known, and the clinical features are not always consistent with either a phototoxic or a photoallergic mechanism. In this study, four NSAIDs were investigated for their phototoxicity potential in human volunteers using an oral dosing protocol. Phototoxicity, consisting of wheal-and-flare reactions following exposure to ultraviolet radiation, was demonstrated following the administration of naproxen and nabumetone, but was not seen in volunteers who received piroxicam, a drug reported to cause photosensitivity. Thus, although certain NSAIDs are potentially capable of producing phototoxicity reactions, others can presumably provoke clinical photosensitivity through other mechanisms.     

Epicutaneous patch testing in drug hypersensitivity syndrome (DRESS)

Background: In some patterns of cutaneous adverse drug reactions, and depending on the culprit drug, patch testing has been helpful in confirming its cause. Its value in Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has not been established in a large cohort of patients.
Objective: The aim of the present study is to evaluate the safety and usefulness of patch testing in DRESS.
Patients/Methods: Between January 1998 and December 2008, we studied 56 patients with DRESS induced by antiepileptic agents in 33 patients (59%), allopurinol in 19 (34%) and sulfasalazine, cotrimoxazole, tenoxicam, and amoxicillin in 1 patient each (7%).
Results: A positive patch test reaction was observed in 18 patients (32.1%), of which 17 were with antiepileptics and 1 with tenoxicam. In the antiepileptic group, carbamazepine alone was responsible for 13 of 17 positive reactions (76.5%). Patch tests with allopurinol and its metabolite were negative in all cases attributed to this drug.
Conclusions: In this study, patch testing was a safe and useful method in confirming the culprit drug in DRESS induced by antiepileptic drugs, whereas it had no value in DRESS induced by allopurinol. The pathogenesis of DRESS is not yet entirely clarified, but positive patch tests suggest a drug-dependent delayed hypersensitivity mechanism.     

Cutaneous ultrastructural changes and photosensitivity associated with amiodarone therapy

Amiodarone, an antiarrhythmic agent, is known to cause photosensitivity and cutaneous hyperpigmentation. Five patients taking this drug for periods of 1 to 48 months were studied. Skin biopsy specimens taken from a sun-exposed site were assessed by light microscopy, electron microscopy, and direct immunofluorescence. Three patients allowed comparative studies to be done on a biopsy specimen from non-sun-exposed skin. Light microscopy findings, including special stains, were not diagnostic of amiodarone-associated cutaneous changes. Electron microscopy, however, displayed distinctive intracytoplasmic inclusions in many cell types, some of which have not been reported previously. These inclusions represent phospholipid membranes associated with amiodarone or its metabolites as the result of a drug-induced lipidosis. Previous reports had postulated the inclusions were lipofuscin. Sun exposure may accelerate the formation of these intracellular deposits because they are more prominent in sun-exposed skin. Four of the above five cases, plus two additional patients, had symptoms compatible with a photosensitivity. Porphyrin assays were normal. Of the six patients phototested, three showed acute reactions to ultraviolet A (UVA) and ultraviolet B (UVB) and significant delayed reactions to UVA and/or UVB. The patients who had normal phototesting were on the drug for shorter periods than those with positive tests.     

Kutane Arzneimittelreaktionen im Kindes- und Jugendalter

Adverse drug reactions (ADR) occur in nearly 10% of hospitalized children and in about 1.5% of ambulatory pediatric patients. The skin is the most frequently affected target organ in drug hypersensitivity (DH) reactions, which account for 20% of all ADR. Due to its pathophysiological heterogeneity and the ensuing morphological diversity, DH often represents a clinical and therapeutic challenge. Urticarial and maculopapular eruptions are usually restricted to the skin and rarely require systemic treatment or hospital admission once the culprit drug has been withdrawn. However, extracutaneous affections should be ruled out promptly in individuals with polymorphous rashes accompanied by fever and lymphadenopathy as well as in patients with bullous skin lesions. Children affected by severe drug reactions usually require in-hospital surveillance and interdisciplinary supportive therapy.     

Photosensitizing drug reactions

Photosensitizing drug reactions are cutaneous eruptions that occur after exposure to ultraviolet radiation in patients using photosensitizing medications. The reactions can be broadly classified into phototoxic and photoallergic, with the former being much more common and well documented. There is an extensive list of photosensitizing medications, especially in the case of phototoxicity. The most common are amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole. Most of the medications implicated in photosensitivity share an action spectrum within the ultraviolet A range. Distinguishing between phototoxicity and photoallergy can be difficult, because some clinical overlap exists between the two disorders. It is often done based on pathogenesis, clinical presentation, and diagnosis. Management is similar for both types of reactions, with the gold standard being prevention. This review provides an overview of the photosensitizing drug reactions and highlights the similarities and differences between phototoxicity and photoallergy, as well as other photosensitizing drug reactions in the phototoxicity family including lichenoid reactions and pseudoporphyria.     

Cutaneous drug eruptions including serum sickness-like reaction,symmetrical drug-related intertriginous and flexural exanthema,and drug-induced lupus

Cutaneous manifestations of drug reactions are common yet vary widely in their appearance and degree of internal organ involvement. Serum sickness-–like reactions, symmetrical drug-related intertriginous and flexural exanthem, granulomatous drug eruption, pseudolymphoma, and drug-induced lupus are medication-induced conditions with dermatologic presentations. Many of the conditions discussed are relatively rare but nonetheless demand our attention and understanding. Some of the conditions presented may be more likely encountered in the hospital setting, as is the case with serum sickness–like reactions and drug-induced lupus, whereas others may present to outpatient clinic for diagnosis. Given the similarities in clinical history of patients presenting with these conditions, an understanding of the clinical presentation, pathophysiology, culprit medications, histologic appearance, and serologic characteristics is warranted to correctly diagnose and manage these uncommon adverse reactions. We also discuss how to differentiate some of these conditions from more serious mimickers, as in the case of pseudolymphoma drug reaction mimicking a true lymphoma and drug-induced lupus mimicking acute systemic lupus erythematosus.     

Novedades en el diagnóstico de las toxicodermias

Drug eruptions affecting the skin or mucosas (toxicoderma) are the most common adverse effects of drugs and represent one of the more common diagnostic challenges for the dermatologist. A better understanding of the pathogenic mechanisms of drug reactions, pharmacogenetics, and pharmacoepidemiology will help us to resolve the main dilemmas and to anticipate and even prevent such reactions. Many drug eruptions are due to T cell–mediated hypersensitivity reactions that can involve activation of different proinflammatory mechanisms, which would explain the varied manifestations. Some aspects defy the classical understanding of antigen processing and presentation. New immunological hypotheses, such as the «p-i concept», have been introduced to complement the hapten theory and, at least in part, help to explain why drug reactions tend to affect the skin and why certain viral infections increase the risk of drug eruptions. In this paper we analyze these pathogenic concepts and the role of HLA genes in the susceptibility to certain severe adverse drug reactions, and also examine other advances in the diagnosis of drug eruptions. We briefly discuss a number of recently described reactions to new drugs.     

The challenge of drug-rechallenge: Facts and controversies

The accurate identification of the culprit drug inducing a patient's cutaneous adverse drug reaction is important to avoid future adverse reactions and to provide safe alternative drugs. The assessment has to rely on the clinical signs, the time course, and response to treatment. Sometimes, additional diagnostic procedures are also needed. If diagnostic procedures such as in vivo skin testing and in vitro laboratory tests do not lead to conclusive results, confirmation of a presumptive diagnosis by a rechallenge test is often the only reliable way to establish a diagnosis. This procedure should be undertaken only with great caution and a compelling need, because a rechallenge test might cause severe or even fatal reactions. Contraindications and ethical considerations should be taken into account and an individual risk-benefit calculation must be performed in every case.     

Adverse cutaneous reaction to celecoxib: 6 cases

INTRODUCTION: Our objective was to characterize adverse cutaneous reactions to celecoxib, a new non steroidal anti-inflammatory drug. PATIENTS AND METHODS: A retrospective study of 6 consecutive patients. RESULTS: The average delay before the onset of the reaction was 10.2 days for patients taking the medication for the first time and 48 hours for one patient taking the drug for the second time. Two patients had fever. Patients presented with an exanthema and in most cases an edema of the face. Buccal mucosa was involved in two patients, and one patient had minimal blister lesions. In five of the six patients, minor and transitory biological abnormalities were found. The intrinsic imputability of the celecoxib was I3 (C3S2) in all the cases. DISCUSSION: Our cases are similar to those reported by the French drug regulatory agency (Pharmacovigilance). Usually the adverse cutaneous reactions were not too severe, with maculo-papulo exanthema and edema of the face. The reactions due to celecoxib are more frequent than those due to other non steroidal anti-inflammatory drugs (7.5% versus 4.1%), but severe cases are rarely reported. Besides, an allergic history to sulphonamide contraindicates celecoxib. However celecoxib does not have the aromatic amine common to antibacterial sulphonamides, and there is no proof of cross reactions between these two families. Furthermore, this amine is usually associated with drug reaction severity, which could explain why severe cases due to celecoxib are rare.     

Photosensitivity: the 9-year experience at a Sydney contact dermatitis clinic

In this retrospective study, 81 patients with photosensitivity were referred to the Contact and Occupational Dermatitis Clinic at The Skin and Cancer Foundation Australia, in Sydney, between 1991 and 1999. Photoallergic contact dermatitis (PACD) was diagnosed in 39.5% of patients, with 87.5% of these reactions being to sunscreen chemicals. Polymorphic light eruption (PMLE) accounted for 19.7% of cases, drug photosensitivity 14.8%, and photoaggravated atopic dermatitis and chronic actinic dermatitis (CAD) each constituted 7.4%. Compared with overseas studies, there was a high incidence of PACD, possibly reflecting the referral bias and widespread use of sunscreens. The incidence of PMLE and CAD was less than studies from cooler climates overseas. No cause could be determined for three photosensitive patients.     

Fotosensibilidad por tiazidas

Thiazides are widely used diuretics that first became available in the 1950s. The first reports of photosensitivity reactions to thiazides were published shortly after the introduction of these drugs, but few cases have been described since.We review all the cases of photosensitivity due to thiazides published up to December 2011. We found 62 cases, 33 in women and 29 in men. The most common presentation was eczematous lesions in a photodistributed pattern, and the most common causative agent was hydrochlorothiazide. The results of photobiological studies were published in only some of the cases reviewed. In most cases, phototesting revealed an abnormal response to UV-A alone or to both UV-A and UV-B. In some cases, the results of phototesting were normal and only photopatch testing yielded abnormal results.Diagnosis of photosensitivity due to thiazides requires a high degree of suspicion. Ideally, diagnosis should be confirmed by a photobiological study.     

UNUSUAL SKIN MANIFESTATIONS OF DRUG PHOTOSENSITIVITY

Photosensitivity from drugs does not always present in a classical fashion involving all areas of exposure. The area of involved skin may be limited and cause confusion in diagnosis. Drug photosensitivity causes both transient and persistent light reactions. The cases described in this paper illustrate in a clinical fashion, the manner in which the diagnosis of drug eruptions can be complicated in our daily clinical work.     

Clinical application of static fluorescence-based cytometry, Cellscan, in cutaneous adverse drug reaction

The aim of the present study was to evaluate the effectiveness of Cellscan in identifying culprit drugs causing cutaneous adverse drug reaction. It was a prospective study with 3 months follow up conducted at the Departments of Dermatology, Internal Medicine and Dermatology Outpatient Clinic, Chaim Sheba Medical Center, Tel Hashomer, Israel. The study included 36 patients with cutaneous reaction suspected to be secondary to drugs, treated with a total number of 148 drugs. All patients and drugs were classified to three probability groups according to accepted clinical criteria. The effectiveness of the Cellscan test in identifying the culprit drug was addressed according to the clinical probability for cutaneous drug reaction, the drug class and the type of rash. Data analysis according to the clinical probability for cutaneous drug reaction revealed that patients in the moderate and high probability groups had a high test sensitivity of 77.7% and 83.3% with specificity of 71% and 63%, respectively, in identifying the culprit drug. Classifying the data according to drug classes, revealed that for the antibiotic and cardiovascular drug classes the sensitivity of the test was 100% and 92% with specificity of 83.3% and 55.5%, respectively, in identifying the culprit drug. Finally, the classification of patients according to the type of rash revealed a high evaluating accuracy for culprit drugs in maculopapular rashes with sensitivity and specificity of 90% and 60.4%, respectively. The results of this study imply that the Cellscan test is it a good practical tool for identifying the culprit drug in cutaneous adverse drug reaction.     

Is drug allergy less prevalent than previously assumed? A 5‐year analysis

Background Rashes are a frequent conundrum in clinical practice as they may be reactive, drug induced or disease specific. Identification of the culprit drug is important as re‐exposure may be harmful or even life‐threatening and unnecessary avoidance of ‘innocent’ drugs leads to limitations of treatment options. Objective To objectify the cause of suspected cutaneous drug reactions in a large patient population. Method Over 5 years (2006–10), 612 patients with suspected cutaneous drug reactions were evaluated. Histology was assessed. About 200 patients were invited for complete work‐up with skin tests (prick/intracutaneous testing and scratch/patch as indicated) and, if necessary, lymphocyte transformation tests (LTT). In special cases, drug provocation tests were conducted. Results A total number of 141 cases with suspected drug reaction underwent full work‐up (age 6–86 years; 75% female, 25% male). In 107 cases (76%) a drug was identified whereas 34 (24%) were reactive rashes or had other causes. Mostly, cutaneous drug reactions were maculopapular rashes, urticaria/angio‐oedema; less frequently, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, systemic drug‐related intertriginous and flexural exanthema, toxic epidermal necrolysis and fixed drug eruptions were present. Of all the cutaneous drug reactions investigated, 39·8% were caused by antibiotics, 21·2% by anti‐inflammatories, 7·6% by contrast media and 31·4% by others (oral antidiabetics, antimycotics, antipsychotics, antiepileptics and others). Conclusion Clinical assessment overestimates the role of drug allergies in cutaneous reactions. Assessment of suspected drug reactions can be greatly improved by thorough evaluation including dermatological and allergological work‐up with skin testing and assays such as LTT.     

A Case Report of Pirfenidone-Induced Lichenoid Drug Eruption in a Patient with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal lung disease characterized by progressive dyspnea and irreversible loss of lung function. Pirfenidone is a novel anti-fibrotic and anti-inflammatory drug, which reduces deterioration in the lung function and prolongs progression-free survival in patients with IPF. However, it has adverse effects including gastrointestinal symptoms, hepatic dysfunction or skin photosensitivity, and rash. Lichenoid drug eruption (LDE) refers to lichen planus-like drug eruption usually presenting symmetric eczematous plaques with a purple hue. To date, numerous cases of LDE due to various drugs and pirfenidone-associated photosensitivity have been reported. However, a case of pirfenidone-induced LDE has been very rarely reported to our knowledge. Herein, is a case of pirfenidone-induced LDE so that clinicians can be aware of the possibility of LDE when using pirfenidone.     

Pattern analysis of drug-induced skin diseases

Drug eruptions are common adverse reactions to drug therapy and are a frequent reason for consultation in clinical practice. Even though any medication can potentially cause an adverse cutaneous reaction, some drugs are implicated more commonly than others. Histologically, drugs can elicit a variety of inflammatory disease patterns in the skin and panniculus, no pattern being specific for a particular drug. The most common pattern elicited by systemically administered medications is the perivascular pattern. Psoriasiform or granulomatous patterns are rarely caused by medications. The usual histologic patterns of drug eruptions are discussed in this review using the basic patterns of inflammatory diseases. Clinicopathologic correlation is established for relevant patterns. However, the changes of drug-induced skin disease must be made considering clinical presentation, histopathological analysis, and course of the disease.