Drug‐induced photosensitivity: new insights into pathomechanisms and clinical variation through basic and applied science

Drug‐induced photosensitivity occurs when a drug is capable of absorbing radiation from the sun (usually ultraviolet A) leading to chemical reactions that cause cellular damage (phototoxicity) or, more rarely, form photoallergens (photoallergy). The manifestation varies considerably in presentation and severity from mild pain to severe blistering. Despite screening strategies and guidelines in place to predict photoreactive drugs during development there are still new drugs coming onto the market that cause photosensitivity. Thus, there is a continuing need for dermatologists to be aware of the different forms of presentation and the culprit drugs. Management usually involves photoprotection and cessation of drug treatment. However, there are always cases where the culprit drug is indispensable. The reason why some patients are susceptible while others remain asymptomatic is not known. A potential mechanism for the phototoxic reactions is the generation of reactive oxygen species (ROS), and there are a number of reasons why some patients might be less able to cope with enhanced levels of ROS.     

A patch testing and cross‐sensitivity study of carbamazepine‐induced severe cutaneous adverse drug reactions

Background The usefulness of the drug patch testing for Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA‐B*1502 is strongly associated with CBZ‐SJS/TEN in Chinese and Southeast Asian populations. Objective To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)‐induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross‐reactivity in patch tests among the aromatic antiepileptic drugs. Methods We measure the frequency of positive patch test reactions and cross‐sensitivity to structure‐related aromatic anti‐epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure‐related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA‐B*1502 genotype and frequency of possible side effects from the patch tests. Results Positive patch test reactions to 30% CBZ in the CBZ‐SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ‐DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross‐sensitivity to other aromatic AEDs was observed in both the CBZ‐SJS/TEN and the CBZ‐DRESS. Only the HLA‐B*1502 genotype was present and strongly associated with the CBZ‐SJS/TEN, but not with the CBZ‐DRESS. Conclusion Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross‐reactivity for these patients.     

Adverse drug reactions in dermatology

Adverse drug reactions (ADRs) – that is, unintended and harmful responses to medicines – are important to dermatologists because many present with cutaneous signs and because dermatological treatments can cause serious ADRs. The detection of ADRs to new drugs is often delayed because they have a long latency or are rare or unexpected. This means that ADRs to newer agents emerge only slowly after marketing. ADRs are part of the differential diagnosis of unusual rashes. A good drug history that includes details of drug dose, time‐course of the reaction and factors that may make the patient more susceptible, will help. For example, Stevens–Johnson syndrome with abacavir is much commoner in patients with HLA‐B*5701, and has a characteristic time course. Newer agents have brought newer reactions; for example, acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib. Older systemic agents used to treat skin disease, including corticosteroids and methotrexate, cause important ADRs. The adverse effects of newer biological agents used in dermatology are becoming clearer; for example, hypersensitivity reactions or loss of efficacy from antibody formation and progressive multifocal leucoencephalopathy due to reactivation of latent JC (John Cunningham) virus infections during efalizumab treatment. Unusual or serious harm from medicines, including ADRs, medication errors and overdose, should be reported. The UK Yellow Card scheme is online, and patients can report their own ADRs.     

Prophylaxis in hereditary angioedema (HAE) with C1 inhibitor deficiency

Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life‐threatening. In the majority of cases, the disease can be adequately treated with an on‐demand approach – in some cases, however, short‐ or long‐term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German‐speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1‐inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long‐term prophylaxis. According to the most recent international consensus papers and our own experience, self‐administered C1‐inhibitors are now the first option for long‐term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE.     

Oral manifestations of adverse drug reactions: guidelines

Background Adverse drug reactions are noxious and unintended responses to a medicinal product. Many drugs have the potential to induce adverse reactions in the mouth. The extent of such reactions is unknown; however, because a lot of them are asymptomatic, many are believed to go unnoticed. Adverse oral drug reactions are responsible for oral lesions and manifestations that can mime local or systemic disease. Their pathogenesis, especially of the mucosal reactions, is largely unknown and appears to involve complex interactions between the drug in question, other medications, the patient's underlying disease, genetics and lifestyle factors. Aim In this study, we have listed the principal signs and symptoms of oral and perioral adverse drug reactions and the responsible drugs. Diagnosis for adverse drug reaction is not easy given also the limited utility of laboratory tests. The association between a drug and an adverse drug reaction is mostly based on the disappearance of the reactions following discontinuance of the offending drug. Sometimes, it is useful to perform rechallenge tests reintroducing the drug to establish cause and effect. Conclusions Knowledge of adverse drug‐induced oral effects helps health professionals to better diagnose oral disease, administer drugs and improve patient compliance during drug therapy and may foster a more rational use of drugs.     

Pharmacology and significance of nonsteroidal anti-inflammatory drugs in the treatment of skin diseases

Intensive studies of the molecular pathways involved in common inflammatory skin disorders, coupled with detailed pharmacologic evaluation of the responses of skin to the end products of these pathways, have resulted in a much clearer understanding of the mode of action of nonsteroidal anti-inflammatory drugs. In particular the development of lipoxygenase inhibitors is prompting intense interest in their possible role as anti-inflammatory agents in psoriasis and other dermatoses. Because of the potency of these and other classes of new anti-inflammatory drugs, careful monitoring of their pharmacokinetics in individual patients, especially those at risk for adverse reactions, will prove necessary, especially in the early stages of treatment. Meanwhile, currently available nonsteroidal anti-inflammatory drugs have a limited but significant place in the treatment of certain dermatoses. Current experience of the high incidence of adverse reactions to existing nonsteroidal anti-inflammatory drugs suggests that this will be no less a problem with new agents under development. The skin is frequently involved in adverse reactions to this class of drug, and past experience suggests that cutaneous reactions are among the earliest unwanted side effects reported in a new drug of this type. The dermatologist, therefore, has an important responsibility to observe, document, and report such "early warning signs" to the appropriate licensing authority and the manufacturer.     

Bad air gets under your skin

Air pollution is increasing beyond previous estimates and is viewed as the world's largest environmental health risk factor. Numerous clinical and epidemiological studies have highlighted the adverse effects of environmental pollutants on health. Although there is comparatively less research investigating the cutaneous effects of ambient pollution, there is growing recognition of the adverse effects on skin. In this article, we provide an overview of the nature of environmental pollution and highlight the current evidence detailing the effects on cutaneous health. There is convincing evidence demonstrating that air pollution has a detrimental impact on skin and can exacerbate skin disease. Further epidemiological and experimental studies are required to assess the short‐ and long‐term deleterious effects of ambient pollutant exposure on skin. The future challenge would be to use this evidence to develop specific strategies to protect against pollution‐induced damage and prevent the effects of “bad air getting under our skin.”     

Drug sampling in dermatology

The use of drug samples in a dermatology clinic is controversial. Drug samples are associated with influencing physician prescribing patterns often toward costlier drugs, increasing health care costs, increasing waste, inducing potential conflicts of interest, and decreasing the quality of patient education. On the other hand, they have the potential to help those in financial need, to improve adherence and convenience, and to expose patients to better drugs. Although some academic centers have banned drug samples altogether, many academic and private practices continue to distribute drug samples. Given the controversy of the topic, physicians who wish to distribute drug samples must do so in an ethical manner. We believe, when handled properly, drug sampling can be used in an ethical manner.     

LEPROSY THERAPY,PAST AND PRESENT: CAN WE HOPE TO ELIMINATE IT?

Leprosy remains an important problem globally. Timely detection of new cases and prompt treatment with MDT continue to be the main intervention strategies. We review the various issues related to classification, treatment, drug resistance and the possible steps to eliminate the disease in the near future. The need for newer anti leprosy agents has been felt and various agents like fluroquinolones, macrolides and minocycline have all been tried in various combinations and duration. Uniform MDT in all leprosy patients might be a logical one too. Drug resistance can be identified by PCR based DNA sequence analysis which saves much time. Drugs like thalidomide analogues, pentoxifylline, selective cytokine inhibitory drugs have proved effective in controlling type-2 reaction in leprosy patients. New drugs for leprosy reactions are still needed. Far from being eliminated as a public health problem, leprosy still causes a considerable long term morbidity in both developing and developed world. New treatment and the optimal length of MDT requires further research. We need genome based technology to address the unresolved issues of transmission of M. leprae.     

Phototoxicity and photoallergy

Photosensitivity may be phototoxic or photoallergic. Phototoxicity is much more common. There are 2 types of phototoxicity: photodynamic, which requires oxygen, and nonphotodynamic, which does not. Reactions induced by porphyrin molecules, coal tar derivatives, and many drugs are photodynamic. The reaction induced by psoralens, for the most part, is nonphotodynamic. Acute phototoxic reactions are characterized by erythema and edema followed by hyperpigmentation. Long-term ultraviolet phototoxicity results in chronic sun damage and skin cancer formation. Also, certain chemicals such as psoralen molecules and coal tar are photocarcinogenic. Phototoxic reactions to certain drugs produce unusual clinical patterns, that is lichenoid eruptions, dyschromia, photo-onycholysis, and pseudoporphyria. Photoallergy is an uncommon acquired altered reactivity dependent on an immediate antibody or a delayed cell mediated reaction. Solar urticaria is an example of the former, whereas photoallergy to exogenous chemicals is an example of the latter. Photoallergy to systemic drugs does occur but is difficult to characterize. The action spectrum for photoreactions to exogenous agents usually at least includes the ultraviolet A rays for both phototoxicity and photoallergy.     

Hydrochlorothiazide‐induced photosensitivity in a psoriasis patient following exposure to narrow‐band ultraviolet B excimer therapy

Drug‐induced photosensitivity develops when the use of oral or topical photosensitizing medications creates a rash after exposure to ultraviolet (UV) radiation. Medications most commonly implicated in photosensitive drug reactions include amiodarone, nonsteroidal anti‐inflammatories, thiazides, tetracycline antibiotics, chlorpromazine, and fluoroquinolones. It is generally believed that drug‐induced photosensitivity is an UVA phenomenon, caused by UV wavelengths between 315 and 400 nm. Here, we present a case of hydrochlorothiazide (HCTZ)‐induced photosensitivity following exposure to 308‐nm narrow‐band (nb) UVB light emitted from an excimer laser in a patient undergoing treatment for plaque psoriasis. This patient had received biweekly treatments with the excimer laser for years prior without any history of adverse reactions. We believe that our patient suffered an acute photosensitivity to UVB due to new‐onset HCTZ. Because nb UVB–emitting lasers are used to treat many dermatologic conditions, physicians should be aware of potential photosensitivity reactions, review medication lists and counsel patients accordingly.     

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.     

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.     

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.     

A systematic review on treatment‐related mucocutaneous reactions in COVID‐19 patients

Most of drugs could have certain mucocutaneous reactions and COVID‐19 drugs are not an exception that we focused. We systematically reviewed databases until August 15, 2020 and among initial 851 articles, 30 articles entered this study (20 case reports, 4 cohorts, and 6 controlled clinical trials). The types of reactions included AGEP, morbiliform drug eruptions, vasculitis, DRESS syndrome, urticarial vasculitis, and so on. The treatments have been used before side effects occur, included: antimalarial, anti‐viral, antibiotics, tocilizumab, enoxaparin and and so on. In pandemic, we found 0.004% to 4.15% of definite drug‐induced mucocutaneous reactions. The interval between drug usage and the eruption varied about few hours to 1 month; tightly dependent to the type of drug and hydroxychloroqine seems to be the drug with highest mean interval. Antivirals, antimalarials, azithromycin, and tocilizumab are most responsive drugs for adverse drug reactions, but antivirals especially in combination with antimalarial drugs are in the first step. Types of skin reactions are usually morbilliform/exanthematous maculopapular rashes or urticarial eruptions, which mostly may manage by steroids during few days. In the setting of HCQ, specific reactions like AGEP should be considered. Lopinavir/ritonavir is the most prevalent used drug among antivirals with the highest skin adverse reaction; ribarivin and remdisivir also could induce cutaneous drug reactions but favipiravir has no or less adverse effects. Logically the rate of dermatologic adverse effects among anivirals may relate to their frequency of usage. Rarely, potentially life‐threatening reactions may occur. Better management strategies could achieve by knowing more about drug‐induced mucocutaneous presentations of COVID‐19.     

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.     

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.     

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.     

Adverse cutaneous reactions to antipsychotics

Antipsychotic agents are known to cause adverse cutaneous reactions in approximately 5% of the individuals for whom they are prescribed. The majority of adverse cutaneous events are benign and easily treated, and do not place the patient at a serious health risk. However, these adverse events may impact on compliance so discussing strategies with the patient to avoid potential adverse cutaneous effects will improve compliance. The most frequently reported cutaneous adverse effects of antipsychotic medications include: exanthematous eruptions, skin pigmentation changes, photosensitivity, urticaria and pruritus. Only a small percentage of adverse cutaneous reactions are life threatening. The most important step in minimizing morbidity is prompt recognition of severe drug reactions with withdrawal of the causative medication. If a skin eruption occurs in an outpatient setting, it is generally advisable to discontinue the drug and to consider switching to another class of agent. If the reaction is mild, and the therapeutic benefits far exceed the risks of the symptomatic treatment, then the antipsychotic agent may be continued.     

Relevance of UV filter/sunscreen product photostability to human safety

Photostability or photo‐instability of sunscreen products is most often discussed in undesirable terms with respect to human safety. The health risks, specifically associated with sunscreens, photostable or photo‐unstable, include phototoxic/photoirritation or photoallergic responses and, longer‐term, an increased risk of skin cancers or photoageing. The aims of this paper are to define photostability/photo‐instability and objectively assess the acute and chronic toxicological consequences from the human exposure to UV filter/sunscreens and any probable photo‐degradation products. The reported prevalence of photoirritation and photoallergic responses to sunscreens is rare compared with adverse events, for example, skin irritation or sensitization, produced by cosmetics or topically applied drugs and do not directly implicate potential photo‐degradation products of UV filters. Moreover, for at least one photo‐unstable combination, octyl methoxycinnamate and avobenzone, the long‐term benefits to humans, i.e., reduction in skin cancers, seem to outweigh any potential adverse consequences attributed to photo‐degradation. Sunscreen products are formulated to achieve maximum efficacy which, by necessity and design, incorporate measures to support and promote photostability since all organic UV filters have the potential to photo‐degrade. Current performance measures, in vivo SPF and in vitro UVA, conducted under standardized conditions, in part account for photostability. The concerns expressed when considering human exposure to potential photo‐unstable UV filters or sunscreen products may not manifest as health risks under conditions of use. Still, improvement in sunscreen product photostability continues to be a key strategic objective for manufacturers.