Abstract Cutaneous adverse drug reactions (ADRs) to antihypertensive drugs have been frequently reported. We describe a peculiar clinical pattern of cutaneous ADR, represented by an eczematous reaction induced by certain antihypertensive drugs that we observed in elderly patients. The case series consisted of 23 hypertensive patients aged 66-87 years; 19 of them were taking another drug in addition to the suspected antihypertensive medication and 15 were on polytherapy with three or more drugs to treat multiple comorbidities. The antihypertensive culprit agents were angiotensin-converting enzyme (ACE) inhibitors in 9 patients, ACE-inhibitors combined to hydrochlorothiazide (HCT) in 7 subjects, angiotensin II receptor blockers alone in 2 patients and associated with HCT in 5 cases. The cutaneous ADR was characterized by an eczematous rash that was generalized in 16 patients and localized in 7 cases, with predominant involvement of lower limbs. Such lesions developed after a latency of 4-30 months and were associated with moderate-to-severe itch, usually unresponsive to oral antihistamines. Histopathological diagnosis was available for 9 cases, confirming the presence of a spongiotic dermatitis with possible associated psoriasiform skin changes.

Abstract

Context:

Cutaneous toxicity is a frequent side effect of new anticancer targeted therapies. Skin reactions can severely impact the patient's physical, psychological and social well-being and may sometimes lead to discontinuations either treatment dose reductions.

Objective:

This study evaluates the impact of cutaneous adverse drug reactions (cADR) of the new therapies bortezomib and lenalidomide and presents a review of their skin side effects. Materials and method: Type, frequency, severity, time of onset and management of cADR were collected and the medical records of all multiple myeloma patients receiving bortezomib or lenalidomide in the Hematology and Medical Oncology Institute of the University of Bologna, were analyzed.

Results:

A total of 17 cADR occurred in 10 patients of 17 (58.8% of patients) treated with bortezomib: 5 rashes, 3 events of pruriginous rash, 1 purpuric rash, 2 records of mouth swelling, 1 stomatitis-mucositis, 3 cases of edema in the lower limbs, 1 patient referred pruritus and another telogen effluvium. Eight skin manifestations were due to lenalidomide in 7 patients of 25 treated (28%): 2 pruriginous rashes, 3 cases of edema, 2 records of pruritus, 1 case of stomatitis-mucositis. Three adverse events linked to bortezomib and 4 to lenalidomide forced to a complete withdrawal of the drug, while 3 reactions due to bortezomib mandated a dose reduction. Dermatological evaluation was performed only in 2 patients treated with bortezomib and 1 with lenalidomide. Discussion: Evaluations of cADR due to bortezomib and lenalidomide were performed. There are no other reports focused on skin events in patients treated with the triple regimen velcade (bortezomib)-thalidomide-dexamethasone (VTD) up to date. Our study suggests that cutaneous toxicities, when researched by Dermatologists, are a side effect even more frequent than the reported data. Limitations: As it is a single institute and retrospective study, ongoing cADR were rarely evaluated by dermatologists; thus, it is possible that cutaneous reactions (especially mild) may have been under reported by Hematologists and Oncologists in clinical records.

Conclusions:

Even with the development of new drugs for cancer treatment, "old" cutaneous side effects may still be present, compromising patients' quality of life. Physicians prescribing bortezomib and lenalidomide should monitor their patients for the spectrum of cADR, and they should involve dermatologists in consultations and management of these events. A multidisciplinar approach is necessary to oncologic patient in order to provide a tailored supportive clinical care.

Skin toxicities are the most common side effects associated with the epidermal growth factor receptor inhibitor erlotinib, occurring in most patients receiving the drug. Clinical trials evaluating erlotinib for the treatment of non-small cell lung cancer have reported a range of skin disorders, the most common being acneiform rash, xeroderma (dry skin), pruritus, and paronychia. Although in the majority of cases these effects are mild and transient, they can have a considerable impact on a patient's quality of life and, if particularly severe and persistent, may necessitate treatment interruption or cessation and compromise treatment outcome. This coupled with recent evidence to suggest a positive correlation between the incidence and severity of rash and clinical outcome among erlotinib-treated patients with advanced or metastatic non-small cell lung cancer highlights the importance of adequately managing epidermal growth factor receptor inhibitor-related skin disorders. Clear treatment strategies are therefore necessary to ensure the prevention and optimal management of erlotinib-related skin toxicities thereby enabling patients to continue erlotinib treatment. In this review we present a practical approach for the treatment of erlotinib-related cutaneous side effects in Japanese patients with advanced non-small cell lung cancer providing details of specific treatment interventions, according to symptom severity, for each of the common skin disorders. In addition, the importance of preventive skin care measures-namely maintaining cleanliness, moisturization, and protection from external stimuli-in preventing the development of serious skin disorders is discussed and guidelines for the practice of proper skin care are presented.

Cutaneous drug eruptions can range from an asymptomatic rash to a life-threatening emergency. Because of the high frequency, morbidity, and potential mortality associated with drug eruptions, patients with possible drug reactions should promptly be recognized, worked up, and treated. Drug reactions are common in the elderly population due to age-related alterations in metabolism, excretion of medications, and polypharmacy. This review discusses the epidemiology, pathogenesis, clinical presentation, diagnosis, and management of drug eruptions that providers commonly encounter in the care of the geriatric population. An algorithm for an approach to patients with a suspected drug eruption is presented.

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.

The differential clinical diagnosis between drug-induced exanthema (DIE) and virus- or bacteria-induced exanthema (VBIE) is frequently not easy because the serologic analysis for virus and bacteria and skin tests are not always exhaustive. In these cases, only the oral challenge test is nullifying.This study wants to identify 1 or more structural changes and/or cytokine markers that might be helpful in discriminating the etiology and the possible correlation with the clinical features, type of the involved drug, blood and skin eosinophilia, and time of skin biopsy.Involved non-sun-exposed skin biopsy specimens were obtained from 36 patients with DIE and 30 patients with VBIE. Blood investigations, skin tests, and oral rechallenge tests were carried out in all subjects. The histopathologic features and the immunohistochemical expression of a cytokine panel [fatty acid synthase-ligand, granzyme B, interleukin (IL) 2, IL-4, IL-5, IL-10, IL-13, interferon γ, perforin, tumor necrosis factor α] were analyzed.Finally, DIE and VBIE have distinct skin cytokine profile (IL-5 alone or in combination with granzyme B and perforin in DIEs was statistically more frequent than in VBIEs, mainly when skin biopsy was carried out within 2 days from clinical onset), which might be helpful in discriminating the etiology.

The development of targeted therapies has ushered in a new era in the management of melanoma. Inhibitors of the RAS-RAF-MEK-ERK pathway have taken the center stage with development at a rapid pace. Vemurafenib was recently approved by regulatory agencies, and other agents (e.g. dabrafenib) are in various stages of clinical testing. These agents are producing remarkable results for patients, but are also presenting new challenges. Clinical toxicities and drug resistance are topmost issues. Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations. Published trials and initial observations reflect a toxicity profile (e.g. squamous cell carcinomas/keratoacanthomas, maculopapular rashes, hyperkeratosis) that is distinct from cutaneous toxicities from EGFR and mTOR inhibitors (acneiform rash, paronychia, xerosis). Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities, skill sets unique to dermatologists. All these pose significant challenges to clinicians, and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life. In this manuscript, we provide an overview of the emerging scientific literature on dermatological adverse events arising out of BRAF inhibition.

Subacute cutaneous lupus erythematosus (SCLE) is a form of cutaneous lupus erythematosus that most often presents as scaly, erythematous, papulosquamous, or annular papules and plaques in a photodistributed pattern. Subacute cutaneous lupus erythematosus is classically considered to be either idiopathic or drug induced. There have been few reports of SCLE arising in the setting of malignancy, raising the possibility that paraneoplastic SCLE may be a rare distinct subset of lupus. We report a case of SCLE arising as a paraneoplastic phenomenon in the setting of small cell lung cancer. Given the close temporal proximity of the detection of malignancy and the development of the rash in our patient, we believe this report presents a case of paraneoplastic SCLE. The presentation of new-onset idiopathic SCLE should prompt a careful review of systems and age-appropriate cancer screening, as SCLE may be a sign of an occult malignancy.

Fixed drug eruption (FDE) is a drug-induced reaction that typically recurs at the same cutaneous and/or mucosal site, with singular or multiple lesions. FDE usually presents with round, sharply marginated, erythematous to violaceous macules, evolving into oedematous plaques and healing with residual pigmentation.1,4 Less common presentations include eczematous, hyperpigmented, papular, targetoid, purpuric,1 psoriasiform,2 urticarial,3 nodular4 or bullous5 lesions. The lips, the extremities and genitalia are frequently involved.1 Sulfonamides are the most commonly implicated drugs, followed by tetracyclines, azoles and nonsteroidal anti-inflammatory drugs (NSAIDs).(1) A 59-years-old woman presented with irritation and foreign body sensation in the left eye. On clinical observation, mild injection and edema of conjunctiva was noted, along with an erythematous plaque with moderate scaling on the lower eyelid (Fig.1a). Ophthalmological evaluation revealed a best-corrected visual acuity of 20/20 in both eyes, no corneal abnormalities, intraocular pressure, fundus examination and Schirmer test within normal limits. Six hours after ocular symptoms development, skin rash occurred, with circular erythematous maculae spreading on the trunk, arms and legs (Fig.1b). The patient reported having ocular symptoms about 12 hours after the ingestion of a 100 mg Nimesulide sachet: she had assumed that drug as a self-prescription for a low back pain. Detailed clinical history did not reveal any significant medical disease nor allergies or previous drug reactions.

Data describing the management of pediatric patients admitted to a hospital under the care of a dermatologist and dermatology hospital consults for pediatric inpatients are limited. We aim to describe the role of an inpatient hospital service jointly run by dermatology and pediatrics and the activities of a pediatric dermatology hospital consult service. We retrospectively identified pediatric (age < 18 yrs) dermatology inpatients and hospital consult patients from January 1, 2009, through December 31, 2010. We examined patient demographics, indications for admission, length of stay, treatment provided, consult-requesting service, and consult diagnosis. One hundred eight admissions were by a dermatologist. The mean age was 5.8 years; the median length of stay was 3 days. Indications for admission included atopic dermatitis (86.1%), psoriasis (3.7%), and eczema herpeticum (2.8%). The main treatment provided was wet dressings (97.2%). Eighty-three dermatology hospital consults were requested. The mean age was 7.4 years. The main indications for dermatology consultation included drug rash (12.1%), cutaneous infections (12.1%), contact dermatitis (9.6%), psoriasis (8.4%), atopic dermatitis (6.0%), and hemangiomas (6.0%). This study describes the utility of the hospital pediatric dermatology inpatient and consult services in treating patients with severe skin disease.