Epidermal growth factor receptor inhibitors side effects

Epidermal growth factor receptor (EGFR) inhibitors are a new group of drugs used in the treatment of several malignancies. Three molecules are approved at the moment: gefitinib and erlotinib for the treatment of non-small-cell lung cancer, and cetuximab for colorectal cancer. These drugs originate cutaneous side effects with a high frequency: acneiform rashes, paronychia and generalized xerodermia. In this paper we review these common side effects and how to manage them.     

Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma

OBJECTIVES: To examine dermatologic adverse effects of lenalidomide in patients with amyloidosis and multiple myeloma and to determine whether the adverse effects are different when lenalidomide is used alone compared with when it is used in combination with dexamethasone. DESIGN: Retrospective review of medical records. SETTING: Tertiary referral center. PATIENTS: Seventy-five patients with multiple myeloma and 23 patients with amyloidosis participating in clinical trials. INTERVENTION: In the 75 patients with multiple myeloma, lenalidomide was the treatment in 24 and lenalidomide and dexamethasone in 51. In the 23 patients with amyloidosis, lenalidomide was used alone. MAIN OUTCOME MEASURES: The frequency, type, severity, and time of onset of all skin eruptions that were temporally related to lenalidomide treatment were recorded. RESULTS: In the patients with amyloidosis treated with lenalidomide, 10 (43%) had rashes. In the patients with multiple myeloma, rashes occurred in 7 (29%) of those receiving lenalidomide alone and in 15 (29%) of those receiving lenalidomide and dexamethasone. The rashes were characterized as morbilliform, urticarial, dermatitic, acneiform, and undefined. Severe rashes required permanent discontinuation of lenalidomide therapy in 2 patients. In 23 patients (72%), rashes occurred in the first month after therapy was initiated; however, delayed-onset rashes occurred in 9 (28%). CONCLUSIONS: The prevalence of dermatologic adverse effects in patients receiving lenalidomide was higher in those with amyloidosis than in those with multiple myeloma. The prevalence of skin eruptions was not diminished by the concurrent use of systemic corticosteroids. Most skin eruptions were mild and did not necessitate withdrawal of lenalidomide therapy.     

Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo‐controlled,randomized phase III clinical trial (LIBERTY AD CAFÉ)

Atopic dermatitis (also called AD or eczema) is a chronic skin disease found in up to 1 in 10 adults, causing itchy rashes that may cover most of the body. Ciclosporin, an oral treatment (taken by mouth) commonly used for AD, doesn't always work and can have significant side effects. Other broadly‐acting oral medications are sometimes used, but not approved, for AD. Dupilumab is a new medication approved in many countries for adults with inadequately controlled moderate‐to‐severe AD. Dupilumab specifically targets pathways in the body that drive AD. Researchers in Europe evaluated how well dupilumab injections improved rashes, itch, and daily lives of people whose AD required ciclosporin, but for whom ciclosporin wasn't working or caused intolerable side effects, or whose medical conditions prevented its use. Among 325 participants, 110 received 300 mg dupilumab once‐weekly, 107 received it every two weeks, and 108 received placebo (dummy drug) once‐weekly. All participants used topical (applied to the skin) corticosteroids during the 16‐week study. Dupilumab improved AD rashes: at Week 0, participants’ Eczema Area and Severity Index (EASI) scores were about 31 (scale: 0–72), but by Week 16, 59% to 62% of dupilumab‐treated participants achieved 75% or greater improvement in EASI, versus 29.6% of people on placebo. Dupilumab also improved itch, other symptoms, mood, and quality of life. Conjunctivitis and injection‐site reactions were more frequent among dupilumab‐treated patients; skin infections (excluding herpes) and AD exacerbations (worsening) were more frequent with placebo. The authors conclude that dupilumab plus topical corticosteroids significantly improved AD even in adults with AD who had previously failed treatment with or were unable to use ciclosporin.     

Arzneimittelnebenwirkungen bei antiretroviraler Therapie

The introduction of highly active antiretroviral therapy (HAART) has resulted in tremendous improvements in morbidity and mortality in HIV-infected patients. However, the use of these drugs has coincided with an increasing number of reports of gastrointestinal, hepatic or metabolic side effects. Soon after beginning antiretroviral treatment drug rashes, hypersensitivity reactions, immune reconstitution syndrome or injection site reaction are frequently seen. Under HAART dyslipidemia, impaired glucose metabolism and elevated liver function are observed. In the later treatment phase, lipodystrophy, a combination of peripheral lipoatrophy and central fat accumulation, occurs.     

Sympathomimetic Drug Allergy

Introduction: Sympathomimetic (α-adrenergic) drugs are mainly used because of their vasoconstrictor properties, for nasal congestion, or as mydriatics. Although sympathomimetic drugs are used often, allergic reactions are rare, especially when the drugs are administered systemically. Cross-reactivity may exist among catecholamine derivatives, although reported data on this are contradictory. In this study, we investigate if there is cross-reactivity in patch tests among these drugs. Material and methods: Patch tests with 10% phenylephrine and 10% pseudoephedrine in petrolatum, and 10% and 20% ephedrine, 10% phenylpropanolamine, 5% fepradinol, 1% methoxamine, and 10% oxymetazoline, all administered in dimethyl sulfoxide (DMSO), were carried out in 14 patients with a history of allergy to any of these drugs. DMSO was used as the negative control. Results: All patients except one (patient number five) showed positive patch-test reactions to at least two different drugs. Nine patients (64.3%) were cross-sensitized to three or more different drugs, and 57.1% of patients were sensitized to four or more sympathomimetic drugs. Patients who experienced generalized rashes caused by orally administered pseudoephedrine had a stronger response and more cross-reactivity with other sympathomimetic drugs in patch tests than those who experienced local contact dermatitis. Conclusions: We conclude that there is cross-reactivity among the different sympathomimetic drugs tested, especially if the drug is administered systemically.     

Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes

Background: Morphologically and histopathologically, drug‐ and non‐drug‐induced maculopapular rashes can be almost indistinguishable. It has been postulated that Fas‐ligand (Fas‐L) is involved in the pathogenesis of drug rashes but not in the genesis of rashes, such as viral exanthems, that are not induced by medications. Aim: This study sought to determine if epidermal Fas‐L is a distinguishing feature in the pathology of drug and non‐drug maculopapular rashes. Methods: Archived skin biopsies of patients with a confirmed diagnosis of drug or non‐drug maculopapular rashes (n = 10 each) and positive and negative controls were retrieved for immunohistochemical staining for Fas‐L. The proportion of Fas‐L‐positive skin biopsies were compared. The presence of tissue eosinophilia was also evaluated. Results: Ten percent of non‐drug‐induced rashes were Fas‐L positive compared to 50% of drug rashes (p = 0.05). Twenty percent of non‐drug exanthems had moderate tissue eosinophilia, while 60% from drug rashes had moderate to dense tissue eosinophilia (p = 0.17). Conclusion: There is a trend toward Fas‐L being more prevalent in the epidermis of drug maculopapular rashes, although this did not reach statistical significance. This is possibly because of the small sample size. Wang ECE, Lee JSS, Tan AWH, Tang MBY. Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes.     

A prospective self-controlled phase II study of imiquimod 5% cream in the treatment of infantile hemangioma

Imiquimod has been reported to be efficacious in the topical treatment of uncomplicated infantile hemangiomas (IH). However, due to the natural tendency of IH to involute spontaneously, prior uncontrolled efficacy and safety studies have been called into question. We conducted a prospective self-controlled phase II study of imiquimod initially applied to uncomplicated, proliferative superficial or mixed IHs treating half of each IH once every other night for 16 weeks, leaving the other half untreated. After 16 weeks, an independent dermatologist evaluated the color, area, and volume of each half of the hemangioma. Of the 44 patients treated, the total effective rate was 80% (n = 35), with an overall resolution rated as excellent or good rate in 39% of lesions (n = 17/44). The relapse rate was 2% (n = 1). Side effects were noted in 61% (n = 27) including erythema or/and edema (n = 16%, 7), local itching (n = 7%, 3), peeling (n = 7%, 3), erosion (n = 5%, 2), crusting (n = 55%, 24), ulceration (n = 9%, 4), and scarring (n = 5%, 2). Some patients had two or more side effects. Most were judged to be mild to moderate and did not result in treatment being interrupted. Crusting or ulceration was noted to cause post-treatment skin reactions, such as texture change, whereas cases without crusting involuted to almost normal skin. No local infection or systemic reaction was observed. The difference in effective rate and side effect incidence between superficial and mixed IH was not statistically significant. Imiquimod 5% cream can be an effective and safe treatment option for superficial mixed IH in which the superficial component predominates. The recurrence rate is low, but local reactions including crusting can develop and result in post-treatment skin changes.     

Therapeutic benefits in dermatological therapy. Evaluation of therapy from the physician's und patient's perspective in psoriasis and atopic dermatitis

BACKGROUND: The patient's opinion has received only little consideration in current health-political discussions so far. This study examines the question of agreement between physicians and patients regarding their expectations of therapy and evaluation of its' usefulness. PATIENTS AND METHODS: 133 patients with psoriasis vulgaris (n=73) or atopic dermatitis (n=60) as well as medical personnel (n= 119) were assessed concerning the priority of therapy goals by means of a specially-designed questionnaire. RESULTS: There was overall agreement on the definition of therapy goals in the improvement of clinical symptoms and the importance of side effects between medical personnel and patients. Psychological distress and social improvements were clearly overrated by the medical staff, whereas the need for less therapeutic expenditure was clearly underestimated. CONCLUSIONS: The conventional evaluation of drugs and therapies covers the effectiveness and the side effects, topics about which patients and physicians are in general accordance. As far as further evaluation criteria are concerned, discussions should reflect the patient's opinion's, since it cannot be assumed that their perspective is adequately represented by physicians.     

Toxic Epidermal Necrolysis Due to Concomitant Use of Lamotrigine and Valproic Acid

Anti-epileptic drugs can be associated with a wide spectrum of cutaneous adverse reactions ranging from simple maculopapular rashes to more severe and life threatening reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis. These rashes are well documented with older antiepileptic drugs like phenytoin, phenobarbitone and carbamazapine. Lamotrigine is a newer, unrelated antiepileptic drug that causes skin rashes in 3-10% of new users. Higher starting dose or rapid escalation, concurrent treatment with valproic acid, and a previous history of a rash with other antiepileptic drugs are well recognized risk factors for lamotrigine related serious rashes. We report two patients with toxic epidermal necrolysis, resulting from concomitant use of lamotrigine and valproic acid. It is emphasized that clinicians adhere to the recommended dosage guidelines and adopt a slow dose titration when initiating treatment with lamotrigine.     

Phototherapy of psoriasis: comparative experience of different phototherapeutic approaches

BACKGROUND: Broad-band UVB alone or in combination with different topical drugs (anthralin, calcipotriol), systemic PUVA and bath-PUVA therapy are very effective and well-established treatment modalities for psoriasis. OBJECTIVE: The aim of this retrospective study was to assess which of these routinely applied phototherapeutic modalities might be most effective and safe for the treatment of plaque-type psoriasis. METHODS: Patients (n = 203) with moderate to severe (pretreatment Psoriasis Area and Severity Index score between 12 and 35) chronic plaque-type psoriasis treated between 1992 and 1998 at our department with either UVB (with/without anthralin or calcipotriol; n = 97), systemic PUVA (n = 19) or bath-PUVA therapy (n = 87) were evaluated for efficacy, duration of treatment, number of treatments necessary for complete remission (CR), cumulative light dose, side effects of therapy and duration of remission after therapy. RESULTS: No statistically significant difference comparing the efficacy of bath-PUVA (CR in 72.4%), PUVA (CR in 89.5%) and UVB phototherapy (CR in 69.1%) was found. Although the duration of therapy was significantly longer for bath-PUVA (66 +/- 42 days) as compared to UVB treatment (50 +/- 27 days), the mean number of treatments did not differ significantly between bath-PUVA (28 +/- 12), UVB therapy (30 +/- 12) and PUVA (26 +/- 13). Significantly fewer side effects of phototherapy were observed with bath-PUVA (14.9%) therapy compared to UVB treatment (30.9%). Also, the duration of remission after successful therapy was significantly longer for bath-PUVA (8.4 +/- 3.5 months) as compared to UVB phototherapy (5.1 +/- 4.2 months). CONCLUSION: Bath-PUVA therapy has some advantages over UVB phototherapy in the treatment of psoriasis: fewer UV-related acute side effects and a longer period of remission after therapy. However, the choice of treatment with either UVB, bath-PUVA or systemic PUVA should also be based on a history of previous response to treatment and patient considerations, including compliance and responsibility for following the precautions to avoid potential side effects.     

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.     

Topical Steroid Awareness and Abuse: A Prospective Study among Dermatology Outpatients

Background:Topical steroids are one of the most commonly abused drugs. There are only a few studies available which have highlighted the severity of this problem in India. However, these studies have concentrated mainly on the topical steroid abuse and its side effects over the face.Aims:The aim of this study was to know the awareness among the people about various commonly available topical steroids and their combinations irrespective of usage and to know the extent of misuse of these drugs. Along with this, we also tried to find the source of recommendation of these medicines which will help to sensitize people about this menace.Results:A total of 1000 adult patients were included in the study, out of which 809 (80.9%) patients had heard about at least one of the topical steroids or its combinations mentioned in the questionnaire. Six hundred and twelve (61.2%) patients had used these creams. Acne and pigmentation were the most common indications for which topical steroid was used. These medicines were recommended by general practitioners in 302 (49.5%) patients and pharmacists in 71 (11.6%) patients. Totally, 318 (51.9%) patients complained of some form of side effect after using these creams. Aggravation of the symptoms and increased pigmentation were the most common adverse effects.Conclusion:Misuse of topical steroids not just over the face but also as a cream for any skin problem is quite common. Most of the times, it is recommended by general practitioners or pharmacists. It is very important to sensitize these people about the possible complications of these drugs and the extent of problem the society is facing because of irrational and unregulated use of these drugs.     

SCLE and dermatomyositis in anti-PD-1 therapy

PD-1 inhibitors are a relatively new type of drug that are used to treat patients with metastatic (widespread) cancers. Examples include drugs called pembrolizumab and nivolumab. Unfortunately this type of treatment can be associated with auto-immune side effects, which means that the body's immune system, which protects against infection, wrongly attacks some parts of the body. Examples of auto-immune side effects linked to PD-1 inhibitors include colitis, thyroid disease and skin inflammation, including eczema-like rashes and vitiligo. The authors of this study, based at Duke University, USA, describe two patients who developed a type of lupus called subacute cutaneous lupus erythematosus (SCLE) while on PD-1. SCLE is an autoimmune disease. In one case, the drug that was being used, nivolumab, was discontinued; the oncologists unsuccessfully treated the patient with infliximab, a type of drug called a TNFα inhibitor, but the eruption came under control with creams and hydroxychloroquine treatment by the dermatologists. Because nivolumab was helping to treat the patient's cancer, the drug was re-introduced but unfortunately he then developed features of another autoimmune condition, dermatomyositis, and the drug was stopped. The second patient developed SCLE following pembrolizumab treatment, which she discontinued as it was not having an effect on her cancer. Again her SCLE came under control with treatment. The authors observed that treatment with a TNF inhibitor would not be ideal in this situation, because it can itself cause lupus. Whereas SCLE is well recognised as a side effect of many drugs, it is unusual to see two different connective tissue diseases, lupus and dermatomyositis, caused by one drug. The authors advise not continuing the drug in this situation.     

Fumaric acid esters in the management of severe psoriasis

BACKGROUND: Fumaric acid esters (FAEs) offer an effective alternative to patients with psoriasis in whom other systemic agents are contraindicated or have failed. OBJECTIVE: We assessed the efficacy and side effect profile of FAEs in a group of patients with psoriasis. METHODS: A retrospective study was carried out on patients treated with FAEs over 21 months. Information was gathered from patients' notes. Dosage, response and side effects were recorded. RESULTS: In total, 31 patients were included. The mean age was 46.8 years. All patients had been treated with other modalities and 61.5% had received previous systemic treatment. There was good to excellent response in 58.6% of patients. Subjective side-effects were common (87.1%), and lymphopenia occurred in 61.3%. The drug was not tolerated by one-fifth of patients. CONCLUSION: The relatively low toxicity and absence of hepatotoxicity makes FAEs a reasonable first-line systemic treatment in selected patients with difficult psoriasis.     

Disease Control for Patients with Psoriasis Receiving Continuous Versus Interrupted Therapy with Adalimumab or Etanercept: A Clinical Practice Study

Background

Studies analyzing the efficacy and safety of interrupted psoriasis therapy with biologic drugs have not reported clear benefits in routine clinical practice.

Objectives

To identify differences in the disease control of psoriasis patients undergoing continuous or interrupted therapy with adalimumab or etanercept.

Methods

This retrospective 3-year cohort study (interrupted vs. continuous therapy) involved 77 patients (47 adalimumab, 30 etanercept) who were managed under clinical practice conditions. The proportion of episodes with a Physician Global Assessment (PGA) ≥3 during the follow-up in each study cohort was the primary effectiveness endpoint. The relative risk of PGA ≥3 episodes in the interrupted therapy cohort was analyzed.

Results

Twenty-one patients receiving adalimumab were included in the interrupted therapy cohort (44.7 %), and 26 were included in the continuous therapy cohort (55.3 %). In the group of etanercept, 21 patients received continuous treatment (70.0 %), and nine patients started at least one interruption period (30.0 %). The proportion of PGA ≥3 episodes in continuous and interrupted groups were 19.2 % vs. 33.3 % for adalimumab patients (p = 0.27), and 42.9 % vs. 55.6 % in patients treated with etanercept (p = 0.52). The relative risk of PGA ≥3 episodes with interrupted therapy was 1.73 (95 % confidence interval 0.64–4.68; p = 0.27), and 1.30 (95 % confidence interval 0.60–2.79; p = 0.52) in the adalimumab and etanercept groups, respectively.

Conclusion

In routine clinical practice, interrupted therapy with adalimumab or etanercept can provide adequate disease control for a subgroup of patients with excellent response to biologic drugs.     

THE TREATMENT OF HIRSUTISM: EXPERIENCE WITH CYPROTERONE ACETATE AND SPIRONOLACTONE

Twenty-three patients were treated with either cyproterone acetate (n = 14) or spirono- lactone (n = 12) for a period of not less than twelve months. Plasma and urinary androgen levels fall significantly with cyproterone acetate but showed little change with spironolactone. Sebum production fell in both groups as did hair diameters. The frequency of cosmetic measures used by the patients was reduced during both forms of therapy. No serious side effects were observed. However, these drugs should not be used in patients without adequate contraception because of the risk to the foetus. Further evaluation of the relative merits of the two drugs is required.     

DRESS syndrome associated with raltegravir

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or drug-induced hypersensitivity is a potentially life-threatening drug hypersensitivity syndrome most commonly associated with anticonvulsants, allopurinol, long-acting sulfonamides, dapsone, and minocycline. In the setting of HIV infection, the antiretroviral medicines abacavir, nevirapine, and efavirenz have all shown well-documented associations with DRESS syndrome. There has only been one case (in a poster presentation) of this syndrome in a patient who was taking raltegravir.     

How to manage hypersensitivity reactions to biological agents?

Biological agents induce cutaneous adverse drug reactions (CADR) different from those observed with xenobiotics. Type alpha is the cytokine release syndrome, type beta are hypersensitivity reactions and type gamma is a cytokine imbalance syndrome. Infusion-reactions, anaphylactoid reactions occur with various biological agents administered intravenously. In non-severe cases the infusion rate has to be reduced, in severe reactions, the treatment must be stopped and resuscitation carried out with corticosteroids and epinephrine. Reactions may be due to an alpha syndrome but a true allergy could be involved as demonstrated in some patients with IgE antibodies to the galactose-alpha-1,3-galactose portion of the cetuximab or anti infliximab-IgE. Some desensitisation protocols have been published. Non allergic itching and eczema-like lesions are frequent with epidermal growth factor receptor inhibitors. Rash or desquamation was observed in 40% of cases with antiangiogenic agents, 90% of patients treated with imatinib have rashes, oedema or pruritus and a non-allergic periorbital oedema. Severe CADR, such as Stevens-Johnson syndrome, can be provoked. Delayed readings of intradermal tests could be of value in managing patients with a maculopapular rash due to interferon. Anaphylaxis attributed to omalizumab seems to be rare (0.2%) and skin rashes occur in 7% of cases. Anaphylactoid reactions occur in 1% of patients treated with natalizumab. In the case of anti-natalizumab antibody-mediated reactions, treatment should be stopped. These allergic-like side effects of new biological agents must be known and reported to Pharmacovigilance agency networks.     

登革热皮疹87例分析

目的 分析登革热皮疹的临床表现及特点.方法 对2007年8-10月本院收治的126例登革热住院患者中伴发皮疹的87例临床资料进行分析.结果 登革热患者69.0%(87/126)出现皮疹,出疹时间在发热后1～11大,59.7%(52/87)于发热后3～7天出疹,67.8%(59/87)出疹无明显顺序.43.7%(38/87)为躯干合并四肢出疹,34.5%(30/87)为四肢出疹.皮疹为斑疹者占14.9%(13/87),斑丘疹占14.9%(13/87),丘疹占18.4%(16/87),各种出血疹占26.4%(23/87),混合皮疹占21.8%(19/87).结论 登革热患者在发热后3～7天出疹;出疹部位以四肢躯干为多;皮疹形态有斑疹、斑丘疹、丘疹、出血疹、疱疹等.