Drug-induced Skin Disease Research Articles

Drug eruption and drug-induced skin diseases in the elderly patients

Drug eruption and drug-induced skin diseases in the elderly patients

Adverse Cutaneous Drug Reaction

Drug-induced skin disease or cutaneous adverse drug reaction (CADR) is a term encompassing clinical manifestations of the skin, induced by drugs or their metabolites. The skin is the organ most commonly affected by drug reactions, affecting up to 10% of hospitalized patients and can occur in 1–3% of her polypharmacy patients. Most CADRs are mild or self-resolving conditions. The most frequently reported are macular papular rash, urticaria/angioedema, fixed drug eruption and erythema multiforme. Less common but more severe patterns include, drug reactions with eosinophilia and systemic symptoms, and the Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Almost any drug can induce CADR, but antibiotics (especially sulfa drugs), nonsteroidal anti-inflammatory drugs, and antiepileptic drugs are most commonly implicated. Various mechanisms are involved in the pathogenesis of CADR, some of which are still unknown. Which may be immune mediated or non-immune mediated Recognition of a specific CADR depends primarily on the physician's ability to perform a detailed clinical examination, an accurate description of the skin lesion morphology, and corroboration of laboratory and/or skin biopsy findings.

Two cases of toxic epidermal necrolysis successfully treated with cyclosporine in covid pandemic

Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. We have two cases of TEN presented within 3 months and successfully treated with cyclosporine.

Drugs and the skin: A concise review of cutaneous adverse drug reactions.

Drug-induced skin disease or cutaneous adverse drug reactions (CADRs) are terms that encompass the clinical manifestations of the skin, mucosae and adnexa induced by a drug or its metabolites. The skin is the organ most frequently affected by drug reactions, which may affect up to 10% of hospitalized patients and occur in 1-3% of multimedicated patients. Most CADRs are mild or self-resolving conditions; however, 2-6.7% of could develop into potentially life-threatening conditions. CADRs represent a heterogeneous field and can be diagnostically challenging as they may potentially mimic any dermatosis. Currently, there are between 29-35 different cutaneous drug-reaction patterns reported ranging from mild dermatitis to an extensively burnt patient. The most frequently reported are maculopapular rash, urticaria/angioedema, fixed drug eruption and erythema multiforme. Less common but more severe patterns include erythroderma, drug reaction with eosinophilia and systemic symptoms, and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Almost any drug can induce a CADR, but antibiotics, nonsteroidal anti-inflammatory drugs and antiepileptics are the most frequently involved. Different mechanisms are involved in the pathogenesis of CADRs, although in some cases, these remain still unknown. CADRs could be classified in different ways: (i) type A (augmented) or type B (bizarre); (ii) immediate or delayed; (iii) immune-mediated or nonimmune-mediated; (iv) nonsevere or life-threatening; and (v) by their phenotype, including exanthematous, urticarial, pustular and blistering morphology. Recognizing a specific CADR will mostly depend on the ability of the physician to perform a detailed clinical examination, the proper description of the morphology of the skin lesions and supporting laboratory and/or skin biopsy findings.

Drug eruptions: Great imitators

Drug eruptions are among the great masqueraders that sometimes cause diagnostic challenges in clinical practice. Pharmacologic agents may induce skin changes, sharing the same pathophysiologic mechanisms of specific dermatoses, or inducing drug eruptions with different pathologic mechanisms that have similar clinical presentations. The former conditions are usually called drug-induced skin diseases, whereas the latter conditions are termed “dermatosis–like drug eruptions.” Both types are great imitators in dermatologic practice and can be easily misdiagnosed as other diseases or lead to unrecognized causative agents.

Toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. The exact pathogenic mechanism of TEN is still uncertain. Recent advances in this field have led to the identification of several factors that might contribute to the induction of excessive apoptosis of keratinocytes. In addition, specific human leukocyte antigen types seem to be associated with certain drugs and the development of TEN. As well-controlled studies are lacking, patients are treated with various immunomodulators (e.g. intravenous immunoglobulin) in addition to the best supportive care.

Expression pattern of human ATP-binding cassette transporters in skin.

ATP-binding cassette (ABC) transporters transport a variety of substrates across cellular membranes coupled with hydrolysis of ATP. Currently 49 ABC transporters consisting of seven subfamilies, ABCA, ABCB, ABCC, ABCD, ABCE, ABCF, and ABCG, have been identified in humans and they are extensively expressed in various tissues. Skin can develop a number of drug-induced toxicities' such as Stevens–Johnson syndrome and psoriasis. Concentration of drugs in the skin cells is associated with the development of adverse drug reactions. ABC transporters play important roles in absorption and disposition of drugs in the cells; however, the expression pattern of human ABC transporters in the skin has not been determined. In this study, the expression patterns of 48 human ABC transporters were determined in the human skin as well as in the liver and small intestine. Most of the ABCA, ABCB, ABCC, ABCD, ABCE, and ABCF family members were highly or moderately expressed in the skin, while ABCG family members were slightly expressed in the skin. Significant interindividual variability was also observed in the expression levels of those ATP transporters in the skin, except for ABCA5 and ABCF1, which were found to be expressed in all of the human skin samples tested in this study. In conclusion, this is the first study to identify the expression pattern of the whole human ABC family of transporters in the skin. The interindividual variability in the expression levels of ABC transporters in the human skin might be associated with drug-induced skin diseases.

In vitro detection of cytotoxic T and NK cells in peripheral blood of patients with various drug‐induced skin diseases

Cytotoxic cells are involved in most forms of drug-induced skin diseases. Till now, no in vitro test addressed this aspect of drug-allergic responses. Our report evaluates whether drug-induced cytotoxic cells can be detected in peripheral blood of nonacute patients with different forms of drug hypersensitivity, and also whether in vitro detection of these cells could be helpful in drug-allergy diagnosis. GranzymeB enzyme-linked immunosorbent spot-forming (ELISPOT) and cell surface expression of the degranulation marker CD107a were evaluated on peripheral blood mononuclear cells from 12 drug-allergic patients in remission state and 16 drug-exposed healthy controls. In 10/12 allergic patients culprit but not irrelevant drug elicited granzymeB release after 48-72 h stimulation. It was clearly positive in patients with high proliferative response to the drug, measured in lymphocyte transformation tests. In patients, who showed moderate or low proliferation and low drug-response in granzymeB ELISPOT, overnight preincubation with interleukin (IL)-7/IL-15 enhanced drug-specific granzymeB release and allowed to clearly identify the offending agent. CD107a staining was positive on CD4+/CD3+, CD8+/CD3+ T cells as well as CD56+/CD3- natural killer cells. None of the drug-exposed healthy donors reacted to the tested drugs and allergic patients reacted only to the offending, but not to tolerated drugs. GranzymeB ELISPOT is a highly specific in vitro method to detect drug-reacting cytotoxic cells in peripheral blood of drug-allergic patients even several years after disease manifestation. Together with IL-7/IL-15 preincubation, it may be helpful in indentifying the offending drug even in some patients with weak proliferative drug-response.

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.

Soluble FAS Ligand: A Discriminating Feature between Drug-Induced Skin Eruptions and Viral Exanthemas

The clinical spectrum of cutaneous eruptions comprises benign variants like maculopapular rashes (MPRs) and potentially life-threatening events such as toxic epidermal necrolysis (TEN). Apoptosis of keratinocytes is a common histopathological feature of all these drug eruptions. As in skin lesions of TEN and Stevens-Johnson syndrome patients, apoptosis of keratinocytes is often accompanied by an only sparse cellular infiltrate, a soluble fatty acid synthetase ligand (sFASL)-mediated mechanism of keratinocyte cell death is postulated. In MPR patients, evidence for the occurrence of a similar process could not be established so far. We therefore examined sera and lesional skin sections from patients with clinical variants of drug eruptions for FASL expression using a sandwich ELISA and immunohistochemistry, respectively. As controls, healthy persons and patients with other inflammatory skin diseases such as viral exanthema were analyzed. Elevated levels of FASL were detected not only in TEN patients but also in sera and lesional skin of patients with MPR. In contrast, sFASL was repeatedly negative in all viral exanthemas and healthy controls tested. Thus, determination of sFASL serum concentration may represent a discriminating tool between drug rashes and viral exanthemas.

Cellular and molecular pathophysiology of cutaneous drug reactions.

Hypersensitivity reactions to drugs can cause a variety of skin diseases like maculopapular, bullous and pustular eruptions. In recent years increasing evidence indicates the important role of T cells in these drug-induced skin diseases. Analysis of such drug-specific T cell clones has revealed that drugs can be recognized by alpha beta-T cell receptors, not only if bound covalently to peptides, but also if the drug binds in a rather labile way to the presenting major histocompatibility complex (MHC)-peptide. This presentation is sufficient to stimulate T cells. In maculopapular exanthema (MPE), histopathological analysis typically shows a dominant T cell infiltration together with a vacuolar interface dermatitis. Immunohistochemical studies demonstrate the presence of cytotoxic CD4+ and to a lesser degree of CD8+ T cells, which contain perforin and granzyme B. They are close to keratinocytes that show signs of cell destruction. Expression of Fas ligand is barely detectable, suggesting that cytotoxic granule exocytosis may be the dominant pathway leading to keratinocyte cell damage. While in MPE, the killing of cells seems to be predominantly mediated by CD4+ T cells, patients with bullous skin disease show a strong CD8+ T cell migration to the epidermis. This is probably due to a preferential presentation of the drug by MHC class I molecules, and a more extensive killing of cells that present drugs on MHC class I molecules. This might lead to bullous skin diseases. In addition to the presence of cytotoxic T cells, drug-specific T cells also orchestrate the inflammatory skin reaction through the release and induction of various cytokines [i.e. interleukin (IL)-5, IL-6, tumor necrosis factor-alpha and interferon-gamma] and chemokines (RANTES, eotaxin or IL-8). The increased expression of these mediators seems to contribute to the generation of tissue and blood eosinophilia, a hallmark of many drug-induced allergic reactions. However, in acute generalized exanthematous pustulosis (a peculiar form of drug allergy), neutrophils represent the predominant cell type within pustules, probably due to their recruitment by IL-8 secreting drug specific T cells and keratinocytes.

Inhibition of Toxic Epidermal Necrolysis by Blockade of CD95 withIntravenous Immunoglobulin

1. Viard I, 2. Wehrli P, 3. Bullani R, 4. et al. (1998) Science. 282:490–493. [OpenUrl][1][Abstract/FREE Full Text][2] #### Purpose of the Study Toxic epidermal necrolysis (TEN) is a severe, drug-induced skin disease characterized by epidermal cell death leading to loss of skin. TEN is most frequently induced by sulfonamides, anticonvulsants, or nonsteroidal antiinflammatory drugs and occurs in 0.8 cases per million with a mortality of 30%. Keratinocyte apoptosis (programmed cell death) is abnormally increased in TEN but the mechanism for the increase is unknown. This study evaluated the role of the “death receptor,” fas (CD95), and its ligand, fas ligand (FasL), in TEN … [1]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.issn%253D0036-8075%26rft.aulast%253DViard%26rft.auinit1%253DI.%26rft.volume%253D282%26rft.issue%253D5388%26rft.spage%253D490%26rft.epage%253D493%26rft.atitle%253DInhibition%2Bof%2BToxic%2BEpidermal%2BNecrolysis%2Bby%2BBlockade%2Bof%2BCD95%2Bwith%2BHuman%2BIntravenous%2BImmunoglobulin%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.282.5388.490%26rft_id%253Dinfo%253Apmid%252F9774279%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=sci&resid=282/5388/490&atom=%2Fpediatrics%2F104%2FSupplement_2%2F367.2.atom

Inhibition of Toxic Epidermal Necrolysis by Blockade of CD95 withIntravenous Immunoglobulin

Viard I, Wehrli P, Bullani R, et alScience.2821998490493Toxic epidermal necrolysis (TEN) is a severe, drug-induced skin disease characterized by epidermal cell death leading to loss of skin. TEN is most frequently induced by sulfonamides, anticonvulsants, or nonsteroidal antiinflammatory drugs and occurs in 0.8 cases per million with a mortality of 30%. Keratinocyte apoptosis (programmed cell death) is abnormally increased in TEN but the mechanism for the increase is unknown. This study evaluated the role of the “death receptor,” fas (CD95), and its ligand, fas ligand (FasL), in TEN and the possible therapeutic use of intravenous gammaglobulin (IVIG) for this disorder.Seven patients (adults and children) with TEN, 4 controls with drug-induced maculopapular rashes, and 7 healthy controls were evaluated.Enzyme-linked immunosorbent assay was used to measure serum concentration of soluble FasL; immunohistochemical staining of skin biopsy tissue was used to detect keratinocyte expression of Fas and FasL. The lytic capacity of keratinocyte FasL was evaluated using Fas-sensitive Jurkat cells overlaid on the skin frozen sections. Keratinocyte apoptosis was evaluated by flow cytometric methodology.Patients with TEN had elevated serum sFasL (concentrations were virtually undetectable in control groups). Keratinocytes expressed increased FasL but similar amounts of Fas compared with controls. The lytic capacity of FasL expressed on keratinocytes was greatly increased, but could be blocked completely by incubation with FasL-blocking antibody. Apoptosis was inducible in human keratinocytes by recombinant sFasL. However, preincubation of keratinocytes with IVIG prevented recombinant sFasL-induced apoptosis. Conversely, incubating the recombinant sFasL with IVIG did not inhibit apoptosis (implicating blockade of Fas receptor as the rescue mechanism). Depletion of anti-Fas immunoglobulin from the IVIG (on an affinity column) also abrogated the ability of IVIG to block Fas-mediated keratinocyte cell death.In an open, noncontrolled pilot study, 10 patients with TEN received IVIG at doses ranging from 200 to 750 mg/kg/day for 4 days. The progression of skin disease was interrupted in all 10 within 2 days. All experienced healing and a favorable outcome.Fas-FasL interactions are directly involved in TEN, a disease in which keratinocyte apoptosis is increased and lytic FasL is up-regulated. IVIG, by blocking the Fas receptor, may be an effective treatment.This study is a wonderful example of research moving from bedside to bench back to bedside. Controlled studies are needed, but an additional indication for IVIG may be on the horizon. In addition, more specific therapies for this disorder, and possibly others, are likely to be developed now that the immunologic mechanism has been elucidated.

DERMATOLOGIC MANIFESTATIONS OF RHEUMATIC DISORDERS

Many rheumatic disorders have cutaneous lesions and sometimes skin lesions are the initial or most problematic manifestation of a patient's rheumatic disease. Many of the skin lesions encountered in these disorders are rather nonspecific. Other lesions, however, have characteristic and sometimes specific gross or histopathologic findings that often help the clinician diagnose the underlying rheumatic disease process. Additionally, drug-induced skin diseases are often encountered in patients being treated for rheumatic disease.

Drug-induced skin disease

Drug-induced cutaneous reactions encompass a wide variety of rashes that depend in part on route of administration (e.g., contact versus systemic) as well as type of cutaneous response and molecular mechanism underlying the reaction. One such reaction is a type IV immunologic reaction (delayed hypersensitivity) manifest as contact dermatitis and commonly elicited by drugs such as antihistamines, antibiotic ointments, local anesthetics, and paraben esters in cosmetic creams and lotions. A generalized eruption of this sort will occasionally occur with systemic administration of a drug to someone previously sensitized by topical application. Systemic administration of agents can cause nonspecific pruritus or maculopapular eruptions that resemble visual exanthems. The pathogenesis is unclear and no immune mechanism has been demonstrated. If the drug is continued, exfoliative dermatitis can result. Other types of reactions are urticarial in nature and include acute urticaria/angioedema, erythema multiforme (bullous and nonbullous), Stevens-Johnson syndrome, urticaria in association with serum sickness-like reactions, and urticaria associated with anaphylactoid reactions. In many of these, an allergic reaction in which there is an immunoglobulin (Ig) E-dependent release of mediators in the skin causes hives or swelling. In others, circulating immune complexes may be present, often involving IgG antibody complexed with drug and complement fixation; hives may then be caused by anaphylatoxin release or a concomitant IgE-mediated reaction. In some instances, a cellular reaction may augment the aforementioned inflammatory reactions, perhaps as part of a late-phase reaction or a true delayed hypersensitivity component. Major offenders involved in such reactions are antibiotics such as penicillin and sulfa, barbiturates, anticonvulsants, and phenothiazines. Urticarial reactions to aspirin and other nonsteroidal anti-inflammatory drugs are in general nonimmunologic. Other types of cutaneous reactions to drugs include erythema nodosum, fixed drug eruptions, purpura (thrombocytopenic or nonthrombocytopenic), phototoxic and photoallergic reactions, and exfoliative dermatitis or toxic epidermal necrolysis. Phototoxic reactions are nonimmunologic, occur on first exposure, and depend on the light absorption spectrum of the drug. Photoallergic reactions resemble contact dermatitis but involve a delayed hypersensitivity reaction to an antigen formed by interaction of the drug with light and binding of the altered drug (hapten) to a cutaneous protein to form a complete antigen. Exfoliative dermatitis or toxic epidermal necrolysis can be severe sequalae of maculopapular eruptions in which the drug is continued or can be severe erythema multiforme-like reactions and are potentially fatal. Superinfection with group 2 staphylococcus may be contributory in some cases. Finally, cases of physically induced allergy such as dermatographism have been reported after drug reactions.

Drug-induced skin diseases.

Drug eruptions are a bit like the Joneses: no one ever quite seems able to keep up with them. The problem is that as soon as the older drugs slip out of use, taking with them their familiar rashes, new fashionable treatments are rushed out of the laboratories. It is often a long time before any one can accept that they also will cause trouble. Practolol was a good example of this : used widely since 1970, it was not until 1974 that its now well-known skin reactions were described.1 In other ways, however, though drugs may change, the clinical problems remain depressingly the same: a patient develops a rash; he is taking many different tablets; which, if any, of these caused his eruption, and what should be done about it ? It is no answer simply to stop all drugs, though the fact that this can often be done casts some doubt on the patient's need for them in the first place. All too often potentially valuable drugs are excluded from further use on totally inadequate grounds. Clearly some guidelines are needed, but no simple set of rules exists that can cover this complex subject. In this short article we can do no more than outline some common-sense steps in the approach to patients with possible drug-induced skin disease. We suggest that the following questions should be asked in every case: (1) Can other skin diseases be excluded ? (2) Are the skin changes compatible with a drug cause ? (3) Which drug is most likely to be responsible ? (4) Are any further tests worth while ? and (5) Is any treatment needed ? These questions are deceptively simple but the answers are often difficult. Each step will be discussed in turn.