Sarah Brenner

Drug-induced pemphigus

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

Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis.

Erythrokeratodermia variabilis (EKV) is an autosomal dominant keratinization disorder characterized by migratory erythematous lesions and fixed keratotic plaques. All families with EKV show mapping to chromosome 1p34-p35, and mutations in the gene for connexin 31 (Cx31) have been reported in some but not all families. We studied eight affected and three healthy subjects in an Israeli family, of Kurdish origin, with EKV. After having mapped the disorder to chromosome 1p34-p35, we found no mutations in the genes for Cx31, Cx31.1, and Cx37. Further investigation revealed a heterozygous T-->C transition leading to the missense mutation (F137L) in the human gene for Cx30.3 that colocalizes on chromosome 1p34-p35. This nucleotide change cosegregated with the disease and was not found in 200 alleles from normal individuals. This mutation concerns a highly conserved phenylalanine, in the third transmembrane region of the Cx30.3 molecule, known to be implicated in the wall formation of the gap-junction pore. Our results show that mutations in the gene for Cx30.3 can be causally involved in EKV and point to genetic heterogeneity of this disorder. Furthermore, we suggest that our family presents a new type of EKV because of the hitherto unreported association with erythema gyratum repens.

Pemphigus vulgaris: a review of treatment over a 19-year period

Background Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes with a high mortality if left untreated.

Drug-Induced versus Drug-Triggered Pemphigus

112 cases of induced pemphigus were reviewed. The causative drugs were divided into three groups according to their chemical structure, and the clinical, prognostic and laboratory characteristics were analyzed and compared. Our literature screening indicates that the biological progress and clinical course of the disease depend upon the type of the inducing/triggering drug in the majority of patients. Patients with penicillamine-induced pemphigus or with pemphigus induced by SH drugs (drugs containing a sulfhydryl radical) showed spontaneous recovery in 39.4 and 52.6%, respectively, once the drug was discontinued. Patients whose pemphigus was induced by other drugs showed spontaneous recovery in only 15% of the cases. These results indicate that in patients with pemphigus induced by penicillamine (or SH drugs), the drug plays a major role in the pathogenesis of the disease, as compared to patients with pemphigus induced by other drugs. It seems that penicillamine (and SH drugs) actually induces pemphigus in most of the cases, whereas other drugs only trigger the disease in patients with a previous predisposition.

Antiproliferative and differentiating effects of benzodiazepine receptor ligands on B16 melanoma cells

In this study, we evaluated the effect of several ligands active at the central-type and peripheral-type benzodiazepine receptor (BzR) (clonazepam, diazepam, PK11195 and Ro5-4864) on the growth and differentiation of B16 melanoma cells. All tested BzR ligands were able to suppress proliferation of the cells at the micromolar range and in a concentration-dependent manner. However, agents selectively active at the peripheral-type BzR (PK11195 and Ro5-4864) exhibited more potent antiproliferative activity. In addition, the BzR ligands were demonstrated to affect the cell cycle by reducing the percent of cells in the S phase and increasing the percent in the G2/M phase. BzR ligands induced cellular phenotypic alterations, which have been previously shown to be associated with melanoma cell differentiation. These alterations included: marked morphological changes, enhancement of melanogenesis, lipid accumulation and increase in the activity of gamma glutamyl transpeptidase. All BzR ligands induced a marked reduction in the concentration of UTP and most of them did the same in GTP and CTP, while ATP levels were not significantly altered. In summary, BzR ligands (clonazepam, diazepam, PK11195 and Ro5-4864) were found to exert antitumor effects in B16 melanoma cells. These findings encourage further studies of a possible therapeutic potential of BzR ligands in treatment of melanoma.

Recognition of pemphigus antigens in drug-induced pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND The clinical appearance and biologic behavior of drug-induced pemphigus depend on the type of inducing drug. OBJECTIVE Our purpose was to investigate patients with drug-induced pemphigus vulgaris and pemphigus foliaceus antigens and compare results of studies to detect antibody reactivity in sera of these patients with the serology of patients with idiopathic pemphigus. METHODS Ten patients with drug-induced pemphigus were studied. Antibody reactivity was determined against the pemphigus vulgaris antigen, desmoglein 3, and against desmoglein 1. RESULTS The patient with pemphigus foliaceus and low levels of autoantibodies precipitated neither antigen. One patient with pemphigus vulgaris and high levels of antibody also failed to precipitate any specific antigen. Sera from eight patients with drug-induced pemphigus vulgaris had circulating autoantibodies directed to either the pemphigus vulgaris or pemphigus foliaceus antigen. Low levels of antibody in two of these eight patients precipitated only the pemphigus foliaceus antigen. High levels of antibody in five of the eight patients precipitated the pemphigus vulgaris antigen; two of these also reacted with the pemphigus foliaceus antigen. CONCLUSION The autoantibody response was similar in both spontaneous and drug-related disease. A similar molecular mechanism in the two types of pemphigus is suggested.

Psoriasis Related to Angiotensin-Converting Enzyme Inhibitors

Two mechanisms have been proposed for the pathogenesis of eruptions induced by angiotensin-converting enzyme (ACE) inhibitors: (1) an allergic, immune-mediated reaction and (2) a pharmacologic, dose-dependent response. Two cases of palmoplantar psoriasis are presented, which can be attributed to the induction (case 1) and exacerbation (case 2) of ACE inhibitors. The first patient developed his eruption 2 months after he had received captopril, probably as a result of an allergic immunologic mechanism. This has been based mainly on circumstantial evidence and is further strengthened by the positive result of the mast cell degranulation test. The second patient developed an atenolol-induced, mild plantar psoriasis. She experienced a dramatic flare-up of her psoriatic lesions shortly after she had received an ACE inhibitor. It is suggested that her reaction occurred as a result of the enalapril-induced augmentation of kinin levels in the skin. These 2 patients represent deductive and unusual examples of the two different mechanisms that are responsible for the cutaneous complications of ACE inhibitors.

An Active Amide Group in the Molecule of Drugs That Induce Pemphigus: A Casual or Causal Relationship?

Traditionally, drugs that are capable of inducing pemphigus are divided into two main groups according to their chemical structure, in particular, the existence of a sulfhydryl group in their molecule. Thus, two groups are formed: (1) drugs containing a sulfhydryl radical (thiol drugs or SH drugs) and (2) nonthiol or other drugs. Much emphasis has been put on the role of the sulfhydryl group in the pathogenesis of drug-induced pemphigus. The effects of this group have been extensively studied, and a logical paradigm on the mode of its action has been created. However, no attempt has been made to search for other biochemical radicals which might have an influence on the activation/triggering of this disease. The aim of the present report is to draw attention to a chemical group common to the molecule of several drugs that have been associated with the induction of pemphigus. Careful analysis of the chemical structure of nonthiol drugs known to induce pemphigus revealed that several of them share an active amide group in their molecule. We believe that this group might be responsible for the induction of the disease; thus, a third group of drugs capable of triggering pemphigus can be formed, namely drugs containing an active amide group. Several drugs of this group are discussed.

The induction of pemphigus by phenol drugs.

drug-induced pemphigus has been extensively studied. In It is well established that the development of pemphigus patients with pemphigus induced by thiol drugs, the drug is the result of the interaction between endogenous, plays a major role and actually induces the disease (‘‘induced genetic factors (the soil) and exogenous factors (the seed). pemphigus’’). Other drugs only stimulate a predisposition The latter include drugs;1–5 nutritional factors;6–9 physical to develop the disease (‘‘triggered pemphigus’’). Thiol drugs agents such as burns, UV radiation, and X-rays;10–13 are able to induce acantholytic changes in tissue cultures,29 infections, in particular viral;14,15 neoplasms;16 hormones for which a number of mechanisms have been suggested: and pregnancy;17,18 contact dermatitis;19–22 and emotional inhibition of enzymes that aggregate keratinocytes, such as stress.23,24 Studies have shown that these factors may affect γ-glutamyl transpeptidase or keratinocyte transglutaminase only genetically predisposed individuals. Both idiopathic (a calcium-dependent thiol enzyme); activation of enzymes and induced pemphigus exhibit the same human leukocyte that disaggregate keratinocytes (proteases, plasminogen antigen (HLA) pattern.25 activator);29 an immunologic reaction in which the drug Drugs implicated in the induction of pemphigus can be binds to adhesion structures by thiol–disulfide interchange, divided into two main groups according to their chemical thereby cleaving the pemphigus antigen or rendering it structure: those containing a sulfhydryl radical (thiol drugs nonfunctional; and alteration of the molecule following or SH drugs) and nonthiol drugs. The causal relationship binding of the drug with the consequent formation of a between drug and disease has been generally based on a neoantigen and the production of autoantibodies.29 temporal correlation in both outbreak and remission, rather The induction of pemphigus by contact with phenols than on in vitro confirmation as rechallenge in pemphigus was first described by Tsankov et al. in 1987,19 who is not a medical option. The diagnosis of drug-induced considered the mechanism to be systemic absorption of pemphigus has been strengthened by various means, the substance with a direct toxic effect. Brenner et al.21 including patch tests, lymphocyte transformation tests, proposed the term ‘‘contact pemphigus’’ and suggested macrophage migration inhibition, and mast cell degranulathat an allergic mechanism was involved and not just tion tests. While they point to the offending drug, they do percutaneous penetration. Recently, Tur and Brenner30 not provide definitive proof of the connection between hypothesized that pemphigus can be induced by contact drug and disease. Such proof was provided recently by with plants containing urushiol (3-pentadecylcatechol) and evidence that immunolabeling with antidesmoglein resulted other chemically similar long-chain phenols. This group in a specific abnormal staining pattern in idiopathic speculated on the possible role of tannins—naturally pemphigus, in contrast to the normal staining in drugoccurring plant polyphenolic compounds—in the induction induced disease.26 or promotion of pemphigus, and implicated such foods

Possible nutritional factors in induced pemphigus

Today it is generally accepted that every drug that possesses an active thiol group in its molecule is capable of inducing pemphigus. Some plants, in particular those belonging to the Allium group, contain several active compounds with stable disulfide and thiol groups in their molecule. The Allium group contains many important vegetables like onion, leek and garlic. Examples of molecules with an active thiol group are: CH2 = CH-CH2-S-S-CH2-CH = CH2 (diallyl disulfide) or CH2 = CH-CH2-S(O)S-CH2-CH = CH2 (allicin). It is suggested that some foods, in particular vegetables of the Allium group that contain active thiol groups in their molecule, could contribute to the induction of pemphigus. In general, nutritional factors should be added to the list of exogenous factors that are capable of inducing pemphigus.