[Cutaneous reactions to drugs]. / Huidreacties door geneesmiddelen.

Exact data concerning the incidence of cutaneous drug eruptions are lacking due to underreporting. Diagnostics of cutaneous drug eruptions is hampered by the fact that one drug may induce different eruptions while the same cutaneous eruption can be caused by several drugs. Important steps in the diagnostics of cutaneous drug eruptions are: suspicion of the drugs as cause of the eruption, precise history-taking with emphasis on medication use and a complete physical examination. The 'golden standard' in the diagnostics of a drug eruption is the dechallenge-rechallenge procedure, but in severe cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis and vasculitis, this procedure can cause severe, sometimes life-threatening reactions. Reporting suspected adverse drug reactions to pharmaco-vigilance centres is important to identify rare drug reactions.

[Skin reactions to dental materials]. / Huidreacties op tandheelkundige materialen.

In dentistry, contact with a wide range of both irritants and contact allergens pose an important occupational hazard. It is important to understand the resulting clinical skin symptoms and their causes to prevent further exposition and to avoid serious problems that may lead to an incompatibility with the dentist profession.

The 500 Dalton rule for the skin penetration of chemical compounds and drugs.

Human skin has unique properties of which functioning as a physicochemical barrier is one of the most apparent. The human integument is able to resist the penetration of many molecules. However, especially smaller molecules can surpass transcutaneously. They are able to go by the corneal layer, which is thought to form the main deterrent. We argue that the molecular weight (MW) of a compound must be under 500 Dalton to allow skin absorption. Larger molecules cannot pass the corneal layer. Arguments for this "500 Dalton rule" are; 1) virtually all common contact allergens are under 500 Dalton, larger molecules are not known as contact sensitizers. They cannot penetrate and thus cannot act as allergens in man; 2) the most commonly used pharmacological agents applied in topical dermatotherapy are all under 500 Dalton; 3) all known topical drugs used in transdermal drug-delivery systems are under 500 Dalton. In addition, clinical experience with topical agents such as cyclosporine, tacrolimus and ascomycins gives further arguments for the reality of the 500 Dalton rule. For pharmaceutical development purposes, it seems logical to restrict the development of new innovative compounds to a MW of under 500 Dalton, when topical dermatological therapy or percutaneous systemic therapy or vaccination is the objective.

Red blood cell rigidification during cyclosporin therapy: a possible early warning signal for adverse reactions.

In a previous retrospective study with kidney-transplant patients, immunosuppressive treatment with Cyclosporin A (CsA) was found to be associated with impaired red blood cell (RBC) deformability. The aim of the present study was to evaluate and substantiate a possible causal relationship between the use of CsA and its effect on RBC deformability in a prospective study on non-transplant patients. Blood samples of 12 patients with psoriasis were taken before and after 2, 4, 8, 12 and 16 weeks of treatment with CsA (3-5 mg/day). Red cell deformability, expressed as Elongation Index (EI), was measured with the Laser-assisted Optical Rotational Cell Analyzer (LORCA), a new ektacytometric instrument. Mean values +/- SD for EI found after 16 weeks of treatment with cyclosporin (0.570 +/- 0.008) were significantly (p < 0.001) lower than the value before treatment (0.589 +/- 0.011). A dose-response relation could not be established within the small range of CsA doses used in this study. Irrespective of the dose, however, a significant correlation (r = -0.55; p = 0.0001) between duration of treatment and decrease in EI was demonstrated. In vitro incubation of blood with cyclosporin was not able to reproduce this effect, suggesting that a direct effect of the drug on RBCs is unlikely. Despite its use in relatively low doses, CsA causes a reduction in RBC deformability, an effect that increases during the course of treatment. It is suggested that this slow, but continuously increasing, RBC rigidification plays a role in the early pathogenesis of the adverse nephrotoxic complications frequently associated with this immunosuppressive regimen.

Ranitidine does not affect psoriasis: a multicenter, double-blind, placebo-controlled study.

BACKGROUND: Data from open studies suggest that ranitidine has a beneficial effect on psoriasis and is well tolerated. OBJECTIVE: Our purpose was to determine the effectiveness of ranitidine in a 24-week, multicenter, double-blind, placebo-controlled, dose-comparing study of 201 patients with psoriasis. METHODS: Patients with moderate to severe psoriasis who had stopped systemic antipsoriatic therapy, including PUVA and UVB, for at least 10 weeks were included. After a washout period of 2 weeks, patients were randomly allocated to use either ranitidine, 150 mg twice a day; ranitidine, 300 mg twice a day; or placebo for up to 24 weeks. Assessment with the Psoriasis Area and Severity Index was performed at weeks 3, 6, 9, 12, 18, and 24 after randomization. Reduction of the Psoriasis Area and Severity Index score by 70% at the completion of the study was considered a treatment success. RESULTS: The success rates at week 24 in the 300 mg, 600 mg, and placebo groups were 11%, 5%, and 12%, respectively. No significant differences were observed between the three treatment groups at any stage of the study. CONCLUSION: This study provides strong evidence that ranitidine does not affect the skin disease in patients with psoriasis.

Methyldibromoglutaronitrile is an important contact allergen in The Netherlands.

From 15 May to 15 December 1994, 2943 patients suspected of having contact dermatitis (1955 women, 988 men) were patch tested with methyldibromoglutaronitrile 0.3%, 0.1% and 0.05% pet. 119 patients (4.0%; women 4.1%, men 3.8%) proved to be allergic. 71% of the reactions were considered to be relevant. In 2/3 of the patients, causative products were cosmetics, in 1/3 moistened toilet tissues. Testing with methyldibromoglutaronitrile at lower concentrations (0.05% and 0.1%) and with commercial allergens (Euxyl K 400 and methyldibromoglutaronitrile, both containing methyldibromoglutaronitrile 0.1%), resulted in a number of false-negative reactions. All preservatives in the European standard series had lower scores than the 4% positive reactions to methyldibromoglutaronitrile (formaldehyde 2.0%, MCI/MI (Kathon CG) 3.2%, parabens 1.0%, quaternium-15 1.3%). It is concluded that methyldibromoglutaronitrile (present in the commercial preservative Euxyl K 400) is an important contact allergen in the Netherlands in cosmetics and moistened toilet tissues. It should be added to cosmetics series and to proctological series. The optimal test concentration is unknow, but may be 0.3% pet. The concentration of 0.1% methyldibromoglutaronitrile in the currently available commercial allergens appears to be too low, resulting in a number of false-negative reactions.

Cross-reactivity of human nickel-reactive T-lymphocyte clones with copper and palladium.

Twenty Ni-reactive T-lymphocyte clones were obtained from eight different donors and analyzed for their ability to cross-react with other metals. All Ni-reactive T-lymphocyte clones were CD4+CD8- and recognized Ni in association with either HLA-DR or -DQ molecules. Based on the periodic table of the elements, the metals Cr, Fe, Co, Cu, and Zn from the same horizontal row as Ni, and Pd and Pt from the same vertical row, were selected to study T-lymphocyte clone cross-reactivity. Distinct cross-reactivity patterns were found that could be divided into three major groups: Ni-reactive T-lymphocyte clones i) cross-reacting with Cu, ii) cross-reacting with Pd, or iii) without cross-reactivity. Major histocompatibility complex class II-restriction patterns of Cu- and Pd-induced proliferative responses did not differ from those for the Ni-induced responses. In vitro cross-reactivities with Cu and Pd may be favored by their bivalency and location next to Ni in the periodic table, and the similarity of these metals to Ni in binding to histidine residues of peptides in the pocket of major histocompatibility complex class II molecules. The present findings suggest that Cu and Pd hypersensitivities, which are occasionally observed in Ni-allergic patients, may be due to cross-reactivities at the T-cell clonal level rather than to concomitant sensitization.

Glycosylphosphatidylinositol (GPI)-anchored membrane proteins are constitutively down-regulated in psoriatic skin.

Hyperproliferation of keratinocytes (KCs) in psoriasis has been found to be associated with excessive activation of a phospholipase C (PLC)/protein kinase C (PKC) signal transduction system. The molecular species of PLCs which are activated in psoriasis have not been thoroughly investigated. It was envisaged that if glycosylphosphatidylinositol (GPI)-specific PLC was activated in the membrane of psoriatic epidermal cells, it would render these cells devoid of those proteins which are anchored to the cell membrane through their GPI moiety. In order to test this possibility, four GPI proteins (CD16, CD55, CD58, and CD59) were determined immunohistochemically in normal and psoriatic skin. In normal skin, CD55 and CD59 were strongly expressed on epithelium and vascular structures, whereas CD16 and CD58 were strongly expressed only on epithelium. The expression of all four GPI proteins was decreased in non-lesional psoriatic skin and virtually abolished in lesional psoriatic skin. A control transmembrane protein, CD46, was strongly expressed in normal and non-lesional psoriatic skin, and its expression was not significantly decreased in psoriatic lesions. The absence or reduction of GPI proteins was not seen in the lesions of several other inflammatory and proliferative diseases studied.

Contact allergy to corticosteroids: the results of a two-centre study.

We report a comparative study of the patch-test results obtained with a corticosteroid series, added to the standard series, in two centres, one in Belgium and the other in the Netherlands. The frequencies of positive reactions to the corticosteroids differed considerably between the two centres, and we suggest several reasons for this.

Frequency of false-negative reactions to the fragrance mix.

To estimate the frequency of false-negative reactions to the fragrance mix, the 8 constituents of the mix in concentrations of 5% (2% for cinnamic aldehyde) were added to the European standard series for routine testing. Patients with positive reactions to individual ingredients in the absence of a reaction to the mix were retested with serial dilutions. In a 4-month period, 677 patients were tested. 61 (9%) reacted to the mix and to 1 or more of the ingredients. 4 patients (0.6% of all patients tested and 6.2% of the patients allergic to fragrances) had false-negative reactions to the mix. They were allergic to cinnamic alcohol, geraniol, isoeugenol and oak moss (1 reaction each), in the absence of a reaction to the fragrance mix. It is concluded that the currently used concentration of the mix (8 x 1%) not infrequently results in false-negative reactions, and that further research should be done to overcome this problem.

Antibodies to mycobacterial 65-kDa heat shock protein and other immunodominant antigens in patients with psoriasis.

An association of microbial agents and autoimmunity has been suggested for the pathogenesis of psoriasis. Mycobacteria are common environmental microbes and their antigens, especially the highly conserved mycobacterial 65-kDa heat shock protein (hps65), have been implicated in the pathogenesis of autoimmune arthritis and other idiopathic diseases. In this context, we investigated a possible mycobacterium-induced humoral immune response in psoriasis. Sera from 17 patients with chronic plaque-type psoriasis were studied by immunoblotting using the whole sonicate of Mycobacterium tuberculosis and purified recombinant mycobacterial hsp65. Immunoblot analysis demonstrated that 58% of the psoriasis patients compared to patients with acne and DLE, and normal controls showed strong antibody activity to 65-kDa and 48/45 doublet antigens from M. tuberculosis sonicate, whereas 47% of the patients showed antibody activity to mycobacterial hsp65. Only 10-20% of the patients had an antibody response to 16-kDa and 80-kDa antigens. Similar antibody activity to 65 kDa and 48/45 kDa was also found consistently with eight different sonicated mycobacterial species by immunoblotting, indicating that these seroreactive antigens are crossreactive and are present in common environmental mycobacteria. Antibody activities to both mycobacterial 65-kDa and hsp65 showed a positive correlation (r = 0.76) with the psoriasis disease activity, whereas antibodies to 48/45-kDa doublet antigens showed a weak correlation (r = 0.54). By enzyme-linked immunosorbent assay (ELISA), 47% of the psoriasis patients showed significantly elevated antibody titers to hsp65 (p < 0.003) as compared to control groups, and the antibody response by ELISA also showed a significant positive correlation (r = 0.76) with disease activity. Anti-mycobacterial antibody activity may be related to severity of disease and may be useful in monitoring disease activity in psoriasis.

Hereditary deficiency of C5 in association with discoid lupus erythematosus.

A 29-year-old woman with discoid lupus erythematosus had undetectable classic pathway complement activity. Hypocomplementemia was due to selective deficiency of C5. One of her children was also deficient. To our knowledge this is the first documented case of an association between discoid lupus erythematosus and C5 deficiency.

Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis.

Since oral cyclosporin A (CsA) has demonstrated its effectiveness in psoriasis and atopic dermatitis, efforts have been made to develop a topical CsA formulation, thus avoiding systemic adverse events. A limited number of publications are available on the use of topical CsA in allergic contact dermatitis and atopic dermatitis. Moreover the response rate of humans to topical CsA is about 50% or less. We now report our results with three new topical CsA formulations on allergic contact dermatitis and atopic dermatitis. No significant improvement was found in 16 atopic dermatitis patients and 7 allergic contact dermatitis (nickel sulphate) patients.

Analysis of side-effects of medium- and low-dose cyclosporin maintenance therapy in psoriasis.

The side-effects of long-term cyclosporin A (CyA) treatment in 26 patients with severe psoriasis were evaluated. These patients had a mean PASI score of 30.2 and were treated with CyA for between 7 and 37 months (mean 19.5 months). There were three groups according to the dose of CyA, less than 2 mg/kg per day, 2-3 mg/kg per day and greater than 3 mg/kg per day. In all three groups, CyA was found to be equally effective. Treatment with CyA was discontinued in 12 of the 26 patients because of nephrotoxicity and/or development of hypertension. One was in the less than 2 mg/kg per day group, three were in the 2-3 mg/kg per day group and eight in the greater than 3 mg/kg per day group. There was no hepatotoxicity with CyA treatment. One patient developed two squamous cell carcinomas of the skin.

Oral cyclosporin A in the treatment of psoriasis: an overview of studies performed in The Netherlands.

This is a review of the clinical studies performed so far in The Netherlands of the treatment of psoriasis with cyclosporin A (CyA), a selective immunosuppressive drug that has caused a major breakthrough in transplant medicine. Data derived from a double-blind placebo-controlled study (5 mg/kg/day of CyA), dose-finding studies (2.5 mg vs 5 mg/kg/day and 1 mg, 2 mg or 3 mg/kg/day), and long-term treatment of chronic plaque-type psoriasis (1.1-7.2 mg/kg/day) suggest an initial starting dose of 3 mg/kg/day irrespective of the severity of the disease. Long-term treatment brought about dose- and time-dependent (reversible) side-effects, including renal dysfunction and hypertension. Efforts to reduce the dose included concomitant administration of drugs known to have anti-psoriatic efficacy. Only combination with topical steroids appeared to add to the clinical efficacy of CyA, but did not allow a dose reduction sufficient to restore renal function. Dose reduction through intermittent treatment, however, postponed exacerbations sufficiently to permit at least partial normalization of serum creatinine levels. A similar effect was seen in the treatment of pustular palmoplantar psoriasis, which responded to doses of 1.1-6.1 mg/kg/day.

Cyclosporin A levels in suction-blister fluid of patients with psoriasis treated systemically.

Oral cyclosporin A (CyA) is highly effective in the treatment of psoriasis. The long-term use is limited by dose-dependent side-effects, and the local concentration of CyA is a determining factor in treatment. The concentration of CyA in suction-blister fluid (SBF) and in whole blood was assessed using a polyclonal radioimmunoassay (RIA). This was carried out in patients with psoriasis following a single dose of CyA and while on adequate oral treatment with the drug. Peak blister fluid levels ranged from 32 to 170 ng/ml, and whole blood levels from 1250 to 2540 ng/ml. CyA trough levels (12 h following taking the drug) in the blister fluid ranged from 22 to 113 ng/ml, and in whole blood from 148 to 935 ng/ml. The trough concentrations in SBF were approximately 10% of whole blood trough levels.