Nikhil Yawalkar

T cell involvement in cutaneous drug eruptions

Background The most frequent side‐effects of drug therapy are skin eruptions. Their pathomechanism is rather unclear.

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 αβ-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 predominately 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-α and interferon-γ] 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.

Zafirlukast has no beneficial effects in the treatment of chronic urticaria

Background Leukotriene receptor antagonists have shown some efficacy in the treatment of asthma. Injection of LTC4, LTD4 and LTE4 into the skin leads to a weal‐and‐flare reaction, suggesting an involvement of leukotrienes in the pathogenesis of urticaria. Indeed, various reports have indicated a beneficial effect for leukotriene receptor antagonists in patients with chronic urticaria.

T-cell reaction to local anaesthetics: relationship to angioedema and urticaria after subcutaneous application--patch testing and LTT in patients with adverse reaction to local anaesthetics.

Local anaesthetics are known to elicit T‐cell reactions after epicutaneous application, namely contact dermatitis. In addition, adverse reactions like urticaria and angioedema are rather common after submucosal or subcutaneous injection. The pathogenesis of these side‐effects, which appear frequently hours after application, is unknown, but thought to be not immunoglobulin E‐mediated, since immediate skin tests are mostly negative.

Efficacy and safety of the Betamethasone valerate 0.1% plaster in mild-to-moderate chronic plaque psoriasis: a randomized, parallel-group, active-controlled, phase III study

Background: Corticosteroids are a versatile option for the treatment of mild-to-moderate psoriasis due to their availability in a wide range of potencies and formulations. Occlusion of the corticosteroid is a widely accepted procedure to enhance the penetration of the medication, thereby improving its effectiveness. Betamethasone valerate (BMV) is a moderately potent corticosteroid that is available as a cream, ointment, and lotion. A ready-to-use occlusive dressing, which provides a continuous sustained release of BMV, has been developed for the treatment of psoriasis.Objective: To evaluate the efficacy and safety of a new BMV 0.1% plaster compared with a BMV 0.1% cream in patients with mild-to-moderate chronic plaque psoriasis.Methods: This was a prospective, randomized, assessor-blind, parallel-group, active-controlled, multicenter, phase III study. Eligible outpatients (aged ≥18 years) with a diagnosis of stable, chronic plaque psoriasis vulgaris with two to four plaques on extensor surfaces of limbs were randomized to receive BMV 0.1% plaster or BMV 0.1% cream for 3–5 weeks; patients with resolution of target plaques then entered a 3-month, treatment-free, follow-up period. The number of patients showing clearing of plaques (remission) at 3 weeks (primary endpoint) and at 5 weeks was independently evaluated from digitized images of target plaques by two blinded assessors, and also assessed by the investigator and patient. Additional endpoints were (i) change from baseline in target plaque size and in Psoriasis Global Assessment (PGA) score, as evaluated by the blinded assessors, investigator, and patient; (ii) change from baseline in symptom (itching, soreness) severity; (iii) treatment satisfaction and ease of use; (iv) clearing and relapse during the follow-up period; and (v) adverse events (AEs).Results: Patients (n = 231) were screened and randomized to treatment with BMV 0.1% plaster (n = 116) and BMV 0.1% cream (n = 115). Significantly more patients achieved clearing after 3 weeks’ treatment with BMV plaster than with BMV cream (Cochran-Mantel-Haenszel test, p < 0.001); this difference was maintained at 5 weeks. The total plaque area decreased to a larger extent for the BMV plaster group compared with the BMV cream group (analysis of covariance [ANCOVA] model, p = 0.017 at week 5). PGA scores were significantly lower after 3 and 5 weeks’ treatment with BMV plaster (ANCOVA model, all p ≤ 0.016 vs BMV cream). Both treatments reduced itching and soreness to a similar degree, and the incidences of relapse during the follow-up period were comparable between treatment groups. There were no significant differences in AEs between treatment groups.Conclusions: BMV 0.1% plaster is more efficacious than BMV 0.1% cream in the treatment of patients with mild-to-moderate chronic plaque psoriasis in a clinical setting resembling daily clinical practice.Clinical trial number: ISRCTN68864186