Use of fumaric acid esters in psoriasis.

Fumaric acid esters (FAE) are chemical compounds derived from the unsaturated dicarbonic acid fumaric acid. The usage of FAEs in treatment of psoriasis was introduced in the late 1950's. In the 1980s more standardized oral preparations of FAEs were developed containing dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) as main compounds. In 1994, Fumaderm an enteric-coated tablet containing DMF and calcium, magnesium and zinc salts of MEF was approved for the treatment of psoriasis in Germany and since then has become the most commonly used systemic therapy in this country. Fumaric acids have been proven to be an effective therapy in patients with psoriasis even though the mechanisms of action are not completely understood. About 50-70% of the patients achieve PASI 75 improvement within four months of treatment and without any long-term toxicity, immunosuppressive effects or increased risk of infection or malignancy. Tolerance is limited by gastrointestinal side effects and flushing of the skin. This article reviews pharmacokinetics, uses, contraindications, dosages and side effects of treatment with FAEs.

Atopic eczema: genetics or environment?

Atopic eczema (AE) is a multifactorial skin disease caused by a variety of factors such as genetic conditions, alterated skin structure, immunologic deviations and environmental factors, among others. There are two main subtypes of AE, i.e. the IgE-associated ("atopic eczema") and the non-IgE-associated type ("nonatopic eczema") with different prognosis concerning the development of respiratory diseases ("atopy march"). Recently, it was demonstrated that Filaggrin (=filament-aggregating protein, FL) is a major gene for atopic eczema. Filaggrin binds to and aggregates the keratin cytoskeleton in the epidermis. Homozygous FLG mutation leads to complete loss of filaggrin expression in skin. Half or more of children with moderate to severe AE carry FLG mutations. Moreover, filaggrin loss-of-function mutations predispose to phenotypes involved in the atopy march. The altered skin structure and a deficiency in antimicrobial peptides favour colonization with Staphylococcus aureus and yeasts (Malassezia sp.). Sensitization to the yeast occurs almost exclusively in AE patients. S. aureus enterotoxins with superantigenic activity stimulate activation of T cells and macrophages. So far, AE skin lesions are orchestrated by the local tissue expression of proinflammatory cytokines and chemokines with activation of T lymphocytes, dendritic cells, macrophages, keratinocytes, mast cells, and eosinophils which lead to the skin inflammatory responses. From the therapeutic point of view, besides emollients and local corticosteroids, topic immunomodulatory drugs (tacrolimus and pimecrolimus) have substantially improved the treatment of AE.

Tolerance to celecoxib in patients with a history of adverse reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal antiinflammatory drugs (NSAIDs) are frequently reported, particularly among asthmatic patients. To date, there is no causal treatment available apart from tolerance induction. Therefore, the search for safe alternative drugs is of pivotal importance in clinical practice. OBJECTIVE: The aim of our prospective study was to investigate the tolerance to celecoxib, a selective cyclooxygenase-2 inhibitor, in a large group of patients with positive case history of NSAID intolerance in comparison to paracetamol and nimesulide. METHODS: 106 NSAID-sensitive patients, 46 (43.4%) of whom had experienced reactions only to one NSAID (single hypersensitivity), 60 (56.6%) to several NSAIDs (multiple hypersensitivity), were included in a single-blinded drug challenge protocol with cumulative doses of 175 mg of celecoxib, 875 mg of paracetamol and 175 mg of nimesulide. Objective and subjective symptoms during challenge were documented. RESULTS: Of 261 challenges in 106 patients, 31 challenges were positive: 5 of 106 (4.7%) for celecoxib, 10 of 64 (15.6%) for paracetamol and 16 of 91 for nimesulide (17.6%). Adverse reactions to celecoxib were mainly mild in character: three patients reported subjective symptoms including generalised pruritus and thoracic oppression, whereas two patients reacted with angio-oedema. CONCLUSIONS: Our results demonstrate that celecoxib is well tolerated by the majority of patients with NSAID intolerance. However, since adverse reactions to celecoxib cannot be ruled out completely, a controlled oral challenge test is still mandatory for proper management of patients with NSAID intolerance.

Microbial colonization and atopic dermatitis.

PURPOSE OF REVIEW: Atopic dermatitis is a chronic relapsing, pruritic inflammation of the skin, affecting 10-20% of children and 1-3% adults worldwide, with increasing prevalence in highly industrialized countries. Here we review relevant studies, published since June 2002, about immunological triggers in atopic dermatitis, with emphasis on the role of microbial colonization. RECENT FINDINGS: During the past 2 years there has been considerable interest in the mechanisms and trigger factors underlying the increased microbial colonization of atopic skin. Staphylococcus aureus appears to play a significant role as it leads to a worsening of disease severity by producing superantigens that induce a strong proliferation of T cells and favour a T helper type 2-like cytokine profile. In addition, different Malassezia species seem to elicit and maintain skin inflammation after sensitization, but the precise immunological pathway has not yet been described. All these microorganisms are not only perceived as aetiological factors but also as agents responsible either for sustained disease activity or resistance to therapy by modulation of the immune response. SUMMARY: New insights into the important role of microorganisms and their key immunomodulatory pathways in atopic dermatitis may have important implications from a therapeutic point of view because patients with atopic dermatitis may benefit from more than just anti-inflammatory treatment in the future.