Fumaric acid ester (FAE) therapy has proved to be safe and effective in patients with severe psoriasis vulgaris. This treatment was introduced nearly 30 years ago, but is only now gaining renewed ...interest among dermatologists. FAE therapy is licensed in Germany and registration is pending in many European countries. Multicentre trials have confirmed the beneficial effect of FAE in psoriasis and have defined the spectrum of its adverse effects. Although the mode of action of FAEs in the treatment of psoriasis is not fully understood, recent experimental data point towards a skewing of the Th1‐dominated T‐cell response in psoriasis to a Th2‐like pattern, and inhibition of proliferation of keratinocytes. This article reviews the experimental and clinical information on FAEs in psoriasis and provides guidelines for the clinical use of FAEs derived from a consensus meeting of leading experts.
Systemic treatment of psoriasis with fumaric acid esters (FAE) has been found effective by empirical means. In recent years clinical studies have confirmed the antipsoriatic activity of a defined ...mixture of different FAE. The aim of the present prospective multicentre study was to investigate further the efficacy and safety of FAE therapy in a large number of patients with severe psoriasis vulgaris. From 101 patients included in the study 70 completed the treatment period of 4 months. Discontinuation was due to adverse events in seven, lack of efficacy in two, and other reasons, such as non‐attendance for scheduled visits, in 22 patients. Evaluation of overall efficacy showed a decrease in psoriasis area and severity index of 80% after 4 months of FAE therapy. Laboratory investigations revealed a slight overall decrease of lymphocytes during the treatment period which was more than 50% below baseline in 10 patients. During weeks 4 and 8 mean eosinophil counts were above the normal range. At the end of FAE therapy elevated eosinophil counts had returned to normal values. None of the patients showed changes in renal function parameters throughout the study. Adverse events were reported in 69% of the patients mainly consisting of gastrointestinal complaints (56%) and flushing (31%). In five patients gastrointestinal complaints and in two patients flushing led to withdrawal from the study. Taken together the results of this multicentre study showed in a large number of patients that systemic FAE treatment is effective in severe psoriasis vulgaris. Transient eosinophilia seems to be a characteristic feature of FAE therapy, while lymphocytopenia is usually mild. Adverse effects are dose‐related and consist mainly of gastrointestinal complaints and flushing.
Transplantation of solid organs has been well established as a mode of therapy for the treatment of various end-stage organ diseases for many years. Up to now, it has benefited more than 1 million ...patients worldwide. The long-term success of organ transplantation depends particularly on the prevention of allograft rejection. Various regimens have been used to suppress hosts' cellular immune responsiveness to the grafted organs. Nowadays immunosuppressive therapies consist mainly in prednisolone, azathioprine, cyclosporine, anti-T-lymphocyte-globulin (ATG), anti-CD 3 antibody (OKT3) and substances of a new generation, such as tacrolimus or mycophenolic acid. However, not only the patient's reactivity to the graft is impaired, but also that to infectious organisms. Chronically altered immune responsiveness is especially associated with a dramatically increased risk of malignancy, most frequently non-Hodgkin's lymphoma and skin cancer. Within the first 5 years of immunosuppression 40% of transplant recipients experience premalignant skin tumors such as actinic keratoses and Bowen's disease, and also such skin cancers as squamous cell carcinomas and basal cell carcinomas. Quite often these have an aggressive biology and an uncommon morphology. Cancer is now responsible for a mortality rate of 5-8% in organ transplant patients. Various risk factors, such as exposure to sun and infections with oncogenic viruses (e.g. HPV) contribute to the already increased risk of dysplasia when lifelong immunosuppression is required. Prophylactic strategies therefore include the development of virus-like particles (VLPs) as anticancer vaccines, which might become a very interesting approach to preventing HPV-associated cancer. The prevention of precancerous conditions and mature skin cancers in grafted patients includes protective clothing and adequate protection of UV-exposed skin regions, including lips, from sunlight with appropriate sunscreen. Close dermatological surveillance through a specialized outpatient department should be ensured to detect potentially fatal skin malignancies at an early stage. Early treatment of precancerous lesions includes topical retinoids, such as tretionin, tazarotene or adapalene. A 5% fluorouracil cream is widely used but shows variable effects on manifest actinic keratoses. As cellular immunity seems to play the major part in the prevention and cure of malignant and premalignant cutaneous neoplasias as well as viral infections, a specific enhancement of the local immunity would be desirable. Imiquimod is one of a class of agents known as immune response modifiers. The drug has been shown to have both antiviral and antitumor activity. Application of immune response activators or modifiers such as imiquimod might be premising in the case of transplant recipients.
Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it ...that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.
Summary
Psoriasis is a chronic, immune‐mediated disorder that usually requires long‐term treatment for control. Approximately 25% of patients have moderate to severe disease and require phototherapy, ...systemic therapy or both. Despite the availability of numerous therapeutic options, the long‐term management of psoriasis can be complicated by treatment‐related limitations. With advances in molecular research and technology, several biological therapies are in various stages of development and approval for psoriasis. Biological therapies are designed to modulate key steps in the pathogenesis of psoriasis. Collectively, biologicals have been evaluated in thousands of patients with psoriasis and have demonstrated significant benefit with favourable safety and tolerability profiles. The limitations of current psoriasis therapies, the value of biological therapies for psoriasis, and guidance regarding the incorporation of biological therapies into clinical practice are discussed.
Summary
Background The presence of eosinophils and/or eosinophil‐derived products in the dermis is characteristic for involved skin of patients with atopic dermatitis and contributes to the observed ...tissue injury. CCL11 is a potent chemoattractant and activator of human eosinophils and interleukin (IL)‐4 is a potent inducer of CCL11 expression in dermal fibroblasts.
Objectives As increased fibroblast CCL11 expression may explain eosinophilic infiltration of involved skin areas in atopic dermatitis, we asked whether dermal fibroblasts from atopic patients differ from fibroblasts of healthy individuals in their ability to express CCL11.
Methods We compared IL‐4‐induced CCL11 mRNA expression using reverse transcription–polymerase chain reaction from cultured dermal fibroblasts derived from biopsies of chronic lesional and acute lesional atopic skin as well as from skin biopsies derived from normal skin of healthy donors.
Results Considerable variability in IL‐4‐induced relative CCL11 mRNA expression was detected in fibroblasts derived from biopsies of different individuals. The lowest median IL‐4 concentration inducing half maximal CCL11 mRNA expression (EC50) was found in fibroblasts derived from acute inflamed atopic lesions.
Conclusions Inducibility of CCL11 in dermal fibroblasts upon stimulation with Th2 cytokines explains the tissue eosinophilia observed in the presence of Th2 cytokines and the localization of eosinophils to the dermis. Decreased EC50 values of IL‐4‐induced CCL11 expression in fibroblasts from acute inflamed atopic skin lesions indicates increased IL‐4 responsiveness in these lesions and further substantiates the special role for IL‐4‐induced dermal fibroblast CCL11 expression in acute lesions. Variable CCL11 expression in fibroblasts from different patients with atopic dermatitis indicates heterogeneity of factors determining atopic phenotype in atopic dermatitis.
ABSTRACT
Patients with psoriasis have an increase in pathogenic CD45RO+ memory‐effector T cells during active disease. The genetically engineered fully human fusion protein alefacept has been ...developed to selectively target this subset of T cells. Alefacept binds to memory‐effector CD45RO+ T cells, inhibiting their activation and inducing T‐cell apoptosis. The selectivity of alefacept for memory‐effector CD45RO+ T cells was evaluated in 229 patients with chronic psoriasis in a randomized, placebo‐controlled, double‐blind study conducted at 22 centres in the USA. Patients received alefacept intravenously at doses of 0.025 mg/kg, 0.075 mg/kg, or 0.150 mg/kg, or placebo once weekly for 12 weeks. Two weeks after completing treatment, patients receiving alefacept showed significant improvement in the Psoriasis Area and Severity Index (PASI) compared with those receiving placebo. Mean reductions in the PASI score were up to 53% lower than baseline scores in the alefacept treatment group, compared with a 21% decline from baseline in the placebo group (P < 0.001). In addition to the significant improvement in psoriasis, treatment with alefacept produced long‐term remission in some patients. Twelve weeks after completion of therapy, 28 patients became clear or almost clear. The therapy was well tolerated and nonimmunogenic. Importantly, during treatment, there was a correlation between improvement in psoriasis and a dose‐dependent reduction in peripheral blood CD45RO+ memory‐effector T cells, but not in CD45RA+ naive T cells. This correlation indicates a relationship between a specific T‐cell subset reduction (CD45RO+) and clinical outcome in psoriasis.
Background Actinic keratoses (AK) are premalignant lesions, which are routinely treated by destructive procedures such as cryotherapy, electrodessication or topical 5‐fluorouracil.
Objectives The aim ...of this study is to report six cases of AK treated with a potential new topical therapy, imiquimod.
Methods Subjects included in this study had suffered with recurrent AK for between 5 and 16 years. All six men were treated with imiquimod 5% cream three times a week for 6–8 weeks. In the event of a local skin reaction treatment was modified to two times per week.
Results All the AK lesions were successfully cleared after treatment with imiquimod cream 5% for 6–8 weeks. Histologically, no apparent signs of persisting AK could be detected, and no recurrences were reported during follow up.
Conclusions This study suggests that imiquimod may be useful as a new therapy for the treatment of actinic keratoses.
Background SDZ ASM 981 is a selective inhibitor of the production of pro‐inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under ...development for the treatment of inflammatory skin diseases.
Objectives This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0·05%, 0·2%, 0·6% and 1·0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies.
Methods This was a double‐blind, randomized, parallel‐group, multicentre dose‐finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0·05%, 0·2%, 0·6%, or 1·0%, matching vehicle cream, or the internal control 0·1% betamethasone‐17‐valerate cream (BMV). Treatment was given twice daily for up to 3 weeks.
Results A clear dose–response relationship for SDZ ASM 981 was evident, with 0·2%, 0·6% and 1·0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0·041, 0·001 and 0·008, respectively) in terms of baseline to end‐point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1·0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0·6% and 1·0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42·9%, 48·9% and 34·9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1·0% cream was similar to that of the lower concentrations.
Conclusions 1·0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.
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