Intermittent use of biologic agents for the treatment of psoriasis in adults.

Current clinical recommendations suggest that continuous treatment of moderate-to-severe psoriasis with biologic agents is more effective than intermittent treatment in terms of achieving remission and maintaining it. Intermittent treatment, however, may provide an alternative approach in patients unwilling or unable to maintain a continuous regimen, such as those who would prefer a 'treatment vacation' after achieving long-term remission, those who require treatment cessation owing to adverse events, and where insurance arrangements do not provide sufficient cover for continuous treatment. We conducted a literature search of PubMed to identify publications reporting data on the efficacy and safety of intermittent treatment with biologic agents in adults with psoriasis, specifically the use of inhibitors of tumour necrosis factor (adalimumab, certolizumab pegol, etanercept and infliximab), interleukin (IL)-12/IL-23 (ustekinumab), IL-23 (guselkumab) and IL-17 (brodalumab, ixekizumab and secukinumab). From our search, we identified 18 relevant publications reporting the intermittent use of the biologic therapies of interest: five described etanercept, three described adalimumab, two each described infliximab, ixekizumab or ustekinumab, and one each described certolizumab pegol, guselkumab, brodalumab and secukinumab. In general, there were large proportions of patients (≥60%) who were able to re-establish disease control (as defined by each study) following re-treatment, and the safety profiles of the various agents during re-treatment were as anticipated from their profiles observed during continuous dosing. The exception to these general findings was infliximab, which showed the lowest rate of efficacy-endpoint achievement (25% and 38% in two dosing groups evaluated) as well as a higher incidence of adverse infusion reactions compared with continuous dosing. In conclusion, the use of biologic agents in psoriasis is changing and current clinical data suggest that intermittent treatment may provide an effective and well-tolerated option for certain patients.

Update on tissue-engineered biological dressings.

Tissue-engineered biological dressings offer promise in the treatment of burns, chronic ulcers, donor site and other surgical wounds, and a variety of blistering and desquamating dermatologic conditions. For example, the prevalence of diabetic foot ulcers ranges from 4.4% to 10.5% of diabetics, resulting in 82,000 lower extremity amputations annually; venous leg ulcers affect 0.18% to 1.35% of the population; and pressure ulcers are found in 5.0% to 8.8% of institutionalized patients and 14.8% of patients in acute care facilities. Despite the large number of potential beneficiaries, cellular tissue-engineered products have suffered setbacks in recent years and have garnered considerably lower market share than commercial promoters anticipated. The mechanism of action of these products is not universally agreed upon, but delivery of growth factors and extracellular matrix components to the wound is thought to be important; graft "take" is not usually considered to occur. These "engineered" products do not specifically match a treatment modality to an underlying pathology. Clinical effect is often modest, and sometimes not justi- fiable from a cost-benefit perspective. Nevertheless, clinical reports in the literature of uses of tissueengineered biological dressings continue to mount, indicating that these products are finding niche applications where clinical utility is high and the cost can be defended. Despite commercial setbacks, the first-approved products, Dermagraft, Apligraf, and Cultured Epidermal Autograft (Epicel) are still being marketed, and new ones, such as OrCel, continue to be developed. The major indications for these products are summarized and a brief review of the available clinical literature is offered.

Cytokine regulation of proliferation and ICAM-1 expression of human dermal microvascular endothelial cells in vitro.

The effects of recombinant human interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF) on the cell proliferation and the expression of intercellular adhesion molecule-1 (ICAM-1) were assessed in cultured human dermal microvascular endothelial cells (HDMEC). IL-1 alpha and IL-1 beta stimulated the proliferation of HDMEC in a dose-dependent manner, whereas in control experiments using human umbilical vein endothelial cells (HUVEC), IL-1 alpha and IL-1 beta did not stimulate HUVEC growth. Also GM-CSF stimulated the proliferation of HDMEC, whereas IL-6 did not affect endothelial cell growth in vitro. Treatment with IL-1 alpha, IL-1 beta, and TNF markedly increased the expression of ICAM-1 on HDMEC in a time- and dose-dependent manner, in contrast to IL-6 and GM-CSF. By pre-embedding immunoelectron microscopy, membrane-bound expression of ICAM-1 was visualized with pronounced labeling in areas of microvillous cell protrusions. The TNF-induced expression of ICAM-1 on HDMEC was blocked by co-incubation with a neutralizing antibody against TNF, but not with neutralizing antibodies against IL-1 alpha, IL-1 beta, or IL-6. In addition, co-incubation of HDMEC with TNF and the retinoid compound acitretin, dexamethasone, or indomethacin did not abrogate the TNF-induced ICAM-1 expression. These results disclose IL-1 as a major, multifunctional endothelial cell-targeted cytokine and further confirm the concept that pro-inflammatory cytokines exert differential regulatory effects on dermal microvascular endothelial cell proliferation and expression of cell-adhesion molecules.

Effects of rIFN alpha, beta, and gamma on the morphology, proliferation, and cell surface antigen expression of human dermal microvascular endothelial cells in vitro.

The influence of recombinant human interferon alpha 2a (rIFN alpha), recombinant human interferon beta 1 (rIFN beta), and recombinant human interferon gamma (rIFN gamma) on human dermal microvascular endothelial cells (HDMEC) cultured in vitro was studied in various rIFN concentrations (0.1 IU/ml-10(4) IU/ml) over 2, 3, 4, 6, 8, and 10 d. Cell morphology and ultrastructure, cell proliferation, expression of class II alloantigens (HLA-DR and HLA-DQ), and intercellular adhesion molecule-1 (ICAM-1) were investigated using an in vitro technique established in our laboratory. All rIFN tested induced alterations of typical HDMEC morphology; the cells became spindle-shaped and fibroblastoid, although they maintained their endothelial cell marker expression. Also, all IFN dose- and time-dependently inhibited the proliferation of HDMEC in vitro (rIFN alpha greater than beta greater than gamma), whereby rIFN alpha exerted the strongest growth-inhibitory effect. Alkaline phosphatase anti-alkaline phosphatase (APAAP) immunocytochemistry of the cultured cells showed dose- and time-dependent stimulation of ICAM-1 and class II antigen expression only by rIFN gamma (HLA-DR greater than HLA-DQ), rIFN alpha and beta did not exert any immunomodulatory activity on HDMEC in vitro. These results indicate that HDMEC are an important target for the action of IFN. Besides growth inhibition, it seems that rIFN gamma in particular may be involved in the modulation of leucocyte adhesion and trafficking by altering the immunophenotype of the endothelial cell population.

Effects of recombinant tumor necrosis factor-alpha on cultured microvascular endothelial cells derived from human dermis.

We investigated the effects of recombinant human tumor necrosis factor-alpha (TNF) on cell proliferation and on expression of MHC class II antigens and intercellular adhesion molecule ICAM-1 in human dermal microvascular endothelial cells (HDMEC) derived from human foreskin. Second-passage HDMEC were treated with 0.1-10,000 U/ml TNF for up to 6 d, and cell growth was assessed by cell counts and a recently developed fluorogenic assay using 4-methylumbelliferyl heptanoate as a substrate. APAAP immunocytochemistry was performed using monoclonal antibodies against HLA-DR, HLA-DQ, and ICAM-1. TNF did not markedly inhibit the growth of HDMEC but induced expression of HLA-DR (1,000 U/ml and more) and of ICAM-1 (1 U/ml and more). Combination with interferon-gamma led to synergistic ICAM-1 induction. These results demonstrate a profound effect of TNF on the activation of dermal microvascular endothelial cells and suggest a major role of TNF in the mediation of leucocyte adhesion to endothelial cells of the skin microvasculature with possible implications for the initiation and maintenance of inflammatory skin processes.

Cultivation of human dermal microvascular endothelial cells in vitro: immunocytochemical and ultrastructural characterization and effect of treatment with three synthetic retinoids.

A new reliable and reproducible technique to culture endothelial cells from the small vessels and capillaries of human skin is introduced, and proliferation and differentiation of the growing cells are characterized. The endothelial origin of the culture cells was confirmed by light- and electron microscopy and by labelling with Ulex europaeus Agglutinin I and an antibody against Factor VIII-related antigen. Further immunocytochemical characterization showed that 92-100% of the cells were positive for beta 2-microglobulin and the entire cell population expressed vimentin, whereas cytokeratins, desmin, HLA-DR antigen, Leu 6 and S 100 protein, could not be detected. As vascular endothelium is a common site of inflammation and retinoids have been shown to be of good clinical efficacy in some chronic inflammatory skin diseases, we investigated the influence of etretinate, etretin and isotretinoin on proliferation and antigen expression of our culture cells. All retinoids applied inhibited proliferation of endothelial cells in a dose- and time-dependent manner whereas they induced neither HLA-DR nor intercellular adhesion molecule-1 (ICAM-1). Furthermore, none of the retinoids applied influenced the gamma-interferon-induced expression of these surface antigens on endothelial cells. Our results suggest that the action of retinoids in skin inflammation is not mediated by modulation of HLA-DR or ICAM-1. The cell culture technique described here is an interesting and reliable model for studying the influence of drugs on endothelial cell growth and differentiation in vitro.

Interferons. New additions and indications for use.

Within the past few years, natural and recombinant cytokines have become available for clinical use. The broadest clinical experience exists with the interferons because these were available first. This article discusses the clinical efficiency and therapeutic value of natural and recombinant interferon-alpha, -beta, and -gamma, alone or as part of a combination therapy of skin disorders. A novel therapeutic schedule for skin tumors such as cutaneous T-cell lymphoma and malignant melanoma and for some inflammatory skin disorders are proposed.

Therapeutic guidelines in vasculitis.

For the treatment of cutaneous vasculitis it is of considerable importance to distinguish clinically between vasculitis as primary disease or as secondary process due to a systemic disease. This implies a thorough diagnosis of the patient to classify the individual case. The currently available therapy of cutaneous vasculitis is rarely causative. In most cases a symptomatically orientated antiinflammatory immunosuppressive therapy is used to control the disease. In this review we will report on the currently used therapy protocols in cutaneous vasculitis.

[Industrial dermatoses among the Belthatów brown coal miners]. / Choroby skóry u pracowników kopalni wegla brunatnego w Belchatowie.

443 subjects were examined, 235 applying to the physician due to the occurrence of skin dermatoses (group I) and 208 workers referred for periodic examinations (group II). In group I skin dermatoses were found in 100, i.e. 85%, of the subjects and in group II in 99 i.e. 48% of the subjects. In both groups the most frequent dermatosis was feet skin inflammation, especially interdigital intertrigo. Oil acne was diagnosed in 15, ordinary acne in 23, pityriasis versicolor in 19. erythrasma in 10, and eczema and contact dermatitis in 7 subjects of the first group and 3 subjects of the other group. 204 subjects with feet skin pathologies underwent mycologic examinations and 36 subjects--also bacteriologic examinations. The results of those studies indicate that in 23% of the subjects, feet interdigital intertrigo results from mycologic infections. Bacterial infections may contribute to etiopathogenesis. Imidazole compounds are useful for the treatment and prevention of interdigital intertrigo.

[Lysozyme activity in the blood serum and lysosomes and lysosomal supernatant of neutrophils in patients with psoriasis treated by the PUVA method]. / Aktywnosc lizozymu w surowicy krwi, w lizosomach i w nadsaczu lizosomalnym granulocytów obojetnochlonnych u chorych na luszczyce leczonych metoda PUVA.

The determinations of the activity of lysozyme in the serum, lysosomes and lysosomal supernatant of neutrophil granulocytes were done in 33 patients with generalized psoriasis and in 19 healthy controls. A decrease of lysozyme activity was demonstrated in the serum, lysosomes and lysosomal supernatant in the patients. During treatment by the PUVA method this activity rose gradually above the values in the control group. Systematic determination of lysozyme activity may help in monitoring of treatment progress.

[Laboratory and oligobiopsy studies of the liver in patients with psoriasis treated by the combination of Tigason-PUVA-cignoline (RePUVA+C)]. / Laboratoryjne i oligobiopsyjne badania watroby u chorych na luszczyce leczonych metoda skojarzona Tigason-PUVA-cignolina (RePUVA+C).

In 10 patients with generalized psoriasis treated by this method biochemical and histological examinations of liver biopsy specimens were done before and after 60 days of the treatment. In some cases a transient rise of A1AT activity, raised activity of alkaline phosphatase and gamma-glutamyltranspeptidase were noted. Histological examinations demonstrated slight hepatocellular damage with microfocal necrosis, fatty infiltration of some cells and increase in the structural elements of cytoplasm.

[Production of superoxide free radicals by peripheral blood leukocytes in patients with psoriasis treated by the Re-PUVA-C method]. / Generowanie wolnych rodników ponadtlenkowych przez leukocyty krwi obwodowej u chorych na luszczyce leczonych metoda Re-PUVA-C.

The investigations were carried out in 20 patients with severe forms of psoriasis, and in 18 healthy subjects. The generation of free superoxide radicals by polymorphonuclear leukocytes of peripheral blood was evaluated by Bellavite et al. (1983) method by use superoxide dismutase of Sigma firm. The obtained results may confirm alterations in PMNL functions in patients with psoriasis observed by many authors. It may confirm the probability of damage of membrane structures and alterations in their bactericidal functions.

[Evaluation of metabolic efficiency of the liver in patients with psoriasis by the antipyrine test]. / Ocena sprawnosci metabolicznej watroby u chorych na luszczyce na podstawie próby antypirynowej.

In 47 patients with generalized psoriasis vulgaris and 23 healthy subjects the effectiveness of the hepatic metabolism reflected by drug biotransformation was assessed with the antipyrine elimination test. In the group of psoriatic patients there were 25 men and 22 women and in the control group--age-matched 12 men and 11 women. The half-time of antipyrine was longer and the clearance index was lower in the patients than those in the control group. The differences were statistically significant. After 2 weeks of PUVA or SUP-therapy the differences were more significant. The findings indicate an impairment of the liver metabolic effectiveness reflected by drug biotransformation in psoriatic patients.

[Retinoids in the treatment of skin diseases in the light of the data of the Dermatology Clinic, Medical Academy, in Lódz]. / Retinoidy w leczeniu chorób skóry w swietle materialu Kliniki Dermatologicznej WAM w Lodzi.

Tigason was applied in 51 patients with psoriasis and 19 with other skin diseases. In 18 patients was applied alone, in 42 combined with PUVA and in 10 with SUP. Roaccutan was applied in 18 patients with acne conglobata et phlegmonous resistant to other methods of treatment. Tigason was found to be a useful drug in psoriasis and some other skin diseases. The combination with PUVA or SUP allowed to reduce the doses of drugs and the dose of radiation. Roaccutan was found to be a useful drug in severe forms of acne vulgaris. The side effects of the treatment with retinoids were transient and they did not create danger to the patients.

[Selective phototherapy (SUP) in the treatment of psoriasis]. / Selektywna fototerapia (SUP) w leczeniu luszczycy.

113 psoriatic patients were treated with SUP combined with 0.1-0.3 per cent cignoline. The lamps produced by Heraeus were used, in 48 patients--Psorilux 3060 and in 65--Psorilux 5050. The first symptoms of improvement were visible after 7-10 days. The mean duration of the treatment was 4 weeks. In 46 per cent of the patients psoriatic eruptions disappeared completely and in the further 44 per cent ones a considerable improvement was observed. The better results were obtained in patients irradiated with lamp of greater power and in those, who received a greater number of irradiations. Severe side effects were observed only in 2 cases. Selective ultraviolet phototherapy was found to be a useful method in the treatment of psoriasis.