Philippe Paquet

Interleukin-6 and the skin

Interleukin-6 is a pleiotropic cytokine with numerous biological activities. It is produced by normal constituents of the skin, including epidermal cells, fibroblasts and dermal endothelial cells. It is also synthesized by inflammatory cells infiltrating the skin in various pathological conditions. We reviewed the presumed activities of interleukin-6 in normal skin and in some diseases with cutaneous involvement. The action of some drugs used in dermatology was also considered with regard to the modulation of the cytokine release. It is concluded that several important cellular lineages of the skin release interleukin-6. The cytokine appears to play a crucial role in the pathogenesis of both local and systemic inflammation, tumor development and autoimmune diseases.

The Beneficial Toxicity Paradox of Antimicrobials in Leg Ulcer Healing Impaired by a Polymicrobial Flora: A Proof-of-Concept Study

Background: Some of the views contrasting the beneficial and toxic effects of antimicrobials upon wound healing remain controversial. Objective: To assess the clinical relevance of histological findings following antimicrobial applications on chronic leg ulcers. Method: The present study was performed in three parallel groups of 17 patients suffering from at least 2 similar chronic leg ulcers. Clinical planimetric assessments were performed before and after 3 and 6 weeks of treatment using hydrocolloid dressings. In addition, 1 ulcer in each patient received applications of povidone-iodine (PVP-I), silver sulfadiazine or chlorhexidine digluconate. Histological examinations were made at inclusion and after the 6-week therapy. Time to healing was also recorded. Results: At entry in the study, fibroblasts, macrophages, neutrophils and vessels were abundant in the ulcers. In addition, focal necrotizing vasculitis was related to the microbiological load. Compared to the control lesions, both the healing rate and time to healing of the leg ulcers showed a modest improvement at the sites receiving silver sulfadiazine (2–7%) or chlorhexidine digluconate (–1 to 5%). By contrast, PVP-I increased significantly the healing rate (4–18%, p < 0.01), and time to healing was reduced by 2–9 weeks (p < 0.01). The 3 antimicrobials decreased the bacterial density, and the vascular margination and migration of inflammatory cells, thus abating the vasculitic changes. PVP-I applications did not alter the microvessels and did not significantly reduce the density in dendrocytes and fibroblasts. By contrast, both silver sulfadiazine and chorhexidine digluconate appeared to alter the superficial microsvasculature including the dendrocyte population. Conclusion: Although topical antimicrobials may apparently achieve almost similar activity on the bacterial load inside chronic leg ulcers, the toxicity upon host cells was different among these agents. PVP-I appeared to be an efficient compound in these respects exhibiting a positive and relevant clinical effect.

Immunoregulatory effector cells in drug-induced toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN) is a rare drug-induced disease for which the pathomechanism remains poorly understood. The effector cells of epidermal injury in TEN were studied by taking skin biopsies of early lesions in 23 TEN patients and by performing immunohistochemical tests using antibodies to factor XIIIa (type I dendrocytes), L1-protein (mainly Mac 387+ monocytes and macrophages), UCLH1 (mainly CD45R0+ T-memory lymphocytes), interleukin-6 (IL-6), and tumor necrosis factor-&agr; (TNF&agr;). Computerized image analysis was used to evaluate the cell density relative to each immunolabeling. A statistical analysis of cellular counts revealed a numeric relation between the cell types in skin with TEN. Factor XIIIa+ dendrocytes were abundant and plump in the dermis, although Mac 387+ macrophages were the most numerous inflammatory cells in the epidermis. Their numbers greatly exceeded those of CD45R0+ T lymphocytes and cells showing immunoreactivity for either IL-6 or TNF&agr;. In the epidermis, IL-6+ cells were significantly less numerous than TNF&agr;+ cells. No quantitative difference was found between IL-6+ and CD45R0+ cell populations. Correlations were observed between either the numbers of TNF&agr;+ cells or Mac 387+ macrophages and CD45R0+ lymphocytes. In the dermis, a significant correlation was also present between the numbers of Mac 387+ and factor XIIIa+ cells. These findings highlight the complex interactions between the inflammatory cells that mediate epidermal damage in skin with TEN. The high density of factor XIIIa+ dendrocytes and Mac 387+ macrophages in lesional skin assigns these cellular populations a prominent role in the pathomechanism of TEN. Despite a lower cell density, CD45R0+ T-memory lymphocytes likely participate in TNF&agr;- andagr;-and IL-6–regulated processes in the epidermis of TEN. TNF&agr; seems to be a major cytokine involved in TEN, although a less prominent role can be ascribed to IL-6.

Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25–30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to massive keratinocyte death in TEN. Dysregulations in the tumor necrosis factor-α (TNF-α) pathway, CD95 system (Fas ligand, CD95L; Fas receptor, CD95R) and calcium homeostasis in the epidermis are involved in this apoptotic process. An active role has also been ascribed to T lymphocytes, macrophages and factor XIIIa-positive dermal dendrocytes. Despite progress, treatment of TEN remains controversial. In the past, systemic glucocorticoids were used in order to target the inflammatory reaction in TEN. However, there was no evidence for improvement of the healing process, while corticosteroids worsened the prognosis by increasing the risk of septicemia. Only a few cases have been treated with other drugs including cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-α antibodies and cyclosporin A. In the recent past, some TEN patients were treated with intravenous human immunoglobulins (IVIG). The rationale for such a treatment was to block the CD95 system on keratinocytes. The early promising clinical results of IVIG treatment in TEN were subsequently challenged. This review compares the effectiveness and drawbacks of the major drugs presently used in TEN treatment. Some future prospects in TEN management are also discussed.

Assessment of Topical Hypopigmenting Agents on Solar Lentigines of Asian Women

Background: So-called darkened age spots encompass distinct pathological processes. The efficacy of topical depigmenting agents is difficult to objectivate. Objective: To assess the hypopigmenting effect of three cosmetic formulations using objective biometrological methods. Methods: 50 women of South-East Asian ancestry were enrolled in this pilot study. They had solar lentigines according to dermoscopic criteria. The lesions were treated by topical hypopigmenting formulations. Products were applied twice daily for 2 or 3 months. Assessments at 1-month intervals were made using narrow-band reflectance spectrophotometry, image analysis of video-recorded ultraviolet light reflection and photodensitometry- and image-analysis-assisted corneomelametry. Results: A 20% azelaic acid formulation and another one containing 5% ascorbyl glucosamine, 1% kojic acid and α-hydroxyacid esters appeared inefficacious on solar lentigines. A stabilized soy extract showed a better although modest lightening effect when assessed by corneomelametry. The subclinical or faint mottled skin revealed by ultraviolet light examination better responded (p < 0.05) to treatments. Conclusion: Focal epidermal hyperpigmentation is better controlled by topical whitening agents when the increase in melanin content reflects a modest functional hyperactivity of melanocytes.

Treatment of drug-induced toxic epidermal necrolysis (Lyell's syndrome) with intravenous human immunoglobulins

Toxic epidermal necrolysis (TEN) is a rare drug-induced life-threatening disease. Currently, the disease is only treated by supportive and antiseptic measures. Quite recently intravenous immunoglobulins (IG) were shown to be a promising TEN treatment. The rationale for their use is based on the fact that keratinocyte apoptosis in TEN involves the CD95 (APO-1/Fas) cell surface receptor-ligand system. We successfully treated a TEN patient with high dose of intravenous IG. The clinical recovery appeared exceptionally rapid. Immunohistochemistry showed that the IG action probably developed on the CD95 receptor-ligand system at the keratinocytes surface.

New Insights in Toxic Epidermal Necrolysis (Lyell's Syndrome): Clinical Considerations, Pathobiology and Targeted Treatments Revisited

Drug-induced toxic epidermal necrolysis (TEN), also known as Lyell’s syndrome, is a life-threatening drug reaction characterized by extensive destruction of the epidermis and mucosal epithelia. The eyes are typically involved in TEN. At present, the disease has a high mortality rate. Conceptually, TEN and the Stevens-Johnson syndrome are closely related, although their severity and outcome are different. Distinguishing TEN from severe forms of erythema multiforme relies on consideration of aetiological, clinical and histological characteristics. The current understanding of the pathomechanism of TEN suggests that keratinocytes are key initiator cells. It is probable that the combined deleterious effects on keratinocytes of both the cytokine tumour necrosis factor (TNF)-α and oxidative stress induce a combination of apoptotic and necrotic events. As yet, there is no evidence indicating the superiority of monotherapy with corticosteroids, ciclosporin (cyclosporine) or intravenous immunoglobulins over supportive care only for patients with TEN. However, the current theory of TEN pathogenesis supports the administration of a combination of antiapoptotic/antinecrotic drugs (e.g. anti-TNF-α antibodies plus N-acetylcysteine) targeting different levels of the keratinocyte failure machinery.

Dermal dendritic cells in anogenital warty lesions unresponsive to an immune-response modifier

Background: Human papilloma viruses (HPV) are responsible for a variety of proliferative epithelial lesions including anogenital condylomas. These lesions may regress during treatment with an immune‐response modifier such as imiquimod. The release of specific cytokines from the monocyte‐macrophage lineage induces a cascade of events abating the HPV replication.

Would Cyclosporin A Be Beneficial to Mitigate Drug-Induced Toxic Epidermal Necrolysis?

Drug-induced toxic epidermal necrolysis (TEN) is a rare life-threatening disease whose mortality remains high. The treatment of the disease is badly settled. Several kinds of drugs have been tested, including systemic corticosteroids, cyclophosphamide, pentoxifylline and thalidomide, but without any clear-cut outcome. Cyclosporin A (CsA) has many inhibitory effects on the main cell populations involved in TEN (T lymphocytes, macrophages and keratinocytes). CsA could also act on tumor necrosis factor α metabolism, a cytokine which is important in TEN epidermal destruction. Moreover, apoptosis is the mechanism leading to keratinocyte death and CsA has antiapoptotic properties. CsA has already been used successfully on a limited series of TEN patients. We have reviewed the potential theoretical useful effects of CsA in TEN. We conclude that CsA could be a good candidate to reverse TEN progression.

Healing rate and bacterial necrotizing vasculitis in venous leg ulcers

Morbidity associated with venous leg ulcers is important in the elderly. The biological processes involved during attempts at healing are much more complex than in most models of experimental wounds. In addition, there is still controversy on deleterious effects elicited by both microorganisms and antiseptics on cells involved in the healing process. Using histology, immunohistochemistry and iterative computerized planimetry, we evaluated the bacterial load, the inflammatory aspects and the healing rate of leg ulcers present in 15 eligible women aged from 57 to 73 years. Each patient had at least 2 chronic ulcers treated with hydrocolloid dressing alone or in combination with daily applications of povidone-iodine solution (PVP-I). The weekly reduction in wound area was superior for hydrocolloid+PVP-I treatment than in hydrocolloid-treated ulcers. After a 4-week treatment, hydrocolloid-treated ulcers contained clumps of microorganisms and showed massive infiltration by phagocytes including Mac 387+ and factor XIIIa+ cells. Leukocytoclastic vasculitis was present as well. These features were less pronounced in ulcers treated with hydrocolloid+PVP-I. In sum, a broad-spectrum antimicrobial such as PVP-I may be beneficial in reducing deleterious bacteria-related inflammation. As a result, the healing rate leg ulcers is enhanced.