Jean Paul Ortonne

Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else?

Abstract:u2002 The pathobiology of vitiligo has been hotly disputed for as long as one remembers, and has been a magnet for endless speculation. Evidently, the different schools of thought – ranging, e.g. from the concept that vitiligo essentially is a free‐radical disorder to that of vitiligo being a primary autoimmune disease – imply very different consequences for the best therapeutic strategies that one should adopt. As a more effective therapy for this common, often disfiguring pigmentary disorder is direly needed, we must strive harder to settle the pathogenesis debate definitively – on the basis of sound experimental evidence, rather than by a war of dogmatic theories.

What are melanocytes really doing all day long...

Abstract:u2002 Everyone knows and seems to agree that melanocytes are there to generate melanin – an intriguing, but underestimated multipurpose molecule that is capable of doing far more than providing pigment and UV protection to skin ( 1 ). What about the cell that generates melanin, then? Is this dendritic, neural crest‐derived cell still serving useful (or even important) functions when no‐one looks at the pigmentation of our skin and its appendages and when there is essentially no UV exposure? In other words, what do epidermal and hair follicle melanocytes do in their spare time – at night, under your bedcover? How much of the full portfolio of physiological melanocyte functions in mammalian skin has really been elucidated already? Does the presence or absence of melanoctyes matter for normal epidermal and/or hair follicle functions (beyond pigmentation and UV protection), and for skin immune responses? Do melanocytes even deserve as much credit for UV protection as conventional wisdom attributes to them? In which interactions do these promiscuous cells engage with their immediate epithelial environment and who is controlling whom? What lessons might be distilled from looking at lower vertebrate melanophores and at extracutaneous melanocytes in the endeavour to reveal the ‘secret identity’ of melanocytes? The current Controversies feature explores these far too infrequently posed, biologically and clinically important questions. Complementing a companion viewpoint essay on malignant melanocytes ( 2 ), this critical re‐examination of melanocyte biology provides a cornucopia of old, but under‐appreciated concepts and novel ideas on the slowly emerging complexity of physiological melanocyte functions, and delineates important, thought‐provoking questions that remain to be definitively answered by future research.

Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method

BACKGROUNDnThe Melasma Area and Severity Index (MASI), the most commonly used outcome measure for melasma, has not been validated.nnnOBJECTIVEnWe sought to determine the reliability and validity of the MASI.nnnMETHODSnAfter standardized training, 6 raters independently rated 21 patients with mild to severe melasma once daily over a period of 2 days to determine intrarater and interrater reliability. Validation was performed by comparing the MASI with the melasma severity scale. The darkness component of the MASI was validated by comparing it with the difference between mexameter scores for affected versus adjacent normal-appearing skin. The area component of the MASI was validated by comparing it with the area of each section of the face determined by computer-based measurement software.nnnRESULTSnThe MASI score showed good reliability within and between raters and was found to be valid when compared with the melasma severity scale, mexameter scores, and area measurements. Homogeneity assessment by raters showed the least agreement and can be removed from the MASI score without any loss of reliability.nnnLIMITATIONSnPatients were limited to Hispanic, African, and Asian backgrounds.nnnCONCLUSIONnThe MASI is a reliable measure of melasma severity. Area of involvement and darkness are sufficient for accurate measurement of the severity of melasma and homogeneity can be eliminated.

The Pigmentary System: Physiology and Pathophysiology: Second Edition

The most comprehensive and integrated book on pigmentation. The Pigmentary System, Second Edition, gathers into one convenient, all-inclusive volume a wealth of information about the science of pigmentation and all the common and rare clinical disorders that affect skin color. The two parts, physiology (science) and pathophysiology (clinical disorders), are complementary and annotated so that those reading one part can easily refer to relevant sections in the other. For the clinician interested in common or rare pigment disorders or the principles of teaching about such disorders, this book provides an immediate and complete resource on the biologic bases for these disorders. For the scientist studying the biology of melanocyte function, the book provides a list of disorders that are related to basic biological functions of melanocytes. New features of this Second Edition include: Completely new section on the basic science of pigmentation explaining the integration of melanocyte functions with other epidermal cells and with various organ systems like the immune system. New chapters on pigmentary disorders related to intestinal diseases, the malignant melanocyte, benign proliferations of melanocytes (nevi) and phototherapy with narrow band UV. All clinical chapters include the latest genetic findings and advances in therapy. More than 400 color images of virtually all clinical disorders. The book is ideal for all dermatologists and especially those interested in disorders of pigmentation. It is of particular use for pediatric dermatologists and medical geneticists caring for patients with congenital and genetic pigmentary disorders. This authoritative volume will fill the gap for dermatology training programs that do not have local experts on pigmentation. Basic and cosmetic scientists studying pigmentation and melanocytes will find the science and clinical correlations very useful in showing human significance and relevance to the results of their studies.

The Efficacy of Afamelanotide and Narrowband UV-B Phototherapy for Repigmentation of Vitiligo

BACKGROUNDnVitiligo is characterized by depigmented patches of skin due to loss of cutaneous melanocytes. Many recent studies have demonstrated defects in the melanocortin system in patients with vitiligo, including decreased circulating and lesional skin levels of α-melanocyte-stimulating hormone (α-MSH). Afamelanotide is a potent and longer-lasting synthetic analogue of naturally occurring α-MSH.nnnOBSERVATIONSnWe describe the preliminary results of 4 patients with generalized vitiligo who developed repigmentation using afamelanotide in combination with narrowband UV-B (NB-UV-B) phototherapy. Patients were treated 3 times weekly with NB-UV-B and starting in the second month received a series of 4 monthly implants containing 16 mg of afamelanotide. Afamelanotide induced faster and deeper repigmentation in each case. All patients experienced follicular and confluent areas of repigmentation within 2 days to 4 weeks after the initial implant, which progressed significantly throughout treatment. All patients experienced diffuse hyperpigmentation.nnnCONCLUSIONSnWe propose that afamelanotide represents a novel and potentially effective treatment for vitiligo. The combined therapy of NB-UV-B and afamelanotide appears to promote melanoblast differentiation, proliferation, and eumelanogenesis. Further studies are necessary to confirm these observations.

Skin and nail responses after 1 year of infliximab therapy in patients with moderate-to-severe psoriasis: a retrospective analysis of the EXPRESS Trial.

Background: The EXPRESS study demonstrated the initial efficacy of infliximab in psoriasis affecting the skin and nails. Objective: To further assess how patients with a positive initial response to infliximab respond to 1 year of continuous infliximab treatment. Methods: A retrospective analysis of patients with moderate-to-severe plaque and nail psoriasis who initiated and continued infliximab treatment up to week 46 was conducted. Results: Among all nail psoriasis patients receiving 1 year of infliximab (n = 186), 74.6 and 54.1% achieved at least 75 or 90% improvement in the Psoriasis Area and Severity Index (PASI) at week 50. These PASI-75 (n = 138) and PASI-90 (n = 100) responders had respective mean improvements from baseline to week 50 of 93.6 and 97.3% for the PASI, 90.6 and 94.1% for the Dermatology Life Quality Index (DLQI) and 78.2 and 80.3% for the Nail Psoriasis Severity Index (NAPSI). Conclusions: Infliximab treatment for 1 year produced sustained improvement in PASI, DLQI and NAPSI scores.

Expression of the chemokine receptor CCR5 in psoriasis and results of a randomized placebo controlled trial with a CCR5 inhibitor.

Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis.

Adult Still's disease associated with hepatitis C virus infection

Several reports have suggested a triggering viral infection in adult Stills disease. We describe a paxad tient in whom the onset of Stills disease was associxad ated with a hepatitis C virus infection. CASE REPORT A 56-year-old woman reported a pruritic eruption, sore throat, polyarthralgias, muscle weakness, and evening spikes of fever lasting 1 month despite treatment with acxad etaminophen and an antihistamine. Examination disxad closed an asthenic, febrile patient with tachycardia; linear urticarial lesions (Fig. 1); axillary and cervical lymph node enlargement; and painful swelling, warmth, tenderxad ness, and erythema of both knee joints. The linear urticarial lesions were randomly scattered and could not be explained by pressure or other mechanical factors. Examination of the pharynx showed diffuse redness. The patient had mild leukocytosis (11,000 white blood cells/ mrrr) and elevated erythrocyte sedimentation rate (96 mm/hr), C-reactive protein (75 mg/L), a high serum ferritin level (447 J1.g/L), and proteinuria (1.2 grn/day). Liver function tests showed only elevations of transamixad nases. The serum creatine kinase level was normal. Cirxad culating immune complexes were absent. The search for an underlying infectious or immunologic process had negative results except for a positive result for hepatitis C on serologic examination. The result of blood testing for hepatitis C RNA by the polymerase chain reaction was positive. The patient denied having undergone a blood transfusion. Cutaneous, hepatic, and synovial biopsy specimens were nonspecificand did not show vasculitis or viral-induced changes. A muscle biopsy specimen and an electromyographic study had normal results. Anechocarxad diagram revealed small pericardial effusions. The diagxad nosis of adult Stills disease was made. Oral prednisone, 60 mg/day, was started and resulted in a dramatic improvement. However, a corticosteroid dependence ne

Cystinosin is a melanosomal protein that regulates melanin synthesis

Cystinosis is a rare autosomal recessive disease characterized by cystine crystal accumulation leading to multiorgan dysfunctions and caused by mutation in CTNS. CTNS encodes cystinosin, a cystine/H+ symporter that exports cystine out of the lysosomes. Patients with cystinosis frequently exhibit blond hair and fair complexion, suggesting an alteration in melanogenesis. However, the pigmentation singularities of these patients have not been studied, and the role of cystinosin in melanogenesis has remained unknown. In our study, a clinical evaluation of 27 patients with cystinosis showed that 44% had a cutaneous pigmentation dilution compared to their relatives. Analysis of the hair melanin content in these patients by HPLC demonstrated a 50% decrease in eumelanin (4360 vs. 9360 ng/mg), and a 2‐fold increase in pheomelanin (53 vs. 20 ng/mg), the yellow/red pigments. Cystinosin‐deficient mice also showed a 4‐fold increase in hair pheomelanin content. In vitro studies showed that cystinosin was located at melanosomes. CTNS silencing led to a 75% reduction of melanin synthesis that was caused by a degradation of tyrosinase by lysosomal proteases. Our results objectify the pigmentation defect in patients with cystinosis. We also identify the role of CTNS in melanogenesis and add a new gene to the list of the genes involved in the control of skin and hair pigmentation.—Chiaverini, C., Sillard, L., Flori, E., Ito, S., Briganti, S., Wakamatsu, K., Fontas, E., Berard, E., Cailliez, M., Cochat, P., Foulard, M., Guest, G., Niaudet, P., Picardo, M., Bernard, F.‐X., Antignac, C., Ortonne, J. P., Ballotti, R. Cystinosin is a melanosomal protein that regulates melanin synthesis. FASEB J. 26, 3779–3789 (2012). www.fasebj.org

Infection cutanée à Mycobacterium fortuitum après lifting

Resume Introduction Les infections cutanees a Mycobacterium fortuitum ( M. fortuitum ) sont rares, le plus souvent iatrogenes. Nous rapportons un cas avec atteinte cervicale survenue apres une intervention pour lifting. Observation Une femme de 65 ans, sans antecedent, avait eu un lifting facial chirurgical bilateral. Il s’etait complique d’une necrose cutanee traitee par cicatrisation dirigee a domicile. Six semaines plus tard, apparaissaient un nodule abcede sous-maxillaire gauche, draine chirurgicalement, puis d’autres nodules inflammatoires pre-auriculaires et cervicaux gauches, sans adenopathie, ni fievre. Les prelevements bacteriologiques isolaient un M. fortuitum . L’antibiotherapie, initialement probabiliste par clarithromycine, secondairement adaptee par amikacine et ciprofloxacine puis amikacine et imipeneme, pour une duree totale de 3 mois, permettait d’obtenir une guerison clinique. Discussion M. fortuitum est une mycobacterie a croissance rapide, ubiquitaire, responsable d’infections nosocomiales chez les sujets immunocompetents, notamment apres chirurgie plastique. La contamination survient en un site de rupture de la barriere cutanee, par contact avec un vecteur (eau, materiel chirurgical, antiseptique…). Le traitement, mal codifie, consiste en l’association d’un traitement chirurgical et d’une antibiotherapie pendant plusieurs mois.