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Purpose: BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) significantly improved metastatic melanoma prognosis. Ocular adverse effects (OAEs) represent an uncommon but disabling toxicity of these drugs. We aimed to characterize the ocular safety profile of BRAFi or MEKi and to detect possible safety signals., Methods: We performed a retrospective, observational, pharmacovigilance study using VigiBase, the World Health Organization global safety database. Ocular adverse effects were classified according to the eye segments and the inflammatory pattern based on the Standardization of Uveitis Nomenclature. Associations among BRAFi monotherapy, MEKi monotherapy, and BRAFi+MEKi combination therapy and OAE reporting were assessed using disproportionality analysis. Results were expressed with the reporting odds ratio (ROR) and its 95% confidence interval (CI)., Results: From January 2010 to October 2019, 1568 OAE cases were reported with BRAFi or MEKi. Among them, 1006 cases with sufficient data were included, corresponding to 310 (30.8%), 124 (12.3%), and 572 (56.9%) cases reported with BRAFi, MEKi, or BRAFi+MEKi combination therapy, respectively. BRAF inhibitor monotherapy was significantly associated with the reporting of iris and ciliary body abnormalities (ROR, 8.7; 95% CI, 6.0-12.5), diffuse abnormalities (ROR, 7.1; 95% CI, 5.4-9.4), anterior uveitis (ROR, 8.6; 95% CI, 6.0-12.1), and panuveitis (ROR, 7.1; 95% CI, 5.4-9.4). MEK inhibitor monotherapy was associated with the reporting of retinal and choroid abnormalities (ROR, 9.5; 95% CI, 7.4-12.2), diffuse abnormalities (ROR, 2.5; 95% CI, 1.1-6.1), and panuveitis (ROR, 2.5; 95% CI, 1.1-6.1). Combinations of BRAFi and MEKi therapies were associated with OAEs from both drugs, with a possible synergistic or additive effect for diffuse abnormalities and panuveitis., Conclusions: Our study characterizes the ocular safety profile of BRAFi and MEKi. We identify possible safety signals for several OAEs not previously reported with BRAFi and MEKi. Our data provide the rationale for a personalized management of OAE in patients with BRAFi+MEKi combination therapy according to the type of ocular reaction., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Zika virus is an emergent virus targeting the skin. Ji-Ae et al. (2018) explore the interactions between Zika virus and skin cells. They showed that human keratinocytes play an important role in control of initial infection via the interaction with retinoic acid-inducible gene receptors., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To identify predictors of treatment success in syphilitic uveitis (SU)., Design: Retrospective multicentric analysis of patients treated for SU., Participants: A total of 95 eyes (66 patients, mean [standard deviation] aged 49 [12.5] years, 31 [47%] of whom were human immunodeficiency virus [HIV]+) were analyzed., Methods: Activity of SU was assessed at 1 week and 1 month after treatment onset, and at last follow-up. Improvement was defined by a ≥2-step decrease of both anterior chamber and vitreous haze inflammation levels, and by the size reduction in chorioretinal lesions., Main Outcome Measures: Recovery was defined as the resolution of inflammation in all anatomic structures at 1 month., Results: Panuveitis and posterior uveitis were the most frequent findings. Inflammatory parameters were higher in HIV+ patients. Recovery was reported in 65% and 85% of eyes at 1 month and at last follow-up, respectively. In multivariate analysis, after adjusting for initial best-corrected visual acuity and the antimicrobial treatment regimen, clinical improvement at 1 week (corrected risk ratios [cRR], 3.5 [2.3-3.8]; P = 0.001) was predictive of recovery at 1 month, whereas the use of periocular dexamethasone injections (cRR, 0.05 [0.02-0.6]; P = 0.01) and methylprednisolone pulses negatively affected the outcomes of eyes., Conclusions: Early improvement is the strongest predictor of ophthalmological recovery in SU., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objectives: Cutaneous manifestations (CM) in ANCA-associated vasculitides (AAV) are frequent, but data on clinical significance and clinical-pathological correlations are lacking., Methods: We conducted a multicenter, retrospective study including 1553 AAV patients. Clinical, biological and pathological features have been analyzed, and tissue samples from 46 biopsies were reviewed in a blind manner., Results: CM were more frequent in EGPA (53.0%) and MPA (51.9%) than in GPA (36.7%). Lesions more frequently associated with GPA were oral ulcers (4.6% vs. 2.5% in EGPA and 0.3% in MPA), while pyoderma gangrenosum and palpebral xanthoma were specific to GPA. Lesions associated with MPA were segmentary edema (19.5% vs. 12.7% in EGPA and 4.3% in GPA) and livedo (12.4% vs. 0.5% and 2.6%, respectively), whereas those associated with EGPA were urticarial lesions (11.5% vs. 1.9% in GPA and 3.5% in MPA) and nodules (12,2% vs. 8.9% in GPA and 4.7% in MPA). In GPA, CM patients had more frequent vasculitis than granulomatous phenotype, and poorer relapse-free and overall survival. Pathological analysis showed vasculitis and/or granulomatous infiltrates in 87.5% of GPA, in 61.1% of EGPA and in all MPA. Vasculitis was more frequently observed in purpura and nodules, while granulomas were differently located and organized within vessels or interstitium according to the type of lesions., Conclusion: Each AAV seemed to be associated with a peculiar pattern of cutaneous lesions. CM are associated with poorer prognosis in GPA. Clinical-pathological correlations showed no specific feature of each AAV, whereas granulomatous infiltrates differ according to the type of lesions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids., Methods: We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589., Findings: Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%])., Interpretation: Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events., Funding: French Ministry of Health, French Society of Dermatology, Roche., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), a life-threatening, virally induced B-cell lymphoproliferative disorder. HHV-8 is a B-lymphotropic γ-herpesvirus closely related to the Epstein-Barr virus (EBV). Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8-related diseases. We analyzed iNKT cells in both blood (n = 26) and spleen (n = 9) samples from 32 patients with HHV-8 MCD and compared them with patients with KS (n = 24) and healthy donors (n = 29). We determined that both circulating and splenic iNKT cell frequencies were markedly decreased in patients with HHV-8 MCD and were undetectable in 6 of them. Moreover, iNKT cells from patients with HHV-8 MCD displayed a proliferative defect after stimulation with α-galactosylceramide. These iNKT cell alterations were associated with an imbalance in B-cell subsets, including a significant decrease in memory B cells, particularly of marginal zone (MZ) B cells. Coculture experiments revealed that the decrease in iNKT cells contributed to the alterations in the B-cell subset distribution. These observations contribute to a better understanding of the complex interactions between HHV-8 and immune cells that cause HHV-8-related MCD., (© 2017 by The American Society of Hematology.)

Syphilis is back since the beginning of this century. The epidemic affects mainly men having sex with men with a high proportion of HIV-infected patients. The classification of syphilis distinguishes early syphilis where patients are contagious (primary, secondary and early latent of less than one year) and late syphilis where patients are not (or less) contagious (late latent of more than one year and tertiary). The clinical presentation of syphilis has not changed. However, we must insist on the early forms of neurosyphilis, notably ophthalmic syphilis often under-diagnosed, as it affects the treatment. Serologic tests may be improved but are very helpful for the positive diagnosis and the follow-up after treatment. Treatment of early syphilis is based on one injection of benzathine benzyl penicillin G. Patients who have had syphilis must be regularly followed-up after treatment, as re-infections are common and are often asymptomatic., (Copyright © 2016 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAF V600 mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p<0.0001). Patients with Day15/Day0 ratio below 0.66 had longer PFS (14 vs 4 months, HR=0.41, CI95%=[0.15-0.77], p=0.0095). In the multivariate Cox model analysis, ECOG PS was the only parameter independently associated with PFS (grade 1 vs 0, HR=3.26, CI95%=[1.29-8.22], p=0.01 and grade ≥2 vs 0, HR=4.77, CI95%=[1.52-14.95], p=0.007). Plasma vemurafenib exposure (p=0.046) and pre-treatment HGF levels (p=0.003) were independently associated with the total lymphocyte ratio Day15/Day0. These findings show that plasma vemurafenib exposure and pre-treatment HGF levels are two factors contributing to the early peripheral lymphocytes depletion which itself is associated with PFS., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Silicone injections, in particular illegal injections, carried out in an aesthetic purpose, can cause serious complications, like silicone embolism syndrome., Case Report: We present a 39-year-old man who presented with a severe acute respiratory distress syndrome related to an alveolar hemorrhage associated with a persistent penis ulcer and a genital lymphedema. It was the complications of silicone injections which revealed a severe personality disorder. Diagnosis of silicone embolism syndrome was made, a few years later, thanks to the histopathology study of a persistent penis ulcer with genital lymphedema. The outcome was favorable., Conclusion: A serious alveolar hemorrhage in a young patient should raise suspicion of silicone embolism syndrome, especially if there are cutaneous lesions compatible with injections., (Copyright © 2015 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Background: Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. The objective of this study was to evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis., Methods: This study consisted of a randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicenter trial lasting 3 months and an open-label study from month 3 to month 6. Adults with a clinical and histologic diagnosis of cutaneous sarcoidosis were included in nine hospital centers in France. Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for 3 months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide, 100 mg to 200 mg daily. The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement in three target lesions scored for area and infiltration, were compared across randomization groups., Results: The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients in the thalidomide group (20%) vs four out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of -1% [95% CI, -26% to +24%] for thalidomide vs placebo, P = 1.0). Eight patients with side effects were recorded in the thalidomide group vs three in the placebo group. We observed a large number of adverse event-related discontinuations in patients taking thalidomide in the first 3 months (four patients with thalidomide, zero with placebo) and in the 3 following months (five patients)., Conclusions: At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis., Trial Registry: ClinicalTrials.gov; No.: NCT0030552; URL: www.clinicaltrials.gov.

Syphilitic cardiovascular disease has been described since the 19th century, mainly on autopsy series. Major clinical manifestations are aortic aneurysm, aortic insufficiency, and coronary ostial stenosis. The diagnosis of syphilitic cardiovascular disease is based mainly on positive serologic tests and overt clinical manifestations. We present here a rare and unusual clinical presentation of a tertiary syphilis with recurrent tamponade and type B aortic dissection, whose positive diagnosis was made by polymerase chain reaction on pericardial fluid analysis., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Vemurafenib and erlotinib are two oral kinase inhibitors approved for the treatment of metastatic melanoma and advanced non-small cell lung cancer, respectively. In contrast with erlotinib, the single published method for analysis of vemurafenib in human plasma is based on mass spectrometry. The purpose of the present study was to develop an HPLC-UV method to simultaneously quantify these two drugs in plasma. Following liquid-liquid extraction, vemurafenib, erlotinib and sorafenib (internal standard) were separated isocratically on a C8 Xterra(®) MS using a mobile phase of glycine buffer (pH 9.0, 100mM)/acetonitrile (45:55, v/v). Samples were eluted at a flow rate of 0.9mL/min throughout the 12-min run. Dual UV wavelength mode was used, with vemurafenib and sorafenib monitored at 249nm, and erlotinib at 331nm. The calibration was linear in the range 1.25-100mg/L and 50-4000μg/L for vemurafenib and erlotinib, respectively. Inter- and intra-day precision was less than 6.7% and 6.6% for vemurafenib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure of these drugs in cancer patients. This accurate method can be used in routine clinical practice to monitor vemurafenib or erlotinib concentrations in plasma from cancer patients., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7 days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Susac's syndrome (SS) is a rare microangiopathy affecting the precapillary arterioles of the brain, retina and inner ear, presumably resulting from an autoimmune endotheliopathy. We report the first case of SS with histologically proven skin involvement, in a 24-year-old male who presented a subacute encephalopathy, branch retinal artery occlusions and bilateral hearing loss, two weeks after the onset of a livedo racemosa of the flanks and feet. Skin biopsies revealed a thrombus in several dermal arterioles, endothelial cells swelling and a mild perivascular lymphocytic infiltrate, which correspond to the same histological findings as previously observed in brain but also in muscle biopsies of patients with SS. A complete recovery was achieved in 4 months with corticosteroids. Follow-up MRI showed centro-callosal "holes". Skin involvement in SS has pathological plausibility since serum antibodies directly binding to central nervous system but also to generic endothelium cells have been reported. Our report supports that SS is a systemic disease that could affect other organs in addition to the brain, retina and inner ear. We suggest careful skin examination should be considered in patients with a suspicion of SS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Acne is a multifactorial chronic disease affecting around 80% of teenage population. The pathogenesis of acne involves inflammatory reactions and colonization by the Propionibacterium acnes (P. acnes) strain. P. acnes stimulates the keratinocytes involved in the innate immune response, the intensity of which could be influenced either by bacterial intrinsic factors or by endogenous factors of the host., (Copyright © 2010. Published by Elsevier SAS.)

First described in the mid 1980s, Carney complex is a rare dominantly heritable multiple endocrine neoplasia syndrome that affects endocrine glands as the adrenal cortex, the pituitary and the thyroid. It is associated with many other nonendocrine tumors, including cardiac myxomas, testicular tumors, melanotic schwannoma, breast myxomatosis, and abnormal pigmentation or myxomas of the skin. The Carney complex gene 1 was identified 10 years ago as the regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24. An inactivating heterozygous germ line mutation of PRKAR1A is observed in about two-thirds of Carney complex patients. This last decade many progresses have been done in the knowledge of this rare disease and its genetics. This review outlines the current state of this knowledge on Carney complex., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

After reaching an all time low at the turn of the millennium in several industrialized countries, the syphilis incidence is rising again, perhaps as a consequence of unsafe sexual behavior in response to improved antiretroviral therapeutic options for HIV. Since the beginning of the HIV pandemic, numerous reports on the various aspects of the interaction between syphilis and HIV have been published. Controversies persist on many issues of the management of coinfected patients. This contribution presents a critical appraisal of the available literature. Few large-scale, properly designed, controlled studies have compared syphilis baseline presentation and treatment response according to HIV status. Among the weakness are (1) high rates of patients lost to follow-up, (2) lack of long-term follow-up, (3) lack of gold standard criteria for treatment response, (4) small sample size, and (5) lack of stratification according to syphilis stage, ongoing antiretroviral treatment, CD4 cell count and HIV viral load. From the available data, and given the ever-possible publication bias, we conclude that if HIV has an effect on the course of syphilis, it is small and clinically manageable in most cases. The controversial issues discussed should furnish the rational for clinical research during the forthcoming decade., (Copyright 2010 Elsevier Inc. All rights reserved.)

Despite the continued efficacy of penicillin since the 1940s, many aspects of the natural history, diagnosis, and management of syphilis remain controversial. A key factor among the numerous factors explaining the persistence of significant areas of controversies is the absence of a gold standard direct method for distinguishing between the different stages of syphilis and appraising treatment response. This contribution presents an overview of some of the most debated aspects of the origins, diagnosis, and management of syphilis in immunocompetent patients. The two main current hypotheses on the origins of Treponema pallidum are the "Columbian" and the "Pre-Columbian" hypotheses. Strong evidence supports that Columbus' crew brought T pallidum to Europe at the time of discovery of the New World. Because T pallidum culture and inoculation to animals are not readily available methods, the gold standard method for the diagnosis of syphilis is the direct identification of T pallidum by dark field microscopy or direct fluorescent antibody tests. These methods, however, are inapplicable in many patients, and thus the diagnosis of syphilis is usually based on the clinical and serologic picture. Serologic tests should only be considered as surrogate markers of the disease and do not provide definite distinction between syphilis stages. The optimal combination of serologic tests is still undefined. Other areas of controversy include the identification of patients who would benefit from a lumbar puncture, the diagnostic criteria of neurosyphilis, and the most relevant markers of treatment response., (Copyright 2010 Elsevier Inc. All rights reserved.)

Lichen planus (LP) is an inflammatory disease of the stratified squamous epithelia of unknown etiology. LP affects most frequently the oral mucosa, but it may also involve other mucosa and the skin. Oral LP (OLP) most frequently affects woman aged between 30 and 60 years. Histopathologic examination typically shows orthokeratotic hyperkeratosis, basal cell degeneration, and a dense well-defined infiltrate of lymphocytes in the superficial dermis. OLP lesions may result from the induction of keratinocytes apoptosis by cytotoxic CD8+ T cells stimulated by a yet unidentified self-antigen on a genetically predisposed patient. The association of OLP with hepatitis C virus (HCV) has been more consistently demonstrated in the Mediterranean area. Although HCV RNA and HCV-specific CD4+ and CD8+ T cells have been retrieved in the mucosal lesions of patients with chronic HCV infection and OLP, the eventual pathophysiology of HCV in OLP lesions remains unclear. Available treatments of OLP are not curative, and many have potentially prominent side effects. The objectives of OLP management should be to prevent and screen for malignant transformation and alleviate symptoms on the long-term. Avoidance of potential precipitating drugs, tobacco, alcohol, and local trauma, as well as strict oral hygiene, is essential. The first-line pharmacologic treatment relies on topical steroids. Systemic steroids should be limited to the short-term cure of severe refractory OLP. Life-long clinical follow-up, at least annually, is fundamental., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Propionibacterium acnes (P. acnes) has been implicated in the inflammatory phase of acne vulgaris. It has been shown to activate interleukin-8 (IL-8) secretion by interacting with Toll-like receptor 2 (TLR-2) on the surface of keratinocytes. Nicotinamide has been shown to be an effective treatment for skin inflammation in various conditions, including acne vulgaris., Objective: To investigate the molecular mechanisms underlying the anti-inflammatory properties of nicotinamide in keratinocytes stimulated by P. acnes., Methods: HaCaT cells and primary keratinocyte cell lines were stimulated by P. acnes in the presence of nicotinamide. IL-8 production was monitored by ELISA on the cell culture supernatant and by qRT-PCR on total RNA extract. A luciferase reporter system assay was used to assess nicotinamide activity with the IL-8 promoter in transfected keratinocytes. We used western blotting to analyze the effect of nicotinamide on activation of the NF-kappaB and MAPK pathways., Results: Nicotinamide significantly decreased IL-8 production in a dose-dependent manner, decreasing both mRNA and protein levels for this chemokine in immortalized HaCaT cells and primary keratinocytes. P. acnes-induced IL-8 promoter activation seemed to be downregulated by nicotinamide, which inhibited IkappaB degradation and the phosphorylation of ERK and JNK MAP kinases., Conclusion: Our results indicate that nicotinamide inhibits IL-8 production through the NF-kappaB and MAPK pathways in an in vitro keratinocytes/P. acnes model of inflammation. Keratinocytes involved in the innate immune response may be a suitable target for treatment during the early phase of inflammation.

Multicentric Castleman disease (MCD) is a devastating human herpesvirus 8 (HHV-8)-related lymphoproliferative disorder that occurs in immunocompromised persons. To determine the role of immune responses in MCD, we studied the frequency, antigenic repertoire, differentiation, and functional profile of HHV-8-specific CD8(+) T cells in MCD patients and in human immunodeficiency virus-coinfected asymptomatic HHV-8 carriers (AC). Screening CD8(+) T-cell responses with ELISpot interferon-gamma (IFN-gamma) assays using 56 peptides on 6 latent and lytic HHV-8 proteins showed that MCD and AC patients had responses of similar magnitude and antigenic repertoire and identified a new 10-mer human leukocyte antigen B7 CD8 epitope in K15. Intracellular IFN-gamma staining showed significantly more CD45RA(-)CCR7(-)CD27(-) CD8(+)IFN-gamma(+) cells (late phenotype) and significantly fewer CCR7(-)CD27(+)CD45RA(-) cells (early and intermediate phenotype) in MCD than in AC patients. This phenotypic shift was not found for Epstein-Barr virus-specific CD8(+) T cells tested as controls. HHV-8 viral loads were negatively correlated with early and intermediate effector memory cells. HHV-8-specific T cells were polyfunctional (secretion of IFN-gamma, tumor necrosis factor-alpha, macrophage inflammatory protein-1beta, and/or CD107a) in both MCD and AC patients. In conclusion, MCD is not associated with a lack of HHV-8-specific CD8(+) T cells or limitation of their functional profile. Their differentiation increases with HHV-8 viral load. These results offer new insight into the pathophysiology of MCD.

Epidemiological aspects of syphilis in Western countries have undergone a significant change with respect to the number of cases. Detection of Treponema pallidum is difficult, and the correct diagnosis of secondary syphilis can be critical. In this study, biopsy samples from skin lesions of 12 patients with secondary syphilis were used. Diagnosis of syphilis was based on clinical presentation, dark-field microscope analysis, and serological tests. Using a polyclonal antibody directed against T. pallidum, we show the presence of T. pallidum in 90% of the samples studied with the bacteria located in the epidermis and the upper dermis. The T. pallidum 47-kDa surface protein gene could be amplified by PCR in 75% of the skin lesions. When combining both techniques, T. pallidum was detected in 92% of the samples from patients with secondary syphilis but not in the control samples. Our work suggests that both immunohistochemistry and PCR could be useful for the diagnosis of secondary syphilis and may be helpful in some rare cases when serological assays failed to detect T. pallidum antibodies.

In this study, we assessed the role of melanocortin 1 receptor (MC1R) variants and of two patched (PTCH) polymorphisms (c.3944C>T (P1315L), insertion 18 bp IVS1-83) as risk factors for basal cell carcinoma (BCC) in the French population. The population investigated comprised 126 BCC patients who were enrolled on the basis of specific criteria (multiple and/or familial BCC and/or onset before the age of 40 years and/or association with another tumor)--and 151 controls matched for ethnicity, age, and sex. MC1R variants appeared as a moderate risk factor for BCC (odds ratio (OR) for one and two variants, 2.17 [1.28-3.68] and 7.72 [3.42-17.38], respectively), independently of pigmentation characteristics (OR = 2.53 [1.34-4.8]). Interestingly, in addition to the predictable red hair color (RHC) alleles, two non-RHC alleles (V60L and V92M) were also closely associated with BCC risk (OR 3.21 [1.91-5.38] and 2.87 [1.5-5.48], respectively), which differs from the situation in the Celtic population. In addition, the PTCH c.3944C/C genotype was also associated with BCC risk (OR 1.94 [1.2-3.1]), especially in the subgroup of patients with multiple tumors (OR 2.16 [1.3-3.6]). Thus, our data show that MC1R and PTCH variants are associated with BCC risk in the French population. We further suggest that assessing MC1R and PTCH status could be useful, combined with the assessment of clinical risk factors, in identifying high-risk patients to be targeted for prevention or more rigorous surveillance.

The level of Kaposi's sarcoma-associated herpesvirus (KSHV) cellular viremia in patients with Kaposi's sarcoma could be related to both the tumor burden and its progression. The origin of the spindle cell, the hallmark cell of Kaposi's sarcoma, is still debated. Two hypotheses may be formulated, favoring a lymphatic endothelial cell or an endothelial-cell precursor evolving into a lymphatic phenotype, both preferentially targeted by KSHV.

Human herpesvirus-8 (HHV-8) is commonly detected in all epidemiologic forms of Kaposi's sarcoma. Despite the broad cellular tropism of HHV-8, studies on mucosal shedding of HHV-8 have shown that infectious particles are restricted to saliva isolated from the oropharynx. We used biotinylated purified HHV-8 particles in a direct binding assay to whole clarified human salivary samples isolated from HHV-8-infected and uninfected individuals. We found that the major binding activity was carried out by a protein of 78-kDa size, which was further characterized as human lactoferrin (hLf) using 2-D electrophoresis and MALDI-ToF analysis. Preliminary comparison of HHV-8 binding activity of 76 salivary samples from HHV-8-infected and uninfected individuals showed that 7.8% of the uninfected population exhibited a form of Lf not recognized by HHV-8. Deglycosylation of hLf by PNGase F did not reduce HHV-8 binding activity, whereas endoproteinase cleavage of native hLf generated a non-glycosylated 8-kDa peptide recognized by HHV-8 particles and was located at the position Ala606-Tyr679 in the native hLf amino acid sequence, corresponding to the C-terminal region of the glycoprotein. This work identify the lactoferrin in saliva as a ligand for HHV-8 and suggests that this glycoprotein could be used as a carrier for the viral particles.

Background: Sexually transmitted infections (STI) in France are reported on a voluntary basis through several sentinel surveillance systems., Methods: To monitor STI, sentinel laboratory- or clinician-based surveillance systems were set up by the Institut de Veille Sanitaire: gonorrhea surveillance (Renago) in 1986, Chlamydia infections surveillance (Renachla) in 1989, and more recently, syphilis surveillance in 2000 and rectal lymphogranuloma venereum (LGV) in 2004., Results: From 2000 to 2003, 1,089 syphilis infections were reported. Most of the cases were diagnosed in men having sex with men (MSM) and were mainly reported by STI clinics located in the Paris area. From 1997 to 2000, an increase of gonorrhea was observed each year. After two years of stable trend, the prevalence of gonorrhea increased again in 2003. From 2002 to 2004, 123 LGV cases were diagnosed in France and were observed only in MSM. Since 2001, Chlamydia infections have steadily increased, particularly in women., Comments: Because STI surveillance is based on a voluntary basis, the number of reported cases is probably lower than the number of STI diagnosed in France. However, the data provided by the different surveillance systems reveals that STI have been increasing in France since 1997. Moreover, the resurgence of syphilis in 2000 and the emergence of rectal LGV in 2004 indicate that these STI occur mainly in MSM. Trends on incidence and patients characteristics observed in France are similar to those of several Europeans countries. European Public Health interventions are becoming necessary to prevent and control STI.

Genital warts are an epidermal manifestation attributed to the epidermotropic human papillomavirus (HPV). Over 100 types of double-stranded HPV have been isolated and completely sequenced thus far. HPV are grouped into low-risk (non-oncogenic) types such as type 6 and type 11, which cause benign anogenital warts (condyloma accuminata), and high-risk (oncogenic) types, such as types 16, 18, 31, and 45, which occasionally lead to cancer.

To assess the clinical benefit of rituximab for HIV-associated Castleman disease, 5 patients infected with HIV with histologic-proven Castleman disease were prospectively enrolled to receive 4 infusions of rituximab. Clinical and biologic parameters (C-reactive protein, CD19 cell count, Kaposi sarcoma-associated herpesvirus [KSHV] viral load in peripheral blood mononuclear cells) were assessed before and at different time points following rituximab infusions. Two patients died very quickly after the beginning of rituximab therapy with no effect on both KSHV viral load and CD19 cell count. Three of 5 patients were considered in complete remission with no more clinical symptoms related to Castleman disease with a follow-up of 4 to 14 months. In 2 cases, clinical remission correlated with a dramatic decrease of KSHV viral load and C-reactive protein levels and a transitory but sharp decrease of CD19 cell count. In 2 responders, we observed an aggravation of Kaposi sarcoma. Our preliminary results suggest that rituximab may be effective in controlling Castleman disease in a subset of patients, although it may exacerbate concomitant Kaposi sarcoma.

Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin 6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with Kaposi sarcoma-associated herpesvirus, also called human herpesvirus type 8 (KSHV/HHV8). Within a prospective cohort study on 60 HIV-infected patients with MCD, and a median follow-up period of 20 months, 14 patients developed KSHV/HHV8-associated non-Hodgkin lymphoma (NHL): 3 "classic" KSHV/HHV8(+) Epstein-Barr virus-positive (EBV(+)) primary effusion lymphoma (PEL), 5 KSHV/HHV8(+) EBV(-) visceral large cell NHL with a PEL-like phenotype, and 6 plasmablastic lymphoma/leukemia (3/3 KSHV/HHV8(+) EBV(-)). The NHL incidence observed in this cohort study (101/1000 patient-years) is about 15-fold what is expected in the general HIV(+) population. MCD-associated KSHV/HHV8(+) NHL fell into 2 groups, suggesting different pathogenesis. The plasmablastic NHL likely represents the expansion of plasmablastic microlymphoma from the MCD lesion and progression toward aggressive NHL. In contrast, the PEL and PEL-like NHL may implicate a different original infected cell whose growth is promoted by the cytokine-rich environment of the MCD lesions.

In a previous study, it was shown that the Kaposi sarcoma-associated herpesvirus (KSHV) was specifically associated with monotypic (IgMlambda) plasmablasts in multicentric Castleman disease (MCD). The plasmablasts occur as isolated cells in the mantle zone of B-cell follicles but may form microlymphoma or frank plasmablastic lymphoma. To determine the clonality and cellular origin of the monotypic plasmablasts, the rearranged Ig genes in 13 patients with KSHV-related MCD, including 8 cases with microlymphomas and 2 with frank lymphomas, were studied. To investigate the role of the interleukin 6 (IL-6) receptor signaling in the pathogenesis of MCD and associated lymphoproliferative disorders, viral IL-6 and human IL-6 receptor expression was examined. KSHV-positive plasmablasts were polyclonal in MCD-involved lymphoid tissues in all cases and microlymphomas in 6 of 8 cases. Monoclonal KSHV-positive plasmablasts were seen in microlymphomas of 2 cases and in both frank lymphomas. Despite their mature phenotype, KSHV-positive plasmablasts did not harbor somatic mutations in the rearranged Ig genes, indicating origination from naive B cells. Viral IL-6 was expressed in 10% to 15% of KSHV-positive plasmablasts, whereas the human IL-6 receptor was expressed in most KSHV-positive cells. Thus, KSHV infects monotypic but polyclonal naive B cells and is associated with a range of lymphoproliferative disorders from polyclonal isolated plasmablasts and microlymphomas to monoclonal microlymphoma and frank plasmablastic lymphomas in MCD patients. Activation of the IL-6 receptor signaling pathway may play a role in differentiation of KSHV-infected naive B cells into plasmablasts and development of lymphoproliferative lesions. (Blood. 2001;97:2130-2136)

Castleman disease (CD) is a lymphoproliferative disorder of unknown etiology that is associated with the development of secondary tumors, including B-cell lymphoma. Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus) sequences have been described in some cases of multicentric Castleman disease (MCD). Using a monoclonal antibody against an HHV-8-latent nuclear antigen, we show that HHV-8 is specifically associated with a variant of MCD in which HHV-8-positive plasmablasts that show lambda light-chain restriction localize in the mantle zone of B-cell follicles and coalesce to form microscopic lymphomas in some cases. Furthermore, we show that the frank plasmablastic lymphoma that develops in patients with this plasmablastic variant of MCD is also positive for HHV-8 and lambda light chain. Plasmablastic lymphoma associated with MCD is a new disease entity associated with HHV-8 infection. (Blood. 2000;95:1406-1412)

We evaluated prospectively the HIV-1 RNA level in CSF as a marker of HIV encephalitis diagnosis. 110 HIV-1 infected patients (mean age: 39 years; sex-ratio M/F: 94/16) were tested for HIV-1 RNA in plasma and CSF. Lumbar punctures were performed to explore cognitive deficit, seizure or fever. HIV encephalitis was diagnosed in 15 patients (14%), other CNS disease in 34 (31%), and fever without CNS disease in 61 (55%). HIV-1 RNA was detectable in 93% of the plasma and in 62% of the CSF. No significant difference was observed in CSF HIV-1 RNA between patients with or without HIV encephalitis. CSF HIV-1 RNA was correlated with plasma HIV-1 RNA (p < 0.01), CSF protein (p < 0.01) and CSF white cell counts (p < 0.01). The absence of any significant difference between patients with or without HIV encephalitis, suggests that the CSF HIV-1 RNA level is not a good marker for its diagnosis.

The number of members in the family Herpesviridae has increased in the last 10 years due to the description of three novel human herpesviruses: human herpesvirus 6 (HHV-6) in 1986, human herpesvirus 7 (HHV-7) in 1990, and human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), in 1994. HHV-6 and HHV-7 were first isolated from blood lymphocyte cultures, while HHV-8 was identified following a specific molecular biology approach in the search for the etiologic agent of Kaposi's sarcoma. The three viruses are lymphotropic, T-cells being the targets of HHV-6 and HHV-7, and B-cells being probably those of HHV-8. The ability to be propagated in cell cultures in vitro differs according to the virus concerned: this can be done readily with HHV-6, with more difficulties in the case of HHV-7, and has not yet been achieved in the case of HHV-8. Human infection with HHV-6 and HHV-7 is ubiquitous, widespread and acquired early in life. HHV-8 epidemiology is still unclear, and there are two hypotheses: a restricted dissemination in the general population like herpes simplex virus type 2, or a widespread infection like all other human herpesviruses. The polymerase chain reaction is the common method for the detection of infection using specific primers and probes for HHV-6, HHV-7 and HHV-8 respectively. Serologic assays are only available for HHV-6 and HHV-7, with limitations being due, in particular, to possible cross-reactions with cytomegalovirus. HHV-6 is the causative agent of exanthem subitum (sixth disease). Its role as an opportunistic agent and immune dysfunction inducer is debated and currently under investigation. The pathogenic role of HHV-7 seems to be modest, with one case of exanthem subitum reported so far. HHV-8 is strongly associated with three diseases: Kaposi's sarcoma, Castleman's disease and body-cavity-based lymphomas. The therapy against these novel viruses has to be considered in the future.

DNA sequences closely related to herpesvirus-like sequences have been found in AIDS-associated Kaposi's sarcoma. Using PCR, we found herpesvirus-like DNA sequences in Kaposi's lesions and normal adjacent skin in five patients with Mediterranean Kaposi's sarcoma. We did not find these sequences in tissues from patients without Kaposi's sarcoma. Semi-quantitative PCR revealed many more herpesvirus-like sequences in Kaposi's lesions than in unaffected skin. Our results reinforce the hypothesis that an infectious agent closely related to gamma-herpesvirus is implicated in the pathogenesis of Mediterranean and AIDS-associated Kaposi's sarcoma.