New hypotheses in the genetics of psoriasis and other 'complex' diseases.

Psoriasis is a complex genetic disorder in which the disease, according to the current concept, is caused by the interplay of many different genes. However, recent genetic studies indicate that the location of these genes varies considerably among populations and families, raising the question of how the same phenotype can be induced by such variable genetic linkages. To circumvent these discrepancies we propose that psoriasis could be induced by the same repetitive DNA sequence, an endogenous retroviral element present at different locations in the genome. The occurrence of the disease could be linked to an abnormal activation of one or more endogenous retroviral element copies due to their location and/or to modification of their sequence. This unifying concept would simplify our understanding of genetically complex diseases.

Merkel cell carcinoma in a liver transplant patient.

Merkel cell carcinoma (MCC) is an aggressive tumor, the incidence of which is seemingly increased in immunocompromised patients. We report on a new case of MCC occurring in a 69-year-old male liver transplant recipient 6.5 years after transplantation. The outcome was marked by early skin and lymph node relapses treated by radiotherapy alone, and the patient ultimately died 30 months after first diagnosis. Together with data from the literature, this case emphasizes the importance of early diagnosis and adequate management of this aggressive disease for which wide initial surgical excision, accurate staging, and close follow-up are of critical importance to outcome, especially in this setting of immunosuppressive treatment, which is usually associated with a higher rate of recurrence.

Genital porokeratosis: treatment with diclofenac topical gel.

Genital porokeratosis (PK) is a rare and probably underestimated subset of PK that mostly affects middle-aged men. As in other clinical variants of PK, management can be difficult. Surgery and CO(2) laser vaporization may be efficient on individual lesions but topical treatment can be considered when the elements are more scattered and/or more numerous. We report the case of a 68-year-old man with a disseminated PK following a 20-year history of lesions restricted to the genitalia for whom 3% diclofenac gel succeeded in stabilizing their evolution and achieving symptomatic relief. In conclusion, topical diclofenac could be worth considering in the management of genital PK with numerous lesions.

Cytosolic RNA:DNA Duplexes Generated by Endogenous Reverse Transcriptase Activity as Autonomous Inducers of Skin Inflammation in Psoriasis.

Psoriasis is a chronic skin disease of unknown ætiology. Recent studies suggested that a large amount of cytosolic DNA (cyDNA) in keratinocytes is breaking keratinocytes DNA tolerance and promotes self-sustained inflammation in the psoriatic lesion. We investigated the origin of this cyDNA. We show that, amongst all the possible DNA structures, the cyDNA could be present as RNA:DNA duplexes in keratinocytes. We further show that endogenous reverse transcriptase activities generate such duplexes and consequently activate the production of Th1-inflammatory cytokines. These observations open a new research avenue related to endogenous retroelements for the aetiology of psoriasis and probably of other human chronic inflammatory diseases.

Human skin cell cultures onto PLA50 (PDLLA) bioresorbable polymers: influence of chemical and morphological surface modifications.

Poly(alpha-hydroxy acid)s derived from lactic and glycolic acid are bioresorbable polymers which can cover a large range of thermal, physical, mechanical, and biological properties. Human keratinocytes have been shown as able to grow on a poly(DL-lactic acid) film. However the keratinocyte growth was delayed with respect to culture on standard tissue culture polystyrene, even though the same plateau level was observed after 2 weeks. In order to improve the performance of poly(DL-lactic acid) films as skin culture support, their surface was modified by creating tiny cavities using a method based on the leaching out of poly(ethylene oxide) from poly(lactic acid)-poly(ethylene oxide) heterogeneous blends. The surface of the films was also chemically modified by alkaline attack with sodium hydroxide and by type-I collagen coating. Murine fibroblast cell line and primary cultures of human fibroblasts and of two types of keratinocytes were allowed to adhere and to grow comparatively on the different films. The presence of cavities affected neither the adhesion of dermal fibroblasts nor that of keratinocytes. Only keratinocyte proliferation was significantly reduced by the presence of cavities. Collagen coating improved skin cell adhesion and proliferation as well, except in the case of murine fibroblasts. In the case of the NaOH treatments, similar trends were observed but their extent depended on the treatment time. In the case of chemical modifications, fluorescence microscopy bore out adhesion and proliferation tendencies deduced from MTT tests.

Correlations between clinical, histologic, blood, and skin polymerase chain reaction outcome in patients treated for mycosis fungoides.

Little information is currently available regarding post-treatment outcome of TCR-targeted PCR in skin and/or peripheral blood in patients with Mycosis Fungoides (MF) when a dominant gene rearrangement is present at time of diagnosis. To address this matter, a study evaluating the correlations between post-treatment clinical, histological, blood and skin PCR data was conducted in MF patients. Twenty-seven MF patients with dominant gene rearrangement in skin lesions at time of diagnosis were selected. Peripheral blood samples were investigated as well before treatment and post treatment molecular data in skin and blood were compared with clinical and histological outcome. A dominant gene rearrangement was detected before treatment in blood of 16/25 patients. The dominant gene rearrangement disappeared from cutaneous lesions in 8/13 patients displaying complete clinical and histological response whereas skin PCR remained positive in all 10 patients with histologically persistent disease. A dominant gene rearrangement was still present in blood in 10/16 patients after treatment and blood data were not correlated with skin molecular response. This study confirms frequent detection of a dominant gene rearrangement in peripheral blood in MF patients and shows that PCR may remain positive in lesional sites even when skin lesions are successfully treated.

High prevalence of an IgG response against murine leukemia virus (MLV) in patients with psoriasis.

Increasing evidence suggests that human endogenous retroviruses (HERV) could participate in the pathogenesis of autoimmune diseases such as multiple sclerosis and lupus erythematosus. To assess a possible association of murine leukemia virus (MLV)-like group of HERVs with psoriasis we searched for antibodies against MLV proteins in the sera of patients. We showed that anti-MLV antibodies (total) were detected in both psoriatic and control sera. However, they were detected with a higher frequency in psoriasis when compared with controls (91 vs. 53%, respectively, P=0.001). In addition, the IgG response was dramatically increased in psoriasis (86 vs. 8%, respectively, P<0.0001). This immunoreactivity was observed against the products of both the gag and env genes, and the most antigenic proteins were the gp65-70. Moreover, we observed that anti-p30 MLV antibodies reacted with an epidermal protein with a molecular weight of 50 kDa in protein extracts from both normal and psoriatic skin cultures. These observations suggest that HERVs of the MLV-like group could contribute to the immunopathogenesis of psoriasis.

Gemcitabine-associated scleroderma-like changes of the lower extremities.

Gemcitabine is a nucleosid analog approved for use in the treatment of metastatic urothelial carcinoma of the bladder. We describe an unusual case of scleroderma-like changes of the lower extremities after treatment by gemcitabine for metastatic carcinoma of the bladder. The patient developed initial inflammatory edema (3 kg) restricted to the lower extremities and subsequent scleroderma-like changes after 2 cycles of gemcitabine. Cutaneous biopsy specimen revealed diffuse sclerosis without involvment of the fascia or muscle. Discontinuation of gemcitabine resulted in dramatic removal of the edema, softening of the skin, and partial reversibility of the fibrotic process. This is the first case report of a scleroderma-like reaction associated with gemcitabine. This antineoplastic agent must be added to the very limited number of cytostatic agents capable of giving rise to scleroderma-like features.

Necrotizing cutaneous lesions complicating treatment with pegylated-interferon alfa in an HIV-infected patient.

Pegylated interferon alfa is a pegylated formulation of recombinant human interferon (IFN) conjugated with polyethylene-glycol (PEG). The major advantages of this formulation, compared to standard IFN, is a prolonged half-life which allows for once-weekly injection. Its antiviral efficacy in association with ribavirin as a new standard treatment of chronic hepatitis C has been recently documented. Efficacy of PEG-IFN in the therapy of HIV infection is currently being evaluated in prospective pilot studies. We describe herein the first observation of cutaneous necrosis at the sites of PEG-IFN injection in an HIV-infected patient. A 50-year-old man, HIV infected, was treated with antiretroviral bitherapy combining zidovudine and didanosine for 30 months. Weekly subcutaneous injections of PEG-IFN-alpha-2b were started at a dose of 1.5 microg/kg. Nine months later, two successive necrotizing cutaneous lesions developed at the site of injection. The cutaneous ulcerations slowly healed under local therapy without interruption or dose modification of the PEG-IFN. We review the literature on previously reported cases of cutaneous necrosis following standard or pegylated IFN-alpha injection and discuss the different pathophysiological mechanisms that might be involved.

Growth of various cell types in the presence of lactic and glycolic acids: the adverse effect of glycolic acid released from PLAGA copolymer on keratinocyte proliferation.

Poly(alpha-hydroxy-acid)s derived from lactic acid (LA) and glycolic acid (GA) are bioresorbable polymers that are currently used in human surgery and in pharmacology to make temporary therapeutic devices. Nowadays, increasing attention is paid to these polymers in the field of tissue engineering. However, the literature shows that a large number of factors can affect many of their properties and the responses of biological systems. As part of our investigation of the biocompatibility of degradable aliphatic polyesters, the effects of LA and GA on the proliferation of various cells under in vitro cell culture conditions were studied. The release of LA and GA from films made of a copolymer synthesized by the zinc lactate method and composed of 37.5% L-lactyl, 37.5% D-lactyl, and 25% glycolyl repeating units was first investigated over a period of 30 days under abiotic conditions in a cell culture medium in order to identify a range of acid concentrations consistent with releases to be expected in real cell cultures. Four cell lines, namely 3T3-J2, C3H10(1/2), A431, and HaCat, and three primary cell cultures, namely rat endothelial cells, rat smooth muscle cells, and human dermal fibroblasts, were then allowed to grow in the presence of LA and GA at various concentrations taken within the selected 10-1000 mg/cm3 range. Little or no effect was observed on the proliferation of all cells except human keratinocytes, whose growth was dramatically inhibited by GA at concentrations as low as 10 mg/cm3. The inhibiting effect of GA was confirmed by considering the growth of keratinocytes on films made of the same copolymer, in comparison with poly(DL-lactic acid) and polystyrene taken as references. This work shows that GA-releasing degradable matrices are not adapted to the culture of keratinocytes with the aim of making skin grafts.

Panniculitis due to non-tuberculous mycobacteria in two immunocompromised patients.

Inflammation of subcutaneous tissue (panniculitis) may occur in association with tuberculosis, but so far only three cases of non-tuberculous mycobacteria-related lobular panniculitis have been reported. We describe two new cases with marked cellular immunity failure due to hypercorticism. Clinical presentation did not differ significantly from lobular panniculitis of other aetiologies. Histological samples displayed signs of lobular panniculitis and clues for mycobacteria infection with granulomatous lesions and presence of numerous acid-fast bacilli on special staining. Both patients responded quickly to a combination of macrolides, ethambutol and fluoroquinolones. However, like in other infections with tuberculous or non-tuberculous mycobacteria, long-term treatment (at least 6 months) was necessary to prevent relapses.

Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis.

BACKGROUND: Calcipotriene and betamethasone dipropionate are topical treatments for psoriasis vulgaris. Their mode of action is different. Improved risk/benefit may result with concomitant use of the two compounds together. A new vehicle has been created with the objective of obtaining optimal stability of both calcipotriene and betamethasone dipropionate in the combination product. OBJECTIVE: We compared the clinical efficacy of a fixed combination of calcipotriene and betamethasone dipropionate in a new vehicle to calcipotriene in the new vehicle, betamethasone in the new vehicle, and the new vehicle alone. METHODS: This was an international, multicenter, prospective, randomized, double-blind, parallel-group, 4-week study in patients with psoriasis vulgaris amenable to topical treatment. RESULTS: The mean percentage reduction in PASI from baseline to end of treatment was 73.2% in the combination group (n = 301), 48.8% in the calcipotriene group (n = 308), 63.1% in the betamethasone dipropionate group (n = 312) and 28.8% in the new vehicle group (n = 107), (P < .001). The mean percentage reduction in PASI during the first week was 48.1%, 28.4%, 41.4%, and 21.5%, respectively (P < .001). CONCLUSION: A combination product of calcipotriene 50 microg/g and betamethasone dipropionate 0.5 mg/g in the new vehicle shows superior efficacy with a more rapid onset of action than the new vehicle containing either constituent alone in the treatment of psoriasis vulgaris.