APHP Hopital Henri Mondor
APHP Hopital Henri Mondor
Heidelberger V.,AP HP Hopital Henri Mondor |
Ingen-Housz-Oro S.,AP HP Hopital Henri Mondor |
Ingen-Housz-Oro S.,University Paris Est Creteil |
Mahevas M.,APHP Hopital Henri Mondor |
And 18 more authors.
JAMA Dermatology | Year: 2017
IMPORTANCE Evidence for the long-term efficacy and safety of anti-tumor necrosis factor a agents (anti-TNF) in treating cutaneous sarcoidosis is lacking. OBJECTIVE To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis in a large observational study. DESIGN, SETTING, AND PARTICIPANTS STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multicenter observational database that receives data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments. Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016.We extracted data for patients with skin involvement at anti-TNF initiation. MAIN OUTCOMES AND MEASURES Response to treatmentwas evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop ≥2 points from baseline but >1 at last follow-up). RESULTS Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93%). Most patients received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were women. The OCRR was 24%after 3 months, 46%after 6 months, and 79% after 12 months. Steroid sparing was significant. Treatment was discontinued because of adverse events in 11 patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate was 44%18 months after discontinuation of treatment. Relapses during treatment occurred in 35%of cases, mostly during anti-TNF or concomitant treatment tapering. CONCLUSIONS AND RELEVANCE Anti-TNF agents are effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered. © 2017 American Medical Association. All rights reserved.
Nouet Y.,Institute Pasteur Paris |
Nouet Y.,French Institute of Health and Medical Research |
Dahan J.,Institute Pasteur Paris |
Dahan J.,French Institute of Health and Medical Research |
And 19 more authors.
Journal of Hepatology | Year: 2012
Background & Aims: The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2). Methods: We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apclox/lox mice. Results: Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc lox/lox animals. Conclusions: Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.