Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial.

BACKGROUND: Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-ß signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes. OBJECTIVES: We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis. METHODS: We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention. RESULTS: Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30-71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. -0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups. CONCLUSIONS: This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements.

Combined hyperlipidemia/hyperalphalipoproteinemia associated with premature spontaneous atherosclerosis in mice lacking hepatic lipase and low density lipoprotein receptor.

BACKGROUND AND METHODS: Hepatic lipase (HL) is an enzyme which hydrolyzes triglycerides from plasma lipoproteins and thus takes part in the metabolism of triglyceride-rich lipoprotein remnants and high density lipoproteins. The search described here concentrated on the description of the double invalidation of the HL and LDL receptor genes in mice in order to better understand the possible role of HL in combined hyperlipidemia/hyperalphalipoproteinemia and development of atherosclerosis. RESULTS: We show here that mice lacking both endogenous HL and LDL receptor (HL-/-:LDLR-/-) dramatically increased their plasma triglyceride-rich lipoproteins and their remnants as a consequence of reduced liver uptake. This result is strenghthened by the fact that HL-/-:LDLR-/- were found to overexpress LRP, LSR, and apoE genes. Interestingly, HL-/-:LDLR-/- mice showed premature spontaneous atherosclerosis and aortic lesions from 1-year-old animals were two-fold larger than those of LDLR-/- single mutants. We confirmed that HL-/- and wild-type mice did not develop atherosclerosis lesion even 1 year after birth. CONCLUSIONS: Analysis of this double HL-LDLR knockout mouse model provides in vivo evidence that HL has a major role in the clearance of TRL remnants when LDLR is deficient and in the reduction of the development of atherosclerosis.

[Subacute ischemia of the lower limb revealing hyperhomocysteinemia in a young woman]. / Ischémie subaiguë d'un membre inférieur révélant une hyperhomocystéinémie chez une femme jeune.

A 51-year-old woman had no known cardiovascular risk factor. She presented with bilateral calf intermittent claudication from February. She was hospitalized in August for acute right leg ischemia without loss of sensorymotor functions, following angiography by one week. She had an occlusion of both superficial femoral arteries and abdominal aorta thrombus, plausible source for embolism. Her condition quickly improved with heparin and iloprost infusion. Since the aortic thrombus was removed on ultrasound, aortic surgery was not performed at this time. Investigations showed hyperhomocysteinemia (25 microg/L after overnight fasting and 115 after methionin load) and decrease in folic acid. This report highlights the occurrence of severe arterial disease in young women with high serum homocysteine levels.

[Thrombosis of the inferior vena caval and right atrium in amoebic abscess of the liver]. / Thrombose de la veine cave inférieure et de l'oreillette droite au cours d'un abcès hépatique amibien.

Amoebic abscess of the liver is sometimes complicated by deep venous thrombosis but extension to the right atrium is rarely observed. The authors report the case of inferior vena caval thrombosis extending to the right atrium in a case of amoebic hepatic abscess. The patient was treated initially by antibiotherapy with metronidazole associated with intravenous anticoagulation. Rapid extension of the thrombus despite this treatment led to the initiation of thrombolysis. There were no embolic complications and the outcome was good. Apart from the rarity of this complication, this case poses the problem of the management of these patients. No previous reports of the use of thrombolysis were found in the medical literature. In the light of previous publications and the present case, the authors suggest investigation by CT scanning, echocardiography and venous Doppler ultrasonography in all cases of hepatic amoebic abscess.

[Lower limb occlusive arteriopathy: retrospective analysis of 73 patients with onset before the age of 50 years]. / Les artériopathies des membres inférieurs débutant avant 50 ans.

OBJECTIVES: Juvenile peripheral obstructive arterial diseases (POAD) have been poorly investigated but account for 1 to 7% of POAD. We analyzed retrospectively a cohort of patients with onset before the age of 50 years. PATIENTS AND METHODS: Seventy-three patients (60 males and 13 females) were divided into 4 groups (Buerger's disease: TAO, atheromatous PAOD, auto-immune POAD, arteriopathy of undetermined origin). RESULTS: The first symptoms occurred at 38 +/- 8 years of age. Fourteen patients (20%) had TAO, 51 (70%) atheromatous POAD, 4 (5%) POAD with systemic or autoimmune disease, and 4 (5%) undetermined POAD. Age of onset was earlier in TAO (35 +/- 8 vs 40 +/- 8 years, p=0.046), smoking greater in the atheroma group (33 +/- 16 vs 24 +/- 14 pack-years, p=0.033). Fifty-three POAD patients had dyslipidaemia and 26% hypertension. Regular cannabis intake was more frequent in the TAO group (21 vs 8%). At the time of medical care, Fontaine's stage was more frequently stage II in atheroma patients (57 vs 14%) and stage IV in TAO patients (86 vs 35%). TAO was diagnosed in 43% cannabis users and in 19% non users. CONCLUSION: The main etiology of juvenile POAD is atheroma, followed by TAO. Cannabis users account for at least 10% of these patients. They are characterized by lower tobacco intake, more distal lesions, more frequent involvement of the upper limbs. They present more frequently as TAO.

[Familial autoimmune hepatitis and C4 deficiency]. / Hépatite auto-immune familiale et déficit en C4.

INTRODUCTION: Familial auto-immune hepatitis is unusual. We report a case in which hepatitis was associated with a deficiency in the C4 component of the complement. EXEGESIS: Type 1 auto-immune hepatitis A was diagnosed in a 38-year-old woman presenting with systemic lupus erythematosus. Her daughter had to undergo a splenectomy for immunologic thrombocytopenic purpura when she was 9 years old. When she turned 13, she further developed type 1 autoimmune hepatitis. During follow-up (4 and 8 years, respectively), both patients had a mild deficiency in C4. CONCLUSION: C4 deficiency is not only frequently observed in relatives of patients with auto-immune hepatitis, but also in familial systemic lupus. This abnormality may have had a crucial pathogenic role in these two patients.

[Deep venous thrombosis in an adult with varicella]. / Thrombose veineuse profonde contemporaine d'une varicelle de l'adulte.

INTRODUCTION: Some viral infections are associated with deep venous thrombosis. We report a case of deep venous thrombosis in an adult with varicella. He had neither known predisposing factors for thrombosis nor thrombophilia. EXEGESIS: Transient significant level of antiphospholipid antibodies and lupus circulating anticoagulant were observed. There was no evidence of thrombophilia. Deep venous thrombosis has been mostly associated with varicella in children. A transient protein S deficiency was present in almost all cases, though it was sometimes related to an anti-protein S antibody. This association is exceptional in adults. Some viruses such as herpesvirus and HIV are responsible for endothelium dysfunction, but this is still unclear in the case of varicella-zoster virus. CONCLUSION: In our observation, endothelium activation or antiphospholipid antibodies might be responsible for thrombosis.

[Which investigations should be performed in chronic urticaria?]. / Quel bilan faut-il réaliser devant une urticaire chronique?

Chronic urticaria is frequent. Apart from physical and allergic urticaria, a cause is infrequently identified. A lot of causes are suspected but frequently not well documented. As a consequence, very different diagnostic recommendations are proposed to the clinician. We have performed an extensive review of the literature, in order to determine the quality of evidence for each suspected etiology. The search has been performed in the following data base Embase, Pascal, Cochrane Library and Medline, on a ten years period. It has been completed with data from the selected articles. Infectious diseases, thyroid diseases, systemic diseases and cancer have been reviewed. When possible, only comparative articles have been included (case-control studies mainly). When not, articles with poor methodology have been included. For each article, methodology and results are reported.