Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Un dépôt d’épées courtes du Bronze ancien La Rouvière à Chusclan (Gard, France)

The short-sword hoard of La Rouviere, Chusclan, in the Rhone valley region of Gard, was discovered accidentally during agricultural work in 1994. The objects were discovered during the excavation of a spoil heap. Surveys conducted later in the field failed to specify the conditions of deposit. The hoard was located on a hillside a few kilometres from the confluence of the Rhône and Cèze rivers. Traces on the blades indicate, with very high probability,that the three swords were originally set in a top-to-tail position. They were certainly tied up together or contained in a perishable bag. The nature and form of the hoard is a strong argument in favour of an interpretation unrelated to any funeral activity. The three short swords belong to three different morphological types. The first is of an Iberian type, with parallels found in the southeast of Spain, in the Argaric culture (swords with six rivets from Fuente Alamo, Pefialosa, El Argar). However, the best comparison is with a sword assembled by four rivets from Meseta in the north of Spain (La Loma, Villaviudas). The second sword is a more continental type, resembling patterns observed on sword and halberd blades in Burgundy and northern France (Sens, Montreuil-sur-Mer), Germany (Cologne museum), and the Ried hoard (Austrian Tyrol) dated to the late Early Bronze Age. The third blade is the only specimen still bearing an incomplete bronze metal haft. It belongs to the Rhone type according to S. Swenzer's definition. These weapons have a southern distribution, in south-eastern France and northern Italy, probably during the late Bronze A2 period. Several comparisons found in the Valais region (Switzerland) and peninsular Italy and the Po plain indicate it was probably manufactured under Italic influence. This is also indicated by the short length of the third sword, which is an exception for the Rhône Valley type. Finally, the three short swords from the La Rouviere hoard are typologically dated to the late Early Bronze Age. We thus acknowledge that there was a production of short swords in Western Europe which was not subject to the influences of the Hajdûsâmson-Apa-Ighiel-Zajta tradition of central Europe. Eleven samples were collected for metal analysis, three from blade 1 (blade and rivet), three from blade 2 (blade and rivet) and five from sword 3 (haft, blade and rivet). The blades are made from tin-free arsenical copper, a very specific composition. The uniqueness suggested by the elemental composition is not confirmed by the lead isotope analyses, which show the use of various unidentified sources of copper. The use of such copper-arsenic metal is well-documented in the south of the Iberian Peninsula, and more broadly on the Atlantic coast and in the British Isles. To identify the provenance of the metal, the method using the lead isotopic composition works by eliminating incompatible sources. In the present case, this method does not allow us to exclude the Iberian Peninsula and the British Isles as sources for the copper of the three blades from Chusclan, or to suggest other univocal origins of the metal. The composition of this set, which includes three exceptional pieces of different cultural traditions (northern Hispanic, Central European, Rhone-Italic), illustrates a particular form of deposition, defined as 'multispecific', and distinct from collections of daggers of the same nature and/or combined with other objects, such as axes. Hoards of this kind have been observed along the major circulation routes of Western Europe: Cissac in the Médoc on the Atlantic coast, the Rhone valley region of Gard at Chusclan, Castione dei Marchesi in the Po plain and Gau-Bickelheim near the Rhine-Main confluence. This wide geographical distribution certainly reflects the hierarchical superiority of such hoards and of the individuals who manipulated their contents, according to H. Vandkilde's hypothesis, developed on the basis of Nordic data. We should also note that the typologically heterogeneous hoard of Chusclan is located on the border of the main areas of western Alpine copper raw material (Isère, Hautes-Alpes) and of the dispersion of Rhone-type daggers. Finally, the question remains as to whether or not circulation networks of multispecific and monospecific hoards overlapped.status: publishe

Amplification of the STOML3, FREM2, and LHFP Genes Is Associated with Mesenchymal Differentiation in Gliosarcoma

Gliosarcoma is a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas that display either glial (glial fibrillary acidic protein positive) or mesenchymai (reticulin-positive) differentiation. Previous analyses have shown identical genetic alterations in glial and mesenchymal tumor areas, suggesting that gliosarcomas are genetically monoclonal, and mesenchymal differentiation was considered to reflect the elevated genotnic instability of glioblastomas. In the present study, we compared genome-wide chromosomal imbalances using array comparative genomic hybridization in glial and mesenchymal tumor areas of 13 gliosarcomas. The patterns of gain and loss were similar, except that the gain at 13q13.3-q14.1 (log, ratio >3.0), containing the STOML3, FREM2, and LHFP genes, which was restricted to the mesenchymal tumor area of a gliosarcoma. Further analyses of 64 cases of gliosarcoma using quantitative PCR showed amplification of the STOML3, FREM2, and LHFP genes in 14 (22%), 10 (16%), and 7 (11%) mesenchymal tumor areas, respectively, but not in glial tumor areas. Results of IHC analysis confirmed that overexpression of STOML3 and FREM2 was more extensive in mesenchymal than in glial tumor areas. These results suggest that the mesenchymal components in a small fraction of gliosarcomas may be derived from glial cells with additional genetic alterations. (Am J Pathol 2012, 180: 1816-1823; DOI: 10.1016/j.ajpath.2012.01.027