Successful long-term systemic sclerosis treatment by high-frequent low-dose B cell-depleting therapy.

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.

COPART Risk Score, Endothelial Dysfunction, and Arterial Hypertension are Independent Risk Factors for Mortality in Claudicants.

OBJECTIVE: The COPART risk score consists of six variables to assess the prognosis of PAOD patients. The flow mediated dilation (FMD) quantifies endothelial function. The aim of this study was to evaluate the mortality prediction of these two variables in a long-term observation of claudicants. METHODS: 184 consecutive claudicants were included in a prospective observational study over a median observation period of 7.9 (IQR 7.2-8.7) years. The endothelial function was assessed on the day of study inclusion using brachial FMD. RESULTS: Three groups were assigned according to the COPART risk score: low risk (LR), n = 72 (39%); medium risk (MR), n = 59 (32%); and high risk (HR), n = 53 (29%). Overall survival rates differed among COPART risk score groups (p < .001, 5 year survival: LR group 83% [95% CI 74-92%]; MR group 73% [95% CI 62-84%]; HR group 57% [95% CI 43-70%]). Survivors had a significantly better median FMD than non-survivors (4.1% [IQR 1.2-6.4] vs. 1.3% [IQR 0.0-4.2]; p < .001). Also the FMD differed significantly among the three COPART risk groups (LR 4.0% [IQR 1.2-6.3], MR 2.3% [IQR 0.0-6.3], HR 1.7% [IQR 0.0-3.6]; p = .033). Finally, independent predictors for disease specific survival were COPART risk score (p = .033; MR group [HR 1.6], 95% CI 0.7-3.6; HR group [HR 2.7], 95% CI 1.2-5.8), FMD (p = .004; FMD ≤2.5 vs. >2.5, HR 2.6, 95% CI 1.4-4.9), and arterial hypertension (p = .039; HR 3.5, 95% CI 1.1-11.3). CONCLUSIONS: COPART risk score, FMD, and arterial hypertension are independent long-term mortality predictors in this group of claudicants. The best mortality assessment is provided by including all three predictors.

COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease.

OBJECTIVES: The COhorte de Patients ARTériopathes (COPART) Risk Score is a risk score assessing the 1 year outcome of patients who received inpatient treatment because of their peripheral arterial occlusive disease (PAOD). The COPART Risk Score consists of six variables each of which is allocated a different number of points (age, history of myocardial infarction, C-reactive protein, ankle-brachial index, estimated glomerular filtration rate, medication with antiplatelet agents, statins and renin-angiotensin system inhibitors). METHODS: 129 consecutive claudicants were included in a prospective trial with an average follow up of 8.8 (± 0.7) years. All patients were hospitalized for their first endovascular procedure to the pelvic and/or femoropopliteal arteries. The endpoints were all cause mortality and cardiovascular (CV) death. The COPART Risk Score was calculated for the three patient cohorts (low risk: 52 patients [40.3%]; medium risk: 41 patients [31.8%]; high risk: 36 patients [27.9%]). RESULTS: During the follow up period 23.1% (n = 12) of patients in the low risk group, 34.1% (n = 14) of patients in the medium risk group, and 63.9% (n = 23) of patients in the high risk group died. CV death occurred in 11.5% in the low, 22.0% in the medium, and 41.7% in the high risk groups. The three groups differed significantly with regard to all cause and CV mortality (p < .0001 and p = .001). CONCLUSIONS: The COPART Risk Score is a suitable instrument to predict long-term all cause and CV mortality in claudicants preceding their first peripheral intervention.

Acute wiiitis representing as thrombosis of the inferior vena cava and left pelvic veins.

Deep venous thrombosis as a result of venous wall injury provoked by trauma is a common finding. It often occurs in patients with sportive overstraining, caused by over fatigue of the body structures. In 2007, the entity of "acute wiiitis" was first described in a letter to the New England Journal of Medicine. Acute wiiitis sums up all affections, mainly skeletal and muscle affections, provoked by playing Nintendo Wii, a very common and loved video-game system. Deep venous thrombosis as a consequence of Nintendo Wii has not been described so far. We present a patient with a massive free floating thrombus of the left pelvic veins originating from the gluteal veins and reaching into the inferior vena cava after playing Nintendo Wii.

Lymphocyte-to-monocyte ratio: a novel marker for critical limb ischemia in PAOD patients.

BACKGROUND: The lymphocyte-to-monocyte ratio (LMR) is easily determined from the white blood cell count. Lymphocytes were previously investigated as a part of the neutrophil-to-lymphocyte ratio (NLR) in patients with atherosclerotic disease and an elevated NLR was negatively associated with cardiovascular endpoints. As monocytes play a leading role in the progression of atherosclerosis, especially in peripheral arterial occlusive disease (PAOD), we investigated LMR and its association with critical limb ischemia and other vascular endpoints in PAOD patients. METHODS AND FINDINGS: We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. LMR was calculated and the cohort was divided into tertiles according to the LMR. An optimal cut-off value for the continuous LMR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI decreased significantly with an increase in LMR. An LMR of 3.1 was identified as an optimal cut-off. Two groups were categorized, one with 1021 patients (LMR < 3.1) and a second one with 1100 patients (LMR ≥ 3.1). CLI was more frequent in LMR < 3.1 patients [426 (41.7%)] than in LMR ≥ 3.1 patients [254 (23.1%)] (p < 0.001), as was also the case with prior myocardial infarction [60 (9.5%) vs. 35 (3.2%), p = 0.003] and congestive heart failure [136 (13.3%) vs. 66 (6.0%), p < 0.001). As to inflammatory parameters, C-reactive protein [median 9.0 mg/l (4.0-30.0) vs. median 4.0 mg/l (2.0-8.0)] and fibrinogen (median 438 mg/dl (350-563) vs. 372 mg/dl (316-459.5)] also differed significantly in the two patient groups (both p < 0.001). A LMR < 3.1 was associated with an odds ratio (OR) of 2.0 (95% CI 1.8-2.2, p < 0.001) for CLI, even after adjustment for other vascular risk factors. CONCLUSIONS: A decreased LMR is significantly associated with a high risk for CLI and other vascular endpoints. The LMR is an easily determinable, broadly available and inexpensive marker that could be used to identify patients at high risk for vascular endpoints.

Unusual deep vein thrombosis sites: magnetic resonance venography in patients with negative compression ultrasound and symptomatic pulmonary embolism.

OBJECTIVES: To evaluate the clinical characteristics of patients with pulmonary embolism (PE), negative compression ultrasound (CUS) of the lower limbs and detection of unusual deep vein thrombosis (DVT) sites by means of magnetic resonance (MR) venography. METHODS: A retrospective data analysis of PE patients hospitalized at our institution from April 2009 to 2011. RESULTS: From April 2009 to 2011, a total of 762 PE patients were treated at our institution. In 169 of these patients CUS for DVT was negative. In these patients MR venography was performed for further evaluation. We found venous thrombosis at unusual sites in 12 of these patients. Due to free floating thrombus masses and fear of life-threatening PE progression we inserted an inferior vena cava filter in three of these 12 patients. The leading venous thromboembolism risk factor in our patients was immobilization (5 patients, 41.7%). CONCLUSIONS: We conclude that especially in patients with PE and negative CUS of the lower limbs a thrombosis of the pelvic veins should be considered in case of symptoms for venous thrombosis in this area. Further diagnostic work-up with MR venography should be scheduled in these patients especially in patients with risk factor immobilization as therapeutic consequences might occur.

Safety and efficacy of periprocedural anticoagulation with enoxaparin in patients undergoing peripheral endovascular revascularization.

BACKGROUND: Periprocedural anticoagulation is primarily used in endovascular procedures to prevent acute reocclusion of the target vessel, but periprocedural anticoagulation might also have an impact on long-term outcome. Consecutive bleeding events are feared complications. Despite changes in peripheral endovascular revascularizations (EVRs), the periprocedural management has remained unchanged for years. Unfractionated heparin is still the treatment of choice during and immediately after EVR. MATERIALS AND METHODS: We performed a prospective, single-center, open-label phase III study comparing 2 different regimes of enoxaparin peri-interventional to peripheral EVR stratified into low- and high-risk groups according to the acute and long-term reocclusion risk due to their vessel morphology. In both groups, 0.5 mg/kg of enoxaparin as a bolus was administered intravenously 10 to 15 minutes before the start of the procedure. In the low-risk group, 40 mg of enoxaparin were administered once daily for 7 days; whereas in the high-risk group, 1 mg/kg of enoxaparin was administered subcutaneously (sc) 2 times a day for 48 hours after the procedure and afterward 40 mg of enoxaparin was administered sc once daily for 5 days. RESULTS: For the analysis of the per protocol population, 44 patients remained in the low-risk group and 140 in the high-risk group. Concerning the primary safety end point, a total of 25 (13.59%) bleeding events occurred until day 30; 5 (11.36%) of them in the low-risk group and 20 (14.29%) in the high-risk group (P = .809 for low vs high risk). None of the bleeding events observed were major according to Thrombolysis In Myocardial Infarction criteria. Concerning our primary efficacy end point, none of the patients showed an acute reocclusion classified as a significant decrease in ankle-brachial index (ABI) or elevated peak systolic velocity ratio confirmed by duplex sonography until day 30. Concerning the second end point of prevention of chronic reobstruction, at day 180 ABI has decreased in the low-risk group from mean 0.94 at day 30 to mean 0.89 and from 1.28 at day 30 to 0.85 after 6 months in the high-risk group. No significant reobstruction was found in the low-risk group, whereas 5 significant reobstruction events were objectified in the high-risk group, all of them in the femoropopliteal arterial segment at day 180. CONCLUSION: We conclude that low-molecular-weight heparin either in a low-dose or high-dose regime during a peripheral EVR is safe concerning bleeding complications and acute reobstructions. The long-term follow-up showed no significant difference between our high- and low-risk groups concerning reobstruction. The periprocedural anticoagulation seems to have no influence on the long-term patency rate after peripheral EVR.

Impaired endothelial-dependent and endothelium-independent vasodilatation in patients with thromboangiitis obliterans.

BACKGROUND: Endothelial dysfunction is the key process in the development of atherosclerosis. The aim of our study was to evaluate endothelial dysfunction measured by the noninvasive technique of Celermajer that plays a role in the pathogenesis of thrombangitis obliterans. METHODS: A total of 36 patients with thrombangitiis obliterans ([TAO]; mean age 44.9 ± 1.3 years) were compared with 30 healthy individuals (mean age 36.1 ± 1.8 years). High frequency ultrasound was used to measure changes in response to reactive hyperemia (leading to flow-mediated endothelium-dependent dilatation) and in response to 0.4 mg sublingual nitroglycerin ([NTG]; leading to NTG-induced, endothelium-independent dilatation). RESULTS: Patients with TAO showed a lower but statistically not significant flow-mediated dilatation and a statistically significant reduced NTG-induced vasodilatation than the control group. CONCLUSION: Our results suggest that both mechanisms play a role in patients with TAO, the endothelium-independent impaired vasodilatation even in a more significant way than the impaired endothelium-dependent vasodilatation.

Intra-arterial injection, a rare but serious complication of sclerotherapy.

Intra-arterial injections represent the most feared complication of sclerotherapy for varicose veins. We present a case of an inadvertent intra-arterial injection of polidocanol at the left medial calf in a 59-year-old woman with subsequent arterial occlusions of the posterior tibial artery and foot arteries. Despite several therapeutic interventions, lower-limb amputation could not be prevented. We conducted a PubMed search for articles reporting arterial complications related to sclerotherapy, in order to evaluate aetiology, clinical presentation, therapeutic management and outcome of sclerotherapy-associated intra-arterial injections during the past 50 years. Intra-arterial injection of a sclerosing solution was reported in 63 cases, mostly after injection near the ankle region or the distal medial calf. Clinical presentation was frequently characterized by immediate pain during injection and distal ischaemia with subsequent tissue loss. Despite several treatment approaches, amputation could not be prevented in 31 cases (52.5%). The pathophysiology of arterial complications related to intra-arterial injection and advisable therapeutic interventions are discussed. Inadvertent intra-arterial injection represents a limb-threatening complication of sclerotherapy. Target-oriented and prompt therapy seems inevitable in order to reduce the risk of permanent tissue loss and amputation.

A high CHA(2)DS(2)-VASc score is associated with a high risk for critical limb ischemia in peripheral arterial occlusive disease patients.

BACKGROUND: The CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age ≥ 75 years (doubled), type 2 diabetes, previous stroke, transient ischemic attack, or thromboembolism (doubled), vascular disease, age 65-75 years, and sex category) score was published as a predictive scoring model for stroke in atrial fibrillation patients. As multiple vascular risk factors are included in this score we evaluated the occurrence of critical limb ischemia (CLI) in peripheral arterial occlusive disease (PAOD) patients according to their CHA(2)DS(2)-VASc score independent of a coexisting atrial fibrillation. METHODS: We evaluated 2237 PAOD patients treated at our institution from 2005 to 2010. CHA(2)DS(2)-VASc score was calculated and the occurrence of CLI was investigated. Furthermore all constituents of the score were investigated concerning association with CLI. RESULTS: Frequency of CLI was higher in patients with a high CHA(2)DS(2)-VASc score. Age ≥ 75 years was associated with an increased risk for CLI (OR 3.0), as was age 65-75 years (OR 1.8), type 2 diabetes (OR 2.8), and the factor previous stroke, transient ischemic attack, or thromboembolism (OR 1.4). The occurrence of arterial hypertension was protective for CLI (OR 0.6). Sex and congestive heart failure were not associated with an increased CLI risk. CONCLUSION: High CHA(2)DS(2)-VASc score is associated with a high CLI risk. As not all constituents are equally associated with CLI and some are even protective, a new score including only some of the factors should be evaluated for the prediction of CLI.

Asymptomatic deep vein thrombosis and superficial vein thrombosis in ambulatory cancer patients: impact on short-term survival.

BACKGROUND: Asymptomatic venous thrombotic events (VTEs) are possible findings in ambulatory cancer patients. Data regarding the incidence and clinical impact of asymptomatic VTEs are conflicting. We therefore conducted a study to evaluate the occurrence of asymptomatic VTEs of the lower limbs in ambulatory cancer patients to further evaluate the association of these asymptomatic VTEs on survival during a 9-month follow-up period. METHODS: In our prospective cohort, we included 150 consecutive ambulatory cancer patients who were free of any clinical symptoms for VTEs. Compression ultrasound to detect deep vein thrombosis (DVT) and superficial venous thrombosis (SVT) of the lower limbs was performed by a vascular specialist in all patients at baseline. In case of pathological findings the patients were treated with low molecular weight heparin (LMWH) because of current established guidelines. The occurrence of death was investigated during a 9-month follow-up period. RESULTS: A total of 27 (18%) patients with VTEs were detected, which included 13 patients (8.7%) with a SVT and 16 patients (10.7%) showing a DVT. Two patients had both, a SVT and a DVT as well. During the 9-month follow-up period the occurrence of a VTE at baseline was associated with a 2.4-fold increased risk for death (HR 2.4 (1.2-5.3); P=0.03). CONCLUSION: Asymptomatic VTEs of the lower limbs in ambulatory cancer patients are frequently occurring concomitant features and are associated with poor survival during a 9-month follow-up period despite anticoagulation with LMWH.

Cystic medial necrosis Erdheim Gsell as a rare reason for spontaneous rupture of the ascending aorta.

Spontaneous rupture of the ascending aorta is a life-threatening condition requiring immediate intervention. The rupture usually leads to sudden death as a result of hemopericardium or hemothorax. The underlying histopathological condition in the cases described so far was mostly an atheromatous plaque. Some other rare underlying conditions were also described. We report a case of cystic medial necrosis Erdheim Gsell as a reason for fatal spontaneous rupture of the ascending aorta.

Proximal lower limb vein thrombosis following vipera berus hand bite.

Vipera berus has a wide geographical distribution throughout Central and Northern Europe. The symptoms after a bite usually are mild, life threatening symptoms are mainly described in children. We describe a case of popliteal vein thrombosis of the right leg after systemic envenoming with Vipera berus venom after a bite in the right hand by a female Vipera berus in the alpine region of Styria, Austria. Changes of the plasmatic coagulation system were obvious in our patient. These changes were due to an activation of the coagulation system and might be the reason for the thrombotic event in this usually healthy young male person.

Are flow-mediated vasodilatation and intima-media thickness of the brachial artery associated with restenosis after endovascular treatment of peripheral arterial occlusive disease?

OBJECTIVE: Restenosis after percutaneous angioplasty of peripheral arteries is still an unsolved matter. Previous studies reported an association between flow-mediated dilatation (FMD), a marker of endothelial dysfunction, and restenosis after coronary angioplasty. This study evaluates the influence of FMD and brachial intima-media thickness (B-IMT) on restenosis after angioplasty of peripheral arteries. METHODS: One hundred and eighty-four patients (124 male) with claudication related to peripheral arterial disease participated in this trial. FMD and B-IMT were assessed before endovascular revascularisation. In a 12-month follow-up duplex ultrasound examinations were performed to detect restenosis. Finally 128 patients (91male, 37 female) were eligible for statistical analysis. RESULTS: Restenosis was found in 54 patients (42.2%). Mean FMD was 3.53 ± 3.56%, with no difference between the patients with restenosis (3.55 ± 3.64%) and those without (3.52 ± 3.48%; p = 0.716). B-IMT had a mean value of 0.326 ± 0.134 mm. B-IMT significantly differed between the patients with restenosis (0.326 ± 0.134 mm) and those without (0.256 ± 0.133 mm; p = 0.007). We confirmed that a B-IMT over 0.21 mm was an independent risk factor for restenosis [OR 2.9 (1.3-6.3)]. CONCLUSION: Endothelial dysfunction is not associated with restenosis. Conversely patients with enlarged B-IMT are at risk of restenosis after angioplasty of peripheral arteries.

Tongue necrosis as first symptom of giant cell arteritis (GCA).

Giant cell arteritis (GCA) is the most common systemic vasculitis affecting people over the age of 50 years, especially in the western world. Nevertheless, the initial diagnosis can be tricky, as some of the patients present at first time with a real unusual initial manifestation. One of these can be tongue necrosis, which is according to the literature in accordance with scalp necrosis, the rarest initial manifestation form of GCA. We describe two patients who presented with tongue necrosis as initial symptom of GCA. The diagnosis was made by the American College of Rheumatology criteria, biopsy and duplex sonography of their temporal arteries. A typical halo was seen as a sign of intimal edema. The patients were put on corticosteroids immediately after diagnosis was proven and their symptoms improved quickly.

Noncompetitive immunoassay of small analytes at the femtomolar level by affinity probe capillary electrophoresis: direct analysis of digoxin using a uniform-labeled scFv immunoreagent.

A general method for noncompetitive immunoassay of small analytes using affinity probe capillary electrophoresis (APCE) is demonstrated using digoxin as a model analyte. A uniform immunoreagent was prepared from a single-chain antibody (scFv) gene specific for digoxin. Site-directed mutagenesis introduced a unique cysteine residue for uniform labeling with a thiol-reactive fluorochrome. After expression in E. coli, the scFv was purified by immobilized metal affinity chromatography (IMAC) using an added C-terminal 6-histidine sequence. The protein was renatured and labeled while immobilized on the IMAC resin. After 0.02-microm filtration to remove microaggregates, the resulting reagent was highly uniform and stable at -12 degrees C for at least 1 year. Three formats of APCE using the scFv reagent were explored. A "mix-and-inject" assay optimized for low detection limits demonstrated analysis of 10 pM digoxin in aqueous standard solutions in 10 min. A rapid mix-and-inject format in a short capillary allowed detection of 1 nM digoxin in 1 min. Digoxin samples in serum and urine were injected directly after 10-fold dilution. In combination with solid-phase extraction, 400 fM digoxin was detected in 1 mL of serum. Including solid-phase extraction, reproducibility was within 2.5%, and the linear range was 3 orders of magnitude. The strategy adopted in this paper should be of general use in the low-level analysis of small analytes.