[Off-label biological therapies in patients with large vessel vasculitis and/or polymyalgia rheumatica : Safety and efficacy analysis of a nationwide German registry (GRAID2)]. / Off-label-Biologikatherapie bei Patienten mit Großgefäßvaskulitiden und/oder Polymyalgia rheumatica : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the safety and clinical outcome of biological therapies in patients with large vessel vasculitis (LVV) or polymyalgia rheumatica (PMR) refractory to standard of care therapy in a real-life setting in Germany. METHODS: GRAID 2 (German Registry in Autoimmune Diseases 2) is a retrospective, noninterventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy treated with an initial off-label biological between August 2006 and December 2013. The retrospective documentation comprised case history, diagnosis, course of disease including safety and overall efficacy. RESULTS: Data from 14 patients were collected, 11 with LVV (78.6%) and 3 with isolated PMR (21.4%). Ten patients were treated with tocilizumab (71.4%), while 3 patients received infliximab infusions (21.4%) and 1 patient was treated with rituximab (7.1%). All clinical as well as laboratory efficacy parameters improved substantially. After the first application, tolerability of biologicals was assessed as "very good"/"good" by the physicians in 92.3% of the patients. Altogether, 8 adverse events (AEs) occurred in 4 patients including 3 infections (1 urogenital infection, 2 diverticulitis) representing a rate of 23.6 infections per 100 patient-years. One of these infections (diverticulitis under infliximab treatment) was rated as serious AE, requiring ICU treatment representing a rate of serious AEs of 7.9 per 100 patient-years. No deaths occurred during the observation period. CONCLUSION: With known limitations of a retrospective database, the results of this survey confirm data of smaller case series and proof-of-concept studies and suggest a substantial response to biological therapies in patients with otherwise refractory LVV or PMR with no new safety signals.

Clinical characteristics and course of plantar vein thrombosis: a series of 22 cases.

OBJECTIVES: To evaluate the clinical presentation and disease course of symptomatic plantar vein thrombosis. PATIENTS AND METHODS: Patients with a first diagnosis of symptomatic plantar vein thrombosis at our institution were retrospectively identified from a prospectively maintained database. All patients underwent complete venous compression sonography extended to the plantar veins because of local symptoms at the sole of the foot. Clinical characteristics were obtained from the medical records. RESULTS: Between 2005 and 2013, 22 patients were diagnosed with a first episode of plantar vein thrombosis (64% women, mean age at diagnosis 58.2 years, range 32-79 years). All patients reported moderate to heavy pain of the sole of the foot. The lateral plantar veins (96%) were more frequently affected than the medial plantar veins (41%) and extension into the deep calf veins was common (27%). Half of the episodes were idiopathic, with subsequent diagnosis of occult malignancy in two of these patients. In seven patients (32%), plantar vein thrombosis occurred in association to physical strain to the foot. All patients were treated with anticoagulation. Symptomatic pulmonary embolism was not observed and during a mean follow up of 21 months, the post-thrombotic syndrome did not occur. However, recurrences were common (27%) and frequently again affected the plantar veins. CONCLUSION: Plantar vein thrombosis should be considered as an important differential diagnosis of acute foot pain.

Lack of association between venous hemodynamics, venous morphology and the postthrombotic syndrome after upper extremity deep venous thrombosis.

OBJECTIVES: To explore the association of the postthrombotic syndrome with venous hemodynamics and morphological abnormalities after upper extremity deep venous thrombosis. METHODS: Thirty-seven patients with a history of upper extremity deep venous thrombosis treated with anticoagulation alone underwent a single study visit (mean time after diagnosis: 44.4 ± 28.1 months). Presence and severity postthrombotic syndrome were classified according to the modified Villalta score. Venous volume and venous emptying were determined by strain-gauge plethysmography. The arm veins were assessed for postthrombotic abnormalities by ultrasonography. The relationship between postthrombotic syndrome and hemodynamic and morphological sequelae was evaluated using univariate significance tests and Spearman's correlation analysis. RESULTS: Fifteen of 37 patients (40.5%) developed postthrombotic syndrome. Venous volume and venous emptying of the arm affected by upper extremity deep venous thrombosis did not correlate with the Villalta score (rho = 0.17 and 0.19; p = 0.31 and 0.25, respectively). Residual morphological abnormalities, as assessed by ultrasonography, did not differ significantly between patients with and without postthrombotic syndrome (77.3% vs. 86.7%, p = 0.68). CONCLUSIONS: Postthrombotic syndrome after upper extremity deep venous thrombosis is not associated with venous hemodynamics or residual morphological abnormalities.

Induction of inducible nitric oxide synthase (iNOS) expression by oxLDL inhibits macrophage derived foam cell migration.

OBJECTIVE: Deletion of inducible nitric oxide synthase (iNOS) in apolipoprotein E knockout mice was shown to mitigate the extent of arteriosclerosis. Oxidized low density lipoprotein (oxLDL) inhibits macrophage migration and traps foam cells, possibly through a mechanism involving oxidative stress. Here, we addressed whether a reduction of iNOS-mediated oxidative stress remobilizes macrophage-derived foam cells and may reverse plaque formation. METHODS: Migration of RAW264.7 cells and bone marrow cells was quantified using a modified Boyden chamber. iNOS expression, phalloidin staining, focal adhesion kinase phosphorylation, lipid peroxides, nitric oxide (NO) and reactive oxygen species (ROS) production were assessed. RESULTS: oxLDL treatment significantly reduced cell migration compared to unstimulated cells (p < 0.05). This migratory arrest was reversed by co-incubation with a pharmacologic iNOS inhibitor 1400 W (p < 0.05) and iNOS-siRNA (p > 0.05). Furthermore, apoE/iNOS double knockout macrophages do not show migratory arrest in response to oxLDL uptake, compared to apoE knockout controls (p > 0.05). We documented significantly increased iNOS expression following oxLDL treatment and downregulation using 1400 W and small inhibitory RNA (siRNA). iNOS inhibition was associated with a reduction in NO and peroxynitrite (ONOO-)- and increased superoxide generation. Trolox treatment of RAW264.7 cells restored migration indicating that peroxynitrite mediated lipid peroxide formation is involved in the signaling pathway mediating cell arrest.. CONCLUSIONS: Here, we provide pharmacologic and genetic evidence that oxLDL induced iNOS expression inhibits macrophage-derived foam cell migration. Therefore, reduction of peroxynitrite and possibly lipid hydroperoxide levels in plaques represents a valuable therapeutic approach to reverse migratory arrest of macrophage-derived foam cells and to impair plaque formation.

[Inflammatory aortic diseases]. / Entzündliche Erkrankungen der Aorta.

Inflammatory diseases of the aorta fall under the umbrella term "aortitis" and encompass a broad spectrum of autoimmune and infectious disorders. Giant cell arteritis and Takayasu arteritis represent the most common causative primary large vessel vasculitides. Isolated aortitis is a further important entity, whilst IgG4-associated systemic disease today represents yet another disease entity belonging to this group. Clinical presentation is highly variable, ranging from asymptomatic incidental findings to acute aortic syndrome due to rupture. Diagnostic imaging techniques form the cornerstone of the diagnostic workup. These techniques should also be used in screening for diseases with frequent aortic involvement. The treatment approach depends on the underlying disease and on the extent of aortic damage secondary to vascular inflammation. Against this background, differentiation between autoimmune and infectious aortitis is therefore necessary due to the contrasting treatment strategies. The present article is intended to provide the internist with an overview of this heterogeneous disease entity.

Sonographic and clinical pattern of extracranial and cranial giant cell arteritis.

OBJECTIVES: The aim of our study was to describe the sonographic pattern and clinical manifestations of extracranial (i.e. carotid and proximal arm arteries) and cranial arterial involvement in patients with giant cell arteritis (GCA). METHODS: One hundred and ten consecutive patients with an established diagnosis of GCA between January 2002 and June 2010 were identified retrospectively from a database. All patients underwent colour duplex sonography (CDS) of the superficial temporal, carotid, and proximal arm arteries at the time of diagnosis. Circumferential, homogeneous, hypoechogenic wall thickening was regarded as a typical sign for GCA. Sonographic and clinical characteristics of patients with and without extracranial vessel involvement were compared. RESULTS: Extracranial GCA was observed in 59 of 110 subjects (53.6%). The axillary artery (48.2%) was most frequently affected and bilateral vessel involvement was present in almost all patients (94.8%). Compared to patients with cranial GCA, patients with extracranial GCA were significantly younger, frequently did not meet the American College of Rheumatology (ACR) criteria for classification of cranial GCA, exhibited a lower rate of permanent visual impairment, and were diagnosed later after onset of clinical symptoms (all p < 0.01). With increasing age, a continuous shift from GCA with extracranial arterial involvement to cranial GCA was observed. CONCLUSION: Using CDS, extracranial GCA is a common finding, most frequently observed in the axillary arteries. The clinical pattern of GCA with extracranial arterial involvement differs from that of cranial GCA.

Patterns of extracranial involvement in newly diagnosed giant cell arteritis assessed by physical examination, colour coded duplex sonography and FDG-PET.

BACKGROUND: The clinical spectrum of giant cell arteritis (GCA) varies from classical temporal arteritis (TA) to generalized large vessel GCA (LV-GCA) and fever of unknown origin (FUO). Extent and distribution of extracranial involvement in these different presentations of GCA is not well known, and its detection may depend on the choice of vascular imaging. PATIENTS AND METHODS: In 24 patients with newly diagnosed GCA we systematically evaluated the presence and distribution of extracranial involvement by physical examination, duplex sonography (DS), and FDG-PET. Analysis of FDG-PET results was performed in comparison with 18 age-matched control-subjects scanned for oncological indications. RESULTS: Initial clinical diagnosis was TA in 11 patients, LV-GCA in 8 patients, and FUO in 5 patients. Clinically detectable arterial obstruction was present in 2 patients (18 %) with TA (only upper extremity), all patients with LV-GCA (upper and lower extremities) and no patient with FUO. Upper and/or lower limb large vessel vasculitis was detectable by DS in 45 % of the patients with TA and in 100 % of the patients with LV-GCA or FUO. FDG-PET confirmed upper extremity involvement in all affected patients, but had a very low specificity for lower limb involvement due to concomitant arteriosclerosis in these elderly patients. Aortitis was detectable by FDG-PET in 27 % of patients with TA and 75 - 80 % of patients with LV-GCA or FUO. CONCLUSIONS: The combination of thorough clinical examination and DS is able to detect symptomatic as well as asymptomatic large vessel involvement in a large proportion of patients with newly diagnosed GCA. Distribution and manifestation of large vessel involvement differs between classical TA and LVGCA or FUO. FDG-PET provided only limited additional information and did not change the clinical diagnosis in any patient.

[Imaging diagnostics of large vessel vasculitis]. / Bildgebende Diagnostik der Großgefäßvaskulitis.

At present non-invasive imaging is of paramount importance in the diagnostic evaluation of large vessel vasculitis. For evaluation of the cranial and extracranial aortic branches color coded sonography is the method of choice, whereas CT and MRI are useful in assessing the thoracic aorta. Positron emission tomography (PET) imaging allows direct visualization of the extent of vascular inflammation. To date the diagnostic benefit of combined PET and morphological imaging (PET-CT) as well as the value of imaging procedures in order to assess disease activity and therapy control remain unclear.

Fever of unknown origin as initial manifestation of large vessel giant cell arteritis: diagnosis by colour-coded sonography and 18-FDG-PET.

OBJECTIVES: To evaluate the clinical characteristics and imaging results (CDS, 18-FDG-PET) of patients with large vessel giant cell arteritis (LV-GCA) presenting as fever of unknown origin (FUO). METHODS: From a series of 82 patients with GCA we identified 8 patients with FUO as initial disease manifestation. Clinical characteristics and results of CDS and 18-FDG-PET were analysed. Patients with FUO and those with other clinical manifestations of GCA were compared. RESULTS: 18-FDG-PET-scans were available for 6/8 patients, revealing enhanced tracer uptake of the thoracic aorta and the aortic branches in all patients. CDS was performed in 8/8 patients, with detection of hypoechogenic wall thickening related to LV-GCA in 7/8 patients. Subjects with FUO were significantly younger (60.9 vs. 69.3 years, p<0.01) and had a stronger humoral inflammatory response (CRP 12.6 vs. 7.1 mg/dl, p<0.01; ESR 110 vs. 71 mm/hour, p<0.01), when compared to the other GCA-patients. CONCLUSIONS: LV-GCA should be considered as important differential diagnosis in patients with FUO. In addition to 18-FDG-PET, which is known to be a valuable method in the diagnostic work-up of FUO, we recommend CDS of the supraaortal and femoropopliteal arteries for the initial diagnostic work-up.