Immature Blood Vessels in Rheumatoid Synovium Are Selectively Depleted in Response to Anti-TNF Therapy

BACKGROUND:Angiogenesis is considered an important factor in the pathogenesis of Rheumatoid Arthritis (RA) where it has been proposed as a therapeutic target. In other settings, active angiogenesis is characterized by pathologic, immature vessels that lack periendothelial cells. We searched for the presence of immature vessels in RA synovium and analyzed the dynamics of synovial vasculature along the course of the disease, particularly after therapeutic response to TNF antagonists. METHODOLOGY/PRINCIPAL FINDINGS:Synovial arthroscopic biopsies from RA, osteoarthritis (OA) and normal controls were analyzed by double labeling of endothelium and pericytes/smooth muscle mural cells to identify and quantify mature/immature blood vessels. To analyze clinicopathological correlations, a cross-sectional study on 82 synovial biopsies from RA patients with variable disease duration and severity was performed. A longitudinal analysis was performed in 25 patients with active disease rebiopsied after anti-TNF-alpha therapy. We found that most RA synovial tissues contained a significant fraction of immature blood vessels lacking periendothelial coverage, whereas they were rare in OA, and inexistent in normal synovial tissues. Immature vessels were observed from the earliest phases of the disease but their presence or density was significantly increased in patients with longer disease duration, higher activity and severity, and stronger inflammatory cell infiltration. In patients that responded to anti-TNF-alpha therapy, immature vessels were selectively depleted. The mature vasculature was similarly expanded in early or late disease and unchanged by therapy. CONCLUSION/SIGNIFICANCE:RA synovium contains a significant fraction of neoangiogenic, immature blood vessels. Progression of the disease increases the presence and density of immature but not mature vessels and only immature vessels are depleted in response to anti-TNFalpha therapy. The different dynamics of the mature and immature vascular fractions has important implications for the development of anti-angiogenic interventions in RA

Detection of risk factors that influence weight loss in patients undergoing radiotherapy

AbstractAimTo identify risk factors that influence weight loss in patients receiving radiotherapy.BackgroundIt is a well-known fact that cancer patients can be affected by malnutrition at the onset of the disease and during treatment due to the toxicity. Pretreatment weight loss alone does not predict those who will need nutritional supplementation. Instead, a variety of nutritional and tumor related factors needs to be taken into account.Material and methodsA retrospective study was conducted on 129 patients with different tumor locations. Weight loss was evaluated during radiotherapy and one month after treatment. The impact of age, ECOG, chemotherapy, pretreatment weight loss, tumor location, previous surgery and TNM were analyzed. We aimed to identify a high-risk group of patients before starting treatment.ResultsThe average net weight loss during radiotherapy and one month after treatment for this group of patients was 0.68kg and 1.6kg, respectively. Median weight loss during radiotherapy was 2.6 kg for head and neck (HN) patients and 0.27 kg for other tumor sites (p=0.028). Median weight loss one month after radiotherapy was 3.7kg for HN patients and 1.1kg for the rest of the patients (p=0.034). The median weight loss one month after treatment was 3.2 kg for patients receiving chemotherapy and 0.5kg for those patients who did not receive chemotherapy (p<0.001). A regression analysis determined that HN tumor location and the use of chemotherapy were independent risk factors.ConclusionsNutritional status must be monitored and managed before, during and after treatment. A variety of nutritional and tumor-related factors must be considered. According to our results, head and neck tumors and the use of chemotherapy are the only two factors considered statistically significant. Because patients continue to lose weight after treatment, we recommend close surveillance after radiotherapy

Clinicopathological correlations of immature blood vessels in RA synovial tissues.

<p>Disease duration, DAS28 score, erosive disease, and synovial tissue infiltration by CD3, CD20 or CD68 cells is shown in groups with (+) or without (−) immature vessels as indicated. Density of mature or immature vessels in patients stratified by disease duration and levels of activity (low: DAS28<3.2, moderate 3.2–5.1, or high>5.1). Spearman's correlation coefficients between immature vessels density and disease duration, DAS28, CD3 or CD20 infiltration are shown. (*) p<0.05 (see text). ¶ p = 0.04 (Kruskall Wallys test and post hoc Dunns test (low versus moderate or high activity groups).</p

Detection of risk factors that influence weight loss in patients undergoing radiotherapy

AimTo identify risk factors that influence weight loss in patients receiving radiotherapy.BackgroundIt is a well-known fact that cancer patients can be affected by malnutrition at the onset of the disease and during treatment due to the toxicity. Pretreatment weight loss alone does not predict those who will need nutritional supplementation. Instead, a variety of nutritional and tumor related factors needs to be taken into account.Material and methodsA retrospective study was conducted on 129 patients with different tumor locations. Weight loss was evaluated during radiotherapy and one month after treatment. The impact of age, ECOG, chemotherapy, pretreatment weight loss, tumor location, previous surgery and TNM were analyzed. We aimed to identify a high-risk group of patients before starting treatment.ResultsThe average net weight loss during radiotherapy and one month after treatment for this group of patients was 0.68[[ce:hsp sp="0.25"/]]kg and 1.6[[ce:hsp sp="0.25"/]]kg, respectively. Median weight loss during radiotherapy was 2.6 kg for head and neck (HN) patients and 0.27 [[ce:hsp sp="0.25"/]]kg for other tumor sites (p[[ce:hsp sp="0.25"/]]=[[ce:hsp sp="0.25"/]]0.028). Median weight loss one month after radiotherapy was 3.7[[ce:hsp sp="0.25"/]]kg for HN patients and 1.1[[ce:hsp sp="0.25"/]]kg for the rest of the patients (p[[ce:hsp sp="0.25"/]]=[[ce:hsp sp="0.25"/]]0.034). The median weight loss one month after treatment was 3.2 kg for patients receiving chemotherapy and 0.5[[ce:hsp sp="0.25"/]]kg for those patients who did not receive chemotherapy (p[[ce:hsp sp="0.25"/]

Clinicopathological changes in patients after anti-TNFα therapy.

<p>CD31+/aSMA–: immature vessels. CD31+/aSMA+: mature vessels. p-value of basal versus post-anti-TNF values.</p><p>(*)Absolute decrease from basal values in patients achieving moderate or good EULAR response (responders) and non responders to anti-TNF.</p

Clinicopathological data stratified by the presence of Immature Vessels (IV).

<p>Data represent baseline data recorded at the time of biopsy. IV: immature CD31+/aSMA– vessels. LN: lymphoid neogenesis; DAS28: disease activity score; CRP: C-reactive protein; NS: Non-significant.</p><p>(*)IV- versus IV+ groups.</p><p>(†)RF or ACPA auto-antibodies.</p><p>(¶)p<0.05 but NS after correction for multiple testing.</p

Variation in the density of immature vessels stratified by the levels of response to anti-TNF-α therapy.

<p>Decrease in immature (left graphics) or mature (right graphics) vessels density between the first and second biopsy after anti-TNF-α therapy is shown stratified by EULAR responses: 0 = : No response; 1: Moderate response; 2: Good response. (*) Kruskall Wallys test and post hoc Dunns test (non-responders versus good responders).</p

Double labeling of lymphatic and CD31-positive vessels in RA synovial tissues.

<p>Lymphatic vessels were detected by immunoperoxidase (brown immunostaining) detection of podoplanin and double immunofluorescent labeling (red fluorescence) of CD31. The same field was photographed by light or fluorescent microscopy to show the position of CD31+ (arrowheads) and podoplanin+ vessels (arrows). Light microscopy image was inverted and merged with CD31 fluorescent image of the same field to show the relative position of podoplanin (blue) and CD31 (red) labeling.</p