Maria De Santis

Functional, radiological and biological markers of alveolitis and infections of the lower respiratory tract in patients with systemic sclerosis

BackgroundA progressive lung disease and a worse survival have been observed in patients with systemic sclerosis and alveolitis. The objective of this study was to define the functional, radiological and biological markers of alveolitis in SSc patients.Methods100 SSc patients (76 with limited and 24 with diffuse disease) underwent a multistep assessment of cardiopulmonary system: pulmonary function tests (PFTs) every 6–12 months, echocardiography, high resolution computed tomography (HRCT) and bronchoalveolar lavage (BAL), if clinically advisable. Alveolar and interstitial scores on HRCT and IL-6 plasma levels were also assessed as lung disease activity indices.Results90 SSc patients with abnormal PFTs and 3 with signs and/or symptoms of lung involvement and normal PFTs underwent HRCT and echocardiography. HRCT revealed evidence of fibrosis in 87 (93.5%) patients, with 55 (59.1%) showing both ground glass attenuation and fibrosis. In 42 patients who had exhibited ground glass on HRCT and consented to undergo BAL, 16 (38.1%) revealed alveolitis. 12 (75%) of these patients had restrictive lung disease (p < 0.0001) and presented diffuse skin involvement (p = 0.0009). IL-6 plasma levels were higher in patients with alveolitis than in patients without (p = 0.041). On logistic regression model the best independent predictors of alveolitis were diffuse skin involvement (OR(95%CIs):12.80(2.54–64.37)) and skin score > 14 (OR(95%CIs):7.03(1.40–34.33)). The alveolar score showed a significant correlation with IL-6 plasma levels (r = 0.36, p = 0.001) and with the skin score (r = 0.33, p = 0.001). Cultures of BAL fluid resulted positive in 10 (23.8%) of the 42 patients that underwent BAL and after one year a deterioration in PFTs occurred in 8 (80%) of these patients (p = 0.01). Pulmonary artery systolic pressure ≥ 40 mmHg was found in 6 (37.5%) patients with alveolitis.ConclusionWe found alveolitis only in 38.1% of the patients who had exhibited ground glass on HRCT and then underwent BAL, probably because the concomitant fibrosis influenced results. A diffuse skin involvement and a restrictive pattern on PFTs together with ground glass on HRCT were judged possible markers of alveolitis, a BAL examination being indicated as the next step. Nevertheless BAL would be necessary to detect any infections of the lower respiratory tract that may cause further deterioration in lung function.

Skin ulcers in systemic sclerosis: Determinants of presence and predictive factors of healing

BACKGROUNDnSkin ulcers are common vascular complications of systemic sclerosis (SSc).nnnOBJECTIVEnThe aim of the study was to identify clinical, biologic, and imaging parameters that constitute risk factors for the occurrence and persistence of skin ulcers.nnnMETHODSnOne hundred thirty Italian SSc patients were examined at entry and after 20 months of follow-up.nnnRESULTSnThe diffuse SSc phenotype with avascular areas on capillaroscopy, thrombophilia, and systemic inflammation as defined by interleukin 6 plasma levels, represented the major risk factors for ulcer development. Infection was associated with a risk of poor or no healing, and cardiopulmonary involvement was a major comorbid factor in patients with ulcers. The presence of infection and avascular areas represented the main determinants for ulcer healing.nnnLIMITATIONSnOur data should be confirmed with a longer follow-up period since skin ulcers represent a frequent vascular complication in scleroderma patients.nnnCONCLUSIONnAggressive therapies aiming at improving angiogenesis and controlling infection and the course of the disease appear to be crucial to obtain ulcer healing.

Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: Potential utility of immunosuppressive therapy in cardiac damage progression

OBJECTIVESnScleroderma heart disease is a major risk of death in systemic sclerosis (SSc). Mechanisms underlying myocardial damage are still unclear. We performed an extensive study of SSc patients with recent-onset symptoms for heart disease and examined the efficacy of immunosuppressive therapy.nnnMETHODSnA cohort of 181 SSc patients was enrolled. Of these, 7 patients newly developed clinical symptoms of heart disease (heart failure, chest pain, and palpitation); all of them showed mild but persistent increase in cardiac enzymes. These patients underwent Holter ECG, 2D-echocardiography, perfusional scintigraphy, delayed-enhancement-cardiac magnetic resonance (DE-CMR), coronary angiography, and endomyocardial biopsy. Patients were treated for at least 12 months and followed-up for 5 years.nnnRESULTSnVentricular ectopic beats (VEBs) were found in 4 patients, wall motion abnormalities in 3, pericardial effusion in 6, and DE in CMR in 6 with T2-hyperintensity in 2. In all patients, histology showed upregulation of endothelium adhesion molecules and infiltration of activated T lymphocytes, with (acute/active myocarditis in 6) or without (chronic/borderline myocarditis in 1) myocyte necrosis. Parvovirus B19 genome was detected in 3. None showed occlusion of coronary arteries or microvessels. Compared with SSc controls, these patients more often had early disease, skeletal myositis, c-ANCA/anti-PR3 positivity, VEBs, pericardial effusion, and systolic and/or diastolic dysfunction. Immunosuppressive therapy improved symptoms and led to cardiac enzyme negativization; however, 2 patients died of sudden death during follow-up.nnnCONCLUSIONSnMyocarditis is a common finding in SSc patients with recent-onset cardiac involvement. Its early detection allowed to timely start an immunosuppressive treatment, preventing cardiac damage progression in most cases.

Modeling the ternary complex TCR-Vβ/collagenii(261-273)/HLA-DR4 associated with rheumatoid arthritis

Background It is known that genetic predisposition to rheumatoid arthritis (RA) is associated with the MHC class II allele HLA-DR4 and that residues 261–273 of type II collagen (huCollp261) represent an immunodominant T cell epitope restricted by the DR4 molecule. Despite recent advances in characterization of MHC and T cell receptor (TCR) contacts to this epitope, the atomic details of TCR/huCollp261/HLA-DR4 ternary complex are not known. Methodology/Principal Findings Here we have used computational modeling to get insight into this interaction. A three-dimensional model of the TCR Vβ domain from a DR4+ patient affected by RA has been derived by homology modeling techniques. Subsequently, the structure of the TCR Vβ domain in complex with huCollp261/HLA-DR4 was obtained from a docking approach in conjunction with a filtering procedure based on biochemical information. The best complex from the docking experiments was then refined by 20 ns of molecular dynamics simulation in explicit water. The predicted model is consistent with available experimental data. Our results indicate that residues 97–101 of CDR3β are critical for recognition of huCollp261/HLA-DR4 by TCR. We also show that TCR contacts on p/MHC surface affect the conformation of the shared epitope expressed by DR alleles associated with RA susceptibility. Conclusions/Significance This work presents a three-dimensional model for the ternary complex TCR-Vβ/collagenII(261–273)/HLA-DR4 associated with rheumatoid arthritis that can provide insights into the molecular mechanisms of self reactivity.

Synovial fluid-derived T helper 17 cells correlate with inflammatory activity in arthritis, irrespectively of diagnosis

We analyzed peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 16 rheumatoid arthritis (RA), 9 spondyloarthritis (SpA), 3 microcrystal arthritis patients, to define the presence of Th17 and Th1 and their relationship with inflammatory activity, and TCR-zeta chain and ZAP-70 levels. Th17 were significantly higher in SF than in PB and more abundant in microcrystal arthritis patients compared to the other groups. Irrespectively of the diagnosis, SF Th17 percentages correlated with joint (SF total leukocyte count, neutrophil percentage) and systemic (C reactive protein [CRP], fibrinogen, erythrocyte sedimentation rate) inflammation markers. SF Th1 percentages directly correlated with inflammation and disease activity (CRP, swollen joint count [SJC]) indices in SpA, but not in RA patients. These observations support the role of Th17 in the pathogenesis of inflammatory arthritides. The TCR-zeta(dim) lymphocytes in SF were found to produce the highest amounts of cytokines including IL-17, whereas no ZAP-70 impairment was associated to Th17.

Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study

OBJECTIVEnTo assess fetal and maternal outcomes in women with systemic sclerosis (SSc).nnnMETHODSnProspectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean ± SD 31.8 ± 5.3 years, and the median disease duration at conception was 60 months (range 2-193 months).nnnRESULTSnSSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (<34 weeks of gestation) (10% versus 5%), intrauterine growth restriction (6% versus 1%), and babies with very-low birth weight (5% versus 1%). Results of multivariable analysis showed that corticosteroid use was associated with preterm deliveries (odds ratio [OR] 3.63, 95% confidence interval [95% CI] 1.12-11.78), whereas the use of folic acid (OR 0.30, 95% CI 0.10-0.91) and presence of anti-Scl-70 antibodies (OR 0.26, 95% CI 0.08-0.85) were protective. The disease remained stable in most SSc patients, but there were 4 cases of progression of disease within 1 year from delivery, all in anti-Scl-70 antibody-positive women, 3 of whom had a disease duration of <3 years.nnnCONCLUSIONnWomen with SSc can have successful pregnancies, but they have a higher-than-normal risk of preterm delivery, intrauterine growth restriction, and babies with very-low birth weight. Progression of the disease during or after pregnancy is rare, but possible. High-risk multidisciplinary management should be standard for these patients, and pregnancy should be avoided in women with severe organ damage and postponed in women with SSc of recent onset, particularly if the patient is positive for anti-Scl-70 antibodies.

Whole-brain radiotherapy combined with surgery or stereotactic radiotherapy in patients with brain oligometastases: Long-term analysis

Objective:To verify whether the treatment of brain oligometastases with whole-brain radiotherapy (WBRT) plus stereotactic radiotherapy (SRT) or surgical resection results in different outcomes.Methods:Files of patients affected by brain metastases submitted to surgical resection followed by WBRT (group A) or WBRT + SRT (group B) were retrospectively selected for this study. The two treatment groups were matched for the following potential prognostic factors: WBRT schedule, age, gender, performance status, tumor type, number of brain metastases, extra-cerebral metastases, and recursive partitioning analysis class (RPA). The outcomes of patients in both groups were evaluated in terms of toxicity, local control, and overall survival.Results:Total of 97 patients were selected (56 male; 42 female) who were respectively submitted to surgical resection followed by WBRT (group A, n = 50 patients) or WBRT + SRT (Group B, n = 47 patients). Median follow-up was 95 months (range, 8–171 months). The 1-year local control rates were 46.0% and 69.0% respectively. No significant difference in local tumor control was observed between group A and B (p = 0.10). Median overall survival was 15 and 19 months in group A and B, respectively. One-year survival was 56.0% and 62%, respectively. No difference was observed in the two groups (p = 0.40).Conclusion:Surgery remains the main therapeutic approach in symptomatic patients; nevertheless, our data support the use of WBRT plus SRT in one or two brain metastases smaller than 3 cm.Zielsetzung:Zu untersuchen, ob die Behandlung von Oligohirnmetastasen mit Ganzhirnbestrahlung (whole-brain radiotherapy, WBRT) plus stereotaktischer Radiotherapie (SRT) oder chirurgischer Resektion unterschiedliche Ergebnisse bringt.Methoden:Krankenakten von Patienten mit operativ entfernten Hirnmetastasen und anschließender WBRT (Gruppe A) oder WBRT + SRT (Gruppe B) wurden retrospektiv für diese Studie ausgewählt. Die zwei Beghandlungsarme wurden für folgende prognostische Parameter gematcht: WBRT-Schema. Alter, Geschlecht, Allgemeinzustand, Art des Primärtumors, Anzahl der Hirnmetastasen, extrazerebrale Metastasen, Recursive-Partioning-Analysis-(RPA-)Klasse. Das Behandlungsergebnis für beide Patientengruppen wurde im Hinblick auf Toxizität, lokale Tumorkontrolle und Gesamtüberleben bewertet.Ergebnisse:Insgesamt wurden 97 Patienten ausgewählt (56 m; 42 w), die entweder mit operativer Entfernung und anschließender WBRT (Gruppe A, n = 50 Pat.) oder mit WBRT + SRT (Gruppe B, n = 47 Pat.) behandelt wurden. Die mediane Beobachtungszeit betrug 95 Monate (Spanne 8–171). Die lokale Tumorkontrolle nach 1 Jahr betrug 46,0% (Gruppe A) und 69,0% (Gruppe B), ohne dass dieser Unterschied statistisch signifikant wäre (p = 0,10). Das mediane Gesamtüberleben betrug jeweils 15 und 19 Monate in Gruppe A and B. Die 1-Jahres-Überlebensrate betrug jeweils 56,0% and 62%. Es wurde kein Unterschied zwischen den beiden Gruppen gefunden (p = 0,40).Schlussfolgerung:Die chirurgische Entfernung bleibt die Behandlungsoption bei symptomatischen Patienten. Unsere Daten sprechen für eine Behandlung mit WBRT plus SRT bei Vorliegen von ein oder zwei Hirnmetastasen, die kleiner als 3 cm sind.

Whole-Brain Radiotherapy Combined with Surgery or Stereotactic Radiotherapy in Patients with Brain Oligometastases

Objective:To verify whether the treatment of brain oligometastases with whole-brain radiotherapy (WBRT) plus stereotactic radiotherapy (SRT) or surgical resection results in different outcomes.Methods:Files of patients affected by brain metastases submitted to surgical resection followed by WBRT (group A) or WBRT + SRT (group B) were retrospectively selected for this study. The two treatment groups were matched for the following potential prognostic factors: WBRT schedule, age, gender, performance status, tumor type, number of brain metastases, extra-cerebral metastases, and recursive partitioning analysis class (RPA). The outcomes of patients in both groups were evaluated in terms of toxicity, local control, and overall survival.Results:Total of 97 patients were selected (56 male; 42 female) who were respectively submitted to surgical resection followed by WBRT (group A, n = 50 patients) or WBRT + SRT (Group B, n = 47 patients). Median follow-up was 95 months (range, 8–171 months). The 1-year local control rates were 46.0% and 69.0% respectively. No significant difference in local tumor control was observed between group A and B (p = 0.10). Median overall survival was 15 and 19 months in group A and B, respectively. One-year survival was 56.0% and 62%, respectively. No difference was observed in the two groups (p = 0.40).Conclusion:Surgery remains the main therapeutic approach in symptomatic patients; nevertheless, our data support the use of WBRT plus SRT in one or two brain metastases smaller than 3 cm.Zielsetzung:Zu untersuchen, ob die Behandlung von Oligohirnmetastasen mit Ganzhirnbestrahlung (whole-brain radiotherapy, WBRT) plus stereotaktischer Radiotherapie (SRT) oder chirurgischer Resektion unterschiedliche Ergebnisse bringt.Methoden:Krankenakten von Patienten mit operativ entfernten Hirnmetastasen und anschließender WBRT (Gruppe A) oder WBRT + SRT (Gruppe B) wurden retrospektiv für diese Studie ausgewählt. Die zwei Beghandlungsarme wurden für folgende prognostische Parameter gematcht: WBRT-Schema. Alter, Geschlecht, Allgemeinzustand, Art des Primärtumors, Anzahl der Hirnmetastasen, extrazerebrale Metastasen, Recursive-Partioning-Analysis-(RPA-)Klasse. Das Behandlungsergebnis für beide Patientengruppen wurde im Hinblick auf Toxizität, lokale Tumorkontrolle und Gesamtüberleben bewertet.Ergebnisse:Insgesamt wurden 97 Patienten ausgewählt (56 m; 42 w), die entweder mit operativer Entfernung und anschließender WBRT (Gruppe A, n = 50 Pat.) oder mit WBRT + SRT (Gruppe B, n = 47 Pat.) behandelt wurden. Die mediane Beobachtungszeit betrug 95 Monate (Spanne 8–171). Die lokale Tumorkontrolle nach 1 Jahr betrug 46,0% (Gruppe A) und 69,0% (Gruppe B), ohne dass dieser Unterschied statistisch signifikant wäre (p = 0,10). Das mediane Gesamtüberleben betrug jeweils 15 und 19 Monate in Gruppe A and B. Die 1-Jahres-Überlebensrate betrug jeweils 56,0% and 62%. Es wurde kein Unterschied zwischen den beiden Gruppen gefunden (p = 0,40).Schlussfolgerung:Die chirurgische Entfernung bleibt die Behandlungsoption bei symptomatischen Patienten. Unsere Daten sprechen für eine Behandlung mit WBRT plus SRT bei Vorliegen von ein oder zwei Hirnmetastasen, die kleiner als 3 cm sind.

Synovial B cells of rheumatoid arthritis express ZAP-70 which increases the survival and correlates with the inflammatory and autoimmune phenotype

B cells have acquired an important role in the pathogenesis of rheumatoid arthritis (RA) since B cell depletion allowed to rescue patients poorly responders to TNFalpha blockers. This study focused on the involvement of ZAP-70 as a bio-marker of B cells immune activation in RA. ZAP-70 expression in synovial fluid (SF) B cells obtained from RA patients was increased compared to SF B cells of osteoarthritis (OA) patients. Moreover we found that ZAP-70 positive/CD38 positive and ZAP-70 positive/CD5 positive B cells were enriched in SF. The analysis of B cell apoptosis in vitro showed that the percentage of ZAP-70 negative B cells spontaneously undergoing apoptosis was significantly higher than ZAP-70 positive B cells. The ZAP-70 positive B cell ratio (SF/peripheral blood (PB)) showed a positive correlation with SF autoantibody levels and with local levels of BAFF and IL6. ZAP-70 positive B cells seem to define a subset characterized by increased survival and high relationship with local inflammation and autoimmunity.

Primary systemic treatment and concomitant low dose radiotherapy for breast cancer: final results of a prospective phase II study.

BACKGROUNDnTo evaluate the efficacy of preoperative low dose fractionated radiotherapy (LD-FRT) and chemotherapy in breast cancer.nnnMATERIALS AND METHODSnPatients with stage IIA-IIIA breast cancer, received LD-FRT (0.40 Gy bid, on day 1 and 2, for 6 cycles) to primary tumor volume and concurrent chemotherapy with non-pegylated liposomal anthracycline and docetaxel. Pathological response was assessed by Mandard Tumor Regression Grade (TRG). We evaluated the pathological major response rate (PMRR) as TRG1 and TRG2. The expected outcome was a PMRR of 60%. The accrual was determined by the single proportion powered analysis (α = 0.05, power = 0.8).nnnRESULTSnTwentyone patients were enrolled. No grade 2-4 acute skin and hematological toxicity was observed. TRG1 was obtained in 3 patients (14.3%), TRG2 in 4 patients (19%). The PMRR was 33.3%; it does not concur with the expected result, but is similar to that of chemotherapy alone. According to molecular subtype, 2/11 luminal A patients and 4/6 luminal B patients obtained a PMRR to preoperative treatment (35.3%); 1/4 basal like patients reported TRG1 (25%).nnnCONCLUSIONSnLD-FRT concomitant with primary systemic treatment has a good toxicity profile. The response rate is consistent with that of chemotherapy alone, and suggests different interactions between low dose radiotherapy and molecular subtypes. Additional investigations are planned.