Giovanni Pomponio

5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases

The percentage of 5-methylcytosine (m5Cyt) has been determined in peripheral blood, synovial mononuclear cells and synovial tissue from patients affected by various rheumatic autoimmune diseases. The determination was performed by reversed-phase high-performance liquid chromatography. Fifteen controls were compared to twenty-one patients affected by rheumatoid arthritis and to nine patients affected by systemic lupus erythematosus. The mean percentage of m5Cyt in normal individuals was significantly higher than in the rheumatoid arthritis and systemic lupus erythematosus patients. In addition, patients with active disease showed lower values than patients in remission. This finding is in agreement with the hypothesis that DNA hypomethylation may play a role in the pathogenesis of the autoimmune diseases, resulting in altered oncogene expression. Therapy with cyclosporin A led to a decrease in the percentage of m5Cyt in three rheumatoid arthritis patients, but a rebound was observed when the cyclosporin A was suspended. The percentage of m5Cyt in the DNA of synovial tissue from four rheumatoid arthritis patients and five patients with osteoarthritis was similar; this observation confirms that, in addition to disease-specific and disease activity-specific variations, the percentage of m5Cyt may also show tissue-specific variations.

Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies

OBJECTIVES A higher incidence of cancer in scleroderma patients compared with the general population has been suggested by several observational studies, reporting, however, different estimates. Therefore, we aimed to perform a systematic review and meta-analysis to definitely assess this association. METHODS We searched MEDLINE and Embase for all original articles of observational studies on cancer incidence in scleroderma patients without language restriction published up to December 2011. Two independent authors reviewed all titles/abstracts and retrieved detailed full-text of potentially relevant articles to identify studies according to predefined selection criteria. Summary estimates were derived using random-effects model and reported as relative risk (RR). Publication bias was evaluated by trim and fill analysis. RESULTS From articles initially identified, 16 original studies, involving more than 7000 patients, were included in the present review. Compared with the general population, the summary RR to develop all invasive cancers in scleroderma patients was 1.75 (95% CI 1.41, 2.18). The results for selected cancer sites indicated a strong association with lung cancer (RR 4.35; 95% CI 2.08, 9.09), and a significant increased risk also for haematological neoplasms (RR 2.24; 95% CI 1.53, 3.29). The relation with breast cancer, suggested in some previous epidemiological studies, was not confirmed (RR 1.05; 95% CI 0.86, 1.29). CONCLUSION The present meta-analysis, the first on scleroderma and cancer risk, provides definite estimates on the association between scleroderma and cancer.

A management of blunt thoracic trauma in an emergency department observation unit: pre-post observational study.

Background: The best management of patients with isolated blunt thoracic trauma at high risk of pulmonary complications (HRPC-BTT: ≥3 isolated rib fractures, sternal fracture, single or few pulmonary contusions or minimal pneumothorax) is still unclear. We compared efficacy and cost-effectiveness of a new clinical pathway involving an Emergency Department Observation Unit (EDOU) with routine care. Methods: Design: Retrospective before-after study. Setting: Level II Trauma Center within a Regional Teaching Hospital. Participants: A consecutive series of patients with HRPC-BTT. Interventions: a new clinical pathway involving EDOU was implemented. Main outcomes: Death rate, tube thoracostomy, and re-admission of discharged patients. Hospital admission rate, length of hospital occupancy, overall costs, and cost-effectiveness were also compared in pre- and post-EDOU period. Results: Two hundred forty patients were eligible for the study: 110 patients in the pre-EDOU period and 130 in the post-EDOU period. Thirteen (12%) of the treated patients were re-admitted to the ED in the pre-EDOU period compared with only five (4%) when the EDOU was available (p = 0.03). The rate of tube thoracostomy performed in admitted patients significantly increased after EDOU implementation: 1 of 54 (1.9%) versus 4 of 32 (12.5%; p < 0.05). The rate of hospitalization decreased from 49% in the pre-EDOU period to 24% in the post-EDOU period (p < 0,005) and the length of stay in hospital in the pre-EDOU period was longer than in the EDOU period: mean 94.7 ± 79.6 versus 65.7 ± 60.6, respectively (p < 0.02). Cost analysis revealed no relevant change in cost-effectiveness per patient (median; interquartile range): &OV0556;487; &OV0556;103 to 1959 versus &OV0556;616; &OV0556;124 to 1455, respectively, in the pre- and post-EDOU period. Conclusions: In managing patients affected by HRPC-BTT, a clinical pathway involving the EDOU seems to be more effective than routine care with little impact on cost.

Acute myocarditis associated with adenoviral infection in a patient with scleroderma

We describe a 40-year-old man with limited scleroderma who presented with acute heart failure following a flu-like illness. He was known to have incomplete left anterior bundle branch block, initial isolated pulmonary hypertension with enlarged right atrium, and no pulmonary fibrosis. He received therapy for acute heart failure and was transferred to a scleroderma centre for specific treatment of scleroderma cardiomyopathy. Investigations showed raised inflammatory markers and diffuse hyperechogenic thickening of the myocardium on echocardiography. Contrast-enhanced (Gd-DOTA) cardiovascular magnetic resonance imaging (CV-MRI) showed multiple areas of non-homogeneous delayed hyperenhancement in the left ventricle, suggestive of myocarditis. Antiadenovirus IgM antibodies were detected with a titer consistent with recent infection. Six weeks later a repeat Gd-DOTA CV-MRI showed an almost complete resolution of the areas of hyperenhancement and there was a significant reduction in the adenovirus antibody titer with serological conversion to IgG. To our knowledge this is the first report of viral myocarditis in scleroderma. Infections are important causes of morbidity and mortality in this disease and should always be included in the differential diagnosis of cardiac symptoms. We propose that contrast-enhanced CV-MRI is valuable in a non-invasive diagnosis of heart disease in patients with scleroderma.

Consensus recommendations for improvement of unmet clinical needs—the example of chronic graft-versus-host disease: a systematic review and meta-analysis

BACKGROUND Consensus recommendations are used to improve the methodology of research about rare disorders, but their uptake is unknown. We studied the uptake of consensus recommendations in steroid-refractory chronic graft-versus-host disease (SR-cGVHD). Although in 2006 the National Institutes of Health (NIH) cGVHD consensus project produced recommendations for clinical trials, guidelines have emphasised the scarcity of valuable evidence for all tested interventions. METHODS We searched Medline (PubMed) between Jan 1, 1998, and Oct 1, 2013, for non-randomised studies of systemic treatment for SR-cGVHD. To measure adherence to NIH recommendations, we applied a 61 item checklist derived from the NIH consensus document. We did a meta-analysis to measure pooled effect size for overall response rate (ORR) and meta-regression analyses to measure the effect of deviations from NIH recommendations on pooled effect size. FINDINGS We included 82 studies related to nine interventions. Conformity to NIH recommendations was evenly low across the analysed timeframe (1998-2013), and did not change significantly after publication of NIH recommendations. The pooled effect size for ORR for systemic treatment of SR-cGVHD was 0.66 (95% CI 0.62-0.70). Increased adherence to NIH recommendations in a score of items defining correct response assessment was associated with a significant reduction in ORR (-4.2%, 95% CI -6.6 to -1.9; p=0.001). We recorded no significant association between ORR and sets of items related to correct diagnostic definition of SR-cGVHD (change in ORR -3.1%, 95% CI -7.7 to 1.5), specification of primary intervention (0, -3.8 to 3.6), or concomitant treatments (-1.6%, -5.4 to 2.3). The score of items defining correct response assessment increased after publication of NIH recommendations. INTERPRETATION Our findings show evidence of bias in the reported efficacy of treatment of SR-cGVHD. The overall effect of NIH recommendations in scientific literature is scarce; however, NIH recommendations improved assessment of response, possibly reducing the overestimation bias. Better implementation of NIH recommendations might reduce false expectations about new interventions, and thus prevent clinical studies with ineffective treatments. FUNDING None.

Chryseomonas luteola : an unusual clinical infection mimicking a mediastinal malignant lymphoma

Correspondence: Gaia Goteri Department of Neurosciences, section of Pathologic Anatomy and Histopathology, Polytechnic University of Marche-United Hospitals, Via Conca 71, 60020 Torrette di Ancona, Italy Tel +39 071 5964811 Fax +39 071 889985 email g.goteri@univpm.it Abstract: Chryseomonas luteola is an infrequent human pathogen. We describe a case of mediastinal location showing Splendore–Hoeppli phenomenon in the abscess clinically mimicking a malignant lymphoma.

Teaching medicine using hypertexts: three years of experience at the Ancona Medical School

The application of computers in medical education is proving to be a more and more powerful supplement to traditional educational methods and tools. Indeed, the hypertext-hypermedia methodology allows the teacher to produce electronic lessons and clinical simulations. Furthermore, the hypertext represents the ideal tool for presenting and discussing data and opinions in clinical meetings. Applications of these methods produced at the Ancona University Medical School and successfully applied in several educational projects are presented. Clinical simulations concerning asthma and other topics of Internal Medicine, as well as interactive lessons about rheumatoid arthritis, lymphomas and lung diseases are described as examples. This material uses hypertext-hypermedia systems available on PCs which combine text, graphics, sound, animations, and high-definition color pictures, and relate chunks of information in an associative manner. The coursewares were tested on students in the final year with encouraging results and have proved to be an ideal complement to bedside practice. The opinions of practitioners about medical therapy for rheumatic diseases have been diseases have been discussed during clinical meetings using a questionnaire structured in hypertext form. The user-friendly interfaces of the systems available allow such courses to be used and developed by physicians who are not literate in software production and without any support from an informatician.

Interleukin-2, soluble interleukin-2 receptor and tumor necrosis factor in sera from patients with rheumatoid arthritis.

SummaryInterleukin-2 (IL-2), soluble interleukin-2 receptor (IL-2R) and tumor necrosis factor (TNF) have been measured in sera from 47 patients affected by classic rheumatoid arthritis (RA) using an enzyme-linked immunosorbent assay. The patients were divided into 4 groups as follows: group A, 18 patients with inactive disease; group B, 19 patients with active disease under treatment with non-steroidal antiinflammatory drugs (NSAID) and second-line drugs; group C, 5 patients with active disease under treatment with NSAID and cyclosporine A (CSA) for at least 4 months; group D, 5 patients in the same condition as patients of group C, but treated with azathioprine (AZA) instead of CSA. IL-2 was undetectable in all patients except two, both characterized by active disease. Soluble IL-2R levels were above the upper limit of the normal range in most of the patients studied, but the mean value (±1 SD) was significantly higher in patients of group B (1,288±421 U/ml) than in patients of group A (686±205 U/ml) and group C (842±414 U/ml). In two patients affected by active RA treated with pulse methylprednisolone therapy (1 g/day for 3 alternate days) the values of soluble IL-2R dropped from 948 to 662 U/ml and from 660 to 518 U/ml, respectively. No statistically significant correlation was observed between the serum level of IL-2R and the RF titre or percentage of C1q-binding activity, respectively. TNF was found within the normal range in all patients except one, who was characterized by active arthritis, high number of rheumatoid skin nodules and extremely high RF titre. Since this patient was not responsive to second- and third-line drugs, an immunomodulatory therapy with high-dose intravenous immunoglobulins was established. Following such treatment a transient clinical improvement as well as a drop in TNF level and RF titre were observed.

AB0358 Efficacy and Safety of Intravenous and Subcutaneous Tocilizumab in A Cohort of Patients Affected by Rheumatoid Arthritis in Real-Life

Background Tocilizumab (TCZ) is a humanized monoclonal anti-interleukin-6 receptor antibody, used for the treatment of moderate to severe rheumatoid arthritis (RA). Although TCZ has been proved to be highly effective and safe in RA patients in large clinical trials, few data are available from real-life practice [1]. Objectives To evaluate efficacy, safety and retention rate of intravenous (IV) and subcutaneous (SC) TCZ in a real-world setting. Methods We evaluated patients affected by moderate-to-severe RA and treated with TCZ from April 2010 to December 2015. Data of patients treated with IV-TCZ until December 2014 were collected retrospectively, while patients treated with either IV or SC-TCZ from January 2015 were included in a prospective cohort and assessed for disease activity, quality of life, treatment discontinuation and/or onset of adverse events (AEs). DAS28-CRP, CDAI and SDAI were used for activity assessment. Treatment retention rate was estimated by Kaplan-Meier method. Results We evaluated 87 patients, 53 treated with IV-TCZ (8 mg/kg every 4 w), 12 with SC-TCZ (162 mg every week) and 22 patients who switched from IV to SC during follow-up (71 females, median age 61 y, median duration of disease 10 y, median follow-up 16 months). Sixty-six patients (76%) were treated in monotherapy and 21 (24%) in combination with methotrexate; 16 (18%) patients were naïve for previous biologic drugs. At baseline, disease activity was severe in 36% of patients, moderate in 59% and mild or inactive in 5%; at month 6, 49% of patients achieved a clinical remission. The mean overall DAS28 was 4.72 at baseline and 2.61 at 6 months (p<0.001 for all comparisons between baseline and subsequent assessments, see Figure). Thirty-three patients (38%) discontinued TCZ because of inefficacy (67%), AEs (24%) or other reasons (9%). Seventy-three infectious AEs occurred in 38 patients (45.1/100 person-years), 3 cases of pneumonia were severe and only one required treatment discontinuation. Other AEs were mild neutropenia (29%), mild hypertransaminasemia (22%), hypercholesterolemia (39%) and hypertriglyceridemia (10%). Infusion reactions were reported in 5/75 IV-TCZ patients, while injection site reactions in 8/34 SC-TCZ patients. We observed an overall high retention rate (85.2%, 70.2%, 61.3%, 54.6%, 43.2% at 6, 12, 24, 48 and 60 months respectively); no significant difference was found between combination or monotherapy (p=0.58) or between IV or SC at 22 months (p=0.51). In multivariate Cox regression analysis longer duration of disease (HR 1.06, 95%CI 1.02–1.11), presence of ≥1 comorbidities (HR 2.25, IC95% 1.39–3.64) and previous treatment with ≥2 biologic drugs (HR 1.55, IC95% 1.04–2.31) were associated with treatment discontinuation. Conclusions TCZ is effective, well tolerated and safe in a population of RA patients followed in a real-life setting. References Gabay C, Riek M, Hetland ML, Hauge EM, Pavelka K, Tomšič M, et al. Effectiveness of tocilizumab with and without synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a European collaborative study. Ann Rheum Dis. 2015 Sep 15. Disclosure of Interest None declared

Biofilm: it is time for consensus

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