Luigi Calvo

Heart involvement in Rheumatoid Arthritis: Systematic review and meta-analysis

OBJECTIVE The aim of our study was to conduct a systematic review with meta-analysis of the current case-control studies about the valvular and pericardial involvement in patients with Rheumatoid Arthritis (RA), asymptomatic for cardiovascular diseases. METHODS Case-control studies were identified by searching PubMed (1975-2010) and the Cochrane Central Register of Controlled Trials (CENTRAL) (1975-2010). Participants were adult patients with RA asymptomatic for cardiovascular diseases, and the outcome measure was the presence of cardiac involvement. RESULTS Quantitative synthesis included 10 relevant studies out of 2326 bibliographic citations that had been found. RA resulted significantly associated to pericardial effusion (OR 10.7; 95% CI 5.0-23.0), valvular nodules (OR 12.5; 95% CI 2.8-55.4), tricuspidal valve insufficiency (OR 5.3; 95% CI 2.4-11.6), aortic valve stenosis (OR 5.2; 95% CI 1.1-24.1), mitral valve insufficiency (OR 3.4; 95% CI 1.7-6.7), aortic valve insufficiency (OR 1.7; 95% CI 1.0-2.7), combined valvular alterations (OR 4.3; 95% CI 2.3-8.0), mitral valve thickening and/or calcification (OR 5.0; 95% CI 2.0-12.7), aortic valve thickening and/or calcification (OR 4.4; 95% CI 1.1-17.4), valvular thickening and/or calcification (OR 4.8; 95% CI 2.2-10.5), and mitral valve prolapse (OR 2.2; 95% CI 1.2-4.0). CONCLUSIONS Our systematic review pointed out the strength and the grade of both pericardial and cardiac valvular involvement in RA patients. Our findings underscore the importance of an echocardiographic assessment at least in clinical research when RA patients are involved. Moreover, further research is needed to understand the possible relationship of our findings and the increased cardiovascular mortality.

Evidence-Based Knowledge Management: an approach to effectively promote good health-care decision-making in the Information Era

The sharing of information and the growth of knowledge together represent a foundation for the promotion of quality improvement of health care systems. This paper concerns knowledge, not only from an epistemological point of view, but also from a pragmatic one. In our paper, knowledge is discussed as the hub to promote better decision making and continuous professional development. Effective thinking is particularly needed. The critical point is to think about how health care systems can develop both an effective knowledge management network and how health-care organizations can actually be based on it. In this way, knowledge and knowledge hierarchy are defined according to Russel Achkoff’s vision. Generally, knowledge is crucial in decision-making, and Evidence-Based Medicine has its roots in knowledge. In particular, information management is the basis for a significant production of knowledge to promote good health-care decision-making. Thus, relationships between knowledge management and Evidence-Based Medicine are discussed, and a new paradigm is proposed: the Evidence-Based Knowledge Management. Finally, the role of Evidence-Based Knowledge Management within Clinical Governance is discussed together with some considerations about clinical governance implementation problems in Italy.

The new criteria for classification of rheumatoid arthritis: what we need to know for clinical practice

The new criteria for classification of Rheumatoid Arthritis have been recently released. They incorporate the anti-Citrullinated Protein antibody testing and the other classic criteria in a score system (the diagnosis of definite rheumatoid arthritis is made by a total score ≥6). These criteria try to meet the pressing needs to gain sensitivity in early disease. Symptoms, elevated acute-phase response, serologic abnormality, joint involvement were all considered for scoring after confirming the presence of synovitis in at least 1 joint in the absence of an alternative diagnosis that better explains the synovitis. However, no sensitivity and specificity has been showed. Moreover, Area Under Curve of the Receiver Operating Characteristic curves (a measure of performance of the test) was not optimal in almost two of the three studied cohorts. On the contrary, the old criteria of the American College of Rheumatology had been tested to calculate sensitivity and specificity. Moreover, sensitivity and specificity of anti-citrullinated peptide auto-antibodies are available for clinical reasoning based on pre-test and post-test probabilities of the disease. The use of likelihood ratios applied to both the old criteria and anti-citrullinated autoantibodies could help clinicians to effectively manage early arthritis patients implementing Bayesian reasoning. Here, we tried to explain the methodology applied to the body of knowledge currently available about rheumatoid arthritis for diagnostic decision-making based on the Bayesian approach.

A meta-analysis of the effect size of rheumatoid arthritis on left ventricular mass: Comment on the article by Rudominer et al

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Rheumatoid arthritis affects left ventricular mass: Systematic review and meta-analysis

BACKGROUND Cardiovascular disease represents one of the most important extra-articular causes of morbidity and mortality in patients with rheumatoid arthritis (RA). Evidences showed that several cardiac structures can be affected during the course of the disease as well as abnormalities of left ventricular diastolic filling. Contrasting data are available about left ventricular mass (LVM) involvement in patients asymptomatic for cardiovascular disease. The purpose of this systematic review and meta-analysis is to summarize the effects of RA on LVM in rheumatoid arthritis patients without cardiovascular disease. METHODS A systematic research of the current case-control studies was conducted in Medline on November 20th, 2013. Studies were included if data of measurements of LVM were reported. The pooled mean effect size estimate was calculated according to methods described by Hedges and Olkin. RESULTS Sixteen eligible studies were included in this meta-analysis. RA determines an increase of absolute and indexed LVM compared with control patients [standardized mean difference (95% CI): 0.41(0.15-0.66) and 0.47(0.32-0.62), respectively]. On the contrary, posterior wall thickness did not show a significant RA effect. Finally, a significant positive effect of RA on interventricular wall thickness was found [standardized mean difference (95% CI): 0.39 (0.07-0.71)]. CONCLUSIONS Results of this meta-analysis suggest that increased absolute and indexed LVM seem to be characteristic of RA patients with a fundamental clinical significance since they are related to an increased risk of cardiovascular morbidity and mortality. Our data suggest the use of LVM as surrogate end-point for clinical trials involving RA patients.

Surgery during etanercept therapy in patients with rheumatoid arthritis: is it time to follow patient preferences?

Tumor necrosis factor (TNF)-a inhibitors, such as etanercept and infliximab, improve symptoms and function in patients affected by rheumatoid arthritis (RA) [1, 2] and, therefore, are playing an increasing role in the management of this disease. However, interference with endogenous TNF-a signalling has been reported to alter both normal inflammatory responses in tissue healing and infection surveillance [2, 3]. To our knowledge, the rates of surgery in RA are decreasing. However, with the duration of antiTNF therapy, the number of patients under these agents having surgery will be increasing. These data raise the question of whether TNF-inhibitors can be safely used in RA patients who should undergo surgery. The aim of the present paper was to discuss the effect of TNF-inhibitor use in RA patients undergoing surgery. A small cohort of patients undergoing different elective surgery while still on etanercept therapy in spite of physician advice was evaluated. Here, we report five cases selected from a large cohort of patients referred to the ‘‘Civico e Benfratelli’’ rheumatologic outpatient clinic (Table 1). The median duration of RA in the whole cohort was 10 years (range 1–23 years). The inclusion criterion was a history of elective surgery during etanercept therapy (25 mg twice weekly) started at least 12 months before surgery. All the assessed patients were on methotrexate (10–20 mg weekly) as diseasemodifying anti-rheumatic drug (DMARD) treatment and non-steroidal anti-inflammatory drugs or low-dose steroids for acute or sub-acute pain treatment.

The challenge of using the rheumatoid arthritis diagnostic criteria in clinical practice

The new 2010 ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) criteria of Rheumatoid Arthritis recently published, have been released to classify and identify patients with early RA who could benefit from early therapy. They recommend anti-citrullinated protein antibody (ACPA) testing as an alternative criterion to Rheumatoid Factor (RF) and ACPA that were introduced together with the other classic criteria in a scoring system. We previously criticized these new criteria because of unavailable specificity and sensibility in the first paper, and the use of ACPA as dichotomous criterion (presence/absent) and alternatives to rheumatoid factor. Our previous work promoted discussion and fostered new research on this issue. By the light of new data, in an effort to improve clinical reasoning, we suggest a more practical probabilistic point of view. In this regard, we analyze the sensitivity and specificity of the diagnostic studies that evaluate the performance of the 2010 classification criteria. Then, we compare the old and the new classification criteria. Subsequently, we describe the use of likelihood ratios applied to the classification criteria and different cutoff levels of ACPA for decision-making in different setting. Moreover, we define some properties of likelihood ratios and their use for diagnosing or excluding rheumatoid arthritis. We want to share this kind of knowledge within the scientific community because we believe that it can help general practitioners and specialists to recognize early arthritis patients implementing a more efficient probabilistic clinical reasoning.

An uncommon clinical picture: Wellens' syndrome in a morbidly obese young man.

A 39-year-old man presented to the emergency department (ED) of the ‘‘Paolo Giaccone’’ Academic Hospital, Palermo (Italy). He had anterior chest pain that did not radiate to the neck or arms. The patient came from home where the chest pain initiated. The patient was morbidly obese (BMI 54 kg/m). At the ED, the patient’s blood pressure was 120/80 mmHg, the serum troponin I concentration was 0.029 ng/ml (normal values \ 0.034, borderline 0.034–0.12), myoglobin 45 ng/ml (normal values \ 120). While experiencing chest pain, the patient underwent a standard 12 lead electrocardiogram (ECG) that was normal. An echocardiogram, also during the chest pain, excluded the presence of hypo-akinetic left ventricle areas. He was admitted to the internal medicine ward of the same hospital for clinical monitoring. Cardiac biohumoral markers were measured every 4 h, and were always within normal range (only troponin I reached 0.12 ng/ml falling to 0.028 ng/ml). On the following morning, anterior chest pain recurred. Another ECG was performed, but showed no abnormalities (Fig. 1a). During the afternoon, the patient underwent another ECG. He had no thoracic discomfort or pain, but the ECG showed a biphasic T wave inversion in V2–V6 precordial leads (Fig. 1b). Cardiac markers resulted again within normal range. An internal medicine resident who was trained to manage uncommon clinical pictures by PubMed searching [1] recognized this abnormal pattern (ECG abnormalities in an asymptomatic patient with prior anterior chest pain) performed a PubMed search using the following simple search string (biphasic T waves AND precordial leads). Six citations were found and Wellens’ Syndrome diagnosis was suggested. An internist confirmed the diagnostic hypothesis, and the patient, was taken to the invasive hemodynamic lab. Coronary arteriography was performed showing a 95% stenosis of the left anterior descending (LAD) coronary artery (Fig. 2a). The patient underwent percutaneous transluminal coronary angioplasty with resolution of the stenosis (Fig. 2b) and was discharged after 6 days in good condition. In 1982, Wellens et al. [2] described a characteristic ECG pattern associated with a critical stenosis of the LAD coronary artery and impending myocardial infarction. Tilkian [3] was the first to use the term Wellens’ syndrome defined as a group of ECG signs that occur during the painfree period in a patient with unstable angina. These ECG abnormalities, in the absence of pathologic Q waves, are predictive of a critical proximal LAD stenosis [2, 4]. They consist of an isolectric or minimally elevated ST segment followed by a concave or straight ST segment and symmetrically inverted (or biphasic) T waves in the precordial leads, frequently in V2–V3, but sometimes involving V4, V5 or V6. [4]. This was the case of our patients who showed a biphasic T wave inversion in V2–V6, leads during a pain-free period. In conclusion, this uncommon clinical picture involves one of the four clinical diagnostic strategies known as pattern recognition. This kind of diagnostic method particularly depends upon the experience of the physician. Nevertheless, we think this kind of clinical picture could be interpreted successfully using PubMed by a non-experienced physician [5]. S. Corrao (&) S. Amico L. Calvo E. Barone G. Licata Dipartimento Biomedico di Medicina Interna e Specialistica, Universita di Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy e-mail: s.corrao@tiscali.it

A methodological look at the controversy about the influence of salt intake on cardiovascular risk

Cardiovascular diseases are a major cause of premature death and disability. They represent an extraordinarily strong financial burden upon health-care systems in ‘‘developed’’ countries. Elevated blood pressure is a major cause of cardiovascular disease. There is much evidence that cardiovascular risk increases from normal blood pressure (i.e., from 115/75 mmHg upwards) [1]. Overwhelming evidence shows that reducing salt intake from 9–12 g/day to 5–6 g/day lowers blood pressure [2]. Blood pressure is a surrogate endpoint, but may be related to a reduction of morbidity and mortality due to cardiovascular causes. Thus, intensive support and encouragement to cut down on the intake of salt in foods might reduce cardiovascular risk. Such a primary prevention strategy might significantly reduce social and health-care costs. The metaanalysis published simultaneously by Taylor et al. [3, 4] in the Cochrane Database of Systematic Reviews and the American Journal of Hypertension deals with this important issue. Specifically, it assesses the long-term effects of interventions aimed at reducing dietary salt upon morbidity and mortality due to cardiovascular causes. They found 7 studies (involving 6,489 participants) that met the inclusion criteria. Three of the seven studies focused on normotensive subjects; two on hypertensives; one in a mixed population of normotensives and hypertensives; and one in subjects with heart failure (n = 232). Despite the large number of collated cardiovascular events (665 deaths in 6,250 participants), the meta-analyses fails to show significant differences in intervention groups compared with controls. There is only limited evidence that dietary advice to reduce salt intake may increase the prevalence of deaths in people with heart failure [relative risk at the end of the trial: 2.59; 95 % confidence interval (CI), 1.04–6.44; 21 deaths]. The authors conclude that there is insufficient power to exclude the clinically important effects of reduced dietary salt on mortality or cardiovascular morbidity in normotensive or hypertensive populations. Moreover, they state that further evidences from randomized controlled trials would be needed to confirm if the restriction of dietary sodium is harmful for people with heart failure. In a recent comment, two preventive-medicine experts, Dr. He and Professor MacGregor [5], criticize the metaanalysis published by Taylor et al. [3, 4]. In their opinion, meta-analysis ‘‘reflects poorly on the reputation of the Cochrane Library and the authors’’. The two experts make statements regarding the fact that one trial in heart failure did not have to be included in the meta-analysis; they claimed that the trial was clinically heterogeneous. Indeed, patients who had been included in that trial were severely depleted of salt and water due to aggressive diuretic therapy. Moreover, the experts re-analyzed the data by combining together the results for hypertensive and normotensive subjects. Their results show a significant reduction in cardiovascular events by 20 % (pooled relative risk: 0.80; 95 % CI, 0.64–0.99). The meta-analysis was undertaken using the fixed-effect model because the heterogeneity among studies did not reach the standard probability value for significance. However, this could be the case of ‘‘not practicing what you preach’’. Despite accepting statistical homogeneity according to Cochrane’s Q test (p = 0.36) and the low value of the I index (only 6 % diversity among trials was detected), pooling data from two populations (hypertensives and normotensives) S. Corrao (&) L. Calvo G. Licata Centre of Research for Effectiveness and Appropriateness in Medicine (C.R.E.A.M.), Biomedical Department of Internal Medicine and Subspecialties, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy e-mail: s.corrao@tiscali.it

The heart in rheumatoid arthritis: Contrasting or misleading data from clinical research? Comment on the article by Giles et al

overall incidence of adverse events among all groups. Fortyfour subjects (15.1%) discontinued the study, and the rate of discontinuation was similar among treatment groups. Though well-tolerated and safe, ERB-041 failed to demonstrate antiinflammatory efficacy in RA patients, despite evidence of strong activity in preclinical arthritis models. Taken together, these 2 studies suggest that selective ER agonism (both ER and ER ) would not have effects on regulation of inflammatory response in RA. There are several possible explanations. ERs are nuclear hormone receptors that can either directly bind to estrogen response elements in gene promoters or serve as cofactors with other transcription factors (i.e., NFB/activator protein 1) (5). Cytoplasmic ER and membrane-associated ER affect specific kinase-signaling pathways. ERs have prominent effects on immune function in both the innate and adaptive immune responses. However, the roles of estrogen receptors may be different between species, significantly limiting the easy translation of preclinical studies (in animal models) into the clinical setting (6). Second, the role of estrogens in RA is the subject of debate since both proinflammatory and antiinflammatory effects have been reported; important evidence of their dual role is provided by their peripheral conversion to various proinflammatory or antiinflammatory metabolites at the level of the RA synovial tissue. Recently, using estrone and 17 -estradiol as substrates, the production of 16 -, 4-, and 2-hydroxylated estrogens and their 4and 2-methylation products in RA and osteoarthritis (OA) synovial cells was evaluated (7). The levels of 16 -hydroxylated estrone/17 -estradiol (16 OH-estrone/ 16 OH-17 -estradiol) were higher than the levels of all other estrogen metabolites. RA synovial cells produced more 16 OH-estrone than did OA synovial cells. Importantly, the 16 OH-estrones did not inhibit tumor necrosis factor (TNF) secretion, whereas all other estrogen metabolites had marked inhibitory effects. These and similar findings indicate that precursor estrogens are converted into proinflammatory metabolites, particularly in RA synovial cells. RA synovial cells mainly produce the proproliferative 16 OH-estrone, which, in addition to 16 OH-17 -estradiol, is one of the only two estrogens studied that does not inhibit TNF secretion (8). A preponderance of 16 -hydroxyestrone is an unfavorable sign in RA synovial inflammation. Therefore, it must be considered that, even in the presence of a normal interaction between endogenous estrogens (or agonists) and their functional ERs, an altered balance in peripheral estrogen metabolites might induce different cell (and clinical) responses in RA patients and promote unexpected effects.