Stylianos Panopoulos

Biological treatments and connective tissue disease associated interstitial lung disease.

Purpose of review There is no specific therapy for interstitial lung disease associated with connective tissue diseases (CTDs-ILD), a potentially fatal condition for some of these patients. This article reviews currently available information on the effects on CTDs-ILD of biological treatments that are increasingly used with considerable success in various systemic diseases. Recent findings A beneficial effect of antitumor necrosis factor (TNF) agents on CTDs-ILD has been described in sporadic patients with rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, and despite the fact that there was no clear evidence of pulmonary toxicity of these agents in randomized-controlled trials comprising thousands of patients with RA and spondylarthropathies, new onset or exacerbation of preexisting ILD with high mortality rates has so far been observed in 144 RA patients following anti-TNF treatment in clinical practice. Likewise, administration of the B-cell depleting anti-CD20 antibody rituximab was beneficial for ILD in SSc patients but associated with new-onset ILD in isolated patients with RA and SLE. Pertinent information on other biological treatments is currently lacking. Summary Data on the therapeutic role of biological agents in CTDs-ILD is preliminary and controversial. Although preexisting ILD is not a contraindication for these agents, until more information is available their administration should be stopped when new pulmonary symptoms occur.

Cardiovascular magnetic resonance imaging in asymptomatic patients with connective tissue disease and recent onset left bundle branch block

BACKGROUND-AIM Recent LBBB in connective tissue diseases (CTDs) is challenging, due to high incidence of underlying pathology that may remain undetected, due to limitations of imaging tests. We hypothesized that cardiovascular magnetic resonance (CMR) may be of diagnostic value in CTDs with recent LBBB and normal echocardiogram. PATIENTS-METHODS 26 CTDs, aged 32 ± 7 yrs (19 F) and 26 controls without CTDs, aged 60 ± 4 yrs (10 F) with recent LBBB and normal echo were evaluated by CMR. The CTDs included 6 sarcoidosis (SRC), 4 systemic sclerosis (SSc), 6 systemic lupus erythematosus (SLE), 6 rheumatoid arthritis (RA) and 4 inflammatory myopathies (IM). CMR was performed by 1.5T. LVEF, T2 ratio (oedema imaging) and late gadolinium enhancement (LGE) (fibrosis imaging) were evaluated. Acute and chronic lesions were characterised by T2>2 and positive LGE and T2<2 and positive LGE, respectively. According to LGE, lesions were characterised as diffuse subendo-, subepicardial/intramural not following and subendocardial/transmural following the distribution of coronaries, indicative of vasculitis, myocarditis and myocardial infarction, respectively. RESULTS CTDs were younger (p<0.001), with higher incidence of abnormal CMR (42.31 vs 30.77%, p=NS), including dilated cardiomyopathy (11.54%), diffuse subendocardial fibrosis (11.54%), myocardial infarction (7.69%) and acute myocarditis (11.54%) vs dilated cardiomyopathy (19.23%), myocardial infarction (7.69%) and acute myocarditis (3.85%), detected in non-CTDs. CONCLUSIONS In CTDs with recent LBBB, CMR documented acute and chronic cardiac pathology, particularly myocarditis. CMR should be considered as an adjunct to conventional diagnostic workup in both patient groups, more so in CTDs.

Beneficial effect of the 5-HT1A receptor agonist buspirone on esophageal dysfunction associated with systemic sclerosis: A pilot study:

Background Esophageal involvement in systemic sclerosis (SSc) carries significant morbidity and is empirically managed with domperidone, albeit with questionable efficacy. The oral 5-HT1A receptor agonist buspirone may enhance esophageal peristalsis and lower esophageal sphincter (LES) function in healthy volunteers. Aim We aimed to test the hypothesis that buspirone may exert a beneficial acute effect on esophageal motor dysfunction in symptomatic patients with SSc. Methods Twenty consecutive patients with SSc reporting esophageal symptoms underwent high-resolution manometry before and 30 minutes after administration of buspirone (10 mg). Ten other patients received domperidone (10 mg) and served as control group. Changes in LES resting and residual pressure, amplitude, duration, and velocity of distal esophageal body contractions were examined. Results Esophageal hypomotility and hypotensive LES was found in 63% and 67% of patients, respectively. Demographic and clinical characteristics, including baseline manometric parameters, were comparable between groups. Resting pressure of LES increased after buspirone from 9.42 ± 2.6 to 11.53 ± 3.4 mmHg (p = 0.0002 by paired t-test), but not after domperidone; a trend for increase of amplitude of contractions was also observed after buspirone (p = 0.09). Comparison of the individual changes revealed that buspirone was superior to domperidone in enhancing LES pressure ( + 2.11 ± 2.0 versus –0.45 ± 2.3 mmHg, p = 0.006). No significant effects of either drug were noted on other examined parameters of esophageal function. Conclusion The beneficial acute effect of buspirone on impaired LES function associated with SSc suggests a role of 5-HT1A receptor-mediated interactions in these patients. Prospective studies to examine whether buspirone is of long-term therapeutic value for SSc-associated esophageal disease are warranted.

Is Vasculopathy Associated with Systemic Sclerosis More Severe in Men

Objective. To identify possible differences in morbidity and mortality between men and women with systemic sclerosis (SSc) by examining a homogeneous cohort at a single academic center. Methods. Demographic, clinical, and outcome data for all 231 patients of Greek origin with SSc who were examined between 1995 and 2011 in our department (200 women) were recorded in consecutive 3-year intervals from disease onset; data were analyzed retrospectively. Results. Factors comparable between sexes were age (yrs ± SD) at disease onset (46 ± 15 vs 46 ± 15), diffuse skin involvement (61.3% of men vs 46.4% of women), and anti-Scl-70 antibody positivity (66.6% of men vs 59.2% of women). Also comparable were prevalence of interstitial lung disease, upper or lower gastrointestinal (GI) tract involvement, and echocardiographic findings during the first, second, and third 3-year intervals from disease onset (2904 patient-yrs). In contrast, vasculopathy occurred earlier in men. During the first 3 years digital ulcers developed in 54% of men versus 31% of women (p = 0.036) and renal crisis developed in 17% of men versus 3% of women (p = 0.006). No significant differences regarding social history, smoking, medical history, or disease management were identified. After excluding non-SSc-related deaths, survival was worse in men (p = 0.005, Kaplan-Meier analysis) with significantly lower 6- and 12-year cumulative rates (77.2% and 53.8%, respectively, in men vs 97.3% and 89.2% in women). Conclusion. Results derived from an unselected SSc population indicate that the disease is more severely expressed in men than in women, a finding that could be related to more rapid development of vasculopathy in men. Studies are warranted in other single-center cohorts to confirm these findings.

Pseudo-infarction pattern in diffuse systemic sclerosis. Evaluation using cardiovascular magnetic resonance.

BACKGROUND Diffuse systemic sclerosis (dSSc) is characterized by vascular lesions and fibrosis. Cardiac involvement, although silent, accounts for 36% of deaths. We hypothesized that cardiovascular magnetic resonance (CMR) can clarify the pathophysiology of Q waves in dSSc patients. PATIENTS-METHODS 105 dSSc, aged 48±2years, with atypical symptoms and normal routine assessment, were evaluated by ECG and CMR using a 1.5 T system. Biventricular function was assessed by steady-state free-precession sequence (SSFP). To identify fibrosis, late gadolinium enhanced areas (LGE) were evaluated 15min after injection of 0.2mmol/kg gadolinium-DTPA and expressed as % of LV mass. RESULTS Q waves in V1-V5 (Group A), II, III, AVF (Group B) and I, AVL, II, III, AVF, V1-V5 (Group C) were found in 25/105, 8/105 and 5/105 dSSc, respectively. In 25 dSSc with Q in V1-V6, patchy intramyocardial LGE was detected in 24/25 and involved 8±2% of LV mass. LGE involved the intraventricular septum (IVS) in 11/24 and the lateral wall (LAT) in 5/24 dSSc. Only in 1/25 dSSc, an anterior, transmural LGE, due to LAD occlusion, was identified. In 8 dSSc with Q in II, III, AVF, patchy intramyocardial LGE was detected in the inferior wall and involved 5±2% of LV mass. In 5 dSSc with Q in V1-V5, II, III, AVF, patchy intramyocardial LGE was detected in anterior and inferolateral wall and involved 9±2% of LV mass. CONCLUSION CMR unveiled that the pattern of myocardial fibrosis in dSSc with Q waves is due to the systemic disease and not to CAD.

Intact calibers of retinal vessels in patients with systemic sclerosis.

Objective. A primary endothelial cell dysfunction is thought to be involved in systemic sclerosis (SSc)-associated fibroproliferative vasculopathy of the microcirculation and small arterioles, even in sites not affected by fibrosis. Because the role of fibroblasts in pathologic modifications and vascular wall remodeling is relatively unclear, and because the retina provides a unique opportunity to assess microcirculation in the absence of resident fibroblasts, we systematically evaluated retinal vessels in patients with SSc. Methods. Digital retinal images were obtained from both eyes of 93 consecutive patients with fully characterized SSc and 29 healthy controls matched 1:1 for age and sex with selected patients without diabetes, hypertension history, or antihypertensive treatment. Internal microvascular calibers (erythrocyte column width in μm) by central retinal arteriolar and venular equivalents and arteriolar to venular ratio were measured using validated software. Results. Arteriolar and venular calibers were similar in patients and their matched controls (mean ± SEM; 187 ± 2 vs 184 ± 3, p = 0.444, and 211 ± 2 vs 216 ± 3, p = 0.314, respectively). Both arteriolar and venular calibers and their ratio in patients with SSc were not associated with disease duration, extent of skin involvement, pulmonary fibrosis, digital ulcers or pitting scars, amputations, digital capillaroscopic findings, inflammatory indices, or autoantibodies. Conclusion. The evidence that retinal microcirculation is spared in SSc suggests that fibroproliferative vasculopathy may depend on specific cellular or soluble factors not present in the retinal environment.

The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial.

BackgroundAcute administration of the oral 5-HT1A receptor agonist buspirone, which is commonly used as an anxiolytic drug, may improve compromised lower esophageal sphincter function. In an open-label trial we assessed the effects of buspirone on esophageal motor function and symptoms in patients with esophageal involvement associated with systemic sclerosis (SSc).MethodsThirty consecutive patients with SSc and symptomatic esophageal involvement, despite treatment with proton pump inhibitors, underwent high resolution manometry and chest computed tomography for assessment of motor function and esophageal dilatation, respectively. Regurgitation, heartburn, dysphagia, and chest pain severity was subjectively scored by visual analog scales. Manometric parameters (primary endpoint) and symptom severity (secondary endpoint) were re-examined after 4-week daily administration of 20 mg buspirone. Other medications remained unchanged.ResultsEight patients did not complete the trial because of buspirone-associated dizziness (n = 2), or nausea (n = 2), or reluctancy to undergo final manometry. In the remaining 22 patients lower esophageal sphincter (LES) resting pressure increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (p = 0.00002) after buspirone administration; other manometric parameters did not change. Statistical analysis revealed negative correlation between individual increases in resting LES pressure and supra-aortic esophageal diameter (r = -0.589, p = 0.017), suggesting a more beneficial effect in patients with less severely affected esophageal function. Heartburn and regurgitation scores decreased at 4 weeks compared to baseline (p = 0.001, and p = 0.022, respectively).ConclusionOur findings warrant more conclusive evaluation with a double-blind controlled study; however, buspirone could potentially be given under observation for objective improvement in all patients with SSc who report reflux symptoms despite undergoing standard treatment.Trial registrationClinicalTrials.gov Identifier: NCT02363478 Registered: 21-02-2014.

Predictors of morbidity and mortality in early systemic sclerosis: Long-term follow-up data from a single-centre inception cohort

OBJECTIVES To determine predictors of morbidity and mortality in systemic sclerosis (SSc) in a long-term follow-up of an inception cohort of early SSc patients. METHODS We evaluated clinical manifestations, laboratory and lung function tests at disease onset as predictors of morbidity and mortality in 3rd, 6th and 9th year in SSc patients recruited within 12 months of disease onset. RESULTS A total of 115 SSc patients (97 women, mean age 48.1 ± 13.5 years, 54 diffuse subtype) were included. In multivariate regression analysis, predictors at disease onset for the presence of pulmonary fibrosis in 6th year of follow-up were diffuse subtype (OR: 4.4, p = 0.033), digital ulcers (OR: 7.9, p = 0.014) and esophageal involvement (OR: 4.79, p = 0.038). Arrythmias at disease onset predicted pulmonary hypertension (OR: 6.05, p = 0.022), while age (OR: 1.12, p = 0.002) and anti-Scl70 (OR: 4.3, p = 0.038) predicted arrhythmias in 6th year. During a follow-up of 101.8 ± 48.5 months, 23/115 patients died. Cox proportional hazard models analysis revealed 6 independent predictors of mortality present at disease onset: age at disease onset (45-59 years (HR: 3.0, p = 0.098), ≥60 years (HR: 4.3, p = 0.073), male gender (HR: 3.63, p = 0.025), diffuse subtype (HR: 2.83, p = 0.095), pulmonary fibrosis (HR: 3.7, p = 0.032), echocardiography-diagnosed pulmonary hypertension (HR = 7.49, p = 0.008) and DLCO < 60% (HR: 3.17, p = 0.035). Mortality rates at 3 and 6 years were 14% and 24% for patients with 3 independent predictors and 46% and 53% for patients with 4-6 predictors, respectively. CONCLUSION Clinical phenotypes at disease onset may predict morbidity and mortality in SSc and guide treatment decisions.

FRI0489 Improvement of Lower Esophageal Sphincter Function in Systemic Sclerosis After Long Term Administration of Buspirone, An Orally Available 5-HT1A Receptor Agonist: A 4-Week Pilot Study

Background Esophagus is commonly affected in Systemic Sclerosis (SSc) and esophageal function is compromised in about 75% of patients. Previous studies have shown that buspirone, an orally available 5-HT1A receptor agonist, enhances esophageal motility in healthy volunteers (1). Recently, we observed that a single dose of buspirone (10mg) improves acutely lower esophageal sphincter (LES) function in patients with SSc and esophageal involvement (2). Objectives To test the hypothesis that buspirone has a sustained beneficial effect on esophageal dysfunction and related symptoms in SSc patients in an open pilot study. Methods Consecutive, consenting symptomatic SSc patients (n=22, aged 51.3±11.8 years and disease duration 8.7±6.7 of years, 19 women, 8 with diffuse SSc, all receiving proton pump inhibitors) completed a 4-week treatment with buspirone (10mg, twice daily). Concomitant therapies remained unchanged. Supra- and infra-aortic coronal diameters of esophagus were measured in computing tomography (CT) performed within the previous 3 months. Possible changes in LES resting pressure, integrated relaxation pressure, amplitude, duration, and velocity of distal esophageal body contractions were examined by high resolution manometry (HRM) at baseline and at 4 weeks. Changes in the severity of esophageal symptoms using a 0-100 VAS scale score were recorded, in parallel. Results CT evaluations revealed that 12 patients had supra-, and 21 had infra-aortic esophagus dilatation (mean diameters 12.4±5.3 and 22.5±11.0 mm, respectively, normal <10 mm). Baseline esophageal hypomotility was observed in 68% and hypotensive LES in 75% of patients. Most intense symptoms were heartburn and regurgitation followed by dysphagia and retrosternical pain (mean scores 39±30, 37±24, 23±27 and 10±24 respectively). After 4 weeks of buspirone, LES resting pressure increased from 6.8±2.7 to 10.6±4.3 mmHg (p=0.007). Percent improvement was less prominent in patients with supra-aortic esophagus dilatation (29.2±19.8% versus 83.9±38.1% in patients without dilatation, p=0.037), whereas bivariate regression analysis revealed a negative correlation between individual increases of resting LES pressure and supra-aortic diameter (r=-0,613 p=0.058), indicating that buspirone exerts a greater effect in patients with less affected esophagus. No significant changes were noted on other examined HRM parameters. Notably, heartburn and regurgitation scores decreased at 4-weeks compared to baseline (p=0.001, and p=0.022, respectively). Conclusions Administration of buspirone may exert a beneficial effect on impaired LES function and improve esophageal symptoms in patients with SSc, suggesting a role of 5-HT1A receptor-mediated interactions. Placebo-controlled studies to confirm that buspirone is of therapeutic value are warranted. References Di Stefano et al. Effect of Buspirone, a 5-HT1A receptor agonist on esophageal motility in healthy volunteers. Dis esophagus, 2012;5:470-6 S. Panopoulos et al. Beneficial effect of acute administration of buspirone on lower esophageal sphincter function in patients with systemic sclerosis. United European Gastroenterol J, 2015 in press Disclosure of Interest None declared