The positive side of the coin: Sars-Cov-2 pandemic has taught us how much Telemedicine is useful as standard of care procedure in real life.

Patients and health workers were at high risk of infection during the Sars-Cov-2 pandemic lockdown. For this reason, other medical and clinical approaches such as Telemedicine were necessary. Despite Telemedicine was born before COVID-19, the pandemic was the opportunity to accelerate a process already underway for at least a decade and to blow all the barriers away. Our aim is to describe the experience of Telemedicine during and immediately after the first lockdown to assure the follow-up in a 'virtual' outpatient clinic dedicated to Rheumatic and Musculoskeletal Diseases (RMDs) and to give an overview of Telemedicine in the rheumatology field. We retrospectively evaluated the patient flow to our rheumatology division from March to September 2020 and, in accordance with local restrictions, three periods were selected. In the 1st period, 96.96% of the outpatient clinic cases were shifted to Telemedicine; these decreased to 52.45% in the 2nd period, while the 3rd period was characterized by the return of the patients at the clinic (97.6%). Diagnostic procedures were postponed during the 1st period, reduced drastically during the 2nd and performed regularly during the third period. Intravenous infusions were maintained as much as possible during the three periods, to assure therapeutic continuity. Shifting stable patients to Telemedicine has the potential to allow continuity of care, while reducing the risk of contagion during a pandemic. In the next future, the integration of Telemedicine as standard of care for specific clinical applications might assure assistance for RMDs patients also in non-pandemic conditions.

Differential expression of junctional adhesion molecules in different stages of systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by early perivascular inflammation, microvascular endothelial cell (MVEC) activation/damage, and defective angiogenesis. Junctional adhesion molecules (JAMs) regulate leukocyte recruitment to sites of inflammation and ischemia-reperfusion injury, vascular permeability, and angiogenesis. This study was undertaken to investigate the possible role of JAMs in SSc pathogenesis. METHODS: JAM-A and JAM-C expression levels in skin biopsy samples from 25 SSc patients and 15 healthy subjects were investigated by immunohistochemistry and Western blotting. Subcellular localization of JAMs in cultured healthy dermal MVECs and SSc MVECs was assessed by confocal microscopy. Serum levels of soluble JAM-A (sJAM-A) and sJAM-C in 64 SSc patients and 32 healthy subjects were examined by enzyme-linked immunosorbent assay. RESULTS: In control skin, constitutive JAM-A expression was observed in MVECs and fibroblasts. In early-stage SSc skin, JAM-A expression was strongly increased in MVECs, fibroblasts, and perivascular inflammatory cells. In late-stage SSc, JAM-A expression was decreased compared with controls. JAM-C was weakly expressed in control and late-stage SSc skin, while it was strongly expressed in MVECs, fibroblasts, and inflammatory cells in early-stage SSc. Surface expression of JAM-A was higher in early-stage SSc MVECs and increased in healthy MVECs stimulated with early-stage SSc sera. JAM-C was cytoplasmic in resting healthy MVECs, while it was recruited to the cell surface upon challenge with early-stage SSc sera. Early-stage SSc MVECs exhibited constitutive surface JAM-C expression. In SSc, increased levels of sJAM-A and sJAM-C correlated with early disease and measures of vascular damage. CONCLUSION: Our findings indicate that JAMs may participate in MVEC activation, inflammatory processes, and impaired angiogenesis in different stages of SSc.

Lung ultrasound for the screening of interstitial lung disease in very early systemic sclerosis.

BACKGROUND: A high percentage of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILD) during the course of the disease. Promising data have recently shown that lung ultrasound (LUS) is able to detect ILD by the evaluation of B-lines (previously called ultrasound lung comets), the sonographic marker of pulmonary interstitial syndrome. OBJECTIVE: To evaluate whether LUS is reliable in the screening of ILD in patients with SSc. METHODS: Fifty-eight consecutive patients with SSc (54 women, mean age 51±14 years) who underwent a high resolution CT (HRCT) scan of the chest were also evaluated by LUS for detection of B-lines. Of these, 32 patients (29 women, mean age 51±15 years) fulfilled the criteria for a diagnosis of very early SSc. RESULTS: At HRCT, ILD was detected in 88% of the SSc population and in 41% of the very early SSc population. A significant difference in the number of B-lines was found in patients with and without ILD on HRCT (57±53 vs 9±9; p<0.0001), with a concordance rate of 83%. All discordant cases were false positive at LUS, providing a sensitivity and negative predictive value of 100% in both SSc and very early SSc. CONCLUSIONS: ILD may be detected in patients with very early SSc. The presence of B-lines at LUS examination correlates with ILD at HRCT. LUS is very sensitive for detecting ILD even in patients with a diagnosis of very early SSc. The use of LUS as a screening tool for ILD may be feasible to guide further investigation with HRCT.

Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage.

OBJECTIVE: To determine serum concentrations and tissue expression of matrix metalloproteinase-12 (MMP-12) and their correlation with clinical features in patients with systemic sclerosis (SSc). METHODS: Serum MMP-12 levels from 72 patients with SSc and 42 healthy volunteers were examined by ELISA. Immunohistochemical expression of MMP-12 was analysed in skin biopsies from 20 patients with SSc and 13 healthy subjects and lung biopsies from three patients with SSc-related interstitial lung disease (ILD) and five controls. RESULTS: Circulating levels of MMP-12 were significantly increased in patients with SSc compared with healthy controls. Serum MMP-12 levels were significantly higher in both patients with limited cutaneous SSc and those with diffuse cutaneous SSc than in healthy controls, and correlated positively with the extent of skin involvement. MMP-12 levels were raised in SSc patients with ILD compared with patients without ILD, and correlated with severity of lung restriction. Increased serum levels of MMP-12 were also associated with the presence of digital ulcers and severity of nailfold capillary abnormalities. In contrast to almost undetectable MMP-12 expression in healthy skin, MMP-12 was strongly expressed in keratinocytes, dermal endothelial cells, fibroblasts/myofibroblasts and inflammatory cells in the skin of patients with SSc. Affected lung tissue from patients with SSc-related ILD showed strong MMP-12 expression in capillary vessels, inflammatory cells, alveolar macrophages and fibroblasts in the thickened alveolar septa, while faint expression was observed in normal lung tissue. CONCLUSIONS: MMP-12 levels are increased in patients with SSc and are associated with severity of skin and pulmonary fibrosis and peripheral vascular damage.

Bone marrow-derived mesenchymal stem cells from early diffuse systemic sclerosis exhibit a paracrine machinery and stimulate angiogenesis in vitro.

OBJECTIVE: To characterise bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic sclerosis (SSc) for the expression of factors implicated in MSC recruitment at sites of injury, angiogenesis and fibrosis. The study also analysed whether the production/release of bioactive mediators by MSCs were affected by stimulation with cytokines found upregulated in SSc serum and tissues, and whether MSCs could modulate dermal microvascular endothelial cell (MVEC) angiogenesis. METHODS: MSCs obtained from five patients with early severe diffuse SSc (SSc-MSCs) and five healthy donors (H-MSCs) were stimulated with vascular endothelial growth factor (VEGF), transforming growth factor ß (TGFß) or stromal cell-derived factor-1 (SDF-1). Transcript and protein levels of SDF-1 and its receptor CXCR4, VEGF, TGFß(1) and receptors TßRI and TßRII were evaluated by quantitative real-time PCR, western blotting and confocal microscopy. VEGF, SDF-1 and TGFß(1) secretion in culture supernatant was measured by ELISA. MVEC capillary morphogenesis was performed on Matrigel with the addition of MSC-conditioned medium. RESULTS: In SSc-MSCs the basal expression of proangiogenic SDF-1/CXCR4 and VEGF was significantly increased compared with H-MSCs. SSc-MSCs constitutively released higher levels of SDF-1 and VEGF. SDF-1/CXCR4 were upregulated after VEGF stimulation and CXCR4 redistributed from the cytoplasm to the cell surface. VEGF was increased by SDF-1 challenge. VEGF, TGFß and SDF-1 stimulation upregulated TGFß(1), TßRI and TßRII in SSc-MSCs. TßRII redistributed from the cytoplasm to focal adhesion contacts. SSc-MSC-conditioned medium showed a greater proangiogenic effect on MVECs than H-MSCs. Experiments with blocking antibodies showed that MSC-derived cytokines were responsible for this potent proangiogenic effect. CONCLUSION: SSc-MSCs constitutively overexpress and release bioactive mediators/proangiogenic factors and potentiate dermal MVEC angiogenesis.

Implantable cardioverter defibrillator prevents sudden cardiac death in systemic sclerosis.

OBJECTIVE: Cardiac involvement means a poor prognosis in systemic sclerosis (SSc). Conduction defects and arrhythmias are frequent in patients with SSc, and may result in sudden cardiac death. We tested whether electrophysiologic studies and implantation of cardioverter defibrillators are recommended when ventricular arrhythmias are present. METHOD: A cardioverter defibrillator was implanted in 10 patients with SSc who had heart involvement. RESULT: After 36 months, analysis of the device showed several episodes of ventricular tachycardia in 3 patients, which were promptly reverted by electrical shock delivery. CONCLUSION: In patients with SSc who are affected by ventricular arrhythmias, the implantation of a cardioverter defibrillator may prevent sudden cardiac death.

Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis.

RATIONALE: Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA. OBJECTIVE: We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc. METHODS AND RESULTS: Here, we show that the endogenous antiangiogenic VEGF(165)b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF(165)b expression correlated with increased expression of profibrotic transforming growth factor-ß1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF(165)b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF(165)b than healthy MVECs. Transforming growth factor-ß1 upregulated the expression of VEGF(165)b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF(165)b and SSc-MVEC-conditioned medium inhibited VEGF(165)-mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF(165)b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC-conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF(165) and anti-VEGF(165)b blocking antibodies. CONCLUSIONS: In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia.

An optimal decision making model for supporting week hospital management.

Week Hospital is an innovative inpatient health care organization and management, by which hospital stay services are planned in advance and delivered on week-time basis to elective patients. In this context, a strategic decision is the optimal clinical management of patients, and, in particular, devising efficient and effective admission and scheduling procedures, by tackling different requirements such as beds' availability, diagnostic resources, and treatment capabilities. The main aim is to maximize the patient flow, by ensuring the delivery of all clinical services during the week. In this paper, the optimal management of Week Hospital patients is considered. We have developed and validated an innovative integer programming model, based on clinical resources allocation and beds utilization. In particular, the model aims at scheduling Week Hospital patients' admission/discharge, possibly reducing the length of stay on the basis of an available timetable of clinical services. The performance of the model has been evaluated, in terms of efficiency and robustness, by considering real data coming from a Week Hospital Rheumatology Division. The experimental results have been satisfactory and demonstrate the effectiveness of the proposed approach.

Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions.

OBJECTIVE: To evaluate in SSc, the frequency of digital lesions and the morphology, characteristics, natural course and time to healing of 1614 digital ulcers (DUs). METHODS: One hundred SSc patients were followed up for 4 years. In the first step, the digital lesions were observed and classified at the time of presentation [digital pitting scar (DPS); DU; calcinosis; gangrene]. In the second step, DUs were divided into subsets according to their origin and main features. In the third step, the time to healing was recorded for each DU and the influence of DU main characteristics on time to healing was also evaluated. RESULTS: In the first step, 1614 digital lesions were observed: DPS, 712 (44.1%) lesions; DU, 785 (48.6%); calcinosis, 110 (6.8%); and gangrene, 7 (0.8%). In the second step, DUs were subsetted as follows: DU developed on DPS (8.8%), pure DU; DU developed on calcinosis (60%); DU derived from gangrene. In the third step, the mean time to healing was 25.6 (15.6) days in DPS, 76.2 (64) days in pure DU, 93.6 (59.2) days in calcinosis ulcers and 281.1 (263.3) in gangrene. CONCLUSIONS: In SSc, digital lesions are represented by DPS, DU, calcinosis and gangrene, and provide an evidence-based DU subsetting according to their origin and main characteristics. Subsetting may be helpful for a precise DU evaluation and staging, and in randomized controlled trials for a precise identification of those DUs that are to be included in therapeutic studies.

High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis.

BACKGROUND: Currently, assessment of dermal thickness in systemic sclerosis (SSc) is performed by palpation and assessment using the modified Rodnan skin score (mRSS). OBJECTIVE: To verify whether high frequency ultrasound (US) may be a reliable and a reproducible method to measure digital dermal thickness. METHODS: In 70 patients with SSc, skin thickness was evaluated with US by 2 observers at 2 different sites on the second digit of the dominant limb to determine the interobserver variability. Patients and controls were examined twice by the first observer for intraobserver variability. Patients were divided into three subgroups according to the phase of the disease (oedematous, fibrotic or atrophic). RESULTS: At both examined areas, US showed a significant dermal thickening (p<0.001) in the whole group of patients with SSc. A low intraobserver and interobserver variability was found. A highly significant correlation between the global mRSS and the local dermal thickness at the two examined sites (p=0.032, p=0.021) was detected. Skin thickness was significantly higher in the oedematous than in the fibrotic group (p<0.001) and significantly higher in the fibrotic and the oedematous group (p<0.001) than in the atrophic group (p<0.002). CONCLUSIONS: US is a reliable tool giving reproducible results, and is able to detect digital dermal thickening in SSc.

The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis.

BACKGROUND: Early endothelial cell (EC) activation/damage and profibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin 33 (IL33) is a novel member of the IL1 family that promotes Th2 responses and inflammation through the ST2 receptor. IL33 is also a chromatin-associated transcriptional regulator in ECs. OBJECTIVE: To investigate the role of the IL33/ST2 axis in SSc. METHODS: Skin biopsies were obtained from 30 patients with SSc (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, oesophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from patients with SSc and controls were also analysed. IL33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, western blotting and RT-PCR. RESULTS: In skin biopsies from control subjects, constitutive nuclear IL33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In skin biopsies from patients with early SSc, IL33 protein was downregulated or absent in ECs and epidermis while IL33 mRNA was normally expressed or even upregulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In skin biopsies from patients with late SSc, IL33 was constitutively found in most ECs while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL33 expression in SSc. CONCLUSION: IL33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage IL33 may be mobilised from ECs to signal through ST2 in key profibrotic players such as inflammatory/immune cells and fibroblasts/myofibroblasts.

Early atherosclerosis and autoantibodies to heat-shock proteins and oxidized LDL in systemic sclerosis.

Autoimmune diseases are characterized by enhanced atherosclerosis. Humoral immune responses to mycobacterial HSP-65, human HSP-60, and to oxLDL have been established in a number of human autoimmune diseases and are considered to be associated with atherosclerosis. The aim of this study was to evaluate carotid artery intima-media thickness (IMT) in patients having systemic sclerosis (SSc) and to find out whether early atherosclerosis is associated with these autoantibodies. Forty-four patients having SSc underwent clinical evaluation and carotid artery IMT measurement. Several autoantibodies were tested among patients and a control group. The antibodies against human HSP-60 were measured by antihuman (IgG/IgM) HSP-60 ELISA kit. IgGs and IgMs antimycobacterial HSP-65 were determined using an ELISA with mycobacterial recombinant HSP-65 antigens. Similarly, anti-oxLDL antibodies were measured by an ELISA kit. Abnormal IMT levels were significantly more common in SSc patients compared with control subjects. Age was found as the sole most significant clinical parameter associated with carotid artery IMT in SSc. Disease duration, type of SSc, lung function tests, and cardiovascular risk factors were not associated with IMT in these patients. Levels of HSP-60, HSP-65, and oxLDL autoantibodies were similar among patients compared with controls, and in patients having "positive" IgM anti-HSP-65, higher IMT values were found. Abnormal carotid IMT is more prevalent in SSc than in normal subjects. Age rather than other clinical parameters is associated with early atherosclerotic changes in SSc. Autoantibodies to oxLDL, HSP-60, and HSP-65 are not elevated in SSc and there is only a borderline association with carotid artery IMT.

Flow-mediated vasodilation and carotid intima-media thickness in systemic sclerosis.

Increased evidence suggests an accelerated macrovascular disease in systemic sclerosis (SSc). Brachial artery flow-mediated vasodilation (FMD) and carotid intima-media thickness (IMT) are two indicators of subclinic cardiovascular disease and are frequently used as surrogate measures of subclinic atherosclerosis. The aim of this study was to evaluate macrovascular involvement in SSc. We studied 35 SSc patients (6 males and 29 females; 11 with diffuse and 24 with limited disease) and 20 healthy controls. Brachial artery FMD was assessed by method described by Celermajer in all patients and 13 control subjects. IMT was measured using high-resolution B-mode ultrasonography in patients and controls. Traditional risk factors for atherosclerosis (hypertension, dyslipidemia, and smoke) were also assessed. FMD was significantly impaired (3.41% +/- 4.56% versus 7.66% +/- 4.24%; P < 0.037) and IMT was significantly elevated compared with healthy controls (0.93 +/- 0.29 mm versus 0.77 +/- 0.13 mm; P < 0.005). FMD was not significantly different in SSc with increased IMT compared with those with normal IMT). No correlation was found between risk factors for atherosclerosis and the impairment of FMD or IMT in SSc patients. The impairment of endothelial function and structural changes of large vessels are evident in SSc, but do not seem associated with traditional risk factors for atherosclerosis. Prospective studies including also clinical outcomes are needed to assess the features and significance of macrovacular involvement in SSc.

Exercise Doppler echocardiography identifies preclinic asymptomatic pulmonary hypertension in systemic sclerosis.

In systemic sclerosis (SSc), the involvement of the interstitium or vascular system of the lung may lead to pulmonary arterial hypertension (PAH). PAH is often asymptomatic or oligosymptomatic in early SSc and, when it becomes symptomatic, pulmonary vascular system is already damaged. Exercise echocardiography (ex-echo), measuring pulmonary artery pressure (PAP) during exercise and allowing to differentiate physiologic from altered PAP responses, may identify subclinical PAH. Our aims were (a) to evaluate by ex-echo the change of PAP in patients with SSc without lung involvement; and (b) to correlate PAP during exercise (ex-PAP) values to clinical and biohumoral parameters of PAH. Twenty-seven patients with limited SSc (ISSc) without interstitial lung involvement were studied. Patients underwent rest and exercise two-dimensional and Doppler echocardiography by supine cycloergometer. Systolic PAP was calculated using the maximum systolic velocity of the tricuspid regurgitant jet at rest and during exercise values of systolic PAP exceeding 40 mmHg at ex-echo were considered as abnormal, and biohumoral markers potentially related to PAH were assessed. Eighteen of 27 SSc patients presented an ex-PAP > 40 mmHg, while in 9 of 27 patients ex-PAP values remained < 40 mmHg (48.8 +/- 4.5 mmHg versus 36.2 +/- 3.1 mmHg; P < 0.001). Other echocardiographic and ergometric parameters, clinical tests, and biohumoral markers were not different in the two groups. Ex-PAP significantly correlated with D-dimer (P = 0.0125; r2 = 0.2029). Ex-echo identifies a cluster of SSc patients with subclinical PAH that may develop PAH. This group should be followed up and may be considered for specific therapies to prevent disease evolution.

Lung CT densitometry in systemic sclerosis: correlation with lung function, exercise testing, and quality of life.

BACKGROUND: To ascertain if analysis of lung density histograms in thin-section CT was more reproducible than visual assessment of lung changes in systemic sclerosis (SSc), and if such density histogram parameters as mean lung attenuation (MLA), skewness, and kurtosis could more closely reflect pulmonary function as well as exercise and quality of life impairment. METHODS: The intraoperator and interoperator reproducibility of visual and densitometric lung CT analysis in 48 SSc patients examined with CT were evaluated by means of weighted kappa statistics. Univariate and multivariate regression analyses were applied to evaluate the relationship of visual and densitometric CT measurements with functional parameters including functional residual capacity (FRC), FVC, FEV(1), diffusion capacity of the lung for carbon monoxide (Dlco), 6-min walking testing (6MWT), and health-related quality of life questionnaire (QLQ) parameters. RESULTS: The intraoperator and interoperator reproducibility of MLA (intraobserver weighted kappa = 0.97; interobserver weighted kappa = 0.96), skewness (intraobserver weighted kappa = 0.89; interobserver weighted kappa = 0.88), and kurtosis (intraobserver weighted kappa = 0.89; interobserver weighted kappa = 0.88) were higher than those of visual assessment (intraobserver weighted kappa = 0.71; interobserver weighted kappa = 0.69). In univariate analysis, only densitometric measurements were correlated with some exercise and QLQ parameters. In multivariate analysis, MLA (square regression coefficient corrected [R(2)c] = 0.70), skewness (R(2)c = 0.78), and kurtosis (R(2)c = 0.77) were predicted by FRC, FVC, Dlco, 6MWT, and QLQ parameters, while visual assessment was associated only with FRC and FVC (R(2)c = 0.40). CONCLUSIONS: In SSc, densitometric analysis is more reproducible than visual assessment of lung changes in thin-section CT and more closely correlated to pulmonary function testing, 6MWT, and QLQ. Density histogram parameters may be useful for cross-sectional and longitudinal studies of lung involvement in SSc.

Hematopoietic stem cell transplantation in autoimmune diseases: algorithm for cardiovascular assessment.

Heart involvement is a frequent cause of morbidity and mortality in autoimmune diseases. All cardiac structures can be involved: pericardium, endocardium, myocardium, coronary circle, and conduction system. In the last decade many patients affected by autoimmune diseases have been treated with hematopoietic stem cell transplantation; the vast majority of these transplants have been autologous, and most have been within the context of phase I and II clinical trials; now, phase III trials are ongoing. Patients affected by autoimmune disease often have cardiac involvement which potentially puts them at higher risk from acute cardiotoxicity due to alkylating agents such as cyclophosphamide. The authors propose an algorithm for cardiac assessment before stem cell transplantation in order to identify those patients at highest risk, prior to administering any drug, to avoid further worsening of heart involvement and possible organ failure.A baseline assessment includes physical examinations, ECG to highlight arrhythmias and conduction abnormalities, chest X-ray to evaluate the presence of pericardial effusion and cardiothoracic ratio.A second-step evaluation includes echocardiography (which assesses the following parameters: left ventricular ejection fraction, diastolic function, tricuspid gradient, pulmonary acceleration time, right ventricular diameter and pericardial effusion, wall motion), Holter ECG that may highlight the presence of arrhythmias and biohumoral parameters such as brain natriuretic peptide and troponin I. If these parameters show abnormalities, a further step is required before transplantation. Cardiac catheterization allows to identify ischemic coronary diseases and pulmonary artery hypertension. Intensive monitoring with life card assessment before inclusion might establish ischemic coronary diseases or complex arrhythmias requiring pacing. Magnetic resonance imaging and single-photon emission computed tomography with dipyridamole are useful tools to evaluate the coronary flow. Treatment of ischemic coronary disease (assessment for revascularization), cardiac failure, pulmonary artery hypertension and arrhythmias constitutes the final step. The aim is to optimize cardiac status in order to allow intense immunosuppressive treatments.

Melatonin is a safe and effective treatment for chronic pulmonary and extrapulmonary sarcoidosis.

Chronic sarcoidosis (CS) is often unresponsive to usual treatments. Melatonin, an immunoregulatory drug, was employed in CS patients in whom usual treatments were ineffective or induced severe side effects. Melatonin was given for 2 yr (20 mg/day in the first year, 10 mg/day in the second year) to 18 CS patients. Pulmonary function tests, chest X rays, pulmonary computed tomography, Ga(67) scintigraphy and angiotensin-converting enzyme (ACE) were assayed at baseline and in the follow-up. Normalization of ACE, improvement of pulmonary parameters and resolution of skin involvement were found in the patients given melatonin. After 24 months of melatonin therapy, hylar adenopathy completely resolved in eight patients and parenchymal lesions were markedly improved in all patients; in the five patients with reduced diffusion capacity of the lung for carbon monoxide, the values normalized after 6 months of therapy and remained stable until month 24. After 24 months, Ga(67) pulmonary and extra-pulmonary uptake was totally normalized in seven patients and, at month 12 months, ACE was normalized in six patients in which the values were high at the baseline. Skin lesions, present in three patients, completely disappeared at month 24 months. No side effects were experienced and no disease relapse was observed during melatonin treatment. Melatonin may be an effective and safe therapy for CS when other treatments fail or cause side effects.