Case Report: Middle lobe syndrome: a rare presentation in eosinophilic granulomatosis with polyangiitis.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by necrotizing inflammation of small- and medium-sized blood vessels and the presence of circulating ANCA. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic ANCA-associated vasculitis, characterized by peripheral eosinophilia, neuropathy, palpable purpuras or petechiae, renal and cardiac involvement, sinusitis, asthma, and transient pulmonary infiltrates. Middle lobe syndrome (MLS) is defined as recurrent or chronic atelectasis of the right middle lobe of the lung, and it is a potential complication of asthma. Case presentation: Herein, we describe a case of MLS in a 51-year-old woman, never-smoker, affected by EGPA, presenting exclusively with leukocytosis and elevated concentrations of acute-phase proteins, without any respiratory symptom, cough, or hemoptysis. Chest computed tomography (CT) imaging documented complete atelectasis of the middle lobe, together with complete obstruction of lobar bronchial branch origin. Fiberoptic bronchoscopy (FOB) revealed complete stenosis of the middle lobar bronchus origin, thus confirming the diagnosis of MLS, along with distal left main bronchus stenosis. Bronchoalveolar lavage (BAL) did not detect any infection. Bronchial biopsies included plasma cells, neutrophil infiltrates, only isolated eosinophils, and no granulomas, providing the hypothesis of vasculitic acute involvement less likely. First-line agents directed towards optimizing pulmonary function (mucolytics, bronchodilators, and antibiotic course) were therefore employed. However, the patient did not respond to conservative treatment; hence, endoscopic management of airway obstruction was performed, with chest CT documenting resolution of middle lobe atelectasis. Conclusion: To the best of our knowledge, this is the first detailed description of MLS in EGPA completely resolved through FOB. Identification of MLS in EGPA appears essential as prognosis, longitudinal management, and treatment options may differ from other pulmonary involvement in AAV patients.

Real life use of prostacyclin analog (iloprost), a multi-centric survey data from the Scleroderma study group Emilia Romagna (Sclero-RER) and review of the literature.

BACKGROUND AND AIM: Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out. RESULTS: All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses). CONCLUSIONS: These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available.

Accrual of organ damage in Behçet's syndrome: trajectory, associated factors, and impact on patients' quality of life over a 2-year prospective follow-up study.

BACKGROUND: This study aimed to investigate the trajectory of damage accrual, associated factors, and impact on health-related quality of life (HR-QoL) in a multicenter cohort of patients with Behçet's syndrome (BS) over 2 years of follow-up. METHODS: Patients recruited in the BS Overall Damage Index (BODI) validation study were prospectively monitored for 2 years and assessed for damage accrual, defined as an increase ≥1 in the BODI score, and HR-QoL was evaluated by the SF-36 questionnaire. Logistic and multiple linear regression models were built to determine factors associated with damage accrual and impairment in the different SF-36 domains. RESULTS: During follow-up, 36 out of 189 (19.0%) patients had an increase ≥1 in the BODI score with a mean (SD) difference of 1.7 (0.8) (p <0.001). The incidence rate of damage accrual was stable over time, regardless of the disease duration. Out of 61 new BODI items, 25 (41.0%) were considered related to glucocorticoid (GC) use. In multivariate analysis, duration of GC therapy (OR per 1-year 1.15, 95% CI 1.07-1.23; p <0.001) and occurrence of ≥1 disease relapse (OR 3.15, 95% CI 1.09-9.12; p 0.038) were identified as predictors of damage accrual, whereas the use of immunosuppressants showed a protective effect (OR 0.20, 95% CI 0.08-0.54, p<0.001). Damage accrual was independently associated with the impairment of different physical domains and, to a greater extent, in emotional domains of the SF-36 questionnaire. Female sex, higher disease activity, and fibromyalgia were also significantly associated with impairment in HR-QoL. CONCLUSION: In BS, organ damage accrues over time, also in long-standing disease, resulting in an impairment of the perceived physical and mental health. Adequate immunosuppressive treatment, preventing disease flares and minimizing exposure to GCs have a crucial role in lowering the risk of damage accrual.

Discordance between patient and physician global assessment of disease activity in Behçet's syndrome: a multicenter study cohort.

BACKGROUND: To compare the patients' and physician's global assessment of disease activity in Behçet's syndrome (BS) and investigate the frequency, magnitude, and determinants of potential discordance. METHODS: A total of 226 adult BS patients with a median (IQR) age of 46.9 (35.6-55.2) years were enrolled across Italy, Greece, Portugal, and Spain. Demographic, clinical, and therapeutic variables, as well as the patient reported outcomes, were collected at the recruitment visit. The physical (PCS) and mental (MCS) component summary scores of the Short Form Questionnaire 36 (SF-36) and the Behçet's syndrome Overall Damage Index (BODI) were calculated. Disease activity was assessed by the patients' (PtGA) and physician's global assessment (PGA) in a 10-cm visual analog scale, as well as the Behçet Disease Current Activity Form (BDCAF). Discordance (∆) was calculated by subtracting the PGA from the PtGA and defined as positive (PtGA>PGA) and negative (PtGA 80%) of disagreements were due to patients rating higher their disease activity. Higher values of BDCAF were associated to increased rate of positive discordance. When BDCAF = 0, the median (IQR) values of PtGA and PGA were 0.2 (0-2) and 0 (0-1), respectively. PCS (adjusted odds ratio (adjOR) 0.96 per unit, 95% CI 0.93-0.98, p = 0.006) and MCS (adjOR 0.96 per unit, 95% CI 0.93-0.99, p = 0.003) were independently associated with positive discordance using both cutoffs. Active ocular involvement emerged as a potential determinant of negative discordance (adjOR 5.88, 95% CI 1.48-23.30, p = 0.012). CONCLUSIONS: PtGA and PGA should be considered as complementary measures in BS, as patients and physicians may be influenced by different factors when assessing active disease manifestations. Particularly, PtGA may be a useful tool in the assessment of BS disease activity, as it carries a low risk to misclassify an inactive disease, and may allow to capture aspects of the patient's health that negatively affect his well-being and the treatment.

Development and preliminary validation of the Behçet's syndrome Overall Damage Index (BODI).

OBJECTIVE: To develop and validate the evidence-based and consensus-based Behçet's Syndrome Overall Damage Index (BODI). METHODS: Starting from 120 literature-retrieved preliminary items, the BODI underwent multiple Delphi rounds with an international multidisciplinary panel consisting of rheumatologists, internists, ophthalmologists, neurologists, and patient delegates until consensus was reached on the final content. The BODI was validated in a cross-sectional multicentre cohort of 228 patients with Behçet's syndrome (BS) through the study of (a) correlation between BODI and Vasculitis Damage Index (VDI) and (b) correlation between BODI and disease activity measures (ie, Behçet's Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA)), c) content and face validity and (d) feasibility. RESULTS: The final BODI consists of 4 overarching principles and 46 unweighted-items grouped into 9 organ domains. It showed good to excellent reliability, with a mean Cohen's k of 0.84 (95% CI 0.78 to 0.90) and a mean intra-class correlation coefficient of 0.88 (95% CI 0.80 to 0.95). Overall, 128 (56.1%) patients had a BODI score ≥1, with a median score of 1.0 (range 0-14). The BODI significantly correlated with the VDI (r=0.693, p<0.001), demonstrating to effectively measure damage (construct validity), but had greater sensitivity in identifying major organ damage and did not correlate with disease activity measures (ie, BDCAF: p=0.807, PGA: p=0.820, PtGA: p=0.794) discriminating damage from the major confounding factor. The instrument was deemed credible (face validity), complete (content validity) and feasible by an independent group of clinicians. CONCLUSIONS: Pending further validation, the BODI may be used to assess organ damage in patients with BS in the context of observational and controlled trials.

Efficacy and retention rate of adalimumab in rheumatoid arthritis and psoriatic arthritis patients after first-line etanercept failure: the FEARLESS cohort.

Few studies have compared the efficacy of switching from etanercept to adalimumab in the real-life setting in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This study evaluated the 2-year retention rate and 12-month efficacy of adalimumab in RA and PsA patients, previously treated with etanercept. RA and PsA patients from 11 Italian Rheumatology Units received adalimumab after first-line etanercept failure. Two-year adalimumab retention rate was calculated by the Kaplan-Meier method and Cox proportional hazard models were developed to examine predictors of drug persistence. Univariate and multivariate logistic regression analyses were developed to examine potential predictors of 12-month DAS-28 remission. The study population included 117 RA (disease duration of 10.1 ± 7.7 years and baseline DAS28-ESR of 4.97 ± 1.3) and 102 PsA (disease duration of 7.1 ± 5.1 years and baseline DAPSA of 24.6 ± 11.8). The 2-year retention rate was 48.2% in RA and 56.5% in PsA patients. Concomitant methotrexate treatment was not associated with increased drug survival in both groups. Similarly, cause of etanercept discontinuation or treatment duration was not associated with retention rate. 12-month remission and low disease activity were achieved, respectively, in 27.3% and 23.9% of RA patients and 27.4% and 23.5% PsA of patients. In multivariate models, etanercept discontinuation due to inefficacy (OR 0.27, 95% CI 1.03-0.73; p = 0.009) and baseline DAS-28 (OR 0.45, 95% CI 0.29-0.69; p < 0.001) remained significant negative predictors of remission in RA patients. No variable was associated with remission in PsA patients. Adalimumab after etanercept failure was highly effective and safe in both RA and PsA patients.

Inflammation and Atrial Electrical Remodelling in Patients With Embolic Strokes of Undetermined Source.

BACKGROUND: About one third of ischaemic strokes are classified as embolic strokes of undetermined source (ESUS). A silent atrial fibrillation (AF) may play a pathogenic role in these strokes and P wave dispersion (PWD), representing an electrocardiographic (ECG) predictor for paroxysmal AF, thereby a potential marker of covert cardioembolism, was found to be increased in cryptogenic stroke. Furthermore, current evidence links AF to inflammation: inflammatory markers, such as high-sensitive C-reactive protein (hsCRP), have been related to the development and persistence of AF, possibly by promoting atrial remodelling. The aim of this study was to evaluate whether a relationship between PWD and hsCRP in patients with ESUS exists, in order to highlight a possible role for inflammation in the atrial electric remodelling, that predisposes to AF. METHODS: We enrolled 174 patients (91 males, 83 females; mean age 69±13years) with ESUS. All patients underwent neuroimaging examination, arterial ultrasound examination, echocardiography and ECG. P wave dispersion and hsCRP were measured in all subjects. RESULTS: A significant positive correlation was found between hsCRP and PWD (Spearman r: 0.35, p<0.0001). In patients with high PWD (>40 msec; n=102), hsCRP was three-fold higher than in patients with normal PWD (≤40 msec; n=72)(1.57±2.9 vs 0.42±0.4mg/dl, p=0.0005). CONCLUSIONS: Our results show increased hsCRP levels in cryptogenic stroke patients with high PWD. These findings provide support for the hypothesis that systemic inflammation plays a role in a fraction of patients with ESUS, by increasing AF risk via atrial electric remodelling.

Previous use of Statins and Atrial Electrical Remodeling in Patients with Cryptogenic Stroke.

BACKGROUND: In the general population the leading cause of cardioembolic stroke is atrial fibrillation (AF). A silent AF is also the possible cause of many cryptogenic strokes. P wave dispersion (PWD), a predictor of AF, has been proposed as a marker of silent AF occurrence in these strokes. PWD correlates with high-sensitive C-reactive protein levels reflecting the role of inflammation in promoting a slowed and inhomogeneous atrial conduction. Statins have a multitude of additional effects beyond lipid lowering, in particular anti-inflammatory effects that may influence atrial conduction. OBJECTIVE: The aim of this study was to evaluate the effects of previous statin use on PWD in patients with cryptogenic stroke, in order to highlight a possible role for statins in preventing atrial conduction alterations that predispose to AF. METHOD: We enrolled 131 patients (67 males, 64 females; mean age 69±13 years) with cryptogenic stroke. All patients underwent neuroimaging examination, arterial ultrasound examination, echocardiography and ECG. PWD was measured in all subjects. RESULTS: Patients previously treated with statins (n: 34) had lower PWD and P index values in comparison with no-statin group (41.7±12.2 vs 48.7±15.2 ms, p=0.01, and 14.2±3.7 vs 16.5±5.3 ms, p=0.02, respectively). CONCLUSIONS: Our results show lower PWD values in cryptogenic stroke patients previously treated with statins. These findings provide support to the hypothesis that statins may play a role in modulating atrial electrophysiological and structural properties, preventing the occurrence of a slowed and heterogeneous atrial conduction and finally, reducing the occurrence of AF.

Prediction risk chart for scleroderma digital ulcers: a composite predictive model based on capillaroscopic, demographic and clinico-serological parameters.

BACKGROUND: Digital ulcers (DU) affect 50% of systemic sclerosis (SSc) patients, representing a challenging clinical problem. Despite a high negative predictive value, capillaroscopic scores proposed to select patients at risk for DU show an inadequate positive predictive value, especially in patients without previous DU. AIM OF THIS STUDY: To increase the predictive value for DU development of capillaroscopy, through a predictive risk chart taking into account capillaroscopic, demographic, and clinico-serological parameters. PATIENTS AND METHODS: Two hundred and nineteen unselected SSc patients from 8 Italian Rheumatology Centers were consecutively enrolled during a 6-month period. Demographic, clinical, serological and instrumental data and capillaroscopy skin ulcers risk index (CSURI) were collected. RESULTS: A multivariate logistic regression analysis showed a significant positive association between DU appearance and male gender, DU history, altered CSURI, and ESR. A prediction risk chart of the development of DU within 6 months were built on the basis of the above parameters. According to the risk level, four risk classes were identified: low (≤19.3%); medium (>19.3%, ≤58.6%); high (>58.6%, ≤89.2%), and very high risk (>89.2%). CONCLUSIONS: The systematic evaluation of the above parameters can be helpful to identify patients at risk to develop DU optimizing preventive vasoactive therapy.

Systemic sclerosis evolution of disease pathomorphosis and survival. Our experience on Italian patients' population and review of the literature.

The clinical spectrum and prognosis of systemic sclerosis (SSc) seem to vary among patients' populations recruited during different time periods. In order to verify this possible evolution we investigated the clinico-serological and survival rate in a large Italian SSc series (821 patients; 746 females, 75 males; mean age 53.7±13.9SD years) recruited between 2000 and 2011. The observed findings were compared with previous studies of the world literature.Compared to older Italian SSc series, the present patients' population showed a significantly increased prevalence of limited cutaneous SSc (from 72 to 87.5%; p ≤.0001) and serum anti-centromere antibodies (from 39 to 47,4%; p ≤.001), with a significant reduction of lung (from 81 to 63.7%; p ≤.0001), heart (from 35 to 20.5%; p ≤.0001), and renal involvement (from 10 to 3.8%; p ≤.0001), and skin ulcers (from 54 to 16.5%; p ≤.0001). Cumulative 10th-year survival showed a clear-cut increase (80.7%) compared to our previous series (69.2%). These findings were mirrored by the results of survival studies published during the last five decades, grouped according to the time periods of patients'' recruitment at the referral centers. A clear progression of 10th-year survival rates was detectable, from the 54% median survival of the oldest studies (1935-1974) to 74% and 83.5% of the more recent SSc series, 1976-1999 and after 1999, respectively. In conclusion, the favorable evolution of SSc pathomorphosis and prognosis during the last decades might be related to more diffuse physician/patient awareness of this harmful disease and availability of diagnostic tools, the consequent wider recruitment of patients in the early stages of the disease, as well as to the improved therapeutic strategies.

Therapeutic options after treatment failure in rheumatoid arthritis or spondyloarthritides.

The prognosis for patients with rheumatoid arthritis or spondyloarthritides has improved dramatically due to earlier diagnosis, recognition of the need to treat early with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), alone or in combinations, the establishment of treatment targets, and the development of biological DMARDs (bDMARDs). Many patients are now able to achieve clinical remission or low disease activity with therapy, and reduce or eliminate systemic corticosteroid use. Guidelines recommend methotrexate as a first-line agent for the initial treatment of rheumatoid arthritis; however, a majority of patients will require a change of csDMARD or step up to combination therapy with the addition of another csDMARD or a bDMARD. However, treatment failure is common and switching to a different therapy may be required. The large number of available treatment options, combined with a lack of comparative data, makes the choice of a new therapy complex and often not evidence based. We summarize and discuss evidence to inform treatment decisions in patients who require a change in therapy, including baseline factors that may predict response to therapy.

Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.

IMPORTANCE: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS: HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54371254.

Capillaroscopic Skin Ulcers Risk Index (CSURI) calculated with different videocapillaroscopy devices: how its predictive values change.

INTRODUCTION: Digital ulcers (DU) occur in about 50% of systemic sclerosis (SSc) patients. Scleroderma DU are responsible for chronic pain and disability with the need of systemic and local treatments. Recently, capillaroscopic skin ulcer risk index (CSURI) has been validated as useful tool in predicting the appearance of new scleroderma ulcers and/or persistence of non-healing lesions, within 3 months from capillaroscopy evaluation. OBJECTIVES: Since the image length of 1.57 mm might represent a critical factor for CSURI calculation, the present study aimed to evaluate the reliability of CSURI using three different videocapillaroscopy devices with distinct image widths. METHODS: One hundred and seventy-six unselected SSc patients were consecutively enrolled for the study during a six-month period, using three different capillaroscopy devices (image widths of 1.33, 1.57, and 1.70 mm). RESULTS: After a three month-follow-up new DU or persisting non-healing ulcers were observed in 46/176 patients (26.1%). The receiver operating characteristic curve analysis for CSURI showed an area under curve respectively of 0.705 for the image width of 1.33 mm, 0.786 for the image of 1.70 mm, and 0.888 for the image width of 1.57 mm. CONCLUSIONS: The good sensitivity, specificity and positive predictive value of CSURI was confirmed in the whole patients' series, as well as in the three subgroups on different image widths obtained with various available devices. In addition, the negative predictive value of the capillaroscopic index remained very high regardless of the picture length adopted.

Epidemiology of systemic sclerosis in a district of northern Italy.

OBJECTIVES: To estimate, using both the American College of Rheumatology-ACR 1980 classification criteria and revised LeRoy and Medsger 2001 criteria, the incidence and prevalence of systemic sclerosis (SSc) in an area in north-eastern Italy with a referral base population of about 346,000 inhabitants. METHODS: Retrospective examination of all patients 16 years and older of native Italian origin and resident in the Ferrara district who had either been admitted to hospital or referred to our outpatient clinic with a diagnosis of SSc between 1st January 1999 and 31st December 2007. SSc subjects were identified both by a search of hospital discharge code 710.1, as per the international classification of disease-9 codes, and using a computerised search for this pathology code in the national health care system. The subjects referred to our outpatient clinic were identified from a dedicated data base. Incidence and prevalence rates were calculated as the number of cases per 100,000 inhabitants (population data based on the October 2001 national census). The medical records of each potential case were accurately examined and reviewed by the same physician who determined whether those patients identified as having a diagnosis of SSc did indeed meet the ACR 1980 classification criteria for SSc and/or the LeRoy and Medsger 2001 criteria. RESULTS: After reviewing all cases, of the 118 patients meeting the LeRoy-Medsger 2001 criteria, only 88 patients had a definitive diagnosis of SSc according to the ACR 1980 criteria. Considering the ACR criteria, the prevalence rate was 25.4 cases per 100,000 (95% CI: 22.2-28.6), and the annual incidence rate over the study period was 3.2 per 100,000 (95% CI: 2.0-4.4). Considering the LeRoy and Medsger criteria epidemiological data were respectively 34.1 cases per 100,000 (95% CI: 30.4-37.8) and 4.3 cases per 100,000 (95% CI: 3.0-5.6). According to the LeRoy and Medsger criteria, the SSc subsets were broken down as follows: 20 limited-SSc (19.2%), 76 limited cutaneous-SSc (62.1%), 22 diffuse cutaneous-SSc (18.7%). The female/male ratio was 9.7:1. CONCLUSIONS: Incidence and prevalence of SSc observed in an area in north-eastern Italy were found to be higher than reported in the various geographical area (UK, US, Australia, etc.) but similar to another Italian study adopting, as here, the LeRoy-Medsger criteria. The different diagnostic criteria adopted may explain some of the differences found in comparison to the studies based only on the ACR criteria, however, regional discrepancies in disease occurrence cannot easily be dismissed only on the basis of methodological approaches to case definition or ascertainment; genetic, ethnic and environmental factors should also be considered. Currently the main challenge remains to determine the scientific basis for the observed differences, distinguishing between changes deriving from geographic/ethnic features and from the analytic methods.

Bronchoalveolar lavage in systemic sclerosis with lung involvement: role and correlations with functional, radiological and scintigraphic parameters.

To evaluate the role and the prognostic value of bronchoalveolar lavage (BAL) in scleroderma patients with interstitial lung disease. We reviewed the records of 79 patients with systemic sclerosis (SSc) who had dyspnea and pulmonary involvement and underwent BAL study. Sixty-two patients were prospectively followed up for 12-36 months and re-evaluated by pulmonary function tests (PFTs). Seventy-nine SSc patients were enrolled (71 F and 8 M), 55 with limited and 24 with a diffuse form; mean age 55 ± 13 years; mean disease duration 55.2 ± 59 months. All patients were ANA positive, of these 30 were anti-topoisomerase-1 positive (anti-Topo1) and 22 were anti-centromere positive (ACA). Thirty-one patients had alveolitis (39.2%) that was neutrophilic in 12 patients, eosinophilic in 3 and mixed (neutrophilic and eosinophilic) in 16 patients. Compared to patients without alveolitis, those with alveolitis had a significant reduction of carbon monoxide diffusing capacity (DLCO), forced vital capacity (FVC) and more elevated lung high-resolution computed tomography (HRCT) scores. Furthermore, alveolar clearance was significantly accelerated. No differences were found between patients with and without alveolitis regarding disease subsets (diffuse vs limited-SSc); a significant predominance of anti-Topo1 antibodies was found in the alveolitis group and of ACA antibodies in the non-alveolitis cohort. During the follow-up, (range: 12-36 months) 62 patients, 26 with and 36 without alveolitis were re-evaluated with PFTs. In the alveolitis group, 12 patients (46.1%) showed stable lung function parameters and 14 had worsened (53.8%). In this group, 20 patients (77%) received cyclophosphamide (CYC): 11 (55%) worsened (5 of them died of cardio-pulmonary complications) and 9 (45%) remained stable. Six patients could not be treated; of these 3 remained stable and 3 worsened. Among 36 patients with normal BAL, 11 (30.5%) showed stable lung function parameters, 13 improved (36.1%) and 12 worsened (33.3%); in this last group, 2 patients died of extra-pulmonary complications. Six patients, with progression of lung fibrosis, were treated with CYC: 3 of them improved and 3 remained stable. Our study revealed a trend toward a more severe course in the SSc patients with BAL alveolitis; probably the non-significant result is related to the low number of the examined subjects and to the selection criteria. However, BAL remains the only tool to exclude lung infections and, in our experience, a useful instrument to evaluate interstitial lung disease in SSc patients.

The tumour necrosis factor-related apoptosis-inducing ligand-osteoprotegerin system in limited systemic sclerosis: a new disease marker?

OBJECTIVE: To investigate the role of the TNF-related apoptosis-inducing ligand-osteoprotegerin (TRAIL-OPG) system in the pathogenesis of limited SSc (lSSc). METHODS: Circulating levels of TRAIL and of its soluble receptor OPG were measured by ELISA in serum samples obtained from 50 lSSc patients and 50 healthy controls. RESULTS: TRAIL serum levels in lSSc patients were similar to those of healthy controls, whereas the OPG serum levels were significantly increased (P < 0.0001). According to different subgroups of lSSc patients, TRAIL was not statistically different between each group and healthy controls; concerning OPG, the statistically different value was also maintained when comparing each single lSSc group with the whole control population. CONCLUSIONS: OPG serum levels, but not TRAIL, are elevated in lSSc patients. Since OPG binding to TRAIL inhibits TRAIL-TRAIL receptor interaction, the relative concentrations of these two molecules in the local micro-environment has to be considered. In this setting, OPG increase in lSSc patients may produce a detrimental effect by counteracting the vasoprotective activity of TRAIL. The TRAIL : OPG ratio and their relative levels of expression in lSSc patients should be taken into consideration as a possible novel marker of vascular damage.

Nicotine-patch therapy on mucocutaneous lesions of Behcet's disease: a case series.

OBJECTIVE: We report the use of nicotine-patch therapy on active mucocutaneous lesions of Behçet's disease (BD). METHODS: Five BD ex-smoker patients with refractory active mucocutaneous manifestations were treated with nicotine patches for 6 months. RESULTS: Four out of five patients quickly responded to nicotine-patch therapy and experienced a complete regression of mucocutaneous lesions. Other manifestations of BD did not respond and new manifestations appeared during this treatment. One patient had no benefit from therapy but on restarting smoking it was promptly effective. CONCLUSIONS: Mucocutaneous lesions associated with BD may be modulated by smoking. Both smoking and nicotine-replacement therapy may be efficacious not only on oral aphthae, but also on other mucocutaneous manifestations, whereas the efficacy in the treatment and prevention of other systemic manifestations of BD is not proven. At least in ex-smokers, nicotine in its pure form is well tolerated and its use could be justified in selected cases of BD with predominant and recurrent refractory mucocutaneous manifestations.

Dysfunctional inflammasome in Schnitzler's syndrome.

OBJECTIVE: IL-1beta plays a key role in the pathogenesis of Schnitzler's syndrome (SS). We have investigated inflammasome activity in peripheral blood mononuclear cells (PBMCs) from a patient affected by a variant type of SS. METHODS: PBMCs were purified by Ficoll and examined for ability to secrete IL-1beta and -18, expression and function of the P2X(7) receptor and expression of apoptosis-associated speck-like protein containing a caspase recruitment domaine (ASC) and NOD-like receptor protein 3 (NLRP3) before and after the therapy with steroid. Furthermore, extracellular adenosine 5'-triphosphate (ATP) blood levels were determined by luciferase assay. Expression of inflammasome components was measured by real time PCR and western blotting. RESULTS: PBMCs of patient with SS showed a high, spontaneous and lipopolysaccharide-stimulated, IL-1beta release but low response to stimulation with the P2X(7) agonist benzoyl ATP. P2X(7) expression was several fold increased, whereas ASC expression was dramatically decreased compared with PBMCs from healthy controls. NLRP3 expression was unchanged. Prednisone treatment induced remission of clinical symptoms and normalized IL-1beta secretion and P2X(7) and ASC expression. CONCLUSION: These findings reveal the presence of an overall derangement of the inflammasome and IL-1beta processing and release in SS.

Whipple disease: unusual presentation of a protean and sometimes confusing disease.

OBJECTIVES: To describe an unusual case of Whipple disease (WD) with confusing clinical features at onset and to discuss the diagnostic challenges for the clinician. METHODS: Description of a new case of this rare disease and thorough discussion of the atypical clinical manifestations at onset. A literature review, concerning the unusual onset, by means of a MEDLINE search from 1966 to 2007 was done. RESULTS: A 39-year-old man with sudden bilateral blurred vision due to retinal vasculitis and concomitant rapidly evolving symmetrical neurosensory bilateral hearing loss as initial features of WD is described. Due to the clinical manifestations resembling systemic vasculitis, high-dose corticosteroid and pulse cyclophosphamide therapy were started with subsequent appearance of gastrointestinal symptoms (diarrhea and weight loss) and spiking fever, suggesting superimposed infection. After a complete evaluation, including gastroscopy, extensive duodenal-jejunal mucosal involvement was seen, while diffuse infiltration of the duodenal lamina propria with periodic acid-Schiff-positive foamy macrophages was observed on the histological sample. The diagnosis was confirmed by reverse transcriptase-polymerase chain reaction for the DNA of Tropheryma whippelii. To our knowledge, no previous similar clinical onset of WD has been described. CONCLUSIONS: To avoid misdiagnosis and therapeutic mistakes, clinicians should be aware of unusual presentations of WD. Because this etiological agent is a difficult to isolate bacterium, diagnosis may be especially problematic in cases without intestinal involvement at onset.

Abnormalities of left ventricular function in asymptomatic patients with systemic sclerosis using Doppler measures of myocardial strain.

OBJECTIVE: To verify whether myocardial impairment can be detected by tissue Doppler imaging (TDI) in patients with asymptomatic systemic sclerosis (SSc), 35 patients with SSc with normal left ventricular (LV) ejection fraction and 35 control subjects were studied. METHODS: Myocardial longitudinal peak systolic velocity, strain, and strain rate (SR) were measured by TDI at a regional level, and for each parameter the average value was calculated using an LV 12-segment model. In addition, the mitral annulus diastolic velocities and the E/Ea ratio were obtained. Myocardial calibrated integrated backscatter (cIB) was used as an index of fibrosis. RESULTS: Compared with controls, patients with SSc showed lower peak strain (-19.5% +/- 2.3% vs -26.1% +/- 2.4%, P < .001), peak SR (-1.34 +/- 0.14 s(-1) vs -1.59 +/- 0.14 s(-1), P < .001), septal cIB (-19.5 +/- 3.1 dB vs -23.8 +/- 1.6 dB, P < .001), and posterior wall cIB (-23.4 +/- 2.9 dB vs -28.6 +/- 2.5 dB, P = .001), and higher E/Ea (11.7 +/- 2.5 vs 9.8 +/- 1.1, P < .001), whereas peak systolic velocities did not differ. Strain, SR, and E/Ea correlated better with cIB than systolic velocities. CONCLUSION: TDI-derived strain, SR, and E/Ea can detect impairment of LV myocardial function in asymptomatic patients with SSc with normal LV ejection fraction better than TDI systolic velocities.