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Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial joint swelling and tenderness, secondary to the immune-system dysfunction, often complicated by extra-articular manifestations. Among them, lung involvement is very frequent and interstitial lung disease (ILD) represents one of the deleterious complications of RA with impact on both therapeutic approach and overall prognosis. Nevertheless, diagnosis of ILD often remains missing or delayed. Objectives: To preliminarily evaluate the predictive value of pulmonary sound recorded by an electronic stethoscope (ES) and elaborated by an ad hoc software in identification of RA-ILD diagnosed by mean of high resolution computed tomography (HRCT) in a multicenter study. Methods: RA patients who underwent HRCT in the last 12 months were enrolled. They were all auscultated with the ES (Littmann 3200TM 3M, USA), bilaterally, at dorsal level, in at least 3 pulmonary fields (medium and basal). All tracks recorded were analyzed by a suitably developed software capable of recognizing pathological crackles in lung sounds. Results were compared with radiologic findings detected in a blind manner by an expert radiologist. Results: One hundred and six RA patients were enrolled (M/F: 1/2.5, mean age 68.7±10.3); among them 45 (42.5%) showed ILD at HRCT. Three patients were excluded because of a low quality of the sound recorded. The algorithm showed a sensitivity and specificity of 72.1% and 84.4%, respectively and a positive/negative predictive value of 69.1% and 86.3%, respectively. Conclusions: Despite preliminary, these data suggest an important role of ES in clinical practice for an early diagnosis of ILD in RA patients and a significant reduction of inappropriate prescription of HRCT. Since very different types of ILD can occur in course of RA, with different radiologic features and localization, proper development of the measurement setup (ES and ad hoc software for the detection of PC) could further increase its predictive value, in particular to avoid incorrect records and misdiagnosis. The routinely employment of ES and proper software, combined to clinical findings (cough, dyspnea) and respiratory lung function, could increase our ability to early identify ILD in RA patients.

Objectives. To investigate the possible association between demographic, serological and clinical features of rheumatoid arthritis (RA) and the lower respiratory tract (LRT) infections. We further analyzed the possible relationships between demographic, serological and clinical features and LRT infections in a sub-group of patients with RA-associated interstitial lung disease (ILD). Materials and Methods. Demographic, serological, clinical and therapeutic features of 563 RA patients were retrospectively analyzed (female/male ratio 3.43, mean age 64.8±13.6SD years, mean disease duration 11.5±9.4SD years). Results. During a mean follow-up of 138.9±131.3SD months, we observed 47 patients with at least one episode of LRT infection.The presence of RA-associated ILD, therapy with steroids, and b-DMARDs were significantly associated to LRT infections (p=0.016, p=0.000, and p=0.01 for ILD, steroids and b-DMARDs, respectively). All variables remained independently associated to infections of LRT also at logistic regression analysis; while no differences were observed with regard to the kind of the b-DMARDs, namely anti-tumor necrosis factors alpha inhibitors, rituximab, abatacept, tocilizumab. Moreover, the presence of ILD was associated to more severe LRT infectious complications, requiring hospitalization in 55.6% of patients, compared to 27.8% of patients without ILD (p=0.042). Since patients with ILD showed a risk to develop an infection of LRT 4.5 times higher of patients without ILD, we further analyzed this peculiar sub-group of patients. Among 33/563 (5.9%) patients with ILD (female/male ratio 2/1, mean age 71.8±10.6 years, mean disease duration 16.1±13.0 years), only b-DMARDs were associated to infections of LRT (p=0.002). Of interest, a combination therapy with b-DMARDs, methotrexate, and corticosteroids was significantly more frequently recorded in RA-ILD patients compared to those without LRT infections (81.8% vs 13.6% of patients; p=0.001). Conclusions. ILD is an important extra-articular complication of RA, involving about 5-10% of patients, and its current therapeutic approach is still under debate, because the lack of evidences that immunosuppressants are effective both on joint and lung involvement. Idiopathic pulmonary fibrosis (IPF) is usually compared to RA-ILD for their similarity in radiological and histological features. In IPF patients, the PANTHER-IPF study showed an excess mortality due to pulmonary infection in azathioprine and prednisone treatment arm, and corticosteroids increase the risk of serious infection fourfold. Our data confirm, with the limit of a low number of patients analyzed, that immunosuppressive treatment increase the risk of LRT infections particularly in RA-ILD patients, suggesting a more careful surveillance in this sub-group of patients. In conclusion, in patients with RA-ILD, it is necessary to balance the control of joint inflammation with the risk of drug-related LRT infections; this latter could be significantly reduced by tailoring both drug combination and doses (corticosteroids, traditional, and b-DMARDs) on individual patients.

Background: Interstitial lung disease (ILD) includes a group of disorders of the pulmonary parenchyma including ILD secondary to environmental exposure, to sarcoidosis and connective tissue diseases, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonitis. Unclassifiable-ILD (U-ILD) is defined when ILD cannot be included in one of these subtypes, because of inadequate findings or impossibility to complete diagnostic iter. Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune diseases characterized by clinical and serological features typical of other CTD, but not fulfilling any of the existing classification criteria. It has been recently suggested that UCTD should be responsible for ILD, although the available classification criteria do not consider lung manifestations. Differential diagnosis between U-ILD or ILD secondary to UCTD (UCTD-ILD) can be difficult, but fundamental for therapeutic implications. Objectives: To evaluate the clinical and serological features of patients with ILD secondary to UCTD compared to unclassifiable ILD, to improve differential diagnosis and identify patients candidate to immuno-suppressive therapy. Secondary outcome was to construct a clinical algorithm, using a priori variables, helpful to predict ILD-UCTD in clinical practice. Methods: From September 2011 to November 2014, 50 patients referred to our Center were diagnosed for UCTD (26/50) or U-ILD (24/50), after a multidisciplinary discussion according to standard available criteria. Results: Main features and comparison between UCTD-ILD and U-ILD are reported in the table. An inconsistent with usual interstitial pneumonia (UIP) pattern at high resolution computerized tomography (HRCT) was more frequently detected in UCTD-ILD compared to U-ILD. A predictive model based on Raynaud's phenomenon, ocular dryness, and antinuclear antibodies showed a predictive value of 85.7% (UCTD-ILD were correctly classified in 90.5% and U-ILD in 78.6%). Clinical and demographic features of patients with interstitial lung disease UCTD U-ILD p Number of patients 26 24 Sex 19F/7M 14F/10M ns Age at diagnosis 61.7±12.7 67.1±9.1 ns Raynaud's phenomenon 68.0% 29.4% 0.027 Oral dryness 60.0% 35.3% ns Ocular dryness 60.0% 13.3% 0.007 Schirmer test 41.6% 4.2% 0.006 Arthritis 19.2% 0 0.05 Skin manifestations 30.4% 0 0.029 Thrombocytopenia 16.7% 18.2% ns Anemia 33.3% 18.2% ns Antinuclear antibodies 87% 52.4% 0.02 ENA 38.1% 10% ns Rheumatoid factor 13.6% 9.1% ns UIP pattern to HRCT 41.2% 58.8% ns Inconsitent with UIP pattern to HRCT 66.7% 33.3% ns Conclusions: Lung involvement is a possible presenting symptom of UCTD; therefore, differential diagnosis with U-ILD is crucial due to the relevant therapeutic implications; a multidisciplinary approach, including rheumatologist, pulmonologist, radiologist, and pathologist, is mandatory. Some clinical-serological features potentially helpful in differential diagnosis should be carefully evaluated

Background Impaired diffusing capacity of the lung for carbon monoxide (DLCO) was frequently observed in systemic sclerosis (SSc) patients, generally related to the presence of interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). However, in clinical practice abnormally low DLCO values may be found also in the absence of these SSc complications. Objectives To investigate the prospective clinical relevance of isolated DLCO reduction at baseline in SSc patients. Methods Ninety-seven SSc female patients (age at the diagnosis: 51.3±14.5 years; disease duration: 10.4±6.6 years; limited/diffuse skin subsets: 92/5), without any clinical, radiological (high resolution computed tomography), and echocardiographic manifestations of ILD or PAH at baseline, nor other lung or heart diseases able to affect DLCO, were recruited at our Rheumatology Centre. Patients with DLCO

An increasing body of evidence shows the importance of the chemokine (C-X-C motif) receptor (CXCR)3 and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10 and CXCL11 in the T helper 1 immune response, and in inflammatory diseases such as bowel inflammatory disorders, allograft rejection, thyroid autoimmune disorders, vascular and renal inflammation, and others. Peroxisome proliferator-activated receptor (PPAR)-γ agonists show a strong inhibitory effect on the expression and production of CXCR3 chemokines in vitro, in various kinds of cells, such as denditric cells, monocytes, macrophages, endothelial and vascular smooth muscle cells, intestinal cells, thyrocytes, fibroblasts, preadypocytes and mesangial cells, and in vivo in animal models. As rosiglitazone has recently been linked to a higher risk of heart failure, stroke, and all-cause mortality in old patients, it has been interrupted from the European market. On the contrary, the safety profile of pioglitazone seems favorable. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of the above mentioned inflammatory disorders, and many interesting patents have been recently applied.

RHEUMATOID ARTHRITIS RELATED INTERSTITIAL LUNG DISEASE. RADIOLOGICAL PATTERNS AND CORRELATIONS WITH CLINICAL, SEROLOGICAL AND DEMOGRAPHIC FEATURES OF DISEASE

Systemic sclerosis (SSc) is often complicated by severe skin ulcers that are unresponsive to traditional treatments. Vascular alterations are responsible for the ischaemic features of the disease in both the skin and visceral organs. Defective neoangiogenesis correlates with an abnormally reduced quantity of circulating endothelial progenitor cells (EPCs) caused by impaired maturation potential and proliferative capacity of bonemarrow endothelial stem cells. We report a patient with nonhealing cutaneous ulcers successfully treated with recombinant human erythropoietin (rHuEPO). The possible biological effects of this drug were also investigated. Before rHuEPO treatment, the bone-marrow sample contained reduced numbers of EPCs, which were functionally impaired. After a 6-month rHuEPO cycle, a marked increase in endothelial progenitor markers was seen, along with a significant reduction in their apoptotic rates. The clinical and laboratory data variations before and after rHuEPO treatment give new insights into the pathogenetic role of impaired endothelial stem-cell maturation and defective neoangiogenesis in patients with SSc.

To measure serum levels of CXCL10 and CCL2 chemokines in patients with SSc, and relate the findings to clinical phenotype and disease progression.Serum CXCL10 and CCL2 were assayed in 72 consecutive newly diagnosed SSc patients and in 72 sex- and age-matched controls. In 37 SSc and 37 controls, serum CXCL10 and CCL2 were re-evaluated 5 yrs later.SSc at onset showed significantly higher CXCL10 serum levels than controls (216 +/- 126 vs 92 +/- 53 pg/ml; P0.0001), as well as CCL2 (388 +/- 172 vs 318 +/- 120 pg/ml; P = 0.01). CXCL10 was significantly increased in SSc with interstitial lung involvement or with kidney involvement (P = 0.01 and P = 0.02, respectively). A significant decrease of CXCL10 was observed from the baseline after 5 yrs in SSc (137 +/- 112 vs 270 +/- 122 pg/ml, respectively; P0.0001), while no significant change was observed for CCL2 (418 +/- 176 vs 405 +/- 164 pg/ml; P = NS); the CCL2/CXCL10 ratio significantly increased at the fifth year (1.7 +/- 0.8 vs 3.5 +/- 2.5; P0.0001). No significant variations were observed in controls from the basal to the 5-yr evaluation with regards to CXCL10, CCL2 or CCL2/CXCL10 ratio.Our study demonstrates high serum levels of CXCL10 (Th1) and CCL2 (Th2) chemokines in newly diagnosed SSc. High values of CXCL10 are associated with a more severe clinical phenotype (lung and kidney involvement). CXCL10 declined during the follow-up, while CCL2 remained unmodified, suggesting that the disease progresses from the early Th1 inflammatory condition to the advanced Th2-like stage.

Interstitial lung disease (ILD) is a relevant extra-articular manifestation of rheumatoid arthritis (RA) and usual interstitial pneumonia (UIP) is considered the most frequent histo-pathological pattern of RA-ILD; high-resolution computed tomography (HRCT) is crucial for the evaluation of ILD patterns without recourse to lung biopsy. In 2011, the ATS/ERS/JRS/ALAT statement for diagnosis and management of idiopathic pulmonary fibrosis (IPF) provided consensus guidelines to identify a definite, possible or inconsistent with UIP pattern on HRCT, based on radiological features; previous studies suggest that the above classification should also be appropriate for RA-ILD. We retrospectively identified 97 unselected RA patients, classified according to 2010 ACR/EULAR classification criteria, referred to our Rheumatology Unit from October 2004 to March 2013, with at least one chest HRCT, regardless of its indication. Demographic, clinical, serological data, and drugs administered before HRCT were collected for all patients (table 1). RA-ILD diagnosis was conventionally identified with HRCT. A thoracic radiologist experienced in interstitial lung disease scored all HRCT images, classifying them as definite, possible or inconsistent with UIP. Among 97 RA patients, 32 showed RA-ILD (15 with definite or possible UIP pattern and 17 with an inconsistent with UIP pattern), while the 65 patients without ILD were used as control group. With the exception of dyspnea, no differences were observed comparing patients with or without ILD. According to radiological classification, we also compared patients with a definite or possible UIP pattern (UIP group), patients with a pattern inconsistent with UIP (non UIP group), and controls. No differences were observed comparing anti-CCP, rheumatoid factor, and ANA positivity, while ENA were more frequent in the UIP group, compared to the controls (p=0.039). Anti-Jo1 and anti-SSA were the prevalent specificities of ENA, without differences between the groups (only 1 patient fullfilled also criteria for Sjogren’s syndrome). All patients with UIP pattern had more than 63 years at the time of HRCT, and they were more frequently males and smokers (table 1). The occurrence of UIP pattern increased according to the number of significantly associated features (namely, male gender, smoking habit, presence of ENA, and age higher than 63 years). In fact, patients with UIP pattern showed the co-presence of 3 or 4 factors in 61% of cases, compared with no cases in non UIP group and 13.6% in control group (p