Margherita Giannini

Clinical Spectrum Time Course in Anti Jo-1 Positive Antisynthetase Syndrome: Results From an International Retrospective Multicenter Study.

AbstractAnti Jo-1 antibodies are the main markers of the antisynthetase syndrome (ASSD), an autoimmune disease clinically characterized by the occurrence of arthritis, myositis, and interstitial lung disease (ILD). These manifestations usually co-occur (for practical purpose complete forms) in the same patient, but cases with only 1 or 2 of these findings (for practical purpose incomplete forms) have been described. In incomplete forms, the ex novo occurrence of further manifestations is possible, although with frequencies and timing not still defined. The aim of this international, multicenter, retrospective study was to characterize the clinical time course of anti Jo-1 positive ASSD in a large cohort of patients. Included patients should be anti Jo-1 positive and with at least 1 feature between arthritis, myositis, and ILD. We evaluated the differences between complete and incomplete forms, timing of clinical picture appearance and analyzed factors predicting the appearance of further manifestations in incomplete ASSD. Finally, we collected 225 patients (58 males and 167 females) with a median follow-up of 80 months. At the onset, complete ASSD were 44 and incomplete 181. Patients with incomplete ASSD had frequently only 1 of the classic triad findings (110 cases), in particular, isolated arthritis in 54 cases, isolated myositis in 28 cases, and isolated ILD in 28 cases. At the end of follow-up, complete ASSD were 113, incomplete 112. Only 5 patients had an isolated arthritis, only 5 an isolated myositis, and 15 an isolated ILD. During the follow-up, 108 patients with incomplete forms developed further manifestations. Single main feature onset was the main risk factor for the ex novo appearance of further manifestation. ILD was the prevalent ex novo manifestation (74 cases). In conclusion, ASSD is a condition that should be carefully considered in all patients presenting with arthritis, myositis, and ILD, even when isolated. The ex novo appearance of further manifestations in patients with incomplete forms is common, thus indicating the need for an adequate clinical and instrumental follow-up. Furthermore, the study clearly suggested that in ASSD multidisciplinary approach involving Rheumatology, Neurology, Pneumology, and Internal Medicine specialists is mandatory.

Clinical follow-up predictors of disease pattern change in anti-Jo1 positive anti-synthetase syndrome: Results from a multicenter, international and retrospective study

OBJECTIVE Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying features, such as Raynauds phenomenon, fever or mechanics hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients. METHODS Anti-Jo1 positive patients presenting with incomplete ASSD (no >2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients. RESULTS 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15months median (IQR 9-51) and 40 (24%) developed new accompanying features after 19months median (IQR 6-56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings (p=0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68-9.21, p=0.002). CONCLUSION Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk for new classic triad manifestation occurrence with respect to patients not presenting ex novo accompanying findings.

Heterogeneous clinical spectrum of interstitial lung disease in patients with anti-EJ anti-synthetase syndrome: a case series

Auto-antibodies against aminoacyl-tRNA-synthetases (anti-ARS Abs) represent the hallmark of the anti-synthetase syndrome that is defined as the clinical association of fever, Raynaud’s phenomenon, myositis, interstitial lung disease (ILD), arthritis and mechanic’s hands. Recently, differences in clinical features depending on specific anti-ARS Abs have been reported. We describe three cases of anti-EJ (anti-glycyl) antibody-positive patients presenting with ILD as a common feature, but with heterogeneous histopathological and radiographic patterns and with different responses to treatment. Relapsing-remittent fever, refractory muscle involvement and seronegative arthritis were also striking clinical manifestations.

A New Immunodot Assay for Multiplex Detection of Autoantibodies in a Cohort of Italian Patients With Idiopathic Inflammatory Myopathies

Autoantibody detection has been assessed as tool for the diagnosis and the definition of idiopathic inflammatory myopathies (IIM). The aim of the study was to characterize the autoantibody profiling of a cohort of Italian patients with IIM.

A rare association of anti-alanine-transfer RNA synthetase (anti-PL12) syndrome and sporadic inclusion body myositis

Unit of Rheumatology (DETO), Policlinico Hospital, University of Bari, Bari, Italy Department of Basic Medicine, Neuroscience and Sense Organs, Unit of Neurodegenerative Diseases, Policlinico Hospital, University of Bari, Bari, Italy Department of Basic Medicine, Neuroscience and Sense Organs, Unit of Neurophysiopathology, Policlinico Hospital, University of Bari, Bari, Italy Institute of General Surgery ‘G Marinaccio’ (DETO), Policlinico Hospital, University of Bari, Bari, Italy

AB0191 Anti-ssa and anti-jo1 levels in interstitial lung disease related to idiopathic inflammatory myopathies

Background The lung is the most frequently involved extramuscular organ in idiopathic inflammatory myopathies (IIMs); the most common form of lung involvement is interstitial lung disease (ILD). Some autoantibodies are strongly associated with ILD and with specific phenotypes and prognosis of ILD. Among myositis-specific auto-antibodies (MSAs), antibodies against aminoacyl-tRNA-synthetases (AsAb) are the strongest predictive factors for ILD, and anti-Jo-1 is the most common AsAb. Among myositis-associated auto-antibodies (MAAs), anti-SSA/Ro52 is frequently found in sera of patients with IIM and ILD, often associated with anti-Jo-1. The coexistence of anti-SSA/Ro52 and anti Jo-1 seems to be related to a more severe and extensive pulmonary fibrosis with higher score in HRCT compared with the patients with only anti-Jo-1 antibodies. Furthermore, some reports suggest that presence of anti-Jo-1 could be a biomarker for good prognosis1. The significance of antibodies levels for the prognosis of ILD in IIMs was not widely investigated. Objectives To investigate the relationship between antibody levels and clinical manifestations, laboratory data, pulmonary function tests (PFTs), disease activity indices in ILD associated to IIMs. Methods Among 130 IIMs admitted to Rheumatology Unit of Bari from January 2010 to January 2018, we retrospectively examined 49 patients (40 F; 22 PM, 25 DM, 1 IBM; mean age at ILD onset 51 years, range: 23–83) because of ILD defined by high resolution computed tomography (HRCT). Clinical manifestations, laboratory data, HRCT pattern, PFTs (FVC, FEV1 and DLCO), therapy, disease activity as Manual Muscle Test (MMT-12), Health Assessment Questionnaire (HAQ), Physician Global Assessment (PGA) at ILD onset, were obtained from medical records. Ferritin levels and autoantibodies were detected in serum samples collected at ILD onset. ANA were tested by IIF on HEp-2 cell substrates, MSAs (JO1, EJO, OJ, PL7, PL12, SRP, HMGCR, Mi2, TIF1γ, MDA5, NXP2, SAE) and MAAs (Ro52, Ku, PM/Scl 75–100, RNP, Scl70) by line-blot method. Anti-SSA and anti-Jo1 were also detected by CLIA method. Correlation analysis were run using parametric and non-parametric test according to data distribution. Results 45 of 49 (91,8%) patients were positive for MSAs and/or MAAs. 40 of 45 (88%) were positive at least one of MSAs. The double presence of MSAs and anti-Ro52 was observed in 21 of 40 (52,5%), showing anti-Jo1/SSA in most cases (15/21, 71,4%). Among all correlations studied between anti-Jo1 or anti-SSA levels and PGA or PFTs, we found a significantly correlation between anti-Jo1 and PGA (p=0,03, R=0,46). We didn’t find significantly correlation between autoantibodies and ferritin serum levels. Conclusions These findigs confirm that ILD was associated with autoantibodies positivity. Further studies in larger cohort need to investigate if autoantibodies levels have a prognostic role in global outcome. Unlikely some controversial works in literature, serum ferritin does not seem a biomarker of severity of lung involvement in IIMs. Reference [1] Labirua A, et al. Interstitial lung disease and idiopathic inflammatory myopathies: progress and pitfalls. Curr Opin Rheumatol2010. Disclosure of Interest None declared

AB0250 The adipose tissue as predictive factor of disease activity in rheumatoid arthritis patients: evaluation of body fat composition by bioelectrical impedance analysis and ultrasonography

Background Adipose tissue (AT) is an endocrine organ able to secrete the “adipokine” molecules that contribute to the low-grade inflammatory state in obese subjects and to the local inflammation that affects joints and bone (1,2). High-grade inflammation, in course of RA, leads to an altered body composition (3,4), characterized by the increasing of fat mass and the decreasing of lean mass, mostly not associated to body mass index (BMI) variations (3,5). The BMI is not able to differentiate visceral (VTH) and subcutaneous (STH) fat tissue and to distinguish between muscle mass and fat mass body composition (BC) (6,7). Alternative methods proposed for assessment of visceral fat deposition, are bioelectrical impedance analysis (BIA) and ultrasonography (US). Objectives The aim of the study is to investigate if BC, assessed by BIA and US, correlates with disease activity (assessed by the Disease Activity Score using 28 joint counts – DAS28) and affects the response to the therapy (DAS 28 variation from first evaluation). Methods 87 consecutive RA patients (pts) (72 women and 15 men; aged 52.4±13.2 years; disease duration of 10.7±8.6 years), treated with DMARDs and/or biologics (bDMARDs), were recruited during their regular visit. The inclusion criteria were the 1987 American College of Rheumatology (ACR) or ACR/EULAR 2010 classification criteria. The pts underwent to anthropometric measures (BMI); abdominal US to assess STH and VTH and derived computing of peritoneal circumference (PC); and BIA to the indices of body composition (fat-free mass index (FFMI) and fat mass index (FMI). Results We observed increasing values of BMI, FMI, VTH (fig. 1) and CP with the worsening of disease activity phases, evaluated by DAS 28. In particular, pts with DAS28≥5.1 had highest BMI (30,9±2; p=0,036), FMI (11,5±1,6; p=0,05), CP (92,7±12,5 cm; p=0,035) and VTH (24,8±5,8 mm; p=0,046) than pts in less severe disease activity. By linear regression analysis the predictor of higher DAS28 is the BMI (p=0,028). As regard the drug response, the predictors of DAS 28 improvement are higher FFMI (p=0,044) and lower BMI (p=0,015), independently by bDMARDs or DMARDs treatment. A trend to higher FMI and US AT measures was observed in female with high disease activity, in particular in menopause pts. Conclusions An altered fat distribution is observed in active RA phases; in particular, the FMI increasing is attributable just to visceral AT (VTH and CP). An inflammatory hyperactivity of visceral adiposity could be supposed in RA. The body composition, in addition to BMI, seems to predict the disease activity and drug response in RA patients. The evaluation of VTH by US could be useful to not overestimate the disease activity; instead the BIA could be a useful tool to support the clinicians in a more aggressive treatment management. References Nat Clin Pract Rheumatol 2007; 3(12):716–24. J Mol Endocrinol 2009; 43(1):11–8. Mediators Inflamm 2013; 2013:710928. Arthritis Care Res (Hoboken) 2012; 64(10):1471–9. Nat Rev Rheumatol 2010; 6(8):445–51. Curr Opin Clin Nutr Metab Care 2003; 6(4):387–93. Ann Rheum Dis 2007; 66(10):1316–21. Disclosure of Interest None declared

SAT0217 Axon Reflex Vasodilatation of Digital Arteries in Systemic Sclerosis Patients, Evaluated by Laser-Doppler Fluxmetry

Background Systemic sclerosis (SSc) is a connective disease characterized by severe microvessels vasculopathy. The important role of endothelial dysfunction in SSc pathogenesis is widely demonstrated, but the SSc related autonomic nervous system impairment is controversial and rarely described. The dysregulation of axon reflex vasodilatation of fingertip microvessels in SSc has been reported in some studies, but the functional involvement of digital arteries in SSc patients had never been investigated. Objectives We aimed at evaluating the blood flux changes mediated by axon reflex response upon heating stimulus in SSc patients. Methods 87 SSc patients (SSc pt) and 22 healthy controls (HC) were recruited in this study. The SSc patients were aged 52,7±16,2 yrs, with disease duration of 8,23±7,8 yrs. The LD Flowmetry (Periflux System 5000, Perimed) with 4 LD heating probes was used to measure the skin blood flux of the middle phalanx of the 2nd, 3rd, 4th and 5th fingers of the left hand. The skin fingers flux was recorded at pre-heating period with probes temperature fixed at 34 °C (PHF) and after 5 min heating at 44 °C (IHF). Therefore, the heating test assesses the variation of digital artery flux in response to local heating stress at 44 °C. The ratio IHF/PHF evaluates the axon reflex mediated vasodilatation (ARMV). The results are expressed as average across 4 fingers at each time. The flux was expressed in perfusion unit (PU) and HC and SSc patients responses were compared by the t-student test. Statistic significance was set at p≤0,05. The data analysis was performed using IBM SPSS statistic 20. Results The ARMV was significantly reduced in SSc patients (2,2±1,4) in comparison with HC (4,8±2,7, p=0,0001). IHF was lower in SSc patients (118,6±54,3) than HC (168±78, p=0,001). Dividing the SSc pts group by the presence of pitting scars (PS), digital ulcers (DU) and digital necrosis (DN), we observed a lower IHF in SSc pts with PS (103,2±48,6) than in SSc pts without (138,1±56, p=0,003), and in SSc pts with DU (97,8±47,6) than in SSc pts without (160,27±120,1, p=0,002). Moreover, SSc pts with ND showed a lower ARMV (1,8±1) than SSc pts without (2,6±1,5, p=0,006), and a lower IHF (98,3±49,1 vs 133,2±54,5, p=0,004). The age, sex, concomitant therapy with Ca-antagonist or Bosentan or cardioaspirin did not influence the digital artery flux. Conclusions This study provided evidence that a functional impairment of DA occurs in SSc, and it worsens with increasing severity of vascular clinical manifestations. Disclosure of Interest None declared

SAT0216 Chest Ultrasound Signs of Interstitial Lung Disease in Systemic Sclerosis Patients: A Comparison between High Resolution Chest Computed Tomography Findings

Background Interstitial lung disease (ILD) is a typical clinical manifestation in Systemic Sclerosis (SSc). The high resolution chest computed tomography (HRCT) is the gold standard to evaluate and grade ILD. The presence of fibrotic tissue in the lung, or other structures beside the air, allows obtaining specific sonography images (such as ultrasound lung comet, higher pleural line thickness, irregular pleural margins and subpleural cysts) by chest ultrasound. In previous studies it was demonstrated that the ultrasound comets number increases in SSc patients. Objectives We aimed at correlating the specific lung sonography signs with ground glass and honeycombing pattern detected by chest HRCT. Methods A total of 60 SSc outpatients (54 female, mean age 56,2 ± 13,8 ys and disease duration of 9,57±8,7 ys), who fulfilled ACR/EULAR 2013 SSc classification criteria, were recruited. All patients underwent chest HRCT and US examination. The US examination was performed with 7,5 Mhz probe and conducted with patients in sitting position from paraspinal line to anterior axillary line, for each intercostals space. The presence of typical ultrasound signs as lung comets (pathological if >35), higher pleural line thickness (pathological if >2mm), irregular pleural margins, subpleural cysts and pleural effusion was detected. The sensitivity, specificity and accuracy of US patterns (compared to chest HRTC) were evaluated by ROC analysis. Statistic significance was set at p<0.05. All results are expressed as mean ± 1 standard deviation. Results 23 patients had the CT honeycombing pattern, of which 92% had the US irregular pleural margins, 70% had US higher pleural line thickness and sub-pleural cysts, just 54% had US lung comets. 16 patients had the CT ground glass pattern, of these in 94% the US irregular pleural margins, in 87% US lung comets, in 60% US higher pleural line thickness were found. As regard the CT ground glass pattern the US sign with the highest specificity (91%), sensibility (85,7%) and accuracy (88%) was the lung comets; while regarding the CT honeycombing pattern the US sign with the highest specificity (92%), sensibility (69,6%) and accuracy (82%). Conclusions The lung US is a good diagnostic technique for its repeatability, low cost and risklessness. Although HRCT remains the best imaging technique to assess the ILD, in SSC the lung US could be a useful tool to detect the presence or the evolution of ILD and to improve the timing of HRTC without exposing the patients to high radiation doses over time. Disclosure of Interest None declared

Recovery of barium swallow radiographic abnormalities in a patient with dermatomyositis and severe dysphagia after high-dose intravenous immunoglobulins.

FIGURE. Barium swallow radiographs. A, At baseline, barium retention in the valleculas and piriform sinus (left panel) and esophageal dyskinesia (right panel) were detected. B, After IVIg therapy, hypopharynx emptying (left panel) and esophageal A 53-year-old white woman complained of asthenia, muscle weakness, and dysphagia, related to initiation of swallowing without symptoms of esophageal reflux. She had Raynaud phenomenon heliotrope rash and Gottron papules with reduction of muscle strength assessed by manual muscle test. Serum creatine kinase levels were increased (1236 U/mL), PM-Scl antibody was present, and electromyography showed typical myositis changes. Muscle biopsy showed hypotrophic irregular myofibers and endomysial foci of inflammatory cells. Dermatomyositis was diagnosed according to Bohan and Peter’s criteria. The patient gave written informed consent. Therapy with prednisone 1 mg/kg per day rapidly ameliorated the manual muscle test, and creatine kinase levels dropped to normal (57 U/mL). Nevertheless, dysphagiaworsened, and initiating swallowing either solids or liquids was difficult. There were no reflux symptoms. The Eating Assessment Tool (EAT-10) score, a self-administered measure of dysphagia, was very high (score, 26; reference value, ≤3). Barium swallow radiograph of hypopharynx and esophagus showed barium retention in the valleculas and piriform sinus due to poor hypopharynx emptying and esophageal dyskinesia (A). The patient undertook therapy with high-dose intravenous immunoglobulins (IVIg 2 mg/kg in 1 day) every 30 days for 3 months, whereas prednisone was withdrawn within 2 months. A quick improvement of dysphagia occurred, and after 3 months, EAT-10 test was normal (score, 0), and the barium swallow radiograph showed normal hypopharynx emptying and esophageal motility with no barium retention (B). Esophageal dyskinesia raised the question whether an overlap with scleroderma was present. The latter was not contemplated as typical scleroderma manifestations, such as skin thickness, organ involvement, and capillaroscopic changes, were lacking. Notwithstanding, development of subsequent scleroderma cannot be ruled out. High-dose IVIg has been proven effective in some cases of glucocorticoid-resistant upper dysphagia in dermatomyositis, and the assessment of clinical outcomes is based on symptoms or esophageal manometry. In this case, barium swallow radiograph pictures provided an impressive direct perception of the recovery of hypopharynx function following IVIg treatment.