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Background While low-dose oral glucocorticoids (GCs) are recommended in the management of early arthritis, their impact on mortality is unclear. The aim of this study is to evaluate the effect of GCs on mortality in patients with early arthritis, by linking clinical and administrative databases. Methods The study included patients with new-onset rheumatoid arthritis (RA) or undifferentiated arthritis (2005–2010), who received DMARDs (MTX in RA or UA with poor prognosis, hydroxychloroquine in UA) and were alive at the second year of follow-up. Low-dose GCs could be prescribed. Clinical and administrative data were linked from Administrative Health Databases (AHD) of the corresponding province, which provided us with information on drug delivery, comorbidities, hospitalization, and mortality. The effect of GCs in the first year was defined using a dichotomous variable or a 3-level categorization (not delivered, ≤7.5 mg/day, or >7.5 mg/day of prednisone) on all-cause mortality, assessed with Cox regression, either crude or adjusted for age, gender, Charlson Comorbidity Index (CCI) or single comorbidities, ACPA, HAQ, and MTX in the first year. A secondary analysis of the effect of GCs on related hospitalizations (for cardiovascular events, diabetes, serious infections, osteoporotic fractures) was also carried. Results Four hundred forty-nine patients were enrolled (mean age 58.59, RA 65.03%) of which 51 (11.36%) died during the study. The median (IQR) follow-up was equal to 103.91 (88.03–126.71) months. Treatments with GCs were formally prescribed to 198 patients (44.10%) at ≤7.5 mg/day, although by the end of the study such treatments were received by 257 patients (57.24%); 88 patients (19.6%) were treated with GCs at >7.5 mg/day. In adjusted analyses, the GC delivery (HR, 95% CI 1.35 (0.74, 2.47)) did not significantly predict mortality — both at a low (HR, 95% CI 1.41 (0.73, 2.71)) and at a high (HR, 95% CI 1.23 (0.52, 2.92)) dosage. When “all-cause hospitalization” was used as an outcome, the analysis did not show a difference between patients receiving GC and patients not receiving GC. Conclusion In patients with early inflammatory arthritis, the initial GC dose was higher than that prescribed by rheumatologists; however, on background treatment with DMARDs, GC treatments did not seem to increase mortality and hospitalizations.

It has been suggested that anti-neutrophil cytoplasmic antibody (ANCA) specificity, rather than clinical diagnosis influences the phenotype and course of ANCA-associated vasculitis (AAV). However, preliminary evidence suggests that further combined levels of categorisation might be of clinical relevance. The aim of this study was to investigate differences in clinical presentation at disease onset and outcomes based on clinical diagnosis and ANCA specificity.Newly diagnosed patients with GPA or MPA assessed in three referral centres between 2000 and 2016 were included. Patients were grouped as MPO-ANCA-positive granulomatosis with polyangiitis (MPO-GPA), PR3-ANCA-positive-GPA (PR3-GPA), and MPO-ANCA-positive microscopic polyangiitis (MPO-MPA).Of the 143 AAV patients included (female 52%), 87 were categorised as PR3-GPA, 23 as MPO-GPA, and 33 as MPO-MPA. Patients with MPO-GPA were significantly younger than MPA patients (age 49±15 versus 63±10; p0.001). MPO-GPA had significantly more frequent subglottic stenosis compared to PR3-GPA. Ear, nose, throat involvement was significantly more frequent in both GPA groups compared to MPA. Type of pulmonary involvement differed between both GPA groups and MPA with diffuse pulmonary haemorrhage being significantly more frequent in the latter (7% in PR3-GPA, 0% in MPO-GPA, 27% in MPOMPA; p0.001). Renal involvement was more frequent in MPO-MPA compared to both MPO-GPA and PR3-GPA (impaired renal function in 84%, 39%, and 36%, respectively; p0.001). PR3-GPA relapsed significantly more than the other two groups. After adjusting for age, MPO-GPA was a significant risk factor for mortality [HR 4.44 (95%CI 1.46-13.52), p=0.009].ANCA specificity identifies specific subsets of disease characterised by different clinical presentation and outcome within the clinical diagnosis of GPA.

Neonatal lupus (NL) is an acquired disease caused by the transplacental passage of anti-SSA/Ro antibodies. The rate of congenital heart block (CHB), its most serious manifestation, ranges from 1 to 5%. The aim of this study was to retrospectively assess the prevalence of CHB in anti-SSA/Ro positive pregnant women with or without systemic autoimmune diseases from 2010 to 2020.Patients underwent monthly visit and a shared follow-up programme of weekly (16th-24th week) foetal heart rate assessment by obstetric ultrasound.322 pregnancies in 258 anti-SSA/Ro patients were included; 314 were followed from the beginning of pregnancy because of the known presence of anti-SSA/Ro autoantibodies and 1 case of CHB occurred in an anti-SSA/Ro+ asymptomatic subject (0.3%). In the same period, 8 additional patients were referred to our clinics after in utero CHB diagnosis and subsequent discovery of anti-SSA/Ro without a disease diagnosis. Globally, 9 cases of congenital CHB (2.8%) occurred: 7 complete, 1 II-III degree and 1 rst degree CHB. Anti-SSB/La positivity was associated with a higher risk of CHB (7.8% vs. 1.2%; p=0.0071). No differences in maternal or foetal outcomes were found in comparison with a large cohort of unselected pregnancies except for caesarian section. Hydroxychloroquine (HCQ) was used in 58.3% pregnancies, with a different prevalence according with maternal diagnosis.Our data suggest that anti-SSA/Ro positive patents with a de ned systemic autoimmune disease undergoing a strict follow-up since positive pregnancy test display a low risk of pregnancy complications, including but not limited to NL.

Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss syndrome) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterised by respiratory manifestations and systemic organ involvement [1]. Particularly, cardiac manifestations occur in 40–60% of patients, representing the leading cause of mortality [2]. Recent reports suggest that venous thromboembolic events might also represent a consistent burden of disease [3, 4], as already known for the other AAVs [5–7], possibly due to eosinophil-mediated vascular inflammation [5]. Nevertheless, the occurrence of arterial and venous thrombotic events (AVTE) has never been systematically explored in EGPA. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Alessandra Bettiol Conflict of interest: Renato Alberto Sinico Conflict of interest: Franco Schiavon Conflict of interest: Sara Monti Conflict of interest: Enrica Paola Bozzolo Conflict of interest: Franco Franceschini Conflict of interest: Marcello Govoni Conflict of interest: Claudio Lunardi Conflict of interest: Giuseppe Guida Conflict of interest: Giuseppe Lopalco Conflict of interest: Giuseppe Paolazzi Conflict of interest: Angelo Vacca Conflict of interest: Gina Gregorini Conflict of interest: Pietro Leccese Conflict of interest: Matteo Piga Conflict of interest: Fabrizio Conti Conflict of interest: Paolo Fraticelli Conflict of interest: Luca Quartuccio Conflict of interest: Federico Alberici Conflict of interest: Carlo Salvarani Conflict of interest: Silvano Bettio Conflict of interest: Simone Negrini Conflict of interest: Carlo Selmi Conflict of interest: Savino Sciascia Conflict of interest: Gabriella Moroni Conflict of interest: Loredana Colla Conflict of interest: Carlo Manno Conflict of interest: Maria Letizia Urban Conflict of interest: Alfredo Vannacci Conflict of interest: Maria Rosa Pozzi Conflict of interest: Paolo Fabbrini Conflict of interest: Stefano Polti Conflict of interest: Mara Felicetti Conflict of interest: Maria Rita Marchi Conflict of interest: Roberto Padoan Conflict of interest: Paolo Delvino Conflict of interest: Roberto Caporali Conflict of interest: Carlomaurizio Montecucco Conflict of interest: Lorenzo Dagna Conflict of interest: Adriana Cariddi Conflict of interest: Paola Toniati Conflict of interest: Dr. Tamanini reports other from Glaxo Smith Kline, outside the submitted work. Conflict of interest: Federica Furini Conflict of interest: Alessandra Bortoluzzi Conflict of interest: Elisa Tinazzi Conflict of interest: Lorenzo Delfino Conflict of interest: Iuliana Badiu Conflict of interest: Giovanni Rolla Conflict of interest: Vincenzo Venerito Conflict of interest: Florenzo Iannone Conflict of interest: Alvise Berti Conflict of interest: Roberto Bortolotti Conflict of interest: Vito Racanelli Conflict of interest: Guido Jeannin Conflict of interest: Angela Padula Conflict of interest: Alberto Cauli Conflict of interest: Roberta Priori Conflict of interest: Armando Gabrielli Conflict of interest: Milena Bond Conflict of interest: Martina Tedesco Conflict of interest: Giulia Pazzola Conflict of interest: Paola Tomietto Conflict of interest: Marco Pellecchio Conflict of interest: Chiara Marvisi Conflict of interest: Federica Maritati Conflict of interest: Alessandra Palmisano Conflict of interest: Christian Dejaco Conflict of interest: Johann Willeit Conflict of interest: Stefan Kiechl Conflict of interest: Iacopo Olivotto Conflict of interest: Peter Willeit Conflict of interest: Domenico Prisco Conflict of interest: Augusto Vaglio Conflict of interest: Giacomo Emmi

Objectives The study aim was to evaluate the estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with respect to mortality in SSc patients from the European Scleroderma Trials and Research Group (EUSTAR) database. Methods SSc patients from the EUSTAR database who had items required for the calculation of eGFR at a baseline visit and a second follow-up visit available were included. A cut-off eGFR value of 60 ml/min was chosen for all SSc patients, and 30 ml/min for those with scleroderma renal crisis (SRC). Cox regression and competing risk analysis were performed to evaluate the use of eGFR as a predictive factor of mortality. Results A total of 3650 SSc patients were included in this study. The median serum level of creatinine and the mean of eGFR were 0.8 mg/dl (interquartile range = 0.6-0.9) and 86.6 +/- 23.7 ml/min, respectively. The eGFR was significantly lower in patients with pulmonary hypertension. Overall survival (OS) was significantly reduced in SSc patients with eGFR < 60 ml/min compared with patients with eGFR >= 60 ml/min [OS at 5 years 0.763 (95% CI: 0.700, 0.814) vs 0.903 (95% CI: 0.883, 0.919; P < 0.001)]. In multivariable analysis, OS was associated with male gender (P < 0.01), systolic pulmonary arterial pressure (sPAP) (P < 0.001) and eGFR (P < 0.001). The cumulative incidence of deaths due to SSc was associated with increased sPAP (P < 0.001) and reduced eGFR (P < 0.05). The OS at 5 years of 53 SRC patients was not significantly different between SSc patients with eGFR > 30 ml/min and those with eGFR Conclusion eGFR represents a predictive risk factor for overall survival in SSc. The eGFR, however, does not represent a risk factor for death in SRC.

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12 +/- 3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.

Aim: To measure the level of agreement and application of 10 international recommendations for treating rheumatoid arthritis (RA) to a target of remission/low disease activity. Methods: A 10-point Likert scale (1=fully disagree, 10=fully agree) measured the level of agreement with each of 10 recommendations. A 4-point Likert scale (never, not very often, very often, always) assessed the degree to which each recommendation was being applied in current daily practice. If respondents answered ‘never’ or ‘not very often’, they were asked whether they would change their practice according to the particular recommendation. Results: A total of 1901 physicians representing 34 countries participated. Both agreement with and application of recommendations was high. With regard to application of recommendations in daily practice, the majority of responses were ‘always’ and ‘very often’. A significant percentage of participants who were currently not applying these recommendations in clinical practice were willing to change their practice according to the recommendations. Conclusion: The results of this survey demonstrated great support of ‘Treating RA to Target’ recommendations among the international rheumatology community. Additional efforts may be needed to encourage application of the recommendations among certain clinicians who are resistant to changing their practice.

OBJECTIVE: Synovial B cells play a critical role in rheumatoid arthritis (RA) being involved in autoantibody synthesis T cell activation and cytokine production. CXCL13 is a B cell chemoattractant that is instrumental in synovial B cell organization; the regulatory determinants of CXCL13 in inflammation are poorly characterized. This study was undertaken to investigate the functional involvement of synovial T cells in the ectopic expression of CXCL13 in RA. METHODS: CXCL13 production and regulation were addressed using immunohistochemistry in situ hybridization quantitative polymerase chain reaction multicolor flow cytometry and enzyme linked immunosorbent assay by in situ ex vivo analysis and in vitro functional assays with rheumatoid synovial tissue and primary cells. RESULTS: CXCL13 messenger RNA and protein expression and spontaneous CXCL13 secretion were detected in RA synovial fluid T cells but were not detected (or were detected only occasionally) in peripheral blood T cells. Analysis of tissue expression confirmed cytoplasm localization of CXCL13 in T lymphocytes infiltrating B cell follicles and small perivascular aggregates. Multicolor characterizations in synovial fluid demonstrated CXCL13 expression in antigen experienced T helper cells frequently characterized by terminal differentiation and the lack of the follicular helper T cell markers CXCR5 and BCL6 protein. In vitro functional assays revealed the enhancing effect of T cell receptor CD28 engagement on CXCL13 production and secretion in primary cells. CONCLUSION: Our findings define a new functional property of synovial T cells demonstrating their active involvement in the local production of B cell chemoattractants and support a direct contribution of the adaptive immune system and antigen dependent signals in the mechanisms of B cell localization in RA.

Objective To develop valid instruments for the assessment of disease-related damage and disease activity in Sjogren's syndrome (SS). Methods Data on 206 patients with primary SS were collected in 12 Italian centers. Each patient was scored by 1 investigator, on the basis of a global assessment of the degree of disease damage and disease activity. Patients judged to have active disease at the time of enrollment underwent a second evaluation after 3 months. Univariate and multivariate analyses were performed to select the clinical and serologic variables that were the best predictors of damage and of disease activity, and these variables were used to construct the Sjogren's Syndrome Disease Damage Index (SSDDI) and the Sjogren's Syndrome Disease Activity Index (SSDAI). The weight of each variable in the index was determined by the β coefficients in multivariate regression models. Scores obtained using the SSDDI and the SSDAI were compared with scores initially given by the investigators. Finally, a receiver operating characteristic (ROC) curve was used to determine the cutoff value in the SSDAI with the highest level of accuracy in identifying patients with a significant level of disease activity. Results A multivariate model with 9 variables was the best predictor of investigator scores of damage. The scores obtained using the SSDDI were closely correlated with investigator ratings (R = 0.760, P < 0.0001). A model composed of 11 variables was the best predictor of investigator scores of disease activity. The scores obtained using the SSDAI were strongly correlated with the investigator ratings both at the time of enrollment and 3 months after enrollment (R = 0.872, P < 0.0001, and R = 0.817, P < 0.0001, respectively). The differences between scores given by investigators at study enrollment and after 3 months, a measure of variation of disease activity over time, were also closely correlated with the differences calculated using the SSDAI (R = 0.683, P < 0.0001). The ROC curve analysis showed that patients with the highest level of disease activity could be identified on the basis of an SSDAI score of ≥5. Conclusion Our findings indicate that the SSDDI is an adequate instrument to objectively measure damage in patients with SS, and that the SSDAI is a valid tool to measure disease activity when used either as a single-state index or as a transition index.

Objectives: To investigate the prevalence of ultrasound (US) detectable inflammation in hips of patients with ankylosing spondylitis (AS) and the relationship between US and measures of disease activity and severity. Methods: Consecutive patients with AS attending the rheumatology units involved in this study were enrolled. Clinical and demographical data were recorded. US examination of bilateral hips was performed at the same time, evaluating anterior longitudinal scan to search for synovial hypertrophy (SH), joint effusion (JE) or power Doppler (PD) positive synovitis. Results: A total of 56 patients were included, median age (interquartile range, IQR) 49 (39, 59.5), median disease duration 98 (72, 204) months, 80.3% were treated with TNF-α inhibitors, median BASDAI 2.65 (1.96, 3.95), 30.3% had hip tenderness. US JE was found in 26.7% of patients, US SH in 16%, no patient had detectable PD. The concordance between clinical findings and US abnormalities was moderate, with a kappa of 0.44. Patients with detectable US abnormalities had higher median visual analogue scale (VAS) pain and C-reactive protein (CRP), while there was no significant association with other measures of disease activity and disability. In the subgroup of patients with no hip tenderness, US alterations were still significantly related to higher CRP levels, while in patients with hip tenderness and no US abnormalities CRP was not higher than in the asymptomatic patients. Conclusions: US assessment of hip joint in AS patients can be considered of value, as suggested by the correlation with relevant clinical and laboratory measures. In asymptomatic patients, US examination might provide further information on subclinical involvement. © Clinical and Experimental Rheumatology 2012.

International audience; OBJECTIVES: To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjogren's syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). METHODS: For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. RESULTS: Low-activity (ESSDAI/=14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI/=5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI>/=5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

To investigate the prevalence of ultrasonographic (US) shoulder abnormalities in patients with rheumatoid arthritis (RA) and to investigate the relationship between US findings and demographic and clinical features.Consecutive patients attending the rheumatology units involved in this study were enrolled. Clinical and demographical data were recorded. US of bilateral shoulders was performed at the same time, examining tendons, bursae, gleno-humeral and acromion-clavicular joints. The presence of signs of inflammation, bone erosions or rotator cuff pathology was evaluated.A total of one hundred patients were enrolled, mean age (SD) 59.6 (14.7) years, median disease duration (IQR) 56.5 (34.7, 96.5) months, 98% of them were on DMARDs and 22% on biologics. Shoulder tenderness was reported by 44% of patients. 34% of patients showed at least one sign of inflammatory involvement, and 25% of them presented with humeral head erosions. Signs of rotator cuff pathology were seen in 49% of patients. Agreement between the presence of spontaneous pain and US inflammatory abnormalities was moderate (kappa 0.501). Patients with inflammatory involvement of the shoulders had significantly higher DAS28, HAQ, VAS pain, acute phase reactants and disease duration compared to patient with no inflammatory signs, they were more frequently RF positive and reported more frequently spontaneous pain.US assessment of the shoulder in RA patients can be considered of value, especially in patients with relevant indicators of disease activity and severity.

Fibromyalgia syndrome (FMS) is a common form of non-inflammatory rheumatism within the general population with symptoms often mimicking those of arthritis or muscle disorders. Arthralgic symptoms in the region of the hip are commonly mentioned by patients with FMS and one of the diagnostic trigger points for the condition is found around the greater trochanter. To date, no formal imaging studies using ultrasound (US) have been performed in FMS. This study describes the correlation between clinical and US findings in patients presenting with primary FMS to rheumatology clinics. In the majority of the patients, no significant pathological US abnormalities were detected.

Hip pain is a common complaint in daily practice and the identification of the underlying pathologic condition is the first step for an adequate treatment. In this review, we discuss the available evidence for the application of conventional radiography, computed tomography and magnetic resonance imaging in rheumatologic patients with painful hip, presenting the main imaging findings due to osteoarthritis, inflammatory arthritis (rheumatoid arthritis and spondyloarthritides), osteonecrosis and some other soft tissue involvement (bursitis and synovial cyst) that could be the cause of hip pain. Because different imaging techniques show different sensitivity and specificity, the choice of technique to use depends on the type and stage of the disease itself.

Vectors combining the heat shock proteins (HSPs) promoter with the catalytic subunit A of the diphtheria toxin (DTA) or its variants, cross-reacting material (CRM) 176 and 197, were engineered to investigate the effect of bacterial toxins on pancreatic cancer (PC) cells. Three heat-inducible enhanced green fluorescent protein (eGFP)-expression vectors were obtained: V1 (91% homology to HSPA6), V2 (five heat shock elements upstream the minimal HSPA6 promoter) and V3 (V1 and V2 combined). The highest eGFP transcription and translation levels were found in V3 transfected PC cells. The V3 promoter was used to control DTA, CRM176 and CRM197 expression, treatment response being investigated in four PC cell lines. DTAwt or CRM176 transfected cell growth was completely arrested after heat shock. CRM197 toxin presumed to be inactive, caused mild distress at 37 degrees C and induced a 25-50% reduction in cell growth after heat shock. Preliminary in vivo findings showed that heat treatment arrests tumor growth in DTA197 stably transfected PSN1 cells. In conclusion, the efficient HSP promoter identified in this study may be extremely useful in controlling the transcription of toxins such as CRM197, which have lethal dose-related effects, and may thus be a promising tool in PC gene therapy in vivo.

To test the reliability of a new enzyme-linked immunosorbent assay (ELISA) to identify anti-RNA polymerase III (RNAP III) positive sera from Italian patients with Systemic Sclerosis (SSc) and other chronic inflammatory disorders.A comparison between the new ELISA for anti-RNAP III and the gold standard technique, immunoprecipitation (IP), was first performed on 106 SSc patients, 16 patients with other connective tissue diseases and 10 healthy subjects. A further ELISA evaluation was performed on 224 SSc patients, 120 subjects with other rheumatic or infectious diseases, and 81 healthy controls.Plotting ELISA and IP data in a Receiver Operator Characteristic curve, the ELISA cut-off value providing the best specificity (99.1%) and sensibility (100%) was 28 U/ml (AUC=0.999; p0.0001). Using this cut-off in the second analysis, anti-RNAP III positive results were found in 41 (18.3%) SSc patients, all negative for anticentromere or anti-topoisomerase I antibodies, while only 3 subjects tested positive among the 120 sera collected from other patients. All the healthy subjects were negative.This new ELISA for anti-RNAP III is highly accurate when a proper cut-off value is employed and represents a valid substitute to IP in a clinical setting.

The present report is devoted to drawing up and disseminating specific recommendations for the use of anti-TNF-alpha therapies in patients with rheumatoid arthritis (RA) in Italy. The document reports and discusses the published literature concerning the criteria for inclusion, assessment of response and for withdrawal of treatment with TNF blocking agents in RA. Several specific points concerning more sensitive warnings are discussed: tuberculosis, hepatitis, lymphoma, and cardiovascular risk and induction of autoimmunity. The recommendations are summarized in an 8-point table approved by the executive committee of the Italian Society for Rheumatology.

The crystals structure of Dlp-1 and Dlp-2 from B. anthracis has been determined. Both proteins belong to the mini-ferritin family. They are compoed of twelve identical subunits arranged with 32 symmetry.

This protein from H. pylori, able to activate neutrophiles, is described in terms of molecular and immunogenic properties.

OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-alpha (TNF-alpha) drugs at outpatient clinics. METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF-alpha blockers. All patients received one TNF-alpha blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month. RESULTS: A total of 1257 patients started TNF-alpha blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male). CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA

In the rheumatology literature, most of the available evidence on three-dimensional ultrasound (3D US) is related to the acquisition process and highlights the virtual operator independence and shortening of the US examination time. The main aim of this study was to compare 3D US using a high-frequency volumetric probe and conventional 2D US at the wrist and hand in patients with rheumatoid arthritis (RA). The 3D US examinations were performed using a Logiq 9 (General Electrics Medical Systems, Milwaukee, WI) with a high-frequency (8-15 MHz) volumetric probe. Overall, there is good-to-excellent agreement between the two modalities relating to both joint inflammation and bone erosion. This study is an initial step towards establishing a methodology necessary for developing multi-centre US studies which are aimed at assessing hand involvement in patients with RA.

Objective: To compare drug survival of different anti-TNF drugs (inliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicentre observational cohort study.Methods: All patients with RA or SpA registered in the MonitorNet database who started their irst course of anti-TNF therapy were included.Overall drug survival was measured, along with speciic reasons of discontinuation (ineficacy or adverse events).A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival.A second set of analyses stratiied by diagnosis (RA and SpA) used INF as reference drug.Adjustment for confounders was performed.The results are presented as adjusted hazard ratios (adjHR) and 95% conidence intervals (95%CI).Results: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses.Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90).In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment.In RA, both ETA and ADA showed a signiicantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively].Similar results were found in SpA.Conclusion: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup.In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

The use of Doppler ultrasound in rheumatology has grown in recent years. This is partly due to the increasing number of rheumatologists who perform US in their daily clinical practise and also to the technological advances of US systems. Both colour Doppler and power Doppler are used to evaluate the degree of intra- and peri-articular soft tissue inflammation. Moreover, Doppler US has been found to be of help in the assessment of vascular pathologies such as the vasculitides. In this review we provide an update of the data regarding the use of colour Doppler and power Doppler in rheumatology.

The knee joint is a frequent focus of attention for rheumatologists when assessing patients presenting to a clinic and may represent underlying intra-articular inflammatory pathology or involvement of the surrounding soft tissues. This study describes the correlation between clinical and ultrasound findings in patients presenting with a variety of rheumatic disorders and knee pain. US imaging provides for a sensitive and detailed identification of different intra- and peri-articular pathology responsible for knee pain.

Objective The aim of this study was to compare the 12-month probability of remission in early inflammatory arthritis with a milder treatment based on the 1987 criteria or a more intensive protocol based on the 2010 criteria. Methods Patients with rheumatoid arthritis (RA) or undifferentiated arthritis (UA) (2005-2012) were included. Before October 2010, patients fulfilling the 1987 criteria received methotrexate (MTX) and possibly low-dose prednisone, while UA hydroxychloroquine (HCQ) (1987-driven cohort). From October 2010, patients fulfilling the 2010 criteria received higher dose MTX and low-dose prednisone, while UA HCQ (2010-driven cohort). Treatment was increased to achieve DAS28 low disease activity. Clinical remission, defined by DAS28, was evaluated at subsequent visits in the whole population. Hazard ratios (HR) adjusted for age, sex, baseline DAS28, symptoms duration, MTX dose and prednisone were calculated by Cox regression. Results 677 patients were included (468 in 1987-driven cohort, 209 in 2010-driven cohort), with no significant differences in age, gender, autoantibodies and pain. The 2010-driven cohort had significantly fewer tender and swollen joints, lower acute phase reactants, DAS28 and HAQ and achieved more frequently remission even when the analysis was adjusted for all confounders (adjusted HR (95% CI) 1.73 (1.34, 2.22)) and limited to per protocol patients (adjusted HR (95%CI) 1.49 (1.11, 2.02). Conclusion Treating patients with early arthritis according to a more intensive protocol leads to higher remission rate. The results of this study support the use of a strategy led by the 2010 criteria with more intensive treatment strategies in the management of early arthritis.

Systemic sclerosis (SSc) presents a great deal of variability in the extent and severity of skin and internal organ involvement. The diagnostic and prognostic significance of autoantibodies in SSc is undisputed and the patient's autoantibody profile represents a fundamental tool for clinicians. Scleroderma is a rare condition in children. Unlike adults, localized scleroderma is more frequent than the systemic sclerosis, nevertheless it represents a disabling condition. In both conditions, no validated outcome measures and proven effective treatment is available to date.Raynaud's phenomenon (RP) is one the most common and significant clinical symptoms of SSc and therefore in patients with RP a capillaroscopic analysis should be carried out as soon as possible. The actual and select advantage of the early nailfold videocapillaroscopic (NVC) analysis is to distinguish between the primary RP and the secondary RP and to allow the early detection of SSc.

In rheumatoid arthritis (RA), low-dose glucocorticoid (GC) therapy has a well-established effect on disease activity. Particularly in early RA, robust evidence demonstrates that GC treatment in association with standard disease-modifying anti-rheumatic drugs (DMARDs) is effective in inducing high remission rates, earlier and more persistently. Despite international recommendations that discourage long-term concomitant GC use, the majority of the clinical trials and observational registries on biologic agents include a high proportion (up to 80%) of patients in treatment with GC. From an analysis of the literature, a substantial lack of reliable information about the efficacy of GC in association with biologic agents emerges; in particular, the role of GC co-therapy in sustaining remission after biological therapy discontinuation remains to be clarified. Given the increasing prevalence of patients in sustained remission, a rational discontinuation strategy should include low-dose GCs in the experimental design to elucidate their role in inducing and maintaining biologic-free remission, for efficacy, safety and pharmacoeconomic considerations.

Objective: To determine the usefulness of plasma procalcitonin (PCT) measurement to suspect infectious etiology in febrile patients with systemic autoimmune disease. Methods: PCT C-Reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell count (WBC) were measured in 44 consecutive inpatients with a diagnosis of systemic autoimmune disease and fever >38°C. After careful microbiologic screening no obvious infection was demonstrated in 24 patients (Group A) while an infectious bacterial complication was diagnosed in 20 cases (Group B). Results: Median PCT levels were signficantly higher in the group B (1.11 vs 0.24 ng/ml; p = 0.0007), whereas the differences for CRP, WBC and ESR did not reach statistical significance. PCT also exhibited a good sensitivity and specificity (75%) in differentiating patients with infection from those with disease flare. With respect to positive and negative predictive values (71.4% and 78.2%), PCT markedly exceeded the other variables. By analyzing PCT values by disease we identified a false positive subgroup of patients suffering from adult onset Still's disease (AOSD), showing markedly elevated PCT levels in absence of infection. By excluding these patients, PCT showed a very good sensitivity and specificity (73.6% and 89.4%) and the area under receiver operating characteristics (ROC) curve rose from 0.801 to 0.904. Conclusion: Our data indicate that elevated PCT concentrations offer go od sensitivity and specificity for the diagnosis of systemic bacterial infection in febrile patients with systemic autoimmune diseases. However, in fever associated with AOSD PCT may be elevated even in the absence of infectious complication.

Objective. To assess the efficacy of tidal irrigation in patients with Milwaukee shoulder syndrome (MSS). Methods. Ten patients with clinical diagnosis of MSS underwent ultrasound examination and tidal irrigation followed by instillation of methylprednisolone and tranexamic acid. A single shoulder was treated in 9 cases; in one patient with bilateral shoulder involvement, both shoulders were treated at different times. Six patients had longlasting disease (Group A) unsuccessfully treated with repeated joint fluid aspirations and intraarticular corticosteroid injections. Four patients had recent-onset illness without radiologic damage but with clinical findings similar to classic MSS (Group B), not previously treated with corticosteroid injections with symptoms dating from 3 months or less. Clinical examination including evaluation of adverse events, range of motion, and pain score by a 100 mm horizontal visual analog scale was scheduled just before tidal irrigation and after 2 and 6 months following the procedure in all cases. Results. Short- and longterm safety was excellent in all patients. Group A patients experienced short-lived improvement so that tidal irrigation had to be repeated within 6 to 10 months. No further therapy was necessary in any of the Group B patients during a mean followup of 16.5 months (range 12-24) due to a persistent clinical improvement without clinically detectable joint effusion. Conclusion. Closed-needle joint irrigation is a minimally invasive procedure, which led to a significant improvement in both pain and active motion in patients with longstanding symptoms. Patients with recent-onset disease recovered completely.

Objective. To evaluate quantitative or qualitative differences in synovial fluid (SF) cytokine levels among patients with systemic juvenile rheumatoid arthritis (JRA), antinuclear antibody positive pauciarticular JRA, or adult RA. Methods. SF levels of interleukin 1 alpha(IL-1 alpha), IL-1 beta, IL-1 receptor antagonist (IL-1Ra) IL-11, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1), leukemia inhibitory factor (LIF), all measured by immunoassays, and of IL-6, measured with a bioassay using B9 cells, were evaluated in 11 patients with systemic JRA, 24 with pauciarticular TRA, and 22 adult patients with RA. Results. SF IL-6 levels were significantly higher in patients with systemic JRA than patients with pauciarticular JRA (p = 0.003) or RA(p = 0.002). IL-1 alpha was detectable in 12/24 SF samples from pauciarticular JRA, in 2/22 SF from RA, and in no sample from systemic JRA (p = 0.004 vs RA; p = 0.005 vs systemic JRA). SF IL-11 levels were significantly higher in patients with RA than patients with systemic JRA (p = 0.012) or pauciarticular JRA (p = 0.005). We found no significant differences in SF levels of IL-1 beta, IL-1Ra, TNF-alpha, sTNFR1, or LIF. Conclusion. In systemic JRA, SF levels of IL-6 are significantly higher than in pauciarticular JRA or in RA; IL-1 alpha is present in a significant proportion of patients with pauciarticular JRA, but not in those with RA or systemic JRA.

Chemokines play a central role in the pathogenesis of rheumatoid arthritis (RA) synovitis which is characterised by new blood vessel formation, thickening of the lining layer and infiltration of immune cells. The inflammatory infiltrate is generated by a series of events which include the recruitment of leukocytes from the blood stream into the tissue, their local retention and activation to effector cells. All these processes are finely regulated by the interplay of different cell adhesion molecules (CAMs) and chemoattractant factors called chemokines (CK). CK are a superfamily of small proteins that play a crucial role in immune and inflammatory reactions. These chemoattractant cytokines share structural similarities including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins. CK mediate their effects by binding specific receptors (CK-R) characterised by a domain structure which spans the cell membrane seven times and signal through heterotrimeric GPT-binding proteins. Activation of the CK network results in an amplification of the inflammatory cascade and consequently in the progressive destruction of RA joints. The recognition of the central role of CK in inflammation has paved the way to the development of new agents capable of interfering with CK and CK-R. This review will focus in particular on the role of CK in regulating leukocyte trafficking in RA joints.