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Carla Galvani,1 Paola Caramaschi,1 Paolo Mura,2 Antonella Paladini,3 Alba Piroli,3 Elisa Arnaudo,4 Lucia De Franceschi,5 Maurizio Evangelista,6 Alice Pari,4 Giovanna Ongaro,1 Gabriele Finco,2 Anna Ciannameo,4 Antonio Carletto,1 Giustino Varrassi,3,7 Domenico Biasi1 1Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy; 2Anesthesia, Intensive Care and Pain Therapy Unit, Department of Medical Science “M. Aresu”, University of Cagliari, Cagliari, Italy; 3Department of MESVA, University of L’Aquila, L’Aquila, Italy; 4Department of Internal Medicine, University of Bologna, Bologna, Italy; 5Internal Medicine Unit, Department of Medicine, University of Verona, Verona, Italy; 6Emergency Department, Institute of Anesthesia, Resuscitation and Pain Medicine, Catholic University of Sacred Heart, Rome, Italy; 7Paolo Procacci Foundation, Rome, Italy Background: Chronic pain is a key symptom in fibromyalgia (FM), and its management is still challenging for rheumatologists in daily practice. FM patients show psychological and psychiatric manifestations, going from mood and emotional disorders to depression and alexithymia that negatively impact their quality of life, limiting their daily activities. Since pharmacological strategies have a limited efficacy in FM pain, alternative or complementary non-pharmacological approaches have been introduced in the clinical management of FM. Patients and methods: This is a retrospective study on FM patients (n=52) treated with a novel integrated postural counseling (PC) rehabilitation program carried out by a counselor physiotherapist. The clinical impact of PC was evaluated by 1) a semi-structured interview using an ad hoc modified questionnaire McGill Illness Narrative Interview (MINI) 1 to obtain data on pain management by highlighting everyday experience of living with pain and 2) an FM impact questionnaire (FIQ) total score. Results: Two main structures of narrative emplotment of FM illness were recognized: 1) the cumulative life narrative structure (46.15%) and 2) the broken life (53.85%) narrative structure. Baseline FIQ score was 77.38±7.77, and it was significantly reduced after PC to 39.12±13.27 (P

Objectives Data on macrovascular involvement in systemic sclerosis (SSc) are still debatable. The aim of this study was to estimate its prevalence and possible determinants in a large cohort. Methods One hundred and fifty-five outpatients with SSc were enrolled. Data about disease characteristics and cardiovascular risk factors were collected and patients underwent ecocolor Doppler ultrasonography of arteries of the neck and lower (LL) and upper (UL) limbs. Results Mean age was 57.9 ± 14.5 years and most were female (88.4%) with a limited subset (63.2%). Mean disease duration was 11.4 ± 8.1 years. Twenty-three (14.8%) had hypertension, 7 (4.8%) diabetes, 64 (41.3%) hypercholesterolemia and 63 (40.6%) were active/past smokers. Seventy-nine (49%) patients had plaques at carotids, 49 (32.9%) at LL and 7 (4.9%) at UL. In multivariate analysis, patients with carotid plaques had more often a limited pattern (P = .001), patients with distal LL plaques pulmonary arterial hypertension (P = .006) and patients with proximal LL plaques lower diffusing capacity for carbon monoxide adjusted to hemoglobin and its ratio to alveolar volume (P = .004). In patients with UL plaques traditional cardiovascular risk factors were not more common, while forced vital capacity was lower (P = .023). Finally, upper limb and proximal LL plaques were as common in early disease patients as in longstanding ones, although the former were younger. Conclusions This study shows that macrovascular involvement is quite common in SSc and that some disease characteristics linked to microvascular involvement are associated with atherosclerotic plaques, which can be present even in early disease. Our study suggests that a complete evaluation of macrocirculation is mandatory for rheumatologists treating SSc patients.

Background: Vitamin D is known to influence the immune system in many different diseases although longitudinal studies on systemic sclerosis (SSc) are still missing. Objectives: this study wants to investigate if variations in vitamin D serum levels (25OHD) over time affect digital ulcers (DU) in SSc. Methods: this is a retrospective study on 65 patients. Data on disease characteristics and 25OHD were collected in 2011 and 2016. Results: The mean age of our cohort was 58 (12) years with a mean disease duration of 9.5 (5.3) years. Most of our patients had a limited subset (69.2%). At baseline 50.8% and 41.5% after 5 years had 25OHD Conclusion: In this study we have shown that a decrease in 25OHD increases the risk of developing DUs and that vitamin D supplementation with the doses currently recommended may be insufficient in SSc. Further studies in wider cohorts are needed to confirm these results and to evaluate the effectiveness of a more aggressive or different vitamin D supplementation. Disclosure of interests: Cristian Caimmi: None declared, Eugenia Bertoldo: None declared, alice Pozza: None declared, Paola Caramaschi: None declared, Giovanni Orsolini Speakers bureau: Grunenthal, Davide Gatti Speakers bureau: abiogen, amgen, Janssen-Cilag, Mundipharma, Pfeizer, Maurizio Rossini: None declared, Ombretta Viapiana Speakers bureau: Novartis, abbvie, Eli-Lilly, Sanofi Genzyme

BackgroundThe European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc).ObjectiveTo assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors.MethodsPatients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Δ≥1 in the Medsger’s severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors.Results549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years.ConclusionThe adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.

AIM Low levels of vitamin D (25OHD) have been found to associated with digital ulcers (DUs) in systemic sclerosis (SSc), although only cross-sectional studies have been performed. We aimed to investigate if variations in vitamin D serum levels over time affect DU in SSc. METHODS This is a retrospective study on 65 patients. 25OHD was measured in 2011 and 2016 and its variations correlated with DU. RESULTS The mean age of our cohort was 58 (SD 12) years with a mean disease duration of 9.5 (5.3) years. Most of our patients had a limited SSc (69.2%). At baseline 50.8% and 41.5% after 5 years had 25OHD

PROBLEM As antiphospholipid antibody-positive women with adverse pregnancy outcomes have higher plasma complement activation product levels, and the placentas of women with antiphospholipid syndrome (APS) exhibit C4d complement component deposition, complement activation involvement has been hypothesized in APS pregnancy complications. METHOD OF STUDY Plasma levels of C5a and C5b-9 complement components of 43 APS non-pregnant patients and 17 pregnant APS women were measured using enzyme-linked immunosorbent assay. The results were compared with those of 16 healthy non-pregnant women and eight healthy pregnant women, respectively. Placenta samples of five APS patients at high risk of pregnancy complications and of five healthy controls were subjected to immunoblotting analysis with specific antibodies to C5b-9 and CD46, CD55, CD59 complement regulators. RESULTS The mean plasma C5a and C5b-9 levels were significantly higher in the non-pregnant APS patients with previous thrombosis ± pregnancy morbidity (P = .0001 and P = .0034, respectively) and in the pregnant APS women with adverse outcomes (P = .0093 for both). Similarly, C5b-9 amounts were significantly higher in the adverse pregnancy outcome placenta (P = .0115) than in those associated to a favorable outcome. The mean CD46, CD55 and CD59 amounts were, instead, lower, although not always significantly, in the placentas of all the high-risk APS women with respect to the control placentas. CONCLUSION Data analysis demonstrated that there was significant complement activation in the more severe subset of APS patients and in only the adverse pregnancy outcome APS women. Further studies will clarify whether the lower CD46, CD55, and CD59 expressions in the APS placentas are limited to only high-risk APS patients.

Objective.To evaluate the relationship between fecal calprotectin (FC) and interstitial lung disease (ILD) in systemic sclerosis (SSc).Methods.The study enrolled 129 outpatients with SSc. Data about disease characteristics, in particular lung involvement, were collected and FC was measured.Results.Patients with ILD (35, 27.1%) had higher values of FC (p < 0.001). In multivariate analysis, these variables were associated with increased risk of ILD: diffuse disease subset, higher modified Rodnan skin score, longer disease duration, higher severity scores, steroid treatment, and higher FC levels, while diverticulosis was protective.Conclusion.ILD is independently associated with increased FC levels in SSc.

Background Interstitial lung disease (ILD) is one of the leading cause of death in systemic sclerosis (SSc). Objectives The aim of this paper was to evaluate the relationship between faecal calprotectin (FC) and ILD. Methods 129 outpatients with SSc were enrolled. Data about disease characteristics, in particular lung involvement, were collected and FC was measured. Results Eighty-seven patients (67.4%) had a limited subset with a mean disease duration of 13.3 (7.1) years. Anti-Scl70 antibodies were found in 35 (27.1%) patients. GI tract involvement was severe/end stage in 3 cases (2.4%). ILD affected 35 patients (27.1%). Median levels of FC were 80 ug/g (157 ug/g). FC was found to be higher in patients with a moderate/severe/end stage score for gastrointestinal tract (p=0.046) and on steroids (p=0.015). In addition, it positively correlated with age (p Other than well-known risk factors such as higher mRSS or diffuse subset, patients with ILD had higher values of FC (p Conclusions in this paper we have found a possible link between gut inflammation and ILD. Many hypothesis may be done but it is intriguing that these data further support what previously found by other authors (Andreasson et al. 2016), that is a correlation between gut inflammation and dysbiosis and non-gastrointestinal disease manifestation. Our study may support the hypothesis of a role of gut dysbiosis in triggering a pathologic immune response leading to ILD. It may also be that increased FC simply reflects a more severe disease but this still doesn’t explain why only ILD was found to be linked with FC. Is it because lung is a filter of molecule (i.e. antigens, cytokines, metabolites, etc.) produced in the gut? Further studies with longitudinal evaluation are warranted. Disclosure of Interest None declared

Background It is well known that systemic sclerosis (SSc) affects microvessels, but data on macrovascular involvement are still lacking or debatable. Objectives Aim of this study was to estimate the prevalence of atherosclerotic plaques and their possible determinants in a large cohort of SSc patients. Methods One-hundred and four outpatients with SSc were enrolled. Data about disease characteristics and cardiovascular risk factors (diabetes, hypertension, dyslipidemia, smoke) were collected and patients underwent a full ecocolorDoppler ultrasonography of arteries of the neck and lower limbs (LL). Results Mean ageof our cohort was 62±13 years and 17 (16.3%) patients were male. Seventy patients (67.3%) had a limited subset and the mean disease duration was 12.7±6.8 years. A previous history of digital ulcers was found in 27 cases (26.0%). Thirty-eight patients (36.5%) were on ongoing or previous treatment with immunosuppressive drugs. Regarding cardiovascular risk factors, 22 (21.2%) had hypertension, 7 (6.7%) diabetes, 52 (50%) dyslipidemia and 45 (43.3%) were active or past smokers. Fifty-seven (54.2%) patients had plaques at carotids, 1 (1%) at LL and 37 (35.9%) at UL. Prevalences were higher in older patients, as expected. Patients with carotid plaques were older (p In multivariate analysis with all variables with a p Conclusions in this study we performed one of the most complete evaluation of macrovascular involvement in one of the most numerous cohort of SSc patients present in literature. The prevalence of carotid and LL plaques did not seem to be higher in SSc patients as compared to what reported in healthy subjects. Intriguing is that patients with limited disease have an increased risk of having carotid plaques even after correcting for possible confounders. Disclosure of Interest None declared

Systemic sclerosis (SSc) is an autoimmune disease which may lead to malnutrition. Previous studies have defined it with different criteria. No thorough evaluations of sarcopenia in SSc are available. The aim of the present study was to assess the prevalence and the potential association of malnutrition and sarcopenia in a large cohort of SSc cases. A total of 141 SSc consecutive outpatients were enrolled. Body composition was analyzed by densitometry. Malnutrition was defined according to recently published ESPEN criteria, whereas sarcopenia was diagnosed in patients with reduced skeletal muscle index. Malnutrition was diagnosed in 9.2% of patients (95% CI, 4.4–14.0%). Malnourished patients had worse gastrointestinal symptoms according to UCLA SCTC GIT 2.0 questionnaire (p = 0.007), lower physical activity (p = 0.028), longer disease duration (p = 0.019), worse predicted DLCO/VA and FVC (p = 0.009, respectively), worse disease severity according to Medsger severity score (p

Objective: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years’ duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets. Method: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud’s SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud’s phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31–59, and ≥ 60 years. We performed descriptive and bivariate analyses. Results: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud’s. Conclusion: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice. (Less)

The aim of the study was to evaluate the adherence of systemic sclerosis (SSc) female patients to cervix and breast cancer screening procedures, as suggested by local guidelines. A cohort of 84 SSc women was asked if they had undergone mammography and Pap test during the previous 2- and 3-year intervals, as indicated according to the Italian recommendations. The results were compared with those collected in patients affected by other chronic rheumatic disorders and in the general population. More than 85% of SSc women declared to comply with an age-related cervix and breast cancer screening schedule. The data were similar to those collected in patients affected by other chronic rheumatic disorders, whereas the subjects belonging to the general population reported to undergo breast cancer screening more frequently. Among SSc women, neither the educational level, nor the lung and skin involvement influenced their cancer screening program compliance. Only a positive history of ischemic digital ulcers seemed to interfere with mammography. Our study reported a very high percentage of SSc female patients who adhered to programs for the early detection of cervical and breast cancer. The significant adherence to guidelines may be due to the schedule adopted by the local health public service, which regularly invites eligible subjects by mail to undergo cancer screening at no charge.

Objective Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc. Methods In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis. Results Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis. Conclusion In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to ‘widen' the still very narrow ‘window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis and composed of two subtypes, limited and diffuse cutaneous forms. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Objectives To expand the list of susceptibility genes and deepen biological insights for SSc. Methods We performed trans-ethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4,436 cases and 14,751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighboring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. Results We identified two significant SNP in two loci, GSDMA and PRDM1 , both of which are related with immune functions and associated with other autoimmune diseases (p=1.4x10 -10 and 6.6x10 -10 , respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3 . PRDM1 encodes BLIMP1, a transcription factor regulating T cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighboring genes, and this could explain the association in this locus. We found different HLA association patterns between the two populations or two subtypes. Enrichment analysis suggested the importance of CD4 naive primary T cell. Conclusions GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc. Disclosure of Interest None declared

Background Systemic sclerosis (SSc) is an autoimmune disease that may affect gastrointestinal tract, leading to malabsorption and malnutrition. Previous studies defined this complication with no widely accepted criteria. No thorough evaluations of sarcopenia are available. Methods 141 SSc consecutive outpatients have been enrolled. A thorough history, blood samples and body composition by densitometry were collected. Malnutrition was defined accordingly to recently published and widely accepted ESPEN criteria (1); sarcopenia was diagnosed in patients with a reduced skeletal muscle index (2). Results The table summarizes cohort9s characteristics. Malnutrition was diagnosed in 9.2% (CI95%: 4.4–14.0%). Malnourished patients were more often treated with steroids (p=0.039), had worse gastrointestinal symptoms accordingly to UCLA questionnaire (p=0.007), lower physical activity accordingly to International physical activity questionnaire (p=0.028), longer disease duration (p=0.019), worse predicted DLCO/VA and FVC (p=0.009, respectively) and worse disease severity accordingly to Medsger severity score (DSS) (p Conclusions Malnutrition defined with widely accepted diagnostic criteria was found to be lower than previously reported (3–7) using screening tool or non-validated criteria. Sarcopenia was found to be somewhat common, although no previous study on comparable cohorts are available. Lung involvement and function was shown to be significantly linked with nutritional status and may not be explained only by muscle weakness given the absence of correlation between muscle weakness and FVC but only with DLCO/VA. References Cederholm et al. Clinical Nutrition 2015;34;335. Baumgartner et al. Am J Epidemiol 1998; 147:755. Baron et al. J Rheumatol 2009;36:2737. Krause et al. Ann Rheum Dis 2010;69:1951. Murtaugh et al. Clin Nutr 2013;32:130. Caporali et al. Clin Nutr 2012;31:666. Rosato et al. Nutrition 2014;30:204. Disclosure of Interest None declared

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases.MethodsWe performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes.ResultsWe identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10−10 and 6.6×10−10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell.ConclusionsGSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.ResultsWe identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.ConclusionCombining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Objective. In this multicentre study, we aimed to evaluate the capacity of a computer-assisted automated QCT method to identify patients with SSc-associated interstitial lung disease (SSc-ILD) with high mortality risk according to validated composite clinical indexes (ILD-Gender, Age, Physiology index and du Bois index). Methods. Chest CT, anamnestic data and pulmonary function tests of 146 patients with SSc were retrospectively collected, and the ILD-Gender, Age, Physiology score and DuBois index were calculated. Each chest CT underwent an operator-independent quantitative assessment performed with a free medical image viewer (Horos). The correlation between clinical prediction models and QCT parameters was tested. A value of P

Takayasu arteritis is a panarteritis of unknown etiology involving the aorta and its main branches, with higher prevalence in women and peak of incidence in the second and third decades of life. Up to 30% of patients have coronary lesions and aortic valve involvement. Presentation mimicking aortic dissection is quite rare. Here described is the case of a young patient, presenting with an acute coronary syndrome associated with severe aortic regurgitation, who underwent emergent surgery with the suspicion of acute aortic dissection. The diagnostic and therapeutic implications are discussed.

Objective Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. Methods Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA-associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. Results Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05–1.21, adjusted P [Padj] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13–1.42, Padj = 1.5 × 10−3 and OR 1.32, 95% CI 1.17–1.48, Padj = 9.0 × 10−5, respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. Conclusion The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc.

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. RESULTS: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p

Objective.To analyze the characteristics of anti-RNA polymerase III antibodies (anti-RNAP3)− positive patients with systemic sclerosis (SSc) in the European League Against Rheumatism Scleroderma Trials and Research group (EUSTAR) registry with a focus on the risk of cancer and the characteristics of malignancies, and the aim to provide guidelines about potential cancer screening in these patients.Methods.(1) Analysis of the EUSTAR database: 4986 patients with information on their anti-RNAP3 status were included. (2) Case-control study: additional retrospective data, including malignancy history, were queried in 13 participating EUSTAR centers; 158 anti-RNAP3+ cases were compared with 199 local anti-RNAP3− controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. (3) A Delphi exercise was performed by 82 experts to reach consensus for cancer screening in anti-RNAP3+ patients.Results.In the EUSTAR registry, anti-RNAP3 were associated in multivariable analysis with renal crisis and diffuse cutaneous involvement. In the case-control study, anti-RNAP3 were associated with gastric antral vascular ectasia, rapid progression of skin involvement, and malignancies concomitant to SSc onset (OR 7.38, 95% CI 1.61–33.8). When compared with other anti-RNAP3+ patients, those with concomitant malignancies had older age (p < 0.001) and more frequent diffuse cutaneous involvement (p = 0.008). The Delphi exercise highlighted the need for malignancy screening at the time of diagnosis for anti-RNAP3+ patients and tight followup in the following years.Conclusion.Anti-RNAP3+ patients with SSc have a high risk of concomitant malignancy. These results have implications for clinical practice and suggest regular screening for cancer in anti-RNAP3+ patients.

The aim of this study was to evaluate in a large size cohort of SSc patients bone mineral density (BMD) and to analyze its possible determinants. 106 consecutive outpatients affected by SSc were enrolled and completely evaluated for bone metabolism and SSc characteristics. For the statistical analysis, we preferred Z score to BMD or T score since the population was composed of patients of different ages and of both sexes. Mean neck Z score was significantly lower than 0. No significant differences were found for other sites. Female patients were shown to have a total femur and neck Z score significantly lower than 0 (p = 0.028 and p

To evaluate in a cohort of 100 consecutive patients affected by primary Sjogren's syndrome (pSS) the incidence of Hashimoto thyroiditis (HT) and to compare the clinical features and the laboratory parameters of patients affected by pSS with and without concomitant HT. In 100 consecutive patients affected by pSS, the occurrence of other autoimmune diseases was recorded and a full examination of thyroid function obtained. HT was associated with pSS in 27 cases. The comparison between pSS cases with and without HT showed that only patients with isolated pSS had low C4 level [p = 0.032, OR (IC 95 %) 230 (13.13-4,046)]. In addition, only patients affected by pSS without HT had evidence of cryoglobulins, cutaneous vasculitis with palpable purpura, peripheral neuropathy, and development of lymphoma, although all these manifestations were observed in a 4.1-8.2 % of the cases, without reaching statistical significance. The association of HT in patients suffering from pSS defines a subset of patients with milder disease and normal C4 levels.

Chikungunya is an arboviral disease transmitted by Aedes mosquitoes. The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia, that can persist for months. Chikungunya virus, a member of the genus Alphavirus, has recently caused a large outbreak on islands in the Indian Ocean and on the Indian subcontinent. The ongoing outbreak has involved more than 1.5 million patients, including travellers who have visited these areas. We describe our casistic of six travellers with Chikungunya arthropathy. All patients experienced fever and rash of short term during a travel in areas of epidemicity. All patients had peripheral poliarthralgias, which duration was >2 months in 4 cases (66%) and >6 months in 1 case (16%).

The objective of this study was to evaluate the incidence of the most severe vascular complications, such as pulmonary arterial hypertension, scleroderma renal crisis, and digital necrosis requiring amputation, in a monocentric group of systemic sclerosis (SSc) patients cyclically treated with intravenous iloprost. We reviewed the record-charts of 115 patients affected by SSc (18 men and 97 women, mean age 58.9.1 ± 14.2 years) regularly receiving iloprost for at least 3 years; the mean duration of the treatment was 98.8 ± 37.5 months (a total of 946.8 years of therapy). Demographic and clinical features were recorded. None of the patients died of SSc-associated vascular complications. After iloprost administration digital gangrene requiring amputation developed in 2 patients who had concomitant peripheral arterial disease (a total of 3 episodes; annual incidence of 0.31 for 100 years of iloprost therapy). Four patients were diagnosed with pulmonary arterial hypertension during iloprost treatment (annual incidence of 0.42 for 100 years of drug therapy); in none of the cases did the complication show a progressive course. No cases of scleroderma renal crisis were observed. With the limits of an observational study and in the absence of a control group, our experience suggests that prolonged cyclic iloprost therapy may limit the incidence/progression of severe digital and visceral SSc-vasculopathy.

Barrett's oesophagus (BE) is the major risk factor for oesophageal adenocarcinoma (EAC). SSc is associated with an increased risk of BE related to chronic reflux. The aim of this study is to determine the outcomes of BE and estimate the EAC risk in SSc patients over a 3-year prospective study.SSc patients were recruited through EUSTAR network centres. Inclusion criterion was a recent histological finding of BE. The patients were then prospectively followed and, as recommended, a second oesophageal endoscopy was performed according to the presence of BE-related dysplasia at baseline.A total of 50 SSc patients with BE (40 without and 10 with dysplasia) were included and 46 completed the follow-up (138 patient-years). During the 3-year follow-up, 4 of the 46 BE patients (3% per year) were diagnosed with high-grade dysplasia/EAC, of which one developed cardial EAC. EAC incidence in the BE subgroup with dysplasia increased to 4% per year compared with the absence of EAC cases in the BE subgroup without dysplasia at baseline.Our results, in accordance with previous published data suggesting an increased risk of EAC or cardial adenocarcinoma in SSc, highlight the need for accurate follow-up of BE SSc patients at risk of developing adenocarcinoma.

Objective.To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID).Methods.A multicenter study was performed in France and Italy to recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases.Results.We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren’s syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren’s syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers.Conclusion.Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.

Resume Contexte L’hypercalcemie hypocalciurique familiale (HHF) associee a la maladie a depots de cristaux de pyrophosphate de calcium dihydrate (PPCD ou CCA) est rare mais elle doit etre prise en compte dans le diagnostic differentiel d’une hypercalcemie. Cette maladie de transmission autosomique dominante se caracterise par une hypercalcemie, une hypocalciurie relative ou absolue et des concentrations seriques de parathormone (PTH) normales ou moderement elevees. La maladie est liee a des mutations qui inactivent le gene codant pour le recepteur sensible au calcium (CaSR). Observation Nous decrivons l’observation d’un patient italien de 77 ans qui a presente des crises de pseudo-goutte en rapport avec une CCA, associee a une hypercalcemie. Les donnees cliniques et biochimiques (calcemie 2,94 mmol/l ; PTH 5,9 pmol/l ; calciurie 24 heures 69,6 mg ; fraction urinaire de calcium [FEC] definie par le rapport clairance de la calciurie des 24 heures/clairance de la creatinine 0,004) ont permis d’evoquer le diagnostic d’HHF. Une hypercalcemie hypocalciurique a egalement ete retrouvee chez cinq des sept membres de la famille, confirmant ainsi le diagnostic ; un seul d’entre eux avait une CCA associee. Conclusion Une HHF doit etre recherchee par le dosage de la FEC chez les patients ayant une CCA associee a une hypercalcemie, afin d’eviter une parathyroidectomie inutile.

Resume Les agents bloquants du TNFalpha sont largement utilises dans le traitement des maladies inflammatoires chroniques et leur administration est parfois associee a la generation d’autoanticorps. Cette revue porte sur les phenomenes auto-immuns lies a l’inhibition du TNFalpha, sur les mecanismes pathogenes et les implications cliniques qui lui sont associes. Alors que la generation d’anticorps antinucleaires et, plus rarement, celle d’anticorps anti-ADN sont frequentes, le developpement de maladies auto-immunes au cours de traitements par anti-TNF est rare et necessite d’etre rapidement identifie pour une prise en charge adaptee. La presence et la nature des autoanticorps associes a la polyarthrite rhumatoide ont ete evaluees avant et apres biotherapie. Cette revue souligne egalement les points communs et les differences entre infliximab, etanercept et adalimumab dans l’induction d’auto-immunite.

Anti-TNFalpha blockers are extensively used in the management of chronic inflammatory disorders. Their administration may be associated with the generation of autoantibodies; this review focuses on the autoimmune phenomena linked to anti-TNFalpha inhibition, on the hypothesized pathogenetic mechanisms and on the clinical implications. While the development of antinuclear and, less frequently, of anti-DNA antibodies is a common finding, the onset of autoimmune diseases during anti-TNFalpha blocker treatment is a rare event, which needs to be promptly recognized in order to plan the appropriate management. Moreover the specific autoantibodies associated with rheumatoid arthritis are considered before and after biotherapy. Similarities and differences among infliximab, etanercept and adalimumab concerning induced autoimmune phenomena are underlined.

Objectives. To evaluate, in patients with ulnar neuropathy at the elbow (UNE), if ultrasonographic differences in ulnar nerve size correlate with severity score determined by electrodiagnostic studies. Methods. We examined prospectively 38 patients (50 elbows) with UNE. Patients were classified into mild, moderate and severe groups according to electrodiagnostic studies. Cross-sectional areas (CSAs) of the ulnar nerve were measured 4cm proximal to the medial epicondyle (CSA-prox), 4cm distal to the epicondyle (CSA-dist) and at the maximum CSA (CSA-max) of the ulnar nerve found between these points. We used a control group of 50 normal elbows. Results. The CSA-max in the patient group was highly correlated with the severity score obtained by electrodiagnostic studies: mild: 11.1 � 3.4mm 2 , moderate: 15.8 � 3.8mm 2 , severe: 18.3 � 5.1mm 2 (P

Objective To characterize the clinical and immunologic patterns of expression, response to therapy, and outcome of patients with Sjogren's syndrome (SS) and associated hepatitis C virus (HCV) infection who developed B cell lymphoma. Methods Various international reference centers constituted a multicenter study group with the purpose of creating a registry of patients with SS-HCV who developed B cell lymphoma. A protocol form was used to record the main characteristics of SS, chronic HCV infection, and B cell lymphoma. Results Twenty-five patients with SS-HCV with B cell lymphoma were included in the registry. There were 22 (88%) women and 3 (12%) men (mean age 55, 58, and 61 years at SS, HCV infection, and lymphoma diagnosis, respectively). The main extraglandular SS manifestations were cutaneous vasculitis in 15 (60%) patients and peripheral neuropathy in 12 (48%); the main immunologic features were positive rheumatoid factor (RF) in 24 (96%) and type II cryoglobulins in 20 (80%). The main histologic subtypes were mucosa-associated lymphoid tissue (MALT) lymphoma in 11 (44%) patients, diffuse large B cell lymphoma in 6 (24%), and follicular center cell lymphoma in 6 (24%). Fifteen (60%) patients had an extranodal primary location, most frequently in the parotid gland (5 patients), liver (4 patients), and stomach (4 patients). Twelve (52%) of 23 patients died after a median followup from the time of lymphoma diagnosis of 4 years, with lymphoma progression being the most frequent cause of death. Survival differed significantly between the main types of B cell lymphoma. Conclusion Patients with SS-HCV and B cell lymphoma are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver, and stomach).

Objective: Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database. Methods: Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile. Results: 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% Cl 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% Cl 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult-onset SSc. The OR was 1.06 and 95% Cl 0.34-3.56. Conclusion: This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult-onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of sderoderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue. (C) 2015 Elsevier Inc. All rights reserved.

Introduction Systemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility. Methods Sixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy). Results We observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, Padj = 7.22 × 10−5), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, Padj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, Padj = 2.49 × 10−4) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (Padj = 4.45 × 10−4 and Padj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (Padj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10−4) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele. Conclusions An analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0572-y) contains supplementary material, which is available to authorized users.

Objective: Systemic vasculitis (SV) are uncommon diseases that rarely affect women during their reproductive age; little data, mainly retrospective, is available on this topic. The aim of our study was to evaluate maternal/neonatal outcome and disease course before, during and after pregnancy. Methods: Sixty-five pregnancies in 50 women with SV were followed by a multispecialistic team in 8 institutions between 1995 and 2014. Clinical data on pregnancy, 1. year before and 1. year after delivery was retrospectively collected. The rate of pregnancy complications was compared to that of a General Obstetric Population (GOP) of 3939 women. Results: In 2 patients the diagnosis of SV was done during pregnancy; 59 out of the remaining 63 started when maternal disease was quiescent. We recorded 56 deliveries with 59 live births, 8 miscarriages and 1 fetal death. In SV, preterm, particularly early preterm (

Purpose. Interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary functional tests (PFTs) and semi-quantitative scores based on extent of ILD detectable on chest computed tomography (CT). CT quantitative indexes (QCTIs) are promising tools to assess extent of ILD. This study's aim is to evaluate the validity of QCTI compared with that of chest CT standard evaluation and PFTs. Moreover, QCTI differences between patients subgroups according to prognostic stratifications were investigated. Methods. ILD-SSc of patients from six rheumatological clinics was routinely assessed with chest CT and PFTs. Patients were clustered according to prognosis based on functional and/or radiological examinations. Finally, chest CTs were processed with OsiriX in order to obtain QCTI. Results. Two hundred fifty-seven SSc patients were enrolled. QCTI correlation between extent of ILD and PFTs range from - 0.60 to 0.58 and from - 0.54 to 0.52, respectively. The majority of QCTI have a different distribution in patients subgroups based on prognosis. Most of QCTI discriminate patients with an ILD severity leading to a poor prognosis. Conclusions. QCTI assessment of ILD-SSc is comparable to the evaluation based on chest CT and/or PFTs. QCTI values corresponding to severe ILD were identified. QCTIs are excellent candidates for a new and more reliable SSc-ILD assessment.

Resume Buts. – Evaluer par thermometrie numerique assistee par ordinateur l'effet des perfusions periodiques d'iloprost sur la temperature cutanee digitale des patients atteints de sclerodermie. Methodes. – Vingt-deux patients ambulatoires atteints de sclerodermie (un homme, 21 femmes, âge moyen 54,2 annees) ont subi trois mesures de la temperature cutanee par thermometrie numerique assistee par ordinateur : la premiere trois jours avant un cycle de cinq jours de perfusions d'iloprost ; la deuxieme juste a la fin du cinquieme jour de perfusion et la troisieme un mois apres le cycle de perfusion. La temperature cutanee etait mesuree dans les conditions de base, immediatement apres un test au froid et apres une periode de recuperation de 18 minutes. Les resultats sont compares a la temperature cutanee mesuree dans les memes conditions de dix sujets temoins apparies pour l'âge et le sexe. Resultats. – Avant les perfusions d'iloprost, la temperature cutanee digitale apres le test au froid et la periode de recuperation etait plus basse chez les patients atteints de sclerodermie par rapport aux sujets temoins alors qu'elle etait identique avant le test au froid. Juste apres le cycle de perfusion et un mois plus tard, la temperature cutanee digitale a la fin de la periode de recuperation est passee de 27,8 ± 5,3 °C avant le traitement a respectivement 30,4 ± 3,5 et 30,0 ± 4,5 °C ( p Conclusion. – L'administration de l'iloprost pendant cinq jours permet de normaliser la temperature cutanee digitale apres une exposition au froid non seulement immediatement apres la fin des perfusions mais egalement a un mois de distance. Malgre sa demi-vie courte, son effet sur l'endothelium est prolonge.

To determine whether homocysteine (Hcy) plasma levels are correlated with molecules indicative of endothelial cell and fibroblast activation, including endothelin-1 (ET-1) and monocyte chemoattractant protein-1 and -3 (MCP-1, MCP-3), in patients with systemic sclerosis (SSc).Eighty-two patients were enrolled in this study; the control group included 75 age- and sex-matched subjects. Plasma Hcy was determined by high-performance liquid chromatography; folic acid, and vitamin B(12) plasma levels were determined by a chemiluminescence method. ET-1, MCP-1, and MCP-3 were determined by enzyme-linked immunosorbent assay (ELISA). Analysis of the 677C--T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was performed by polymerase chain reaction (PCR) and digestion with the enzyme HinfI.Hcy levels were lower in patients whereas ET-1 was significantly higher in patients and correlated with MCP-1. Stratification of the patients on the basis of Hcy levels was not associated with any statistical difference in the concentration of ET-1, MCP-1, and MCP-3. Patients with diffuse disease presented the highest levels of ET-1 and MCP-1. The distribution of the MTHFR genotypes was not different in patients and controls.In SSc, Hcy plasma concentration does not influence ET-1, MCP-1, or MCP-3 levels. On the contrary, ET-1, a marker of vascular activation, correlates with MCP-1, a chemokine involved in the fibrotic process of SSc.

To evaluate antibodies against cyclic citrullinated peptides (anti-CCP) together with rheumatoid factor (RF), antinuclear antibodies (ANA) and C-reactive protein (CRP), in patients affected by rheumatoid arthritis (RA), before and after infliximab treatment. Twenty-seven patients (five men and 22 women, mean age of 51.9 years, mean duration of disease 12.6 years) affected by RA, refractory to conventional DMARDs, were treated with infliximab, at the conventional dosage. Before starting infliximab and after 22 weeks, on the occasion of the fifth infusion, anti-CCP antibodies were tested by ELISA method. At the same time IgM RF, ANA and CRP level were measured. Before infliximab therapy, anti-CCP antibodies resulted positive in 23 patients (85.1%); the serum level did not change after infliximab treatment; only one case negative at baseline became slightly positive after treatment. Before and after therapy RF resulted positive in 22 cases (81.4%) and 21 cases (77.7%) respectively; comparing values at baseline with those after 22 weeks of treatment with infliximab, RF levels significantly decreased, as well as CRP values. In contrast to both anti-CCP antibodies, which remained stable, and to RF, which fell after infliximab, ANA were positiveor = 1: 160 in four cases at baseline and in 12 after treatment. The titre of anti-CCP antibodies did not significantly change after anti-TNFalpha blocker administration; instead the positivity of RF significantly decreased. As opposed to antinuclear and anti-dsDNA antibodies, which may appear or increase in titre during infliximab treatment, the typical autoantibodies detectable in RA show a different trend; in fact, anti-CCP antibodies remained stable and RF decreased.

Interstitial lung disease (ILD) often complicates the course of systemic sclerosis (SSc), mainly in patients with the diffuse subset of disease and with anti-Scl70 antibody positivity1,2. Postmortem examination gives evidence that nearly all patients with SSc develop pulmonary fibrosis, although to a very different extent individually; high-resolution computed tomography (HRCT) shows interstitial lung involvement in about two-thirds of the cases2. Together with pulmonary arterial hypertension, severe pulmonary fibrosis is the leading cause of SSc-related death, as demonstrated by Steen and Medsger among the very large Pittsburgh cohort3. These data were confirmed by a study of the SSc population included in the European League Against Rheumatism Scleroderma Trials and Research group database4. With regard to the course of ILD, some patients develop severe and rapidly progressive interstitial lung involvement during the early phase of the disease, while others may show an indolent course without a relevant influence on pulmonary function or survival1,5. Assessment of lung involvement and close monitoring of lung function are therefore mandatory. During the last decade efforts have been undertaken to identify predictors of rapid deterioration in SSc lung interstitial involvement. The Scleroderma Lung Study (SLS) and the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) assembled the largest cohorts for this purpose6,7. These efforts were intended mainly to drive treatment choice, but also to avoid serial HRCT scans for patient followup to reduce radiation exposure. One of the most important findings was that, similar to idiopathic pulmonary fibrosis8, the decline in forced vital capacity (FVC) and DLCO turned out to mirror the degree of changes observed on HRCT9. An accelerated rate of decline in FVC is associated with poor survival7. Despite these attempts, … Address correspondence to Dr. F. Bonella, Department of Pneumology and Allergy, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Tuschener Weg 40, 45239 Essen, Germany. E-mail: francesco.bonella{at}ruhrlandklinik.uk-essen.de

The aim of the study was to evaluate a panel of autoantibodies in patients affected by rheumatoid arthritis (RA) treated with anti-TNFalpha blockers, and to consider a different autoantibody induction effect by infliximab and etanercept; and in addition to evaluate in these cases a relationship between antinuclear antibody (ANA) titre and both C-reactive protein (CRP) and Blys levels. Fifty-four patients (8 men, 46 women, mean age 51.4 years, mean duration of disease 13.6 years) affected by refractory RA were treated with anti-TNFalpha blockers for 12 consecutive months; 43 patients were given infliximab and 11 etanercept. At baseline and every 4 months a panel of autoantibodies consisting of rheumatoid factor, antinuclear, anti-double-stranded DNA, anti-ENA, anti-mitochondrial, anti-thyroid and anti-neutrophil cytoplasmic antibodies (ANCA) was tested. At the same time CRP level was measured. Blys level was determined at baseline and after 1 year in five cases that developed a strong positivity for ANA during infliximab therapy. In 41 cases (95.3%) treated with infliximab, ANA were detected on at least one occasion, and in almost half of these cases the titre was very high, equal to or higher than 1:1.280. On the other hand, patients treated with etanercept presented ANA positivity in a lower percentage of cases and at a low titre. No correlation was found between ANA titre and CRP level; Blys level did not present a constant trend in patients who developed a very high positivity for ANA. Anti-double-stranded DNA, anti-thyroid or ANCA were found only in a few patients, in the absence of a clinical picture indicative of systemic lupus erythematosus, autoimmune thyroiditis or ANCA-associated vasculitis. A different incidence of ANA positivity was found in infliximab- and etanercept-treated RA patients; this finding might be due to the partially different method of inhibition of TNFalpha between the two drugs. Both CRP and Blys do not seem to participate in this phenomenon. Other autoantibodies were detected in a few patients, but no case of onset of new autoimmune disorders was observed.

Salivary gland mucosa-associated lymphoid tissue (MALT) lymphomas (SGML) are rare, as are data concerning their behaviour. We analysed clinical features at presentation, particularly the association with Sjoegren syndrome (SS) and hepatitis C virus (HCV) infection, and outcome in 33 cases of SGML diagnosed between March 1985 and April 2003. There were five males and 28 females, with a median age of 61 years. At presentation, 12/33 (36%) had multiple salivary glands or mucosal involvement and four had bone marrow infiltration. Ann Arbor stage was IE in 15 (46%), IIE in four (12%) and IV in 14 patients (42%). Fifteen patients had a history of SS (46%), two of other autoimmune diseases, seven of HCV infection. No case had both SS and HCV. Of the 29 treated patients, 17 received surgery or local radiotherapy; 69% achieved complete remission. Histological transformation occurred in four (12%). Five patients died (three of lymphoma, two of unrelated causes). The 5 year-overall survival (OS), cause-specific survival and progression-free survival was 85 +/- 8%, 94 +/- 6% and 65 +/- 10% respectively. Overall, the disease course was indolent, despite the advanced stage at diagnosis, and local therapy often appeared to be adequate. The only prognostic factors influencing OS were histological transformation and age. The close association of SGML with either autoimmune diseases or HCV infection in our series (73%) confirms their possible role in the pathogenesis of these lymphomas.

Resume Objectifs . Etude de la frequence, de la specificite et de la correlation avec la clinique, des anticorps anti-cytoplasme des polynucleaires neutrophiles (ANCA) chez les patients atteints de sclerodermie. Methodes . Il a ete recherche, chez 62 patients atteints d’une sclerodermie systemique, a forme cutanee limitee ou diffuse, des anticorps anti-proteinase 3 (PR3) et anti-myeloperoxydase (MPO) par methode ELISA. Resultats . Il a ete trouve des ANCA chez deux patients atteints d’une sclerodermie systemique diffuse. Un patient avait un faible taux d’anti-MPO en l’absence d’atteinte renale. L’autre patient avait une atteinte cutanee et pulmonaire rapidement progressive associee a un taux eleve d’anti-PR3. Conclusion . Notre etude confirme la faible incidence des ANCA au cours de la sclerodermie (3,2 %). Nous rapportons le premier cas de presence d’anti-PR3 dans cette maladie.

Objective\ud \ud The role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region.\ud \ud Methods\ud \ud C5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method.\ud \ud Results\ud \ud Even though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases.\ud \ud Conclusions\ud \ud Our results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation.

Objective. The objective of this study was to analyse an association between nailfold capillary abnormalities and the presence and severity of erectile dysfunction (ED) in men with SSc. Methods. A cross-sectional analysis of the prospective European League Against Rheumatism (EULAR) Scleroderma Trial and Research database was performed. Men with SSc were included if they had undergone nailfold capillaroscopy and simultaneous ED assessment with the 5-item International Index for Erectile Function (IIEF-5). Results. Eighty-six men met the inclusion criteria. Eight men (9.3%) had not had sexual intercourse and could not be assigned an IIEF-5 score. Sixty-nine of the 78 men (88.5%) with an IIEF-5 score had nailfold capillary abnormalities, of whom 54 (78.3%) suffered from ED. Nine men (11.5%) had no nailfold capillary abnormalities, of whom six (66.7%) had ED (P = 0.44). ED was more frequent in older men (P = 0.002) and in men with diffuse disease (P = 0.06). Men with abnormal capillaroscopy had a higher median EULAR disease activity than men without (P = 0.02), a lower diffusing capacity of the lung (P = 0.001) and a higher modified Rodnan skin score (P = 0.04), but mean IIEF-5 scores did not differ [15.7 (S.D. 6.2) vs 15.7 (S.D. 6.3)]. IIEF-5 scores did not differ between men with early (n = 12), active (n = 27) or late (n = 27) patterns (IIEF-5 scores of 17.9, 16.3 and 14.7, respectively). There were no differences in the prevalence of early, active and late capillaroscopy patterns between men with or without ED. Conclusion. Neither the presence or absence of abnormal capillaroscopy findings nor the subdivision into early, active and late patterns is associated with coexistent ED in SSc.

SummaryPrevious thrombosis, diagnosis of systemic lupus erythematosus (SLE) and triple antiphospholipid (aPL) antibody positivity have recently been found to be independent factors associated to pregnancy failure during conventional therapy in women with antiphospholipid syndrome (APS). This study aimed to assess the effect of various treatment strategies on pregnancy outcomes in women with APS and the risk factors for pregnancy failure. One hundred ninety-six pregnancies of 156 patients diagnosed with APS were analysed: 118 (60.2%) of these had previous thrombosis, 81 (41.3%) were diagnosed with SLE, and 107 (54.6%) had triple aPL positivity. One hundred seventy-five (89.3%) were treated with conventional therapies (low-dose aspirin [LDA] or prophylactic doses of heparin + LDA or therapeutic doses of heparin + LDA), while 21 (10.7%) were prescribed other treatments in addition to conventional therapy. The pregnancies were classified into seven risk profiles depending on the patients’ risk factors – thrombosis, SLE, and triple aPL positivity – and their single, double or triple combinations. It was possible to find significant difference in outcomes correlated to treatments only in the thrombosis plus triple aPL positivity subset, and logistic regression analysis showed that additional treatments were the only independent factor associated to a favourable pregnancy outcome (odds ratio=9.7, 95% confidence interval= 1.1–88.9, p-value