Manuel Ramos-Casals

IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcino, Catalonia, Spain

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Publications (292)1564.21 Total impact

  • P. Brito-Zeron · PM Izmirly · M. Ramos-Casals · JP Buyon · MA Khamashta
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    ABSTRACT: Autoimmune congenital heart block (ACHB) is an immune-mediated cardiac disease included among the manifestations collectively referred to as neonatal lupus. The placental transference of maternal Ro/La autoantibodies may damage the conduction tissues during fetal development leading to blocking of signal conduction at the atrioventricular (AV) node in an otherwise structurally normal heart. Irreversible complete AV block is the main cardiac manifestation of ACHB, but some babies may develop endocardial fibroelastosis, valvular insufficiency, and/or frank cardiomyopathies with significantly reduced cardiac function requiring transplant. The severity of ACHB is illustrated by a global mortality rate of 20% and pacemaker rates of at least 64%, often within the first year of life. This review analyses the main complex and/or unusual clinical situations associated with ACHB, including unusual maternal immunological profiles, infrequent maternal autoimmune diseases, cardiac damage unrelated to AV block, fetal invasive management, late complications after birth, risk of congenital heart block (CHB) in ovodonation and in vitro fertilization techniques, the role of maternal features other than autoimmunity, the influence of the birth order or the risk of CHB in twins and triplets.
    No preview · Article · Feb 2016 · Lupus
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    ABSTRACT: Sjögren's syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands, leading to generalized mucosal dryness. However, primary SjS may initially present with non-sicca (systemic) manifestations. When these features appear before the onset of an overt sicca syndrome, we may talk of an underlying 'occult' SjS. The European League Against Rheumatism (EULAR) has promoted and supported an international collaborative study group (EULAR-SS Task Force) aimed at developing consensual recommendations to provide a homogeneous approach to the patient with primary SjS presenting with systemic involvement. This review summarizes the key factors that should be taken into account in the diagnostic approach in a patient with suspected SjS according to the main clinical patterns of presentation, and is especially focused on organ-specific systemic disease presentations, including a consensus set of recommendations in order to reach an early diagnosis. Close collaboration with the different specialties involved through a comprehensive multidisciplinary approach is essential in SjS patients presenting with systemic involvements.
    No preview · Article · Dec 2015 · Expert Review of Clinical Immunology
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    ABSTRACT: The objective was to estimate the prevalence of chronic widespread pain (CWP) and compare the quality of life (QoL), cardiovascular risk factors, comorbidity, complexity, and health costs with the reference population.A multicenter case-control study was conducted at three primary care centers in Barcelona between January and December 2012: 3048 randomized patients were evaluated for CWP according to American College of Rheumatology definition. Questionnaires on pain, QoL, disability, fatigue, anxiety, depression, and sleep quality were administered. Cardiovascular risk and the Charlson index were calculated. We compared the complexity of cases and controls using Clinical Risk Groups, severity and annual direct and indirect healthcare costs.CWP criteria were found in 168 patients (92.3% female, prevalence 5.51% (95%CI: 4.75% - 6.38%)). CWP patients had worse QoL (34.2 vs 44.1, p<0.001), and greater disability (1.04 vs 0.35; p<0.001), anxiety (43.9% vs 13.3%; p<0.001), depression (27% vs 5.8%; p<0.001), sleep disturbances, obesity, sedentary lifestyle, high blood pressure, diabetes mellitus and number of cardiovascular events (13.1% vs 4.8%; p = 0.028) and higher rates of complexity, severity, hospitalization, and mortality. Costs were &OV0556; 3,751 per year in CWP patients vs. &OV0556; 1,397 in controls (p<0.001).In conclusion, the average CWP patient has a worse QoL and a greater burden of mental health disorders and cardiovascular risk. The average annual cost associated with CWP is nearly three times higher than that of patients without CWP, controlling for other clinical factors. These findings have implications for disease management and budgetary considerations.
    Full-text · Article · Dec 2015 · Pain
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    ABSTRACT: Introduction We conducted a study to analyze how infection by hepatitis C virus (HCV) may influence the immunological serum pattern of patients with Sjögren syndrome (SS). Methods Since 1994, we have tested serum HCV-IgG antibodies in 783 patients with SS diagnosed according to the 1993 European classification criteria. The immunological profile at diagnosis was compared according to the presence or absence of HCV. Results Of the 783 patients with SS, 105 (13.4 %) tested positive for HCV-IgG antibodies (88 females, 17 males, mean age at SS diagnosis: 62.9 years). Multivariate analysis showed that patients with SS-HCV had a higher mean age and a higher frequency of low C3/C4 levels, cryoglobulins, and hematological neoplasia compared with patients without HCV. The frequency of anti-La antibodies compared with anti-Ro antibodies was higher in patients with SS-HCV (17 % vs. 15 %) and lower in patients without HCV infection (30 % vs. 43 %). The frequency of concomitant detection of the three main cryoglobulin-related markers (cryoglobulins, rheumatoid factor activity, and C4 consumption) was threefold higher in patients with SS-HCV compared with patients without HCV. SS-HCV patients with genotype 1b showed the highest frequencies of immunological abnormalities related to cryoglobulins and the lowest frequencies of anti-Ro/La antibodies. Conclusions We found HCV infection in 13 % of a large series of Spanish patients with SS. The HCV-driven autoimmune response was characterized by a lower frequency of anti-Ro/La antibodies, an abnormal predominance of anti-La among anti-Ro antibodies, and a higher frequency of cryoglobulinemic-related immunological markers in comparison with patients without HCV infection. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV.
    Preview · Article · Dec 2015 · Arthritis Research & Therapy
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    ABSTRACT: Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan-Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors.
    No preview · Article · Oct 2015 · Medicine
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    ABSTRACT: To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort. Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores. There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P < 0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P ≤ 0.02) scores compared to patients with normal values. LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Sep 2015 · Rheumatology (Oxford, England)
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    ABSTRACT: Background and aims: We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. Methods: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. Results: We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point). Conclusions: Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.
    Full-text · Article · Sep 2015 · Annals of the rheumatic diseases
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    ABSTRACT: Objective: To reach a European consensus on the definition and characterization of the main organ-specific extraglandular manifestations in primary SS. Methods: The EULAR-SS Task Force Group steering committee agreed to approach SS-related systemic involvement according to the EULAR SS Disease Activity Index (ESSDAI) classification and proposed the preparation of four separate manuscripts: articular, cutaneous, pulmonary and renal ESSDAI involvement; muscular, peripheral nervous system, CNS and haematological ESSDAI involvement; organs not included in the ESSDAI classification; and lymphoproliferative disease. Currently available evidence was obtained by a systematic literature review focused on SS-related systemic features. Results: The following information was summarized for articular, cutaneous, pulmonary and renal involvement: a clear, consensual definition of the clinical feature, a brief epidemiological description including an estimate of the prevalence reported in the main clinical series and a brief list of the key clinical and diagnostic features that could help physicians clearly identify these features. Unfortunately we found that the body of evidence relied predominantly on information retrieved from individual cases, and the scientific information provided was heterogeneous. The analysis of types of involvement was biased due to the unbalanced reporting of severe cases over non-severe cases, although the main sources of bias were the heterogeneous definitions of organ involvement (or even the lack of definition in some studies) and the heterogeneous diagnostic approach used in studies to investigate involvment of each organ. Conclusion: The proposals included in this article are a first step to developing an optimal diagnostic approach to systemic involvement in primary SS and may pave the way for further development of evidence-based diagnostic and therapeutic guidelines.
    No preview · Article · Jul 2015 · Rheumatology (Oxford, England)
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    ABSTRACT: Hemophagocytic syndromes (hemophagocytic lymphohistiocytosis, HLH) are characterized by a wide range of etiologies, symptoms, and outcomes, but have a common etiopathogenic pathway leading to organ damage: an excessive inflammatory response. Biological therapies have been proposed as a therapeutic option for refractory HLH, but have also been related to the development of HLH in severe immunosuppressed patients. The purpose of this study was to analyze the clinical characteristics and outcomes of adult patients who developed HLH after receiving biological therapies. We identified 30 patients (29 from the PubMed search and one unpublished case), including 19 women and 11 men, with a mean age of 46.5 years. Underlying diseases consisted of rheumatologic/autoimmune diseases in 24 patients and hematological neoplasia in the remaining 6. Biological agents received before the development of HLH were mainly anti-TNF agents (n = 19). Search for microorganisms confirmed systemic infection in 20 (67%) patients, including Mycobacterium tuberculosis (n = 5), cytomegalovirus (CMV) (n = 4), Epstein-Barr virus (EBV) (n = 3), Histoplasma capsulatum (n = 3), Escherichia coli (n = 2), Staphylococcus aureus, Leishmania amastigotes and Brucella melitensis (n = 1, respectively); viral infections were mainly reported in inflammatory bowel disease (IBD) patients. Patients with infections had more frequently received previous immunosuppressive therapies (p = 0.036) and had lower leukocyte counts (p = 0.020) in comparison with patients without associated infections. The outcome was described in 29 patients. After a mean follow-up of 6.3 months, 8 patients died (28%) and 6 had received anti-TNF agents. There was a high mortality rate in patients aged >65 years and those with tuberculosis (62% and 60%, respectively). In patients receiving biological therapies who develop HLH, searching for a concomitant infectious process is mandatory, and specific surveillance for EBV/CMV infections (in patients with IBD) and for bacteria, including mycobacteria (in elderly patients receiving anti-TNF therapy), is recommended. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Seminars in arthritis and rheumatism
  • John H Stone · Pilar Brito-Zerón · Xavier Bosch · Manuel Ramos-Casals
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    ABSTRACT: IgG4-related disease (IgG4-RD) is a systemic disease characterized by the infiltration of IgG4-bearing plasma cells and, more importantly, distinctive histopathological features: storiform fibrosis, obliterative phlebitis, a lymphoplasmacytic infiltrate, and mild-to-moderate tissue eosinophilia. The diagnostic approach is complex and relies on the coexistence of various clinical, laboratory, and histopathological findings, none of which is pathognomonic in and of itself. IgG4-related disease should be suspected in patients presenting with unexplained enlargement or swelling of 1 or more organs or tissue organs. Four laboratory abnormalities often provide initial clues to the diagnosis of IgG4-RD: peripheral eosinophilia, hypergammaglobulinemia, elevated serum IgE levels, and hypocomplementemia. Elevated serum IgG4 levels provided critical information in identifying the first cases of IgG4-RD, but recent studies have reported substantial limitations to the measurement of serum IgG4 concentrations, precluding reliance on serum IgG4 concentrations for diagnostic purposes. In contrast, new studies have suggested a promising role of flow cytometry studies in the diagnosis and longitudinal management of IgG4-RD. Demonstration of the classic histopathological features of IgG4-RD remains crucial to diagnosis in most cases, and biopsy proof is preferred strongly by most disease experts before the initiation of treatment. Of note, the multiorgan nature of IgG4-RD was first established in 2003. This review intends to provide most recent knowledge about the clinical, laboratory, radiological, and pathological characteristics of IgG4-RD that may guide the physician to establish an early diagnosis. We searched PubMed and MEDLINE for relevant articles published between January 1, 2000, and November 1, 2014, using the search terms IgG4 and IgG4-related. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Mayo Clinic Proceedings
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    ABSTRACT: Objectives To analyze the main maternal-fetal characteristics of pregnancies affected by autoimmune congenital heart block (CHB) associated with maternal anti-Ro/La antibodies, the outcomes and management of affected pregnancies with CHB. Methods The REBACC Spanish Multicenter Registry was created in March 2014. It is integrated by 11 centers with substantial experience in the management of systemic autoimmune diseases. Autoimmune CHB was defined as: a) CHB of any type (I, II or III), fetal endocardial fibroelastosis (EFE) and/or cardiomyopathy, b) cardiac block diagnosed in utero or in the first postpartum month, and c) mothers carrying anti-Ro52, Ro60 and/or La autoantibodies. Results On January the 15th, 2015, the REBACC Registry included a total of 40 anti-Ro and/or anti-La+ mothers with 45 single pregnancies with CHB. Mean maternal age at the time of first affected pregnancy with CHB was 31.77 years (range: 22-44). Twenty-eight (70%) mothers did not have any autoimmune disease and the remaining 30% had Sjögren syndrome (n=5), SLE (n=5) and undifferentiated disease (n=2). All mothers were anti-Ro60 (+), 13/13 anti-Ro52 (+) and 29/39 (74%) anti-La (+). The mean gestational age at diagnosis of CHB was 23 weeks (range 16-37). AV blocks were of type I in 2 pregnancies (5%), type II in 13 (32.5%) and type III in 24 (60%); 1 had an isolated EFE (2.5%). Therapies used in 26/40 (65%) pregnancies included dexamethasone or betamethasone (n=24), intravenous immunoglobulins (n=5), plasmapheresis (n=3), beta2-adrenergic agonists (n=2), isoproterenol (n=1). A change of block type was seen in 4 (10%) pregnancies: 1 type II regressed to normal sinus rhythm after birth and 2 type II and 1 type I progressed to type III block. Nine pregnancies were interrupted due to bad fetal prognosis (22.5%) and 31 (77.5%) were successfully carried to term. Pacemaker implantation was required in 16 babies (55%), 14 after birth, 1 at 5 years and another at 12 years of age. Of the 30 women who initially did not have any autoimmune disease, 19 (63%) developed a systemic autoimmune disease at the end of the index pregnancy: SS (n=13), SLE (n=5), SS/SLE (n=1). After the index pregnancy, 12 mothers had another pregnancy with 3 (25%) babies affected with CHB: 2 type III AV block and 1 type I AV block. Four mothers subsequently had a third pregnancy, of which, 2 (50%) were affected by type III CHB diagnosed at 23.5 and 20 weeks. One mother had a fourth and firth pregnancy, none affected by CHB. Conclusions More than half alive-babies with CHB required pacemaker implantation. The recurrence rate of CHB after a first affected baby was of 25% for the second baby, and of 50% for the third baby. Two out of 3 asymptomatic mothers at the time of diagnosis of the index CHB case developed a systemic autoimmune disease (overwhelmingly Sjögren syndrome) at the end of follow-up. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives To analyse the epidemiological, clinical and immunological characteristics of an international cohort of patients diagnosed with primary Sjögren syndrome (SS) according to the 2002 AE criteria. Methods The Big Data Sjögren Project is an international, multicentre registry formed in 2014 to take a “high-definition” picture of the main features of primary SS at diagnosis by merging international SS databases. By January 2015, 5027 consecutive patients fulfilling the 2002 classification criteria for primary SS were included from 9 European and 4 American countries. Results The cohort included 4714 (94%) women (female:male ratio, 15:1), with a mean age at diagnosis of primary SS of 54 years (range, 10-97), of which 94% were Caucasian and 88% lived in European countries. The frequency of fulfilment of the 2002 criteria was: 94.4% for dry eye, 92.9% for dry mouth, 88.5% for positive salivary gland biopsy, 85.9% for positive ocular tests, 74.8% for positive oral tests and 70.9% for positive Ro/La autoantibodies. As a minimum of 4 of the 6 criteria are required for fulfilment, the percentage of diagnostic tests performed varied: Ro/La autoantibodies were tested in 99.5% of patients, ocular diagnostic tests (Schirmer's test and/or corneal stainings) were made in 90.2%, oral tests in 76.7% and salivary gland biopsy in 72% of patients. Systemic involvement at diagnosis was retrospectively measured using ESSDAI definitions in 3314 patients and included articular involvement (35.2%), glandular involvement (19.3%), lymphadenopathy (10.7%), cutaneous involvement (9%), constitutional involvement (8.4%), respiratory involvement (7.3%), peripheral nervous system involvement (5.2%), renal involvement (2.2%), central nervous system involvement (1.7%) and muscular involvement (1.2%). With respect to laboratory abnormalities, 43.3% of patients showed biological abnormalities and 24.7% haematological abnormalities according to ESSDAI definitions. Conclusions In this international cohort of 5027 patients with primary SS, most non-sicca clinical features and laboratory abnormalities present at diagnosis are not included in the current criteria; their inclusion in future proposed classification criteria should be evaluated. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives To evaluate extrapulmonary activity and correlate baseline features at diagnosis with survival in a large cohort of patients with sarcoidosis. Methods We studied 170 patients consecutively diagnosed with sarcoidosis in the last 10 years. The diagnosis of sarcoidosis was based on clinical criteria and imaging studies, together with the histopathological demonstration of non-necrotizing granulomas, and the exclusion of other granulomatous diseases, especially infections (tuberculosis). Extrapulmonary involvement was defined according to the criteria defined by Judson et al, 2011. Results There were 111 (65%) women and 59 (35%) men, with a mean age at diagnosis of 47.49 years (range 17-92). The main clinical manifestations present at diagnosis were respiratory symptoms in 112 (66%) patients, erythema nodosum in 35 (21%), articular involvement in 35 (21%) and fever in 34 (20%) patients; incidental imaging findings in asymptomatic patients was found in 12% of cases. After a mean follow-up of 107.4 months, 21 (12%) patients died. The main causes of death were infections in 4 patients, cardiovascular disease in 2, pulmonary sarcoidosis in 1, neoplasia in 1 and other causes in 2 patients; in the remaining 11 patients, the cause of death was unknown or unclassifiable. Survivors had a lower mean age (44.82 yrs. vs. 65.95 yrs. p<0.001) and a statistical trend to higher mean levels of serum angiotensin-converting enzyme (ACE) (105.78 U/L vs. 64.58 U/L, p=0.16). The mortality rate was higher in patients born in Spain (16% vs. 0% in those born outside Spain, p=0.008). Extrapulmonary involvement was unrelated to death (mortality rate of 11% vs. 14% in patients with pulmonary involvement). Multivariate analysis identified mean age at diagnosis (p<0.001) as an independent risk factor associated with death. Conclusions Extrapulmonary involvement in sarcoidosis is not associated with mortality. An older age at diagnosis was the principal risk factor associated with death, while patients born outside Spain had a lower mortality rate, and mean ACE levels at diagnosis were inversely associated with survival. The very-low rate of deaths caused directly by sarcoidosis might explain our results. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives To analyse the epidemiological, clinical and analytical features at diagnosis and the use of the European systemic activity index (ESSDAI) to predict the development of cancer in a large cohort of Spanish patients with primary Sjogren syndrome (SS). Methods The GEAS-SS multicenter registry was formed in 2005 with the aim of collecting a large series of Spanish patients with primary SS, and included thirteen Spanish reference centers with substantial experience in the management of SS patients. By January 2015, the database included 1216 consecutive patients fulfilling the 2002 classification criteria for primary SS. ESSDAI scores were retrospectively calculated at diagnosis. Disease activity states (DAS) were defined according to the baseline ESSDAI score (low DAS for an ESSDAI <4, moderate DAS for an ESSDAI between 5 and 13, and high DAS for an ESSDAI higher than 13). Cancer was categorized as hematological or solid neoplasia. Results After a mean follow-up of 114 months, 84 (7%) patients developed solid cancer and 52 (4%) hematological neoplasia. The following baseline features at diagnosis were associated with the development of hematological neoplasia: male gender (19% vs 6%, p<0.001), age at diagnosis (59 vs 54 yrs, p<0.001), baseline systemic activity (75% vs 51%, p=0.001), neutropenia (19% vs 9%, p=0.028), C3 values <0.82 g/L (19% vs 10%, p=0.048), C4 values <0.07 g/L (24% vs 12%, p=0.02), monoclonal serum band (27% vs 8%, p<0.001) and cryoglobulins (30% vs 9%, p<0.001). In contrast, only age (59 vs 54 yrs, p<0.001) and neutropenia (21% vs 9%, p=0.001) were related to the development of solid neoplasia. High systemic activity (high-DAS) was found in a higher frequency in patients who developed hematological in comparison with those who developed solid neoplasia or those without neoplasia (79% vs 24% vs 21%, p<0.001). Conclusions Systemic and biological activity is closely related to the development of lymphoma in primary SS. Etiopathogenic factors such as B-cell hyperactivity and monoclonal, cryoglobulinemic-driven immunological responses have a dual effect, enhancing the risk of development of both systemic involvement and hematological neoplasia, but not the risk of solid neoplasia, whose development is independent of systemic Sjögren. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives To score systemic activity at diagnosis and correlate baseline activity classified according to the ESSDAI disease activity states with poor outcomes in a large cohort of patients with primary Sjögren syndrome (SS). Methods We include 1216 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of systemic activity were assessed at diagnosis as predictors of poor outcomes (lymphoma and death) using Cox proportional-hazards regression analysis adjusted for age at diagnosis. European systemic activity index (ESSDAI) scores were retrospectively calculated at diagnosis. Disease activity states (DAS) were defined according to the baseline ESSDAI score (low DAS for an ESSDAI <4, moderate DAS for an ESSDAI between 5 and 13, and high DAS for an ESSDAI higher than 13). Results After a mean follow-up of 114 months, 52 (4%) patients developed hematological neoplasia and 139 (11%) died. The most frequent systemic activity reported at the time of SS diagnosis included articular (37%), biological (35%), hematology (30%) and glandular (24%) involvements. At diagnosis, 138 (11%) patients showed a high DAS, 385 (32%) a moderate DAS, 422 (35%) a low DAS and 266 (22%) had no systemic activity (ESSDAI =0). No significant differences in the main baseline features were found according to the DAS except for the age at SS diagnosis, which was higher in patients with a high DAS (57 yrs vs 53 yrs for moderate DAS, 54 for low DAS and 56 for no activity, p=0.019). Patients who showed a high DAS at diagnosis of SS developed more frequently hematological neoplasia and had a poor survival in comparison with patients who showed no systemic activity (ESSDAI =0) (19% vs 2%, p<0.001, and 19% vs 11%, p=0.032, respectively). Patients with a high-DAS at diagnosis developed more frequently cancer in comparison with those without high baseline activity (21% vs 10%, p<0.001); however, a high DAS was related to a higher frequency of hematological neoplasia but to a lower frequency of solid neoplasia (18% vs 2.5%, 2.9% vs 7.5%, p<0.001). Conclusions Categorization of baseline systemic activity using the ESSDAI disease activity states at diagnosis of primary Sjögren syndrome is useful to identify patients with a high risk of developing poor outcomes; patients who present at diagnosis with ESSDAI≥14 (high DAS) should be considered a high-risk population and should be followed more closely than those with no systemic activity. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Serum cryoglobulins (SC) may be found in many diseases (1), and the presence of serum cryoglobulins is a known risk factor for lymphoma evolution in some non malignant diseases. Objectives The aim of this study was to distiguish the role of cryoglobulinemic vasculitis (CV), classified according to the recent validated criteria (1,2), and primary Sjögren's syndrome (pSS) as risk factors of lymphoma in patients positive serum cryoglobulins. Importantly, SC, CV and pSS may occur together. Methods 950 charts from consecutive patients with positive SC were evaluated. Patients carrying both pSS and HCV infection, as well as incomplete charts, were excluded. Results 657 patients with SC were selected, 374 with CV and 283 without CV, according to the published criteria (2,3). PSS, classified according to the American-European Group Criteria was present in 96 patients (44 with CV, 52 without). Lymphoma was reported in 61/657 (9.8%) patients with SC. Among them, CV was present in 44/61 (72,1%; 14 also with pSS), and pSS in 17/61 (27,9%; and 14/17 had CV). Patients with SC with CV showed an higher prevalence of lymphoma than patients with SC without CV (44/374, 11.5% vs.17/283, 6.3%; p=0.025, OR=1.93 [95%IC: 1.08-3.39]. Patients with pSS, SC and CV also showed a higher prevalence of lymphoma than patients with pSS, SC but without CV (14/44, 31.8% vs. 3/52, 7.4%; p=0.001, OR=7.62 [95%CI 2.02-28.74]. CV and pSS were confirmed as independent risk factor for lymphoma by multivariate analysis (OR 2,18 95%CI 1,18-3,83, p=0,012; OR 2,65 95%CI 1,04-6,76, p=0,042, respectively). Infection by the hepatitis C virus (HCV) was detected in 467/561 (83,2%) patients with SC without pSS, and did not statistically predispose to lymphoma when associated with CV in this subset (p=1,0). Conclusions Cryoglobulinemic vasculitis and pSS are independent risk factors for lymphoma in patients with evidence of SC. Patients with both the conditions (CV and pSS) have the highest risk. In the follow-up of SC positive patients, a very high attention should be deserved to pSS, in particular when CV is present. References Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Antimitochondrial antibodies (AMA) are autoantibodies directed against proteins of the outer and inner mitochondrial membrane. M2 antibodies stand out because of their high sensitivity and specificity for the identification of primary biliary cirrhosis. Objectives To analyse the prevalence of AMA and M2 autoantibodies in a large cohort of Spanish patients with primary Sjogren syndrome (SS), and to correlate positive results with epidemiological, clinical and immunological expression of the disease. Methods The GEAS-SS multicenter registry was formed in 2005 with the aim of collecting a large series of Spanish patients with primary SS. The cumulated ESSDAI index (2010 EULAR-SS disease activity index) was retrospectively calculated at diagnosis. AMA were detected by indirect immunofluorescence in triple rat tissue and M2 autoantibodies by ELISA against M2 proteins (PDC-E2, BCOADC-E2, OGDC-E2). Results AMA were tested consecutively in 733 patients with primary SS (688 women, mean age at diagnosis of 54.65 yrs), of whom 63 (9%) showed positive results. No significant differences were found in the main epidemiological, clinical and immunological features according to the presence or absence of AMA, except for a higher frequency of anti-Ro/SSA antibodies (83% vs 68%, p=0.015) and leucopenia (33% vs 21%, p=0.038) in AMA+ patients in comparison with those with negative AMA. M2 autoantibodies were tested in 210 patients, of whom 19 (9%) were positive. Comparison of the main epidemiological, clinical and immunological features according to the presence or absence of anti-M2 antibodies showed a higher frequency of anti-Ro/SSA antibodies (95% vs 74%, p=0.049), leucopenia (53% vs 19%, p=0.002), neutropenia (48% vs 22%, p=0.025), low C4 levels (26% vs 6%, p=0.008) and biological activity measured by the ESSDAI (84% vs 50%, p=0.007). We have the paired determination of AMA and anti-M2 in 23 patients with positive results: 12 have concordant positive results and 11 discordant (7 had negative AMA with positive M2, and 4 positive AMA with negative M2). The mean value of M2 autoantibodies in AMA+ patients was twice than in those with negative AMA, although the difference was not statistically significant (85.67 vs 41.51, p=0.126). Conclusions The study showed three key messages: i) the prevalence of AMA/M2 in primary SS was of 9%; ii) AMA/M2 correlated with the coexistence of Ro autoantibodies but not with systemic Sjögren; and iii) nearly half the patients showed discordant results between AMA and M2 positivities. We recommend the use of M2-ELISA to test for AMA in patients with primary SS. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives To characterize and quantify systemic involvement at diagnosisinalarge international cohort of patients diagnosed with primary Sjogren syndrome (SS). Methods The Big Data Sjögren Project is an international, multicenter registry formed in 2014 with the aim of taking a “high-definition” picture of the main features of primary SS at diagnosis by merging international SS databases. By January 2015, the database included 5027 consecutive patients fulfilling the 2002 classification criteria for primary SS from 13 countries (9 European, 4 American). Systemic involvement was defined according to the ESSDAI and retrospectively calculated. Results Baseline ESSDAI data was collected in3314 patients (94% female, mean age at diagnosis 54.25 years). The main features of systemic involvement at diagnosis included biological activity in 43%of patients, articular involvement in 35%, hematological activity in 25%and glandular involvementin 19%. The mean ESSDAI score at diagnosis of the entire cohort was 5.63 (range, 0-62). Low DAS was reported in 1267 (38%) patients, moderate DASin 943 (28%) and high DAS in 378 (11%) patients; in the remaining 726 patients (22%), the ESSDAI score at diagnosis was 0. The mean baseline ESSDAI was higher in males (7.33 vs 5.52, p<0.001), patients diagnosed ≤35 years (6.71 vs 5.63, p=0.001), those with positive ocular tests (5.75 vs 4.98, p=0.023) and those with positive immunological markers including ANA (6.71 vs 4.63, p<0.001), RF (7.46 vs 5.49, p<0.001), anti-Ro/SSA (6.77 vs 5.48, p<0.001) and anti-La/SSB (6.91 vs 6.0, p<0.001). According to the number of criteria fulfilled at diagnosis, a higher mean baseline ESSDAI was found in patients fulfilling the six criteria (7.67 vs 5.65 in those fulfilling 5 criteria and 5.23 in those fulfilling 3-4 criteria, p<0.001). Conclusions Epidemiological features (male sex, younger age at diagnosis) and positive autoantibodies at diagnosis were closely-related to greater systemic activity. Using the ESSDAI in real-life situations may help identify epidemiological and immunological subsets with high systemic activity at diagnosis and, therefore, at high risk of suffering a complicated clinical course. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives The aim of this study was to evaluate the temporal association between the diagnosis of neoplasia and sarcoidosis in a large cohort of Spanish sarcoidosis patients. Methods We included 170 patients consecutively diagnosed with sarcoidosis. The diagnosis of sarcoidosis was based on clinical criteria and imaging studies, together with the histopathological demonstration of non-necrotizing granulomas, and excluding other granulomatous diseases. The diagnosis of neoplasia was recorded before and after the diagnosis of sarcoidosis. Hematological neoplasias were classified according to the 2008 WHO Classification. Results There were 111 (65%) women and 59 (35%) men (mean age at diagnosis, 47 years); 23 (13.5%) patients developed 25 neoplasias (two patients developed 2 neoplasias, before and after the diagnosis of sarcoidosis). There were 13 (52%) solid neoplasias, including pulmonary (n=3), thyroid (n=2), breast (n=2), melanoma (n=2) and cervix, testicular, renal and gastric cancer (1 case each). The remaining 12 (48%) were hematological neoplasias, mainly mature B-cell neoplasms (3 chronic lymphocytic leukemia, 3 extranodal MALT lymphomas and 2 diffuse large B-cell lymphoma), but also 2 acute leukemias (1 acute promyelocytic PML-PARA, 1 acute myeloid leukemia), 1 mature T-cell neoplasia (mycosis fungoide) and 1 myeloid neoplasia (essential thrombocytopenia). No significant differences were found in the main epidemiological, clinical or radiological features of sarcoidosis in patients with or without associated neoplasia, except for a statistical trend to a higher frequency of extrathoracic sarcoidosis in patients with associated cancer (70% vs 50%, p=0.11). Of the 23 patients with cancer, 5 were diagnosed before sarcoidosis and 16 after the diagnosis of sarcoidosis (10 solid and 6 hematological neoplasia); the 2 remaining patients developed a second neoplasia after the diagnosis of sarcoidosis. Conclusions We identified four states of association between sarcoidosis and malignancy: i) patients with sarcoidosis who develop solid tumors (43%); ii) development of hematologic malignancies, mainly sarcoidosis-lymphoma syndrome (26%); iii) development of sarcoidosis in patients with neoplasia, including paraneoplastic sarcoidosis (cancer discovered concurrently ±1 year of the diagnosis of sarcoidosis) in 3 patients (22%); iv) patients with sarcoidosis and previous cancer who developed a second and different neoplasia (9%). Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background ESSDAI is a validated activity index in primary Sjögren's syndrome more and more used in clinical trials but also for finding biomarkers associated with activity of the disease. In this context, the presence of the biological domain in the ESSDAI score may induce circular reasoning and colinearity of data. Objectives To develop the ClinESSDAI, derived from the ESSDAI score after deleting biological domain, and to validate if by comparison with the original ESSDAI. Methods The 702 fictive vignettes created using data from 96 real cases of pSS for the study of development ESSDAI were used. As for the development of the original score, the assessment by the 39 experts who participated to the development study of disease activity using a scale ranging from 0-10 was used as the “gold standard” for weighting domains in the robust regression model. The explanatory variables included all domain of ESSDAI except the biological domain. The ClinESSDAI was compared to original ESSDAI to assess if it could be a surrogate of the original score by assessing its reproducibility using ESSDAI as gold standard. The validity of ClinESSDAI (including construct validity, reliability and sensitivity to change) was then assessed and compared to that of ESSDAI. Validation populations included the 96 real cases and the 395 patients of the EULAR cohort. Results In the multivariate model, each of the 11 areas was significantly associated with disease activity. The weight of the domains was slightly different from the fields of ESSDAI (table). The ClinESSDAI was an excellent surrogate of the original ESSDAI, since the ICC between ESSDAI and ClinESSDAI were0.98 [0.97; 0.98] for fictive vignettes, 0.99 [0.98; 0.99] for the real case and0.90 [0.87; 0.92] in the EULAR cohort. Psychometric properties of the ClinESSDAI (construct validity, reliability and sensitivity to change) were very close to that of ESSDAI. Conclusions Declination of the ESSDAI score without biological domain appears valid and very close to the original score. In this score, weights of some domains changed. This score will allow an evaluation of disease activity that is independent ofB-cell biomarkers, which will be useful in biological studies to avoid circular reasoning and colinearity of data. In addition, it may be helpful in clinical practice to assess disease activity when immunological tests have not been carried out. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases

Publication Stats

9k Citations
1,564.21 Total Impact Points

Institutions

  • 2000-2016
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2015
    • University of Udine
      Udine, Friuli Venezia Giulia, Italy
  • 2010-2015
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 1998-2015
    • University of Barcelona
      • Department of Medicine
      Barcino, Catalonia, Spain
    • Hospital Clínic de Barcelona
      • Servicio de Enfermedades Autoinmunes y Sistémicas
      Barcino, Catalonia, Spain
  • 2014
    • Universidad de Cádiz
      Cádiz, Andalusia, Spain
  • 2011
    • Hospital do Meixoeiro
      Vigo, Galicia, Spain
  • 2006
    • Hospital Clínico, Maracaibo
      Maracaibo, Zulia, Venezuela
  • 2002
    • Hospital Son Dureta
      Palma, Balearic Islands, Spain
    • Hospital Egas Moniz
      Lisboa, Lisbon, Portugal
  • 2000-2002
    • Meritorious Autonomous University of Puebla
      Ejido Puebla, Baja California, Mexico
  • 2001
    • University of Cape Town
      • Department of Medicine
      Cape Town, Province of the Western Cape, South Africa
    • Johns Hopkins University
      Baltimore, Maryland, United States