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To analyze the frequency and clinical phenotype of neurosarcoidosis (NS) in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe. NS was evaluated according to the Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently proposed by Stern et al. Pathologic confirmation of granulomatous disease was used to subclassify NS into definite (confirmation in neurological tissue), probable (confirmation in extraneurological tissue) and possible (no histopathological confirmation of the disease). Of the 1532 patients included in the cohort, 85 (5.5%) fulfilled the Stern criteria for NS (49 women, mean age at diagnosis of NS of 47.6 years, 91% White). These patients developed 103 neurological conditions involving the brain (38%), cranial nerves (36%), the meninges (3%), the spinal cord (10%) and the peripheral nerves (14%); no patient had concomitant central and peripheral nerve involvements. In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. According to the classification proposed by Stern et al., 11 (13%) were classified as a definite NS, 61 (72%) as a probable NS and the remaining 13 (15%) as a possible NS. In comparison with the systemic phenotype of patients without NS, patients with CNS involvement presented a lower frequency of thoracic involvement (82% vs 93%, q = 0.018), a higher frequency of ocular (27% vs 10%, q

To analyze whether immune-mediated diseases (IMDs) occurs in sarcoidosis more commonly than expected in the general population, and how concomitant IMDs influence the clinical presentation of the disease.We searched for coexisting IMDs in patients included in the SARCOGEAS-cohort, a multicenter nationwide database of consecutive patients diagnosed according to the ATS/ESC/WASOG criteria. Comparisons were made considering the presence or absence of IMD clustering, and odds ratios (OR) and their 95% confidence intervals (CI) were calculated as the ratio of observed cases of every IMD in the sarcoidosis cohort to the observed cases in the general population.Among 1737 patients with sarcoidosis, 283 (16%) patients presented at least one associated IMD. These patients were more commonly female (OR: 1.98, 95% CI: 1.49-2.62) and were diagnosed with sarcoidosis at an older age (49.6 vs. 47.5years, P0.05). The frequency of IMDs in patients with sarcoidosis was nearly 2-fold higher than the frequency observed in the general population (OR: 1.64, 95% CI: 1.44-1.86). Significant associations were identified in 17 individual IMDs. In comparison with the general population, the IMDs with the strongest strength of association with sarcoidosis (OR5) were common variable immunodeficiency (CVID) (OR: 431.8), familial Mediterranean fever (OR 33.9), primary biliary cholangitis (OR: 16.57), haemolytic anemia (OR: 12.17), autoimmune hepatitis (OR: 9.01), antiphospholipid syndrome (OR: 8.70), immune thrombocytopenia (OR: 8.43), Sjögren syndrome (OR: 6.98), systemic sclerosis (OR: 5.71), ankylosing spondylitis (OR: 5.49), IgA deficiency (OR: 5.07) and psoriatic arthritis (OR: 5.06). Sex-adjusted ORs were considerably higher than crude ORs for eosinophilic digestive disease in women, and for immune thrombocytopenia, systemic sclerosis and autoimmune hepatitis in men.We found coexisting IMDs in 1 out of 6 patients with sarcoidosis. The strongest associations were found for immunodeficiencies and some systemic, rheumatic, hepatic and hematological autoimmune diseases.

Introduction: Biological drugs are therapies designed to target a specific molecule of the immune system that have been linked with the development of autoimmune diseases. Areas covered: The BIOGEAS Registry currently collects information about nearly 13,000 reported cases of autoimmune diseases developed in patients exposed to biologics, including more than 50 different systemic and organ-specific autoimmune disorders, of which psoriasis (n=6375), inflammatory bowel disease (n=845), demyelinating CNS disease (n=803), interstitial lung disease (n=519) and lupus (n=369) were the most frequently reported. The main biologics involved were anti-TNF agents in 9133 cases (adalimumab in 4154, infliximab in 3078 and etanercept in 1681), immune checkpoint inhibitors in 913 (ipilimumab in 524 and nivolumab in 225), B-cell targeted therapies in 741 (rituximab in 678), and growth factor inhibitors in 549 cases (bevacizumab in 544). Even though targeting a particular immune molecule may be associated with an excellent clinical response in most patients, an unexpected autoimmune disease may arise in around 8 out of 10,000 exposed patients. Expert opinion: Following the increased use of biologics, the number and diversity of induced autoimmune diseases is increasing exponentially. Management of these disorders will be an increasing clinical challenge in the daily practice in the next years. Fil: Pérez De Lis, Marta. Hospitalario Universitario de la Coruña; España Fil: Retamozo, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Hospital Clínic; España. Hospital Privado Universitario de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Flores Chávez, Alejandra. Hospital Clínic; España. Hospital de Especialidades; México. Universidad de Colima; México Fil: Kostov, Belchin. Primary Care Research Group; España Fil: Perez Alvarez, Roberto. Hospital Alvaro Cunqueiro; España Fil: Brito Zerón, Pilar. Hospital Clínic; España. Hospital CIMA; España Fil: Ramos Casals, Manuel. Hospital Clínic; España. Universidad de Barcelona; España

Introduction: Sarcoidosis is a complex systemic disease with a silent, long-term evolution, and a heterogeneous clinical presentation. The diagnostic approach is complex with no single diagnostic test that may confirm the disease. Areas covered: A large list of serum biomarkers has been tested during the last 40 years. In this review, we analyse the potential usefulness in the diagnosis and prognosis of sarcoidosis of serum biomarkers classified according to their corresponding cellular source. Expert commentary: Diagnosis of sarcoidosis must always be approached as a multistep process based on a case-by-case integration of clinical, radiological, histological and serological data, none of which being pathognomonic. We found sIL-2R, CRP, SAA and chitotriosidase to be the best markers to confirm sarcoidosis (highest sensitivity), while ACE, gammaglobulins and lysozyme may be more useful for discarding sarcoidosis (highest specificity), taking into account that with the use of a higher cut-off we can increase specificity and with a lower cut-off we can increase sensitivity. Other biomarkers (TNF-a and CCL18) could help to identify patients with an enhanced risk of developing pulmonary fibrosis or progressive disease. The future scenario of the serological diagnostic approach of sarcoidosis will be the use of multi-assays including biomarkers from different cellular sources. Fil: Ramos Casals, Manuel. Sociedad Española de Medicina; España. Instituto Clínic de Medicina y Dermatología; España Fil: Retamozo, Maria Soledad. Instituto Clínic de Medicina y Dermatología; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Instituto Modelo de Cardiología Privado; Argentina Fil: Siso Almirall, Antoni. Instituto de Investigaciones Biomédicas August Pi i Sunyer; España Fil: Pérez Alvarez, Roberto. Sociedad Española de Medicina; España Fil: Pallarés, Lucio. Sociedad Española de Medicina; España. Sarco GEAS SEMI Study Group; España Fil: Brito Zenón, Pilar. Sociedad Española de Medicina; España. Sarco GEAS SEMI Study Group; España

Objectives To analyse the clinical features and outcomes of patients presenting with life-threatening systemic disease in a large cohort of Spanish patients with primary Sjogren syndrome (SjS). Methods The GEAS-SS multicenter registry was formed in 2005 with the aim of collecting a large series of Spanish patients with primary SS. By January 2018, the database included 1535 consecutive patients fulfilling the 2002/2016 criteria. Life-threatening systemic disease was defined as an activity level scored as “High” in at least one ESSDAI domain. Results 209 (14%) were classified as presenting with a life-threatening systemic disease: 194 presented one ESSDAI domain classified as high, 14 two domains and only one presented three high activity domains. The high-ESSDAI domains included lymphadenopathy in 78 (37%) cases, CNS in 28 (13%), PNS in 25 (12%), pulmonary in 25 (12%), renal in 22 (10%), cutaneous in 18 (9%), articular in 18 (9%), haematological in 7 (3%) and muscular in 4 (2%); the most frequent clinical presentations in each domain were, respectively, parotid lymphoma (n=41), focal neurological deficit (n=20), ganglionopathy (n=11), usual interstitial pneumonitis (n=9), renal failure (n=11), ulcerated cutaneous vasculitis (n=9), symmetric polyarthritis (m=17), severe thrombocytopenia (n=3) and severe myositis (n=3). With respect to therapeutic approach, 144 (69%) required glucocorticoids, 65 (31%) immunosuppressive agents and 42 (20%) biological therapies. During the follow-up, 36 (17%) patients died, mainly due to lymphoma (n=16), pulmonary fibrosis (n=5), end-stage renal failure (n=4), CNS progressive disease (n=3) and systemic vasculitis (n=3). Conclusions A 14% of patients with primary SjS develop a potentially life-threatening systemic disease (mainly lymphoma, but also severe internal organ involvements including nervous system, the lungs and the kidneys). This subset of patients requires intensive therapeutic management with a mortality rate of nearly 20% of cases. Disclosure of Interest None declared

Objectives To characterise the development of autoimmune diseases triggered by the new biological therapies used as immunotherapy in patients with advanced cancer in a real-life clinical setting. Methods In 2006, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use and safety of biological agents in adult patients. In December 2016, the cBIOGEAS-SEMI multicenter registry was formed with the aim of collecting patients with cancer treated with biological immunotherapies who developed autoimmune diseases. Results By January 2018, the cBIOGEAS-SEMI Registry includes 40 patients (26 men and 14 women, mean age of 59.7 years) who developed 54 triggered autoimmune diseases, including interstitial lung disease (n=11), enterocolitis (n=8), hypophysitis (n=6), polyarthritis (n=4), thyroiditis (n=3), vasculitis (n=3), severe cutaneous involvement (n=3), adrenalitis (n=2), Sjogren syndrome (n=2), cardiomyopathy (n=2), pancreatitis (n=2), Guillain-Barre syndrome (n=2), hepatitis (n=2) and CNS involvement, sclerosing cholangitis, glomerulonephritis and sarcoidosis (one case each). Underlying neoplasia consisted mainly in pulmonary neoplasia (n=16), melanoma (n=11) and breast cancer (n=3). The main pharmacological groups of cancer immunotherapies included PD1 inhibitors (n=26), CTL4 inhibitors (n=7), growth factor/adhesion molecules inhibitors (n=4), combined PD1/CTL4 blockade (n=2) and TK inhibitors (n=1); biologics included nivolumab (n=20), ipilimumab (n=9), pembrolizumab (n=8), trastuzumab (n=3), catumaxomab (n=1) and vemurafenib/combimetinib (n=1). Glucocorticoids were used in all cases but 4, and 9 patients required intravenous methylprednisolone pulses); 5 patients required additional immunosuppressive therapies (intravenous immunoglobulins in 4, methotrexate in one). All cases responded to treatment with glucocorticoids except 4 patients who died (3 due to ILD and one due to neurological disease). Conclusions A wide variety of systemic and organ-specific autoimmune diseases triggered by the new cancer immunotherapies is emerging. In this nationwide real-life Registry, immune checkpoint inhibitors are the biologics involved in nearly 90% of cases. We found an excellent response to glucocorticoids, with a poor prognosis in those patients who developed pulmonary and neurological autoimmune diseases. Disclosure of Interest None declared

Objectives The increasing use of biological agents has been linked with the paradoxical development of autoimmune processes. The scenario has dramatically change in recent years due to the increased number of biologics used in daily practice and the emerging use of biologics in patients with solid cancers. Methods In 2006, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use and safety of biological agents in adult patients. The aeBIOGEAS Registry (autoimmune events) was designed to collect data on autoimmune diseases secondary to the use of biologic agents, with the aim of formulating a standardised, consensual protocol for these patients, through a systematic and yearly MEDLINE search. We present the updated results of the aeBIOGEAS Registry (cases collected until Dec 31, 2017). Results The aeBIOGEAS Registry currently includes 16 123 cases of more than 50 different systemic and organ-specific triggered autoimmune diseases related to the administration of 46 different biological molecules in patients with inflammatory diseases (9907 cases, overwhelmingly rheumatic diseases in 8639) and cancer (6216 cases, overwhelmingly solid neoplasia in 5955). The main biological agents identified consisted of anti-TNF agents in 9514 cases (mainly adalimumab in 4147, infliximab in 3028 and etanercept in 1648), checkpoint inhibitors in 5264 (overwhelmingly the CTL4 inhibitor ipilimumab in 4980 cases), thyrosine kinase inhibitors in 952 (mainly imatinib in 377 cases) and B-cell targeted therapies in 298 cases. Organ-specific classification of triggered autoimmune diseases included cutaneous (n=7140), digestive (n=2323), endocrine (n=1701), pulmonary (n=1683), systemic/rheumatic (n=1230), neurological (n=1172), ocular (n=349), cardiac (n=322), haematological (n=106) and renal (n=96) diseases. The most frequently reported induced individual autoimmune diseases were psoriasis (n=6401), enterocolitis (n=1947), interstitial lung diseases (n=1680), thyroiditis (n=1076), hypophysitis (n=492), demyelinating CNS diseases (n=452), peripheral neuropathies (n=431), lupus (n=371), vasculitis (n=339), uveitis (n=298), vitiligo (n=256) and sarcoidosis (n=185). Conclusions The number and diversity of induced autoimmune disorders is increasing exponentially in parallel with the increased use of biological therapies in neoplasic diseases, which are currently representing 40% of reported cases. Management of these biologic-induced autoimmune diseases will be an increasing multidisciplinary clinical challenge in the daily practice in the next years. Disclosure of Interest None declared

Objectives To analyse whether thoracic involvement at diagnosis is associated with a specific clinical presentation of sarcoidosis. Methods The SARCOGEAS-SEMI is a nationwide registry of patients with sarcoidosis. Radiographic stages at diagnosis were classified as stage 0 (normal), stage I (only bilateral hilar lymphadenopathy -BHL-), stage II (BHL +pulmonary infiltrates), stage III (only infiltrates) and stage IV (fibrosis). Results The cohort consisted of 1245 patients (722 women, 523 men, mean age at diagnosis 47 years). Pulmonary imaging data at diagnosis was available in 1230 patients including 395 (32%) with stage I, 500 (40%) with stage II, 195 (16%) with stage III and 42 (3%) with stage IV. Patients with no thoracic involvement (stage 0) were more frequently women (73% vs 56%, p=0.002), older (52.1 vs 46.8 years, p=0.001) and had a higher frequency of skin (54% vs 34%, p Conclusions A specific clinical and epidemiological pattern of disease presentation was found in patients with no thoracic involvement and in those presenting with interstitial lung disease at diagnosis. Disclosure of Interest None declared

Objectives To characterize the main features at presentation of sarcoidosis associated with the development of end-stage organ failure in a large multicenter cohort of patients from Southern Europe. Methods In January 2017, the Spanish National Registry of Sarcoidosis (SARCOGEAS-SEMI) included 1082 consecutive patients diagnosed with sarcoidosis according to the ATS/ERS/WASOG 1999 statement and extrathoracic involvement to the 2014 WASOG instrument. The development of end-stage organ failure was assessed at the last visit. Results The cohort consisted of 618 (57%) women and 464 (43%) men, with a mean age at diagnosis of 47yrs. After a mean follow-up of 82 months, 90 (8%) patients developed end-stage organ failure, including respiratory failure (n=56), chronic renal failure (n=13), cardiac failure/permanent cardiac device (n=8) and liver cirrhosis (n=3). The following baseline features were associated with end-stage organ failure in the univariate analysis: patients born in Spain (p=0.008), a higher mean age at diagnosis (p Conclusions Nearly 10% of patients with sarcoidosis developed end-stage organ failure. Respiratory failure represented two thirds of cases of sarcoidosis-related organ failure, followed by renal (15% of cases) and cardiac (9%). Older patients, as well as those presenting with advanced radiological stages, had an enhanced risk of developing end-stage organ failure. Disclosure of Interest None declared

Objectives To characterize the main features at presentation of sarcoidosis in a large multicenter cohort from Southern Europe. Methods In January 2016, the Autoimmune Diseases Study Group (GEAS-SEMI) created a national registry (SARCOGEAS) of patients with sarcoidosis. Sarcoidosis was diagnosed in agreement with the criteria proposed by the ATS/ERS/WASOG 1999 statement, and extrathoracic disease was classified with the 2014 WASOG instrument. Results The cohort consisted of 1082 patients (82% biopsy-proven), including 618 (57%) women and 464 (43%) men, with a mean age at diagnosis of 47yrs; 140 (13%) patients were born outside Spain, 965 (89%) were White, 69 (6%) Hispanic, 30 (3%) Black/African American and 18 (2%) Asian. Thoracic involvement was present at diagnosis in 979 (90%) patients, including 437 (40%) patients with stage I, 374 (35%) with stage II, 123 (11%) with stage III and 26 (2%) with stage IV. The most frequently reported extrathoracic involvements at diagnosis were cutaneous in 385 (36%) patients, extrathoracic lymph nodes in 218 (20%), liver involvement in 151 (14%) and ocular involvement in 118 (11%). Potentially life-threatening WASOG involvements were reported in frequencies less than 10%, including neurological involvement in 77 (7%) patients, kidney involvement in 59 (5%) or cardiac involvement in 21 (2%). Therapeutic approaches at diagnosis included the use of oral glucocorticosteroids in 637 (59%) patients, immunosuppressive agents in 84 (8%, mainly methotrexate in 63 patients) and biological agents in 15 (1%, mainly infliximab in 10 cases). Conclusions In this large series of sarcoidosis from Southern Europe, clinical presentation is dominated by adenopathies (both thoracic and extrathoracic) and cutaneous involvement (erythema nodosum), with lower frequencies in the main extrathoracic involvements than that reported in US and Japanese series. Disclosure of Interest None declared

Objectives To evaluate the temporal association between the diagnosis of neoplasia and sarcoidosis in a large cohort of Spanish patients with sarcoidosis. Methods In January 2016, the Autoimmune Diseases Study Group (GEAS-SEMI) created a national registry (SARCOGEAS) of patients with sarcoidosis. Sarcoidosis was diagnosed with the criteria proposed by the ATS/ERS/WASOG 1999 statement, and extrathoracic disease by the 2014 WASOG instrument. Diagnosis of neoplasia was recorded before and after the diagnosis of sarcoidosis. Results The cohort included 1082 patients (82% biopsy-proven, 618 women, mean age 47yrs). Association with neoplasia was detected in 135 (13%) patients who developed 140 neoplasms (110 solid and 30 hematological neoplasia). The neoplasia more frequently reported were breast (n=18), lymphoma (n=16), non-melanoma skin (n=15) and colon (n=15). Association with neoplasia was more frequent in patients born in Spain (97% vs 86%, p Conclusions Association between sarcoidosis and cancer was found in 13% of patients (80% solid and 20% hematologic malignancies). Elderly patients and those born in Spain were at high risk of having associated cancer. Asymptomatic sarcoidosis was more frequently observed in those patients with a previous history of neoplasia, while the association with hematological neoplasms was linked to a higher frequency of sarcoidosis involving ENT and bone marrow. Disclosure of Interest None declared

Objectives To characterize the risk of solid and hematological cancer in a large, well-characterized cohort of patients with primary Sjogren syndrome (SjS). Methods The GEAS-SS multicenter registry is a network of Spanish reference centers with specific clinical experience in the management of SjS patients. By January 2016, we had analyzed the development of cancer in 1300 consecutive patients fulfilling the 2002 SjS classification criteria. Multivariate Cox proportional-hazards regression analysis allowed adjustment for age at diagnosis, gender and the statistically-significant baseline variables associated with cancer in the univariate analysis. The sex- and age-specific incidence rates (SIR) of cancer were estimated from 2012 Spanish mortality data modeling, using a set of age-, sex- and site-specific incidence:mortality ratios. Results After a mean follow-up of 91 months (9922.3 person-years), 127 (9.8%) patients developed 133 cancers. The most frequent type of cancer was B-cell lymphoma (34% of cancers, including 27 MALT and 19 non-MALT B-cell lymphomas). Systemic activity at diagnosis of primary SjS correlated with the risk of hematological neoplasia (HR 1.06, p Conclusions One third of cancers developed by patients with primary SjS are B-cell lymphomas. The prognostic factors identified at SjS diagnosis differed according to the subtype of B-cell lymphoma developed. Primary SjS is also associated with an enhanced risk of development of some types of non-hematological cancers (thyroid, oral cavity and stomach). Disclosure of Interest None declared

Background and aims Studying the distribution of SLE across geographic regions using a big data-driven approach may facilitate understanding of the corresponding genetic and environmental underpinnings. Methods We explored the potential of the Google search engine to collect and merge cohorts (>100 patients) of patients with systemic lupus erythematosus (SLE) reported in the Pubmed library. We made a text-word search in Google between 8th and 15th May 2015 using SLE and ”100...100000000 patients” and “site:http://www.ncbi.nlm.nih.gov/pubmed”. We collected the available data about study design, country, ethnicities, age and gender, clinical features and immunological markers. Results We merged the data of 133 SLE cohorts including 1 71 000 patients; gender was detailed in 130 cohorts:88% women(female:male ratio, 8,4). mean age at onset (29.89±3.48), at diagnosis (32.33±2.99).The countries contributing the most cohorts were the USA (31), Japan (8) and Spain (5). The main clinical features included arthritis in 72%,haematological abnormalities in 62%,malar rash in 50%,photosensitivity in 48%, renal involvement in 38%, oral ulcers in 34%, serositis in 30% and neurological involvement in 14%. Haematological abnormalities included lymphopenia in 43%,leukopenia in 38%,thrombocytopenia in13% and hemolytic anaemia in 4%.Positive autoantibodies included ANA in 91%,dSDNA in 62%,anti-Ro/SSA in 35%,antiRNP in 25%,antiSm in 21% and anti-La/SSB in 15%. Conclusions This is the largest reported study in SLE including nearly 2 00 000 cases that provides a big data picture of the worldwide expression of the disease, with a female:male ratio of 8,4, a mean age at diagnosis of 32 years, and with joints, haematological, skin and kidneys being the most frequent organs involved.

Background and aims Lupus nephritis is the most severe involvements of internal organs that may develop patients with systemic lupus erythematosus (SLE). Studying the worldwide distribution of this feature across geographic regions and ethnic groups using a big data-driven approach may help obtain a more high-definition resolution of lupus nephritis Methods We made a text-word search in Google between 8th and 15th May 2015 using SLE and 100...100000000 patients. We selected the cohorts in which the frequency of renal involvement was detailed, and we analysed the influence on this frequency of the characteristics of the cohorts. Results Of the 63 263 patients included, renal involvement was reported in 24 790 patients(38%).The rate of renal involvement was influenced by the predominant ethnicity:it was lower in cohorts in white patients in comparison with a multiethnic origin(p=0.008).The mean age at SLE diagnosis was higher in cohorts in which the mean age was Conclusions This big data analytical approach confirm that the rate of renal involvement is influenced by ethnicity, the mean age at SLE diagnosis and the frequency of positive autoantibodies.The higher rates of renal involvement being found in US and Asian studies,with the youngest patients at the time of SLE diagnosis and highest rates of immunopositive patients.

Sjogren syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands and causes dryness of the main mucosal surfaces. When symptoms appear in a previously healthy person, the disease is classified as primary SjS. However, the clinical spectrum of SjS extends from dryness to systemic involvement (extraglandular manifestations) and includes a large number of organ-specific manifestations. Cardiovascular involvement is one of the extraglandular involvements less frequently studied in primary SjS, although a growing interest on investigating cardiovascular features in SjS patients has emerged from studies reported in the last 10 years.

Sarcoidosis is a systemic disease of unknown etiology characterized by the development of non-caseating epitheloid granulomas. The lungs are the most commonly involved organ (90% of cases), followed by the lymph nodes, the skin, and the eyes. Areas covered: This review summarizes current pharmacotherapy options and future directions for the development of new therapies. Glucocorticoids are the first-line therapy for sarcoidosis. For patients with the most severe forms of sarcoidosis (who will need glucocorticoids for long periods) and for those intolerant or refractory, immunosuppressive drugs are used as sparing agents. The management of extrathoracic sarcoidosis must be tailored to the specific organ or organs involved; however, there is limited data from controlled trials to guide the treatment of these patients. The emergence of biological therapies has increased the therapeutic armamentarium available to treat sarcoidosis, with monoclonal anti-TNF agents being the most promising, but their use is still limited by a lack of licensing and costs. Expert commentary: The treatment of sarcoidosis is still not totally standardized. New effective therapies are urgently needed to enable the reduction or replacement of long-term therapy with glucocorticoids in patients with sarcoidosis.

Objectives To analyze the clinical characteristics, outcomes, and patterns of association with the different biologic agents used in all reported cases of adult patients developing interstitial lung disease (ILD) after biologic therapy. Methods In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project. One objective was to collect data on autoimmune diseases secondary to the use of biologic agents by quarterly Medline search surveillance of reported cases. For this study, the baseline included articles published between January 1990 and March 2010, including the MeSH term "lung diseases, interstitial" as the key research term. In addition, we report an unpublished case of ILD secondary to biologic therapy. Results There are 122 reported cases of new-onset or exacerbation of ILD secondary to administration of biologic therapies. Biologic agents associated with ILD were overwhelmingly anti-tumor necrosis factor agents (etanercept in 58 cases and infliximab in 56) and were administered for rheumatoid arthritis in 108 (89%) patients. ILD appeared a mean of 26 weeks after initiation of biologic agents. ILD was confirmed by pulmonary biopsy in 26 cases, although a specific histopathologic description was detailed in only 20: 7 patients were classified as usual interstitial pneumonia, 6 as nonspecific interstitial pneumonia, 5 as organizing pneumonia, 1 as diffuse alveolar damage, and 1 as lymphoid interstitial pneumonia. Treatment of ILD included withdrawal of biologic agents in all cases but 1. The outcome of ILD was detailed in 52 cases. Complete resolution was reported in 21 (40%) cases, improvement or partial resolution in 13 (25%), and no resolution in 18 (35%). Fifteen (29%) patients died during the follow-up, the majority (70%) during the first 5 weeks after initiating biologic therapy. In comparison with survivors, patients who died were aged >65 years (67% vs 33%, P = 0.036), with later onset of ILD (46 weeks vs 15 weeks, P = 0.006), received immunosuppressive drugs more frequently (33% vs 8%, P = 0.036), and more often had a previous diagnosis of ILD (67% vs 29%, P = 0.025). Conclusions We found that 97% of cases of ILD associated with biologic agents were associated with agents blocking tumor necrosis factor-α, a cytokine that has been implicated in the pathophysiology of pulmonary fibrosis. Strikingly, drug-induced ILD had a poor prognosis, with an overall mortality rate of around one third, rising to two thirds in patients with preexisting ILD.

We evaluated the prevalence and clinical significance of cardiovascular risk factors in a large series of patients with primary Sjögren’s syndrome (SS), focusing on the possible association with clinical and immunological SS features, the therapies administered, and the impact on cardiovascular disease. The study cohort included 312 patients fulfilling the 2002 classification criteria for primary SS, consecutively evaluated and followed in our department between 1984 and 2009. The control group consisted of 312 age- and sex-matched patients without systemic autoimmune diseases followed during the study period in a primary care centre. In comparison with the age- and sex-matched control group, patients with primary SS showed a higher frequency of diabetes mellitus (27% versus 13%, p < 0.001) and hypertriglyceridaemia (22% versus 15%, p = 0.023), and a lower frequency of hypertension (30% versus 46%, p < 0.001) and smoking (19% versus 31%, p < 0.001). The adjusted, multivariate analysis showed that SS patients with at least three cardiovascular risk factors had a higher mean age at SS diagnosis (p < 0.001), a higher frequency of liver involvement (p = 0.01) and central nervous system involvement (p = 0.001), higher mean levels of C-reactive protein (CRP, p = 0.001), a lower percentage of circulating gamma globulins (p = 0.001), and had received corticosteroids more frequently (p = 0.003) in comparison with patients without cardiovascular risk factors. Patients who had received corticosteroids showed a higher frequency of hypertension (37% versus 25%, p = 0.032), diabetes mellitus (37% versus 21%, p = 0.002), and hypertriglyceridaemia (33% versus 15%, p < 0.001). Patients with primary SS showed a twofold higher prevalence of diabetes mellitus and a 1.5-fold higher prevalence of hypertriglyceridaemia in comparison with primary care patients. Corticosteroid use was closely associated with cardiovascular risk factors. These results suggest that cardiovascular risk factors should be taken into account in the management of patients with primary SS and show the importance of recognizing and controlling both traditional and SS-related modifiable risk factors.

To continue our investigation of the epidemiology of giant cell arteritis (GCA) in southern Europe, we assessed the potential presence of trends, peaks, and fluctuations in the incidence of this vasculitis over a 25-year period in the Lugo region of northwestern Spain. We also sought to determine whether changes in the clinical spectrum of the disease existed. From 1981 to 2005, biopsy-proven GCA was diagnosed in 255 Lugo residents. The age- and sex-adjusted annual incidence rate was 10.13 (95% confidence interval [CI], 8.93-11.46) per 100,000 population aged 50 years and older. The mean age +/- SD at the time of diagnosis was 75.0 +/- 6.9 years. The annual incidence rate in women (10.23; 95% CI, 8.60-12.08) was slightly greater than that in men (9.92; 95% CI, 8.19-11.89) (p = 0.15). The annual incidence rate increased with advancing age up to a maximum of 23.16 (95% CI, 19.52-27.28) in the 70-79 year age-group. A progressive increase in the incidence was observed from 1981 through 2000 (p = 0.001). However, the age- and sex-adjusted incidence rate for biopsy-proven GCA in the Lugo region did not show peaks in the annual incidence of GCA. Likewise, we observed no seasonal pattern for the diagnosis of the disease. Visual ischemic manifestations and irreversible visual loss were observed in 57 (22.4%) and 32 (12.5%) of the 255 patients, respectively. A negative trend manifested by a progressive decline in the number of patients with visual ischemic manifestations (p = 0.021) or permanent visual loss (p = 0.018) was found over the 25-year period of study. The decline in the frequency of visual manifestations of GCA could not be attributed to a shorter delay to diagnosis, as no significant differences were observed when the delays to diagnosis in the 5 consecutive 5-year periods were compared. In conclusion, the current study confirms a progressive increase in the incidence of biopsy-proven GCA in northwestern Spain, and suggests that there has been a change in the clinical spectrum of the disease.

Objective.To analyze the etiopathogenic role of genetic polymorphisms and serum levels of surfactant protein-D (SP-D) in primary Sjögren syndrome (pSS).Methods.We analyzed 210 consecutive patients with pSS.SFTPDgenotyping (M11T polymorphism rs721917) was analyzed by sequence-based typing and serum SP-D by ELISA.Results.Thirty-two patients (15%) had the Thr11/Thr11 genotype, 80 (38%) the Met11/Met11 genotype, and 96 (46%) the Met11/Thr11 genotype; 2 patients could not be genotyped. Patients carrying the Thr11/Thr11 genotype had a higher prevalence of renal involvement (13% vs 1% and 4% in comparison with patients carrying the other genotypes, p = 0.014). Serum SP-D levels were analyzed in 119 patients (mean 733.94 ± 49.88 ng/ml). No significant association was found between serum SP-D levels and the SP-D genotypes. Higher mean values of serum SP-D were observed in patients with severe scintigraphic involvement (851.10 ± 685.69 vs 636.07 ± 315.93 ng/ml, p = 0.038), interstitial pulmonary disease (1053.60 ± 852.03 vs 700.36 ± 479.33 ng/ml, p = 0.029), renal involvement (1880.64 ± 1842.79 vs 716.42 ± 488.01 ng/ml, p = 0.002), leukopenia (899.83 ± 661.71 vs 673.13 ± 465.88 ng/ml, p = 0.038), positive anti-Ro/SS-A (927.26 ± 731.29 vs 642.75 ± 377.23 ng/ml, p = 0.006), and positive anti-La/SS-B (933.28 ± 689.63 vs 650.41 ± 428.14 ng/ml, p = 0.007), while lower mean values of serum SP-D were observed in patients with bronchiectasis (489.49 vs 788.81 ng/ml, p = 0.019).Conclusion.In pSS, high SP-D levels were found in patients with severe glandular involvement, hypergammaglobulinemia, leukopenia, extraglandular manifestations, and positive anti-Ro/La antibodies. The specific association between SP-D levels and pulmonary and renal involvements may have pathophysiological implications.

Objective To analyze the monoclonal expression of SS through the detection of serum monoclonal immunoglobulins (mIgs) in a large series of patients with Sjogren syndrome (SS), focusing on the etiology, characterization and evolution of the monoclonal band and the association with SS clinical expression and outcomes. Methods Serum immunoelectrophoresis (IE) was performed to 408 consecutive patients who were evaluated by our unit between 1992 and 2011: 221 patients who fulfilled the 2002 American–European criteria for primary SS, 122 primary SS patients who fulfilled exclusively the 1993 European criteria and 65 patients with SS-associated hepatitis C virus infection. IE was performed at diagnosis and every year during the follow-up. Results Of the 221 patients with primary SS, 48 (22%) had monoclonal gammopathy. In the control groups, the prevalence was 16% in patients with SS who fulfilled the 1993 criteria ( p > 0.05) and 52% in SS-HCV patients ( p n = 21), IgM ( n = 16), IgA ( n = 5) and free light chains ( n = 5); the light chain was κ in 28 patients and λ in 19 (κ:λ ratio 1.5). Primary SS patients with monoclonal gammopathy had a higher prevalence of parotidomegaly (38% vs 20%, p = 0.021), vasculitis (21% vs 6%, p = 0.003), neurological involvement (42% vs 23%, p = 0.016), higher mean values of circulating gammaglobulins (23.4 vs 20.6%, p = 0.026), ESR (56.6 vs 37.6 mm/h, p = 0.003), a higher prevalence of RF (69% vs 50%, p = 0.022), low C3 levels (24% vs 11%, p = 0.028), low C4 levels (24% vs 7%, p = 0.003), low CH50 activity (28% vs 11%, p = 0.008) and cryoglobulins (23% vs 8%, p = 0.012) compared with those without monoclonal gammopathy. Of the 48 patients with primary SS and monoclonal gammopathy, 8 developed hematologic neoplasia after a mean follow-up of 10 years, a higher prevalence than observed in patients without monoclonal gammopathy (17% vs 5%, p = 0.009). Survival rates according to the presence or absence of monoclonal gammopathy were 83% and 97%, respectively (log rank 0.004). Conclusion Monoclonal gammopathy was detected in 22% of patients with primary SS fulfilling the 2002 criteria, with mIgGκ being the most frequent type of band detected. In HCV-associated SS patients, the prevalence was higher (52%) with IgMκ being the most prevalent band detected. Monoclonal gammopathy was associated with a higher prevalence of parotid enlargement, extraglandular features, hypergammaglobulinemia, cryoglobulinemia and related markers (rheumatoid factor, hypocomplementemia), and with a poor prognosis (development of neoplasia and death).

Objective: To describe the main characteristics of patients with primary Sjogren syndrome (SS) and white matter abnormalities (WMA) seen by a specialist SS unit. Methods: The study cohort included 321 consecutive patients fulfilling the 2002 classification criteria for primary SS. We retrospectively analyzed the results of neuroimaging studies performed in patients who presented with neurological symptoms. Patients were further evaluated by three neurologists to determine fulfillment of the McDonald criteria for the diagnosis of multiple sclerosis (MS). Results: Fifty-one (16%) patients had at least one neuroimaging study, and 25 of these had WMA. WMA were classified as vascular pathological changes in 21 patients: 10 had multiple small focal lesions, 7 had beginning confluence of lesions and 4 had diffuse involvement of the entire region. WMA were classified as inflammatory/demyelinating lesions (MS-like) in 4 patients who fulfilled the MRI Barkhof criteria. Patients with inflammatory/demyelinating lesions were younger (53.7 vs. 73.5 years, P = 0.001) and had a lower frequency of hypertension (25% vs. 86%, P = 0.031) and altered glomerular filtration rate (0% vs. 70%, P = 0.047) in comparison with patients with vascular lesions. The multivariate age–sex adjusted model including the seven variables which were statistically significant in the univariate analysis (antimalarial therapy, leukopenia, anti-La/SSB antibodies, diabetes, hypertension, metabolic syndrome and HDL-c levels) identified hypertension ( P = 0.019) and HDL-c levels ( P = 0.032) as independent predictors of WMA in primary SS patients. Conclusion: Neuroimaging studies disclosed WMA in 49% of patients with primary SS and suspected neurological involvement. WMA were identified as vascular pathological changes in 80% of the patients, and hypertension and HDL-c levels as predictive factors for this association.

The emergence of tumor necrosis factor-α (TNF-α)-targeted therapies as a key therapeutic option for patients with rheumatic, digestive, and dermatologic autoimmune diseases has been associated with increasing reports of liver damage in patients with hepatitis B virus (HBV) infection. We studied the current evidence on the use of anti-TNF agents in patients with HBV through a systematic analysis of cases reported in the MEDLINE and EMBASE databases using the MeSH term "hepatitis B virus" combined with the terms "infliximab," "etanercept," "adalimumab," "certolizumab," "golimumab," and "anti-TNF agents," and summarize the results here. We analyzed 257 patients with positive HBV markers who received anti-TNF therapy (255 identified in the search strategy and 2 new cases), 89 HBsAg+ carriers, and 168 anti-HBc+ persons. HBV reactivation was reported in 35 (39%) HBsAg+ carriers. The percentage of reactivation was higher in patients previously treated with immunosuppressive agents (96% vs. 70%, p=0.033) and lower in those who received antiviral prophylaxis (23% vs. 62%, p=0.003). Acute liver failure was reported in 5 patients, 4 of whom died. Infliximab was associated with a higher rate of induced liver disease (raised transaminase levels, clinical signs, viral reactivation, and acute liver failure) compared with etanercept. In anti-HBc+ persons, reactivation was reported in 9 (5%) cases, including 1 patient who died due to fulminant liver failure.In summary, our search of the current evidence identified 257 reported HBV+ patients treated with anti-TNF agents, with a significant percentage of liver damage in HBsAg+ carriers, including raised transaminase levels (42%), signs and symptoms of liver disease (16%), reappearance of serum HBV-DNA (39%), and death related to liver failure (5%). The rate of reactivation in anti-HBc+ persons was 7-fold lower than in HBsAg+ carriers. The increasing number of reported cases of HBV reactivation following TNF-targeted therapies and the associated morbidity and mortality demand specific preventive strategies.

Sjogren’s syndrome (SS) is a systemic autoimmune disease that presents with sicca symptomatology of the main mucosa surfaces. The spectrum of the disease extends from sicca syndrome to systemic involvement (extraglandular manifestations) and may be complicated by the development of lymphoma. Patients with SS may present with a broad spectrum of autoantibodies and laboratory abnormalities. Most of the laboratory abnormalities have been described more frequently in patients with positive immunological markers. Some may be the first manifestation of primary SS, while others have no clinical significance.

Biological agents emerged at the end of the 20th century as effective therapies for a wide spectrum of diseases. Several drugs (principally directed against cytokines or lymphocytic receptors) are ...

Objectives To describe how systemic disease is treated in a large cohort of Spanish patients with primary Sjogren syndrome in daily practice, focusing on the adequacy of drug therapies for the level of systemic activity measured by the ESSDAI score. Methods By December 2014, our database included 1120 consecutive patients who fulfilled the 2002 classification criteria for primary SS. Therapeutic schedules were classified into 4 categories: no systemic therapies, hydroxychloroquine and/or low dose of glucocorticoids (≤20 mg/d), high dose of glucocorticoids (>20 mg/d) and use of second-line therapies (immunosuppressive agents, intravenous immunoglobulins and/or rituximab). Results The cohort consisted of 1120 patients, including 1048 (94%) females and 72 (6%) males, with a mean age at diagnosis of 54 years. The main drug-based therapeutic approaches for systemic Sjogren ever used during the follow-up were hydroxychloroquine (HCQ) in 282 (25%) patients, glucocorticoids in 475 (42%, used at doses >20 mg/d in 255 -23%>), immunosuppressive agents in 148 (13%), intravenous immunoglobulins (IVIG) in 25 (2%) and rituximab in 35 (3%) patients. The use of systemic therapies was more frequent in males (p=0.036) and was associated with the presence at diagnosis of anemia (p 20 mg of corticoids and 21/148 (14%) of those treated with immunosuppressive agents patients as inadequately treated, mainly associated with articular involvement of low/moderate activity. Conclusions The management of systemic Sjogren should be organ-specific, using low doses of corticoids in patients with moderate systemic activity, limiting the use of high doses of corticoids and second-line therapies to refractory or potentially-severe scenarios. The use of systemic therapies for dryness, chronic pain or fatigue is not warranted. Disclosure of Interest None declared

Objectives To analyze the main epidemiological and clinical characteristics of patients with neurological involvement related to sarcoidosis. Methods In May 2013, the Study Group on Autoimmune Diseases (GEAS-SEMI) created the national registry of patients with sarcoidosis (SARCOGEAS-SEMI Registry). Patients presenting with neurological features were specifically evaluated. Results In December 2013, a total of 719 patients with sarcoidosis were included in the SARCOGEAS-SEMI Registry; 52 (7.2%) had neurosarcoidosis, 22 men and 30 women, with a mean age at diagnosis of neurosarcoidosis of 50.1 years (range 23-84 years). The main neurological involvement consisted of cranial neuropathies in 27 (52%) patients, followed by CNS involvement in 23 (44%), peripheral neuropathies in 6 (10%) and muscular involvement in 4 (8%). The most frequent cranial neuropathies included involvement of VII pair (17 cases) followed by VIII pair (5 cases) and V and VI pairs (4 cases each); other cranial nerves affected included IX (n=3), III (n=3), XI (n=2), I (n=1), II (n=1) and XII (n=1); 12/27 (44%) patients showed multiple cranial neuropathies. With respect to CNS involvement, meningeal involvement (15%) and vascular/demyelinating lesions (10%) were the most frequent involvements; other features consisted of parenchymatous cerebral lesions (n=4), encephalopathy (n=4), hypothalamic involvement (n=3), seizures (n=2) and hydrocephalia (n=1). All patients received corticosteroids (10 received methylprednisolone pulses) and 9 immunosuppressants (methotrexate in 5, azathioprine in 4, cyclophosphamide in 2). One patient refractory to standard therapy was treated with infliximab. Nearly half the cases showed improvement or stabilization (46%), 34% showed complete resolution, 16% worsened and 4% died. Conclusions Nearly 10% of patients with sarcoidosis present with neurological involvement. The main involvement of neurosarcoidosis consisted of cranial neuropathies in half the cases. Twenty percent of patients showed a worse outcome, with a mortality rate of 4%. Neurological involvement is a significant cause of morbidity and mortality in patients with sarcoidosis. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5374

Objectives To analyze the main epidemiological, clinical and immunological characteristics and baseline predictors associated with survival in a large cohort of patients with systemic amyloidosis. Methods In May 2013, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the national registry of patients with amyloidosis (RAMYD). The classification of amyloidosis was based on the chemical characterization of the precursor protein. The 4 main types of systemic amyloidosis are AL, AA, ATTR, and Aβ2M type/others. Patients with localized deposition of amyloid were excluded. Results A total of 570 patients with amyloidosis were included, 311 men, 259 women (mean age at dx: 64 years, range 19-93). Associated diseases were: hematological diseases 19%, inflammatory rheumatic diseases 10%, systemic autoimmune diseases 8%, non-hematologic neoplasms 6% and chronic infections 6%. We were able to classify amyloidosis in 71% patients: 36% AA amyloidosis, 135% AL, 20% ATTR and 9% others. Vital status was obteined in 478 patients, of which 298 (62%) died. Patients who died had an older mean age at diagnosis (67.29 vs 57.58 years in survivals, p Conclusions The rate of mortality of patients diagnosed with systemic amyloidosis exceeds 60% of cases, with AL amyloidosis having the highest mortality rate. The main baseline prognostic factors associated with death were older age, hematological diseases, and involvement of kidneys, lungs, heart. Our results, which demonstrated a global mortality rate of two-thirds of cases, serve to emphasize that the optimal management for systemic amyloidosis remains to be defined. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5896

Background A close association between hepatitis C virus (HCV) chronic infection and Sjogren syndrome (SS) was reported 10 years ago. Recently, human La protein has been implicated in facilitating the internal initiation of translation as well as replication of HCV RNA. It could be hypothesized that patients carrying anti-La antibodies could be protected against chronic HCV infection. Objectives To analyse the possible association between anti-La antibodies and chronic HCV infection in a large series of patients with SS. Methods The study cohort included patients who were consecutively tested for IgG antibodies against HCV. Inclusion criteria were the fulfillment of at least 4 of the classification criteria for SS proposed by the European Community Study Group and repeated positive HCV serology; we retrospectively evaluated confirmation of HCV infection using recombinant immunoblot assay and detection of serum HCV-RNA by polymerase chain reaction, and HCV genotyping. Results Six hundred sixty three patients with SS were included (602 female and 61 male; mean age, 58 yr). One hundred and four patients (16%) showed IgG antibodies against HCV; 9 patients showed a positive serology result with negative HCV viremia, suggesting a past/cured HCV infection. In comparison with the remaining 64 patients with chronic HCV infection (IgGHCV+, RNAHCV+), the 9 patients IgGHCV+/RNAHCV- were more frequently female (100% vs 80%, p>0.05) and had a lower frequency of hypocomplementemia (22% vs 70%, p=0.008) and positive serum cryoglobulins/monoclonal band (33% vs 71%, p=0.032); interestingly, none of these 9 patients had anti-La antibodies (0% vs 19%, p>0.05). HCV genotyping was available in 42 patients (1b in 30 patients, 1a in 7 and non-1 in the remaining 4; one patient was non typable). In the whole cohort of patients with SS, patients with associated chronic HCV infection showed a differentiated immunological expression, with a lower frequency of autoantibodies including antinuclear antibodies (71% vs 85%, p=0.001), anti-Ro (15% vs 38%, p Conclusions The main differential aspect between primary and HCV-related SS is the immunological pattern, with a predominance of cryoglobulinemic-related markers (mixed cryoglobulins, RF, hypocomplementemia, monoclonal band) over SS-related specific markers (anti-Ro/SS-A and anti-La/SS-B autoantibodies) in HCV-related SS. Cryoglobulinemia is the key immunological marker of SS associated with HCV, while anti-La antibodies were less frequently detected in HCV patients and do not seem that could influence in protecting against chronic HCV infection in SS patients. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4158