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Objective We aimed to investigate the association between the different antiphospholipid antibodies (aPL) and both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) manifestations. Methods Patients from the RELESSER registry, a Spanish retrospective, cross-sectional, forty-five hospital registry of adult SLE patients, were included. Results Out of a total of 3,658 SLE patients, 1372 were aPL positive (555 of them fulfilled criteria for APS). All aPL types showed a negative association with cutaneous SLE manifestations. Lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) were both associated with haematological, ophthalmological and neuropsychiatric manifestations. IgG isotypes were associated with a higher risk of lupus manifestations compared with IgM. We found that the risk of neuropsychiatric and ophthalmological manifestations significantly increased with a higher number of positive aPL whereas the risk of cutaneous symptoms showed a negative correlation. All types of aPL, and more strongly LA, were associated with non-criteria antiphospholipid syndrome (APS) manifestations such as thrombocytopenia and haemolytic anaemia. Moreover, LA and aCL (particularly IgG isotype) were also associated with Libman-Sacks endocarditis and cognitive impairment. This association was stronger with more than one positive aPL. All types of aPL were also associated with classic APS manifestations, although LA, IgG isotypes, and patients with more than one aPL displayed a higher risk. Conclusion There is a hierarchy for aPL and the risk of APS and SLE manifestations. aCL, and especially LA, confer a higher risk for major organ involvement in SLE. IgG isotypes seem to have a more important role. The load of aPL confer a higher risk for APS and certain SLE manifestations.

espanolEl registro de lupus de la Sociedad Espanola de Reumatologia (RELESSER) es un registro multicentrico de pacientes con lupus eritematoso sistemico seguidos en servicios de reumatologia espanoles, que contiene cuantiosa informacion sobre 4.024 pacientes. Hasta la fecha han sido publicados 14 analisis sobre la fase transversal del registro. Se describen los resultados mas relevantes, a criterio de los autores, concernientes a las caracteristicas clinicas acumuladas, nivel de actividad, tratamientos, refractariedad, dano y mortalidad. Se revisan asimismo los resultados de analisis especificos sobre el lupus incompleto, la nefritis lupica, las manifestaciones respiratorias, los eventos cardiovasculares, las infecciones graves, las neoplasias, la fibromialgia, el lupus en varones, el lupus en latinoamericanos y el lupus de inicio juvenil, comparando los diferentes subgrupos con el total de la cohorte. RELESSER se ha constituido como uno de los registros clinicos de lupus eritematoso sistemico mas importantes del mundo, resultando altamente productivo en terminos de generacion de conocimiento de la enfermedad en pacientes espanoles, util tambien para toda la comunidad cientifica. EnglishThe lupus register of the Spanish Society of Rheumatology (RELESSER) is a multicentre register of patients with systemic lupus erythematosus (SLE) under follow-up by Spanish Rheumatology Services. It contains data on a total of 4024 patients with SLE. So far, 14 studies have been published from the transversal phase of RELESSER. Here we report the more relevant contributions of those studies, according to the authors’ perspective, concerning cumulative clinical characteristics, level of activity, treatments, refractory disease, damage and mortality. We also review the main results of the analysis regarding incomplete SLE, lupus nephritis, respiratory manifestations, cardiovascular disease, serious infection, malignancies, fibromyalgia, SLE in males, SLE in Hispanics and juvenile-onset SLE, comparing the main characteristics of each subgroup to the global cohort. RELESSER has become one of the most important clinical SLE registers around the world, with a high yield in terms of knowledge generation about the disease in Spain, also useful for the entire scientific community.

The lupus register of the Spanish Society of Rheumatology (RELESSER) is a multicentre register of patients with systemic lupus erythematosus (SLE) under follow-up by Spanish Rheumatology Services. It contains data on a total of 4024 patients with SLE. So far, 14 studies have been published from the transversal phase of RELESSER. Here we report the more relevant contributions of those studies, according to the authors' perspective, concerning cumulative clinical characteristics, level of activity, treatments, refractory disease, damage and mortality. We also review the main results of the analysis regarding incomplete SLE, lupus nephritis, respiratory manifestations, cardiovascular disease, serious infection, malignancies, fibromyalgia, SLE in males, SLE in Hispanics and juvenile-onset SLE, comparing the main characteristics of each subgroup to the global cohort. RELESSER has become one of the most important clinical SLE registers around the world, with a high yield in terms of knowledge generation about the disease in Spain, also useful for the entire scientific community.

Objectives To assess the characteristics and risk of lymphoma in a large cohort of patients with SLE. Methods A case–cohort analysis was performed within a dynamic cohort of SLE patients from the Spanish Society of Rheumatology Lupus Registry (RELESSER). Clinical and analytical features were compared between the lymphoma SLE group and the control SLE group using an independent-sample Student’s t-test or Mann–Whitney test for continuous variables and the χ2 test for categorical variables with Fisher’s exact test if necessary. The multivariate analysis was based on a generalized linear model. Results Twenty-one patients with SLE and lymphoma and 3965 non-lymphoma controls with SLE were studied. Most lymphomas were of B cell origin (n = 15/21), with diffuse large B cell lymphoma being the most frequent histological type (8/21, 38.1%). As in the general population, the risk of lymphoma in SLE was higher in male than in female patients and increased with age. In the lymphoma SLE group, bivariate analysis showed a significantly higher percentage of pericarditis, organic brain syndrome, seizures, vasculitis, haemolytic anaemia, splenomegaly, venous thrombosis and mean modified (excluding lymphoma) SLICC/ACR damage index. In contrast, renal involvement, positive anti-dsDNA, and antimalarials ever were less frequent. Conclusions In this large multicentre Spanish cohort, we identified characteristics of SLE that are associated with a higher risk of lymphoma. Antimalarials were significantly negatively associated with risk of lymphoma in SLE patients. Nevertheless, further prospective studies are needed to clarify these findings.

The aim of the study was to assess the direct costs for the Spanish Health System of patients with chronic inflammatory arthropathies treated with biological therapies in daily clinical practice and to establish possible factors associated with lower costs.A descriptive, observational and retrospective study was conducted. Patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis who started a biological therapy between 1 January 2009 and 31 December 2016 were included. Variables related to socioeconomic status, disease and biological therapy were included. The annual cost of biological treatment and other direct medical costs were calculated for each disease. The analysis of costs was based on the National Health Service perspective. The time horizon comprised the 8-year long study period.A total of 422 biological therapy lines were analysed. The annual biological therapy cost per patient was €12,494±3,865 for rheumatoid arthritis, €11,248±2,763 for ankylosing spondylitis and €12,263±35,155 for psoriatic arthritis (p=0.008). The cost of biological therapies entailed about 80% of the total cost of these diseases. Hospital admission was a factor which contributed to an increasing cost in all these conditions. A longer duration of the biological therapy was associated with lower cost in all the diseases.The cost of ankylosing spondylitis is lower than that of rheumatoid arthritis and psoriatic arthritis. The biological therapy is the factor with the highest impact on the overall cost of these diseases. Preventing hospital admissions and a higher persistence to the biological therapy can contribute to lower costs for the system.

The lupus register of the Spanish Society of Rheumatology (RELESSER) is a multicentre register of patients with systemic lupus erythematosus (SLE) under follow-up by Spanish Rheumatology Services. It contains data on a total of 4024 patients with SLE. So far, 14 studies have been published from the transversal phase of RELESSER. Here we report the more relevant contributions of those studies, according to the authors' perspective, concerning cumulative clinical characteristics, level of activity, treatments, refractory disease, damage and mortality. We also review the main results of the analysis regarding incomplete SLE, lupus nephritis, respiratory manifestations, cardiovascular disease, serious infection, malignancies, fibromyalgia, SLE in males, SLE in Hispanics and juvenile-onset SLE, comparing the main characteristics of each subgroup to the global cohort. RELESSER has become one of the most important clinical SLE registers around the world, with a high yield in terms of knowledge generation about the disease in Spain, also useful for the entire scientific community.

Muscular symptoms, which may be due to multiple causes, are one of the most common early complaints in a rheumatology practice. Musculoskeletal symptoms in rheumatic conditions are very varied, ranging from mechanical problems to muscular symptoms derived from inflammatory and systemic autoimmune diseases. Several drugs commonly used by different specialists and certain drugs used in rheumatology can also cause a wide variety of muscle symptoms. A description of different systemic autoimmune diseases follows to describe the different forms of involvement of the musculoskeletal system that they cause, as well as the main causes with which a differential diagnosis should be made. In this chapter, we will try to give some clues to reach an early diagnosis using clinical criteria, particularly based on a directed anamnesis and physical examination, discussing possible guidelines for the complimentary tests that may be required in patients with muscle complaints.

The aims of the study were to quantify adherence, determine the factors that can predict adherence and identify the consequences of poorer adherence in patients with chronic inflammatory arthropathies treated with biological therapies in daily clinical practice.A descriptive, observational and retrospective study was carried out. Patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis who started a biologic therapy between 1 January 2009 and 31 December 2016 were included. Variables related to socioeconomic status, the disease, the biological therapy and hospital resources were included. Adherence was calculated by using the medication possession ratio.Three hundred and sixty-two patients and 423 lines of biological therapy were included. Mean age ± standard deviation was 50.3 ± 13.9 years, and 228 (53.9%) were women. The percentage of adherent patients was 187 out of 216 (87%) in rheumatoid arthritis, 91 out of 107 (85%) in ankylosing spondylitis and 84 out of 100 (84%) in psoriatic arthritis. Greater adherence was associated with more frequent visits to the pharmacy service (odds ratio 1.2, 95% confidence interval: 1.1-1.3 [p = 0.001]) and poorer adherence with a failure to attend scheduled appointments at the rheumatology clinic (odds ratio 0.2, 95% confidence interval: 0.1-0.9 [p = 0.030]). There were no differences between adherent and non-adherent patients in terms of the number of hospital resources used.There are no differences in adherence to biological therapies among patients with chronic inflammatory arthropathies. Adherence correlates with attendance at outpatient appointments, but this does not imply an increase in the use of hospital resources.Objetivo: Los objetivos del estudio fueron cuantificar la adherencia, determinar los factores predictivos y conocer las consecuencias de una menor adherencia, en la práctica clínica diaria, en pacientes con artropatías inflamatorias crónicas tratados con terapias biológicas. Método: Estudio descriptivo, observacional y retrospectivo. Se incluyeron pacientes con artritis reumatoide, espondilitis anquilosante y artritis psoriásica que iniciaron una terapia biológica entre el 1 de enero de 2009 y el 31 de diciembre de 2016. Se recogieron variables sociodemográficas, relacionadas con la enfermedad, sobre las terapias biológicas y los recursos hospitalarios. La adherencia se calculó mediante la ratio media de posesión.Resultados: Se incluyeron 362 pacientes y 423 líneas de terapia biológica. La media de edad ± desviación estándar fue de 50,3 ± 13,9 años; 228 (53,9%) fueron mujeres. El porcentaje de adherentes fue de 187 de 216 (87%) en artritis reumatoide, 91 de 107 (85%) en espondilitis anquilosante y 84 de 100 (84%) en artritis psoriásica. La adherencia se relacionó con acudir con más frecuencia a la consulta del servicio de farmacia(odds ratio de 1,2; intervalo de confianza 95%: 1,1- 1,3 [p = 0,001]) e inversamente con no acudir a las consultas de reumatología en la fecha prevista (odds ratio de 0,2; intervalo de confianza 95%: 0,1-0,9 [p = 0,030]). No hubo diferencias en el número de recursos hospitalarios utilizados por pacientes adherentes y no adherentes.Conclusiones: La adherencia a las terapias biológicas entre las artropatías inflamatorias crónicas es similar. Dicha adherencia se correlaciona con la frecuentación a consultas externas, pero no implica un aumento del consumo de recursos.

Author(s): Clowse, Megan EB; Wallace, Daniel J; Furie, Richard A; Petri, Michelle A; Pike, Marilyn C; Leszczynski, Piotr; Neuwelt, C Michael; Hobbs, Kathryn; Keiserman, Mauro; Duca, Liliana; Kalunian, Kenneth C; Galateanu, Catrinel; Bongardt, Sabine; Stach, Christian; Beaudot, Carolyn; Kilgallen, Brian; Gordon, Caroline; EMBODY Investigator Group | Abstract: ObjectiveEpratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double-blind, placebo-controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).MethodsPatients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti-double-stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG-2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5-60 mg/day). BILAG-2004 grade A scores in the renal and central nervous system domains were excluded. Patients were randomized 1:1:1 to receive either placebo, epratuzumab 600 mg every week, or epratuzumab 1,200 mg every other week, with infusions delivered for the first 4 weeks of each 12-week dosing cycle, for 4 cycles. Patients across all 3 treatment groups also continued with their standard therapy. The primary end point was the response rate at week 48 according to the BILAG-based Combined Lupus Assessment (BICLA) definition, requiring improvement in the BILAG-2004 score, no worsening in the BILAG-2004 score, SLEDAI-2K score, or physician's global assessment of disease activity, and no disallowed changes in concomitant medications. Patients who discontinued the study medication were classified as nonresponders.ResultsIn the EMBODY 1 and EMBODY 2 trials of epratuzumab, 793 patients and 791 patients, respectively, were randomized, 786 (99.1%) and 788 (99.6%), respectively, received study medication, and 528 (66.6%) and 533 (67.4%), respectively, completed the study. There was no statistically significant difference in the primary end point between the groups, with the week 48 BICLA response rates being similar between the epratuzumab groups and the placebo group (response rates ranging from 33.5% to 39.8%). No new safety signals were identified.ConclusionIn patients with moderate or severely active SLE, treatment with epratuzumab + standard therapy did not result in improvements in response rates over that observed in the placebo + standard therapy group.

Background: Immune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. Methods: Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls. Results: In the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (P-FDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (PFDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an overrepresentation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways. Conclusions: This study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.

Systemic lupus erythematosus (SLE) is a complex rheumatic multisystemic disease of autoimmune origin with significant potential morbidity and mortality. It is one of the most common autoimmune diseases with an estimated prevalence of 20-150 cases per 100,000 inhabitants. The clinical spectrum of SLE is wide and variable both in clinical manifestations and severity. This prompted the Spanish Ministry of Health, Social Services and Equality to promote and fund the development of a clinical practice guideline (CPG) for the clinical care of SLE patients within the Programme of CPG in the National Health System which coordinates GuiaSalud. This CPG is is intended as the reference tool in the Spanish National Health System in order to support the comprehensive clinical management of people with SLE by all health professionals involved, regardless of specialty and level of care, helping to standardize and improve the quality of clinical decisions in our context in order to improve the health outcomes of the people affected. The purpose of this document is to present and discuss the rationale of the recommendations on the general management of SLE, specifically, clinical follow-up, general therapeutic approach, healthy lifestyles, photoprotection, and training programmes for patients. These recommendations are based on the best available scientific evidence, on discussion and the consensus of expert groups.

Tumour necrosis factor-alpha antagonist drugs represent a significant advance in the treatment of inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies, and intestinal inflammatory disease. The increase in tuberculosis with infliximab is known, but there is less data available that specifically associates tuberculosis with adalimumab. We present the cases of 2 patients with rheumatoid arthritis and one patient with ankylopoietic spondylitis on treatment with adalimumab, who developed pulmonary and disseminated tuberculosis despite following the screening and prophylaxis measures recommended in guidelines. We also review the association between treatment with tumour necrosis factor-alpha antagonists and tuberculosis.

Tumour necrosis factor-alpha antagonist drugs represent a significant advance in the treatment of inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies, and intestinal inflammatory disease. The increase in tuberculosis with infliximab is known, but there is less data available that specifically associates tuberculosis with adalimumab. We present the cases of 2 patients with rheumatoid arthritis and one patient with ankylopoietic spondylitis on treatment with adalimumab, who developed pulmonary and disseminated tuberculosis, despite following the screening and prophylaxis measures recommended in guidelines. We also review the association between treatment with tumour necrosis factor-alpha antagonists and tuberculosis.