Single-cell transcriptomic profiling reveals a pathogenic role of cytotoxic CD4+ T cells in giant cell arteritis.

Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4+ T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4+ T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4+ T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4+ T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4+ T cells in GCA and suggest targeting CTLs as a potential therapeutic option.

Real-World Persistence and Treatment Patterns in Patients with Psoriatic Arthritis Treated with Anti-IL17 Therapy in Spain: The PerfIL-17 Study.

INTRODUCTION: Given the growing interest and use of interleukin-17 inhibitors (anti-IL17) for the treatment of psoriatic arthritis (PsA), an observational study has been conducted to characterize the patient profile, treatment patterns, and persistence of ixekizumab or secukinumab in patients with PsA receiving them as first anti-IL17. METHODS: This is a multicenter retrospective study, conducted at eight Spanish hospitals where data from adult patients with PsA were collected from electronic medical records. Three cohorts of patients, initiating treatment with an anti-IL17 [secukinumab 150 mg (SECU150), secukinumab 300 mg (SECU300), or ixekizumab (IXE)] between January 2019 and March 2021, were included. Demographic and clinical patient characteristics, treatment patterns, and persistence were analyzed descriptively. Continuous data were presented as mean [standard deviation (SD)] and categorical variables as frequencies with percentages. Persistence rates at 3, 6, and 12 months were calculated. RESULTS: A total of 221 patients with PsA were included in the study [SECU150, 103 (46.6%); SECU300, 38 (17.2%); and IXE, 80 (36.2%)]. Treatment patterns differed by clinical characteristics: SECU150 was initiated more frequently in patients with moderate PsA and less peripheral joint involvement, while patients on SECU300 included those with a higher rate of enthesitis and active skin psoriasis, and patients on IXE showed a longer time since PsA diagnosis, more frequent comorbidities, joint involvement, and diagnosed skin psoriasis. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) were previously administered in 88.2% of patients and biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) were administered in 72.9%. The mean number of previous b/tsDMARDs was 2.4 (SD 1.5) in the IXE cohort, 1.7 (SD 0.9) in the SECU300 cohort, and 1.6 (SD 1.0) for those in the SECU150 cohort. The global persistence on all anti-IL17 was 97.2%, 88.4%, and 81.0% at 3, 6, and 12 months, respectively. The most frequent reason for discontinuation across the three cohorts was lack of effectiveness (16.7%; 37/221). CONCLUSIONS: Most of the patients with PsA treated with anti-IL17 in Spain had moderate to severe disease activity, high peripheral joint and skin involvement, and had received previous b/tsDMARDs. More than 80% of patients with a 1-year follow-up persisted on anti-IL17, with the highest rate observed in the IXE cohort, followed by the SECU150 then SECU300 cohorts.

Pregnancy outcomes in 1869 pregnancies in a large cohort from the Spanish Society of Rheumatology Lupus Register (RELESSER).

INTRODUCTION: Obstetric complications are more common in women with systemic lupus erythematosus (SLE) than in the general population. OBJECTIVE: To assess pregnancy outcomes in women with SLE from the RELESSER cohort after 12 years of follow-up. METHODS: A multicentre retrospective observational study was conducted. In addition to data from the RELESSER register, data were collected on obstetric/gynaecological variables and treatments received. The number of term pregnancies was compared between women with pregnancies before and after the diagnosis of SLE. Further, clinical and laboratory characteristics were compared between women with pregnancies before and after the diagnosis, on the one hand, and with and without complications during pregnancy, on the other. Bivariate and multivariate analyses were carried out to identify factors potentially associated with complications during pregnancy. RESULTS: A total of 809 women were included, with 1869 pregnancies, of which 1395 reached term. Women with pregnancies before the diagnosis of SLE had more pregnancies (2.37 vs 1.87) and a higher rate of term pregnancies (76.8% vs 69.8%, p < 0.001) compared to those with pregnancies after the diagnosis. Women with pregnancies before the diagnosis were diagnosed at an older age (43.4 vs 34.1 years) and had more comorbidities. No differences were observed between the groups with pregnancies before and after diagnosis in antibody profile, including anti-dsDNA, anti-Sm, anti-Ro, anti-La, lupus anticoagulant, anticardiolipin or anti-beta-2-glycoprotein. Overall, 114 out of the 809 women included in the study experienced complications during pregnancy, including miscarriage, preeclampsia/eclampsia, foetal death, and/or preterm birth. Women with complications had higher rates of antiphospholipid syndrome (40.5% vs 9.9%, p < 0.001) and higher rates of positivity for IgG anticardiolipin (33.9% vs 21.3%, p = 0.005), IgG anti-beta 2 glycoprotein (26.1% vs 14%, p = 0.007), and IgM anti-beta 2 glycoprotein (26.1% vs 16%, p = 0.032) antibodies, although no differences were found regarding lupus anticoagulant. Among the treatments received, only heparin was more commonly used by women with pregnancy complications. We did not find differences in corticosteroid or hydroxychloroquine use. CONCLUSIONS: The likelihood of term pregnancy is higher before the diagnosis of SLE. In our cohort, positivity for anticardiolipin IgG and anti-beta-2- glycoprotein IgG/IgM, but not lupus anticoagulant, was associated with a higher risk of poorer pregnancy outcomes.

Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity.

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Zücker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg/kg of melatonin, but not at 0.1 mg/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg/kg (by ~11%) and 10 mg/kg (by ~12%). This effect was associated with a dose-dependent increase in the thermal response to the baseline condition or acute cold challenge in the interscapular area measurable by infrared thermography, with the highest thermal response being recorded at the 10 mg/kg dose. Upon histology, melatonin treatment markedly restored the typical brownish appearance of the tissue and promoted a shift in size distribution toward smaller adipocytes in a dose-dependent fashion, with the most pronounced brownish phenotype being observed at 10 mg/kg of melatonin. As a hallmark of thermogenesis, the protein level of uncoupled protein 1 (UCP1) from immunofluorescence and Western blot analysis increased significantly and dose-dependently at all three doses of melatonin, reaching the highest level at the dose of 10 mg/kg. Likewise, all three doses of melatonin modulated iBAT mitochondrial dynamics by increasing protein expression of the optic atrophy protein type 1 (OPA1) fusion marker and decreasing that of the dynamin-related protein1 (DRP1) fission marker, again dose-dependently, with the highest and lowest expression levels, respectively, being reached at the 10 mg/kg dose. These findings highlight for the first time the relevance of the dose-dependency of melatonin toward BW control and BAT thermogenic activation, which may have potential therapeutic implications for the treatment of obesity. To clinically apply the potential therapeutic of melatonin for obesity, we consider that the effective animal doses that should be extrapolated to obese individuals may be within the dose range of 1 to 10 mg/kg.

Biologic therapy in refractory neurobehçet's disease: a multicentre study of 41 patients and literature review.

OBJECTIVES: To assess efficacy and safety of biologic therapy (BT) in neurobehçet's disease (NBD) refractory to glucocorticoids and at least one conventional immunosuppressive drug. METHODS: Open-label, national, multicentre study. NBD diagnosis was based on the International Consensus Recommendation criteria. Outcome variables were efficacy and safety. Main efficacy outcome was clinical remission. Other outcome variables analysed were glucocorticoid-sparing effect and improvement in laboratory parameters. RESULTS: We studied 41 patients [21 women; age 40.6 (10.8) years]. Neurological damage was parenchymal (n = 33, 80.5%) and non-parenchymal (n = 17, 41.5%). First BTs used were infliximab (n = 19), adalimumab (n = 14), golimumab (n = 3), tocilizumab (n = 3) and etanercept (n = 2). After 6 months of BT, neurological remission was complete (n = 23, 56.1%), partial (n = 15, 37.6%) and no response (n = 3, 7.3%). In addition, median (IQR) dose of oral prednisone decreased from 60 (30-60) mg/day at the initial visit to 5 (3.8-10) mg/day after 6 months (P < 0.001). It was also the case for mean erythrocyte sedimentation rate [31.5 (25.6)-15.3 (11.9) mm/1st h, P = 0.011] and median (IQR) C-reactive protein [1.4 (0.2-12.8) to 0.3 (0.1-3) mg/dl, P = 0.001]. After a mean follow-up of 57.5 months, partial or complete neurological remission persisted in 37 patients (90.2%). BT was switched in 22 cases (53.6%) due to inefficacy (n = 16) or adverse events (AEs) (n = 6) and discontinued due to complete prolonged remission (n = 3) or severe AE (n = 1). Serious AEs were observed in two patients under infliximab treatment. CONCLUSIONS: BT appears to be effective and relatively safe in refractory NBD.

Do all antiphospholipid antibodies confer the same risk for major organ involvement in systemic lupus erythematosus patients?

OBJECTIVES: 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. CONCLUSIONS: 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.

Digestive involvement in primary Sjögren's syndrome: analysis from the Sjögrenser registry.

OBJECTIVES: Digestive involvement (DI) has been reported in 10-30% of primary Sjögren's syndrome (pSS) patients, and few studies have systematically analysed the prevalence of DI in pSS patients. The aim of this study was to describe DI prevalence in pSS patients from the Sjögrenser Study, and to analyse its clinical associations. METHODS: All patients included in the Sjögrenser study, a Spanish multicentre randomised cohort, containing demographic, clinical and histologic data, have been analysed retrospectively. Patients were classified according to the presence of DI (oesophageal, gastric, intestinal, hepatic and pancreatic), and we have performed DI clinical associations, descriptive statistics, Student t or χ2 test, and uni and multivariate logistic regression. RESULTS: From 437 included patients, 95% were women, with a median age of 58 years, 71 (16.2%) presented DI: 21 (29.5%) chronic atrophic gastritis, 12 (16.9%) oesophageal motility dysfunction, 3 (4.2%) lymphocytic colitis, 18 (25.3%) primary biliary cholangitis, 15 (21.1%) autoimmune hepatitis, 7 (9.8%) pancreatic involvement and 5 (7%) coeliac disease. Half of them developed DI at the same time or after pSS diagnosis. Patients with DI were significantly older at pSS diagnosis (p=0.032), more frequently women (p=0.009), presented more autoimmune hypothyroidism and C3 hypocomplementaemia (p=0.040), and were treated more frequently with glucocorticoids, immunosuppressant and biologic therapies. Patients with pancreatic involvement presented more central nervous system and renal involvement, Raynaud's phenomenon, lymphoma and C3/C4 hypocomplementaemia. CONCLUSIONS: DI is frequent in Sjögrenser patients, mainly in the form of autoimmune disorders, and seem to be associated with a more severe phenotype. Our results suggest that DI should be evaluated in pSS patients, especially those with more severe disease.

Antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE) implies a more severe disease with more damage accrual and higher mortality.

INTRODUCTION: Antiphospholipid antibodies (aPL) have been associated with organ damage and certain features in systemic lupus erythematosus(SLE) patients. Our aim was to investigate the differences between SLE patients according to the presence of aPL and/or clinical antiphospholipid syndrome (APS). MATERIALS AND METHODS: Patients from the RELESSER-T registry were included. RELESSER-T is a Spanish multicenter, hospital-based, retrospective, SLE registry. RESULTS: We included 2398 SLE patients, 1372 of whom were positive for aPL. Overall 1026 patients were classified as SLE, 555 as SLE-APS and817 as SLE-aPL. Regarding cardiovascular risk factors, SLE-APS patients had higher rates of hypertension, dyslipidemia and diabetes than those with SLE-aPL and SLE (p < 0.001). SLE-APS patients showed higher rates of neuropsychiatric, cardiac, pulmonary, renal and ophthalmological manifestations than the other groups (p < 0.001). SLE-APS patients presented greater damage accrual with higher SLICC values (1.9 ± 2.2 in SLE-APS, 0.9 ± 1.4 in SLE-aPL and 1.1 ± 1.6 in SLE, p < 0.001) and more severe disease as defined by the Katz index (3 ± 1.8 in SLE-APS, 2.7 ± 1.7 in SLE-aPL and 2.6 ± 1.6 in SLE, p < 0.001). SLE-APS patients showed higher mortality rates (p < 0.001). CONCLUSIONS: SLE-APS patients exhibited more severe clinical profiles with higher frequencies of major organ involvement, greater damage accrual and higher mortality than SLE-aPL and SLE patients.

Prevalence and factors associated with osteoporosis and fragility fractures in patients with primary Sjögren syndrome.

This study aimed at determining socio-demographic and clinical factors of primary Sjögren syndrome (pSS) associated with osteoporosis (OP) and fragility fracture. SJOGRENSER is a cross-sectional study of patients with pSS, classified according to American European consensus criteria developed in 33 Spanish rheumatology departments. Epidemiological, clinical, serological and treatment data were collected and a descriptive analysis was conducted. Bivariate and multivariate analyses were performed using a binomial logistic regression to study the factors associated with OP and fragility fracture in pSS. 437 patients were included (95% women, with a median age of 58.6 years). 300 women were menopausal (76.4%). Prevalence of OP was 18.5% [in men (N = 21) this measured 19%]. A total of 37 fragility fractures were recorded. In the multivariate analysis, there was an association between OP and age: in the 51-64 age range (menopausal women), the OR measured 9.993 (95% CI 2301-43,399, p = 0.002); In the age > 64 years group, OR was 20.610 (4.679-90.774, p < 0.001); between OP and disease duration, OR was 1.046 (1.008-1085, p = 0.017); past treatment with corticosteroids, OR 2.548 (1.271-5.105, p = 0.008). Similarly, an association was found between fragility fractures and age: in the 51-64 age group, OR measured 5.068 (1.117-22,995, p = 0.035), age > 64 years, OR was 7.674 (1.675-35,151, p < 0.009); disease duration, OR 1.049 (CI 1.003-1097, p < 0.036) and the ESSDAI index, OR 1.080 (1.029-1134, p = 0.002). Patients with pSS can develop osteoporosis and fragility fractures over the course of the disease. Age, corticosteroids treatment and disease duration were associated with the development of OP. Disease duration and ESSDAI were associated with the development of fractures in patients with pSS.

Associated factors to serious infections in a large cohort of juvenile-onset systemic lupus erythematosus from Lupus Registry (RELESSER).

OBJECTIVE: To assess the incidence of serious infection (SI) and associated factors in a large juvenile-onset systemic lupus erythematosus (jSLE) retrospective cohort. METHODS: All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥4 ACR-97 SLE criteria and disease onset <18 years old (jSLE), were retrospectively investigated for SI (defined as either the need for hospitalization with antibacterial therapy for a potentially fatal infection or death caused by the infection). Standardized SI rate was calculated per 100 patient years. Patients with and without SI were compared. Bivariate and multivariate logistic and Cox regression models were built to calculate associated factors to SI and relative risks. RESULTS: A total of 353 jSLE patients were included: 88.7% female, 14.3 years (± 2.9) of age at diagnosis, 16.0 years (± 9.3) of disease duration and 31.5 years (±10.5) at end of follow-up. A total of 104 (29.5%) patients suffered 205 SI (1, 55.8%; 2-5, 38.4%; and ≥6, 5.8%). Incidence rate was 3.7 (95%CI: 3.2-4.2) SI per 100 patient years. Respiratory location and bacterial infections were the most frequent. Higher number of SLE classification criteria, SLICC/ACR DI score and immunosuppressants use were associated to the presence of SI. Associated factors to shorter time to first infection were higher number of SLE criteria, splenectomy and immunosuppressants use. CONCLUSIONS: The risk of SI in jSLE patients is significant and higher than aSLE. It is associated to higher number of SLE criteria, damage accrual, some immunosuppressants and splenectomy.

Tocilizumab in giant cell arteritis: differences between the GiACTA trial and a multicentre series of patients from the clinical practice.

OBJECTIVES: A potential point of concern among clinicians is whether results derived from the clinical trials can be reasonably applied or generalised to a definable group of patients seen in real world. It can be the case of the GiACTA study that is a phase III randomised controlled trial of tocilizumab (TCZ) in giant cell arteritis (GCA). To address this question, we compared the clinical features and the responses to TCZ from the GiACTA trial patients with those from a series of GCA seen in the daily clinical practice. METHODS: Comparative study of clinical features between patients from the GiACTA trial (overall n=251) and those from a multicentre series of real-world GCA patients undergoing TCZ therapy (n=134). The diagnosis of GCA in the GiACTA trial was established by the ACR modified criteria whereas in the series of real-world patients it was made by using the ACR criteria, a positive biopsy of temporal artery or the presence of imaging techniques consistent with large-vessel vasculitis in individuals who presented cranial symptoms of GCA. GiACTA trial patients received subcutaneous TCZ (162 mg every 1 or 2 weeks) whereas those from the clinical practice series were treated using standard IV dose (8 mg/kg/month) or subcutaneous (162 mg/week). RESULTS: Real-life patients undergoing TCZ were older with longer disease duration and higher values of ESR and had received conventional immunosuppressive therapy (mainly methotrexate) more commonly than those included in the GiACTA trial. Despite clinical differences, TCZ was equally effective in both GiACTA trial and clinical practice patients. However, serious infections were more commonly observed in GCA patients recruited from the clinical practice. CONCLUSIONS: Despite clinical differences with patients recruited in clinical trials, data from real-life patients confirm the efficacy of TCZ in GCA.

Hormonal Dependence and Cancer in Systemic Lupus Erythematosus.

OBJECTIVE: To estimate the incidence and analyze any cancer-associated factors in patients with systemic lupus erythematosus (SLE), differentiating between hormone-sensitive (HS) and non-HS cancers. METHODS: This was a retrospective multicenter study of a patient cohort from the Systemic Lupus Erythematosus Registry of the Spanish Society of Rheumatology. Included were the first cancer post-SLE diagnosis, clinical and sociodemographic information, cumulative damage, severity, comorbidities, treatments, and refractoriness. Cancers were classified as HS (prostate, breast, endometrium, and ovarian) and non-HS (the remainder). The standardized incidence ratio (SIR) was calculated and logistic regression models were built. RESULTS: A total of 3,539 patients (90.4% women) were included, 154 of whom had cancer (91% female), and 44 had HS cancer (100% female). The cancer SIR was 1.37 (95% confidence interval [95% CI] 1.15-1.59), with higher values in women age <65 years (SIR 2.38 [95% CI 1.84-2.91]). The SIR in women with HS versus non-HS cancer was 1.02 (95% CI 0.13-1.91) and 1.93 (95% CI 0.98-2.89). In HS versus non-HS cancers, SLE diagnostic age (odds ratio [OR] 1.04 [P = 0.002] versus 1.04 [P = 0.019]), and period of disease evolution (OR 1.01 [P < 0.001] versus 1.00 [P = 0.029]) were associated with cancer. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (OR 1.27 [P = 0.022]) and angiotensin-converting enzyme (ACE) inhibitor prescriptions (OR 2.87 [P = 0.048]) were associated with non-HS cancers. CONCLUSION: Cancer incidence in patients with SLE was higher than in the Spanish population, particularly among young women. This increase might be due to non-HS cancers, which would be associated with SLE involving greater cumulative damage where more ACE inhibitors are prescribed.

Bacteremia in Systemic Lupus Erythematosus in Patients from a Spanish Registry: Risk Factors, Clinical and Microbiological Characteristics, and Outcomes.

OBJECTIVE: To describe the incidence of bacteremia in a large multicentric cohort of patients with systemic lupus erythematosus (SLE) and their clinical characteristics and to identify risk factors. METHODS: All bacteremic episodes from the Spanish RELESSER registry were included. Clinical and laboratory characteristics concerning bacteremia and SLE status, as well as comorbidities at the time of infection, were retrospectively collected. A comparison with sex- and age-matched SLE controls without bacteremia was made. A logistic regression was conducted. RESULTS: The study included 114 episodes of bacteremia in 83 patients. The incidence rate was 2.7/1000 patient-years. At the time of bacteremia, the median age was 40.5 (range: 8-90) years, and 88.6% of patients were female. The Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index was 4 [interquartile range (IQR) 8]; 41% had an SLE flare (66% severe); Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was 3 (IQR 4). A comorbidity was recorded in 64% of cases. At the time of bacteremia, 88.6% received corticosteroids (68.6% > 10 mg/day) and 57% immunosuppressors. Gram-negative bacilli, most frequently Escherichia coli (29.8%), caused 52.6% of the episodes. The bacteremia-related mortality was 14% and bacteremia was recurrent in 27.2% of cases. A dose-response relationship was found between corticosteroids and bacteremia risk. In the multivariate analysis, these factors were associated with bacteremia: elevated creatinine (OR 1.31, 95% CI 1.01-1.70; p = 0.045), diabetes (OR 6.01, 95% CI 2.26-15.95; p < 0.001), cancer (OR 5.32, 95% CI 2.23-12.70; p < 0.001), immunosuppressors (OR 6.35, 95% CI 3.42-11.77; p < 0.001), and damage (OR 1.65, 95% CI 1.31-2.09; p < 0.001). CONCLUSION: Bacteremia occurred mostly in patients with active SLE and was frequently associated with severe flares and corticosteroid use. Recurrence and mortality were high. Immunosuppressors, comorbidities, and disease-related damage were associated with bacteremia.

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept.

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

Pure Membranous Lupus Nephritis: Description of a Cohort of 150 Patients and Review of the Literature / Nefritis lúpica membranosa pura: descripción de una cohorte de 150 pacientes y revisión de la literatura

Objectives: The course and long-term outcome of pure membranous lupus nephritis (MLN) are little understood. The aims of this study are to evaluate the clinical features, course, outcome and prognostic indicators in pure MLN and to determine the impact of ethnicity and the type of health insurance on the course and prognosis of pure MLN. Methods: We conducted a retrospective review of medical records of 150 patients with pure MLN from Spain and the USA. Results: Mean age was 34.2±12.5 and 80% were women. Sixty-eight percent of patients had nephrotic syndrome at diagnosis. The average serum creatinine was 0.98±0.78mg/dl. Six percent of patients died and 5.3% developed end-stage renal disease (ESRD). ESRD was predicted by male sex, hypertension, dyslipidemia, high basal 24h-proteinuria, high basal serum creatinine and a low basal creatinine clearance. Age, cardiac insufficiency, peripheral artheriopathy, hemodialysis and not having received mycophenolate mofetil or antimalarials for MLN predicted death. Conclusions: Pure MLN frequently presents with nephrotic syndrome, high proteinuria and normal serum creatinine. Its prognosis is favourable in maintaining renal function although proteinuria usually persists over time. Baseline cardiovascular disease and not having a health insurance are related with poor prognosis

Objetivos: Los conocimientos sobre el curso y el desenlace a largo plazo de la nefritis lúpica membranosa (NLM) pura son todavía escasos. El objetivo de este estudio es evaluar las características clínicas, curso, desenlace e indicadores pronósticos de la NLM y determinar el impacto de la etnicidad y tipo de cobertura sanitaria en el curso y pronóstico de la NLM. Métodos: Se realizó una revisión retrospectiva de las historias de 150 pacientes con NLM de España y Estados Unidos. Resultados: La edad media fue 34,2±12,5 y el 80% eran mujeres. El 68% de los pacientes tenían síndrome nefrótico al diagnóstico. La creatinina sérica media fue 0,98±0,78mg/dl. El 6% de los pacientes fallecieron y el 5,3% desarrollaron insuficiencia renal terminal (IRT). El sexo masculino, la hipertensión, la dislipemia, la alta proteinuria basal, la alta creatininemia y un aclaramiento de creatinina reducido predijeron el desarrollo de IRT. La edad, la insuficiencia cardíaca, la arteriopatía periférica, la hemodiálisis y el no haber recibido micofenolato de mofetilo o antimaláricos predijeron el fallecimiento. Conclusiones: La NLM pura suele debutar con síndrome nefrótico, alta proteinuria y creatininemia normal. Su pronóstico es favourable en términos de mantenimiento de la función renal aunque la proteinuria habitualmente persiste durante el seguimiento. La enfermedad cardiovascular basal y no tener cobertura sanitaria se relacionan con mal pronóstico

Tocilizumab in giant cell arteritis. Observational, open-label multicenter study of 134 patients in clinical practice.

OBJECTIVE: Tocilizumab (TCZ) has shown efficacy in clinical trials on giant cell arteritis (GCA). Real-world data are scarce. Our objective was to assess efficacy and safety of TCZ in unselected patients with GCA in clinical practice Methods: Observational, open-label multicenter study from 40 national referral centers of GCA patients treated with TCZ due to inefficacy or adverse events of previous therapy. Outcomes variables were improvement of clinical features, acute phase reactants, glucocorticoid-sparing effect, prolonged remission and relapses. A comparative study was performed: (a) TCZ route (SC vs. IV); (b) GCA duration (≤6 vs. >6 months); (c) serious infections (with or without); (d) ≤15 vs. >15 mg/day at TCZ onset. RESULTS: 134 patients; mean age, 73.0 ± 8.8 years. TCZ was started after a median [IQR] time from GCA diagnosis of 13.5 [5.0-33.5] months. Ninety-eight (73.1%) patients had received immunosuppressive agents. After 1 month of TCZ 93.9% experienced clinical improvement. Reduction of CRP from 1.7 [0.4-3.2] to 0.11 [0.05-0.5] mg/dL (p < 0.0001), ESR from 33 [14.5-61] to 6 [2-12] mm/1st hour (p < 0.0001) and decrease in patients with anemia from 16.4% to 3.8% (p < 0.0001) were observed. Regardless of administration route or disease duration, clinical improvement leading to remission at 6, 12, 18, 24 months was observed in 55.5%, 70.4%, 69.2% and 90% of patients. Most relevant adverse side-effect was serious infections (10.6/100 patients-year), associated with higher doses of prednisone during the first three months of therapy. CONCLUSION: In clinical practice, TCZ yields a rapid and maintained improvement of refractory GCA. Serious infections appear to be higher than in clinical trials.

Pure Membranous Lupus Nephritis: Description of a Cohort of 150 Patients and Review of the Literature.

OBJECTIVES: The course and long-term outcome of pure membranous lupus nephritis (MLN) are little understood. The aims of this study are to evaluate the clinical features, course, outcome and prognostic indicators in pure MLN and to determine the impact of ethnicity and the type of health insurance on the course and prognosis of pure MLN. METHODS: We conducted a retrospective review of medical records of 150 patients with pure MLN from Spain and the USA. RESULTS: Mean age was 34.2±12.5 and 80% were women. Sixty-eight percent of patients had nephrotic syndrome at diagnosis. The average serum creatinine was 0.98±0.78mg/dl. Six percent of patients died and 5.3% developed end-stage renal disease (ESRD). ESRD was predicted by male sex, hypertension, dyslipidemia, high basal 24h-proteinuria, high basal serum creatinine and a low basal creatinine clearance. Age, cardiac insufficiency, peripheral artheriopathy, hemodialysis and not having received mycophenolate mofetil or antimalarials for MLN predicted death. CONCLUSIONS: Pure MLN frequently presents with nephrotic syndrome, high proteinuria and normal serum creatinine. Its prognosis is favourable in maintaining renal function although proteinuria usually persists over time. Baseline cardiovascular disease and not having a health insurance are related with poor prognosis.

Identification of a 3'-Untranslated Genetic Variant of RARB Associated With Carotid Intima-Media Thickness in Rheumatoid Arthritis: A Genome-Wide Association Study.

OBJECTIVE: To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). METHODS: We performed a genome-wide association study (GWAS) in which, after quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analyzed in 2,989 RA patients of European origin. Data on subclinical atherosclerosis, obtained through assessment of carotid intima-media thickness (CIMT) and presence/absence of carotid plaques by carotid ultrasonography, were available for 1,355 individuals. RESULTS: A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome-wide level of significance (minor allele [G] ß coefficient 0.142, P = 1.86 × 10-8 ). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biologic pathway enrichment and predictive protein-protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (Gene Ontology no. 0032964; false discovery rate-adjusted P = 4.01 × 10-3 ). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 × 10-4 , P = 5.94 × 10-4 , and P = 2.46 × 10-4 , respectively). CONCLUSION: The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA.

Correction to: The beliefs of rheumatoid arthritis patients in their subcutaneous biological drug: strengths and areas of concern.

In the original publication, the family name of the last author was incorrect. The correct name should read as Jaime Calvo-Alén.

The beliefs of rheumatoid arthritis patients in their subcutaneous biological drug: strengths and areas of concern.

Patients' beliefs about their prescribed medication are an important factor influencing intentional non-adherence. This study describes rheumatoid arthritis (RA) patients' beliefs about their subcutaneous (SC) biological medication through the Beliefs about Medicines Questionnaire (BMQ), and potential associations. As part of the ARCO study (Study on Adherence of Rheumatoid arthritis patients to subCutaneous and Oral drugs), patients completed the BMQ specifically for their SC biological medication, encompassing a necessity and a concerns scale. The medication possession ratio (MPR) was calculated to assess adherence to the SC biological medication. The BMQ was completed by 321 patients. Between 71.0 and 89.7% of patients agreed/strongly agreed with necessity scale statements, and only 7.2% had low necessity scores. Between 20.0 and 49.8% of patients agreed/strongly agreed with four of five concern scale statements, and 72.3% agreed/strongly agreed with the concern statement regarding long-term medication effects. The percentage with high concerns was 58.9%, and was higher in patients not satisfied with, or with less fulfillment of, tolerability expectations. Non-adherence percentages were, respectively, 13.8 and 13.0% (p = 0.919) in those with high or low necessity, and 16.0 and 10.6% (p = 0.171) in those with high or low concerns. Most patients were categorized as 'ambivalent' (58.5%; high necessity/high concerns) or 'accepting' (36.1%; high necessity/low concerns) of their SC biological medication. The BMQ identified patients' concerns with their SC biological medication. Because patients' concerns could influence non-adherence to medication and future outcomes, physicians should address this issue in the clinic by informing patients and setting clear expectations.