Semaphorin3B promotes an anti-inflammatory and pro-resolving phenotype in macrophages from rheumatoid arthritis patients in a MerTK-dependent manner.

Previous works from our group show that Semaphorin3B (Sema3B) is reduced in RA and plays a protective role in a mouse arthritis model. In turn, MerTK plays a protective function in murine arthritis models, is expressed by synovial tissue macrophages and is linked to remission in patients with RA. In this study, we examined the role of Sema3B in the phenotypic characteristics of RA macrophages and the implication of MerTK. Peripheral blood monocytes from RA patients were differentiated into IFN-γ (RA MØIFN-γ) or M-CSF (RA MØM-CSF) macrophages and stimulated with LPS, Sema3B or their combination. Alternatively, RA fibroblast like synoviocytes (FLS) were stimulated with RA MØIFN-γ and RA MØM-CSF supernatants. Gene expression was determined by qPCR and protein expression and activation by flow cytometry, ELISA and western blot. Sema3B down-regulated the expression of pro-inflammatory mediators, in both RA MØIFN-γ and RA MØM-CSF. We observed a similar reduction in RA FLS stimulated with the supernatant of Sema3B-treated RA MØIFN-γ and RA MØM-CSF. Sema3B also modulated cell surface markers in macrophages towards an anti-inflammatory phenotype. Besides, MerTK expression and activation was up-regulated by Sema3B, just as GAS6 expression, Resolvin D1 secretion and the phagocytic activity of macrophages. Importantly, the inhibition of MerTK and neuropilins 1 and 2 abrogated the anti-inflammatory effect of Sema3B. Our data demonstrate that Sema3B modulates the macrophage characteristics in RA, inducing a skewing towards an anti-inflammatory/pro-resolving phenotype in a MerTK-dependant manner. Therefore, here we identify a new mechanism supporting the protective role of Sema3B in RA pathogenesis.

Clinical characteristics and risk factors associated with lymphoma in patients with systemic lupus erythematosus: a nationwide cohort study.

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.

Recommendations for prevention of infection in systemic autoimmune rheumatic diseases.

OBJECTIVES: To develop recommendations for the prevention of infection in adult patients with systemic autoimmune rheumatic diseases (SARD). METHODS: Clinical research questions relevant to the objective of the document were identified by a panel of experts selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network criteria. Specific recommendations were made. RESULTS: Five questions were selected, referring to prevention of infection by Pneumocystis jirovecii with trimethoprim/sulfamethoxazole, primary and secondary prophylactic measures against hepatitis B virus, vaccination against human papillomavirus, vaccination against Streptococcus pneumoniae and vaccination against influenza virus, making a total of 18 recommendations, structured by question, based on the evidence found for the different SARD and/or expert consensus. CONCLUSIONS: There is enough evidence on the safety and efficacy of vaccinations and other prophylactic measures against the microorganisms reviewed in this document to specifically recommend them for patients with SARD.

Recommendations for prevention of infection in systemic autoimmune rheumatic diseases. / Recomendaciones SER sobre prevención de infección en enfermedades reumáticas autoinmunes sistémicas.

OBJECTIVES: To develop recommendations for the prevention of infection in adult patients with systemic autoimmune rheumatic diseases (SARD). METHODS: Clinical research questions relevant to the objective of the document were identified by a panel of experts selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network criteria. Specific recommendations were made. RESULTS: Five questions were selected, referring to prevention of infection by Pneumocystis jirovecii with trimethoprim/sulfamethoxazole, primary and secondary prophylactic measures against hepatitis B virus, vaccination against human papillomavirus, vaccination against Streptococcus pneumoniae and vaccination against influenza virus, making a total of 18 recommendations, structured by question, based on the evidence found for the different SARD and/or expert consensus. CONCLUSIONS: There is enough evidence on the safety and efficacy of vaccinations and other prophylactic measures against the microorganisms reviewed in this document to specifically recommend them for patients with SARD.

Contributions of the lupus register of the Spanish Society of Rheumatology (RELESSER) to the knowledge of systemic lupus erythematosus in Spain. / Aportaciones del registro de lupus de la Sociedad Española de Reumatología (RELESSER) al conocimiento del lupus eritematoso sistémico en España.

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.

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.

Anti-CD26 autoantibodies are involved in rheumatoid arthritis and show potential clinical interest.

OBJECTIVES: Rheumatoid arthritis (RA) patients show low serum levels of the Ag dipeptidyl peptidase IV (DPP-IV/CD26), both soluble CD26 (sCD26) concentration and its DPP-IV activity. The aim of this study was to test if anti-DPP-IV/CD26 Abs (Anti-CD26) cleared sCD26. DESIGN & METHODS: Serum Anti-CD26 and Total titers (as comparison) of isotypes IgA, IgM and IgG as well as sCD26 concentration and DPP-IV activity were measured in a cohort of RA patients undergoing different biological and non-biological therapies (n=105) and controls (n=50). RESULTS: Anti-CD26 levels were increased approximately two-fold for each isotype in RA, were not related to the sCD26 clearance, showed several correlations with disease activity parameters, were significantly higher in smokers and they were not ACPA. Anti-CD26 Igs showed high diagnostic power (82% sensitivity and 96% specificity) and their levels differed amongst the different groups of patients stratified by the type of therapy. CONCLUSIONS: As DPP-IV/CD26 is associated to factors triggering RA in the lung and periodontal tissue, these results suggest that Anti-CD26 isotypes may participate in pathogenesis and may be useful as biomarkers for earlier diagnosis and/or precision medicine.

[Clinical practice guidelines for systemic lupus erythematosus: Recommendations for general clinical management]. / Guía de práctica clínica para el lupus eritematoso sistémico: recomendaciones para el abordaje clínico general.

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.

CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis.

We studied dipeptidyl peptidase IV (DPP-IV, CD26) expression in different T helper cells and serum soluble DPP-IV/sCD26 levels in rheumatoid arthritis (RA) patients, correlated these with disease activity score (DAS), and examined how they were affected by different therapies, conventional or biological (anti-TNF, anti-CD20 and anti-IL6R or Ig-CTLA4). The percentage of CD4+CD45R0+CD26- cells was greatly reduced in patients (up to 50%) when compared with healthy subjects. Three other subsets of CD4 cells, including a CD26high Th1-associated population, changed variably with therapies. Data from these subsets (frequency and staining density) significantly correlated with DAS28 or DAS28 components but different in each group of patients undergoing the different therapies. Th17 and Th22 subsets were implicated in RA as independent CCR4+ and CCR4- populations each, with distinct CD26 expression, and were targeted with varying efficiency by each therapy. Serum DPP-IV activity rather than sCD26 levels was lower in RA patients compared to healthy donors. DPP-IV and sCD26 serum levels were found related to specific T cell subsets but not to disease activity. We conclude that, according to their CD26 expression, different cell subsets could serve to monitor RA course, and an uncharacterized T helper CD26- subset, not targeted by therapies, should be monitored for early diagnosis.

[Löfgren syndrome: a study of 80 cases]. / Síndrome de Löfgren: estudio de 80 casos.

BACKGROUND AND OBJECTIVE: Löfgren's syndrome is characterized by hiliar adenopathies, erythema nodosum and arthritis. It is a benign variant of sarcoidosis, common in the Mediterranean area. To describe the clinical characteristics, treatment and outcome of a series of patients diagnosed with Löfgren's syndrome. PATIENTS AND METHODS: Retrospective design (1984-2013). SETTING: Two university hospitals with a reference population of 1,015,000 inhabitants. RESULTS: Eighty patients were diagnosed: 29 men and 51 women (mean age 42.3 years). Forty eight patients (60%) presented with the classical triad: hiliar adenopathies, erythema nodosum and arthritis; 18 (22%) with hiliar adenopathy and arthritis; 13 (16%) hiliar adenopathies and erythema nodosum. All showed abnormalities in the chest study. According to the radiological pattern, patients were classified in stage i-ii. Biopsy was performed in 39 patients and was diagnostic in 28. Treatment was based on non-steroidal anti-inflammatory drugs (54 patients, 67%) and corticosteroids (33 patients, 41%). Fourteen patients (17%) suffered a recurrence of the disease. CONCLUSIONS: Löfgren's syndrome is a benign form of sarcoidosis with a well defined clinical pattern. Biopsy is usually not required. Recurrence is scarce. The disease has a good prognosis.

Biological therapy for systemic vasculitis: a systematic review.

OBJECTIVE: Relapses and failure are frequent in systemic vasculitis (SV) patients. Biological agents have been prescribed as rescue therapies. The aim of this systematic review is to analyze the current evidence on the therapeutic use of biological agents for SV. METHODS: MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched up to the end of April 2013. Systematic reviews and meta-analysis, clinical trials, cohort studies, and case series with >3 patients were included. Independent article review and study quality assessment was done by 2 investigators with consensus resolution of discrepancies. RESULTS: Of 3447 citations, abstracts, and hand-searched studies screened, 90 were included. Most of the studies included ANCA-associated vasculitis (AAV) patients and only a few included large vessel vasculitis (LVV) patients. Rituximab was the most used agent, having demonstrated efficacy for remission induction in patients with AAV. A number of studies used different anti-TNFα agents with contrasting results. A few uncontrolled studies on the use of abatacept, alemtuzumab, mepolizumab, and tocilizumab were found. CONCLUSION: Current evidence on the use of biological therapies for SV is mainly based on uncontrolled, observational data. Rituximab is not inferior to cyclophosphamide for remission induction in AAV and might be superior in relapsing disease. Infliximab and adalimumab are effective as steroid-sparing agents. Etanercept is not effective to maintain remission in patients with granulomatosis with polyangiitis, and serious adverse events have been reported. For LVV, both infliximab and etanercept had a role as steroid-sparing agents, and tocilizumab might be effective also for remission induction in LVV.

Respiratory manifestations of systemic lupus erythematosus: old and new concepts.

The respiratory system is commonly involved in systemic lupus erythematosus. Lung disorders are classified as primary (due to lupus) and secondary to other conditions. Pleuritis and pulmonary infections are the most prevalent respiratory manifestations of each type. Other infrequent manifestations include interstitial lung disease, acute lupus pneumonitis, diffuse alveolar haemorrhage, pulmonary arterial hypertension, acute reversible hypoxaemia and shrinking lung syndrome. Even when current diagnostic tests contribute to an earlier diagnosis, the treatment of these manifestations is based on clinical experience and small series. Larger controlled trials of the different therapies in the treatment of those lung manifestations of lupus are needed. Overall malignancy is little increased in lupus, but lung cancer and non-Hodgkin's lymphoma are among the most frequent types of cancer found in these patients. As survival in lupus patients has improved over recent decades, avoiding pulmonary damage emerges as an important objective.

Systemic lupus erythematosus: pharmacological developments and recommendations for a therapeutic strategy.

The management of systemic lupus erythematosus (SLE) has improved thanks to a better understanding of the immunopathogenesis of the disease and important advances in drug development. In contrast to the worrying paucity of new therapies for SLE at the end of the last century, several agents have emerged as useful treatments for this condition in the last decade. The efficacy of mycophenolate mofetil in the treatment of patients with lupus nephritis has been recently established in several clinical trials. There are increasing data from open-label studies to support the belief that B-cell depletion using the chimeric antibody rituximab is useful in the treatment of SLE. However, larger double-blind clinical trials to confirm this belief are awaited. Other specific targeted therapeutic agents that act by inducing B-cell depletion, inhibiting co-stimulatory molecules necessary for T-cell activation, tolerising B and T cells, blocking pro-inflammatory cytokines or complement and immunoablation are exciting advances in the race towards improving the outcome for patients with SLE.