Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of ...significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE.
We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software.
We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10
): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10
), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10
), interleukin-4 signaling (p = 3.97 × 10
) and cell surface interactions at the vascular wall (p = 4.63 × 10
).
Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.
Abstract Objective To analyse the efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus (SLE). Methods We systematically searched MEDLINE, EMBASE and the ...Cochrane Central Register of Controlled Trials up to June 2013. The following were the selection criteria: (1) adult patients with SLE, (2) rituximab treatment, (3) placebo or active comparator, (4) outcome measures assessing efficacy and/or (5) safety. Meta-analysis, systematic literature reviews, randomised control trials (RCT), open clinical trials and cohort studies were included. Independent extraction of articles by 2 authors using predefined data fields was performed. The quality of each study was graded using the Oxford Levels of Evidence and Jadad׳s scale. Results A total of 26 articles met our inclusion criteria: one RCT and its exploratory analysis, 2 open studies and 22 cohort studies, which analysed 1,231 patients. Overall, patients had active disease refractory to steroids and/or immunosuppressant drugs. Acceptable evidence suggested improvements in disease activity, arthritis, thrombocytopaenia, complement and anti-dsDNA, with a steroid-sparing effect. But relapses of disease were demonstrated too. Weak evidence suggested a response in anaemia, cutaneous and neuropsychiatric manifestations. Available evidence revealed few major adverse events. Studies had medium methodological quality and in general were applicable to current practice. Conclusion Rituximab has been shown to be safe and effective in the treatment of non-renal SLE, especially in terms of disease activity, immunologic parameters and steroid-sparing effect. However, it can only be recommended for organ-specific manifestations such as arthritis and thrombocytopaenia. High-quality studies are needed in order to consider the long-term effects of re-treatment on different organ-specific manifestations.
Abstract Objectives To estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large Systemic Lupus Erythematosus (SLE) retrospective cohort. ...Methods All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥ 4 ACR-97 SLE criteria were retrospectively investigated for severe infections. Patients with and without infections were compared in terms of SLE severity, damage, comorbidities and demographic characteristics. A multivariable Cox regression model was built to calculate hazard ratios (HRs) for the first infection. Results A total of 3,658 SLE patients were included: 90% female, median age 32.9 years (DQ 9.7) and mean follow-up (months) 120.2 (±87.6). A total of 705 (19.3%) patients suffered ≥ 1 severe infection. Total severe infections recorded in these patients numbered 1,227. The incidence rate was 29.2 (95% CI:27.6–30.9) infections per 1,000 patient years. Time from first infection to second infection was significantly shorter than time from diagnosis to first infection (p<0.000). Although respiratory infections were the most common (35.5%), bloodstream infections were the most frequent cause of mortality by infection (42.0%). In the Cox regression analysis, the following were all associated with infection: age at diagnosis (HR 1.016; 95% CI:1.009–1.023), Latin-American (Amerindian-Mestizo) ethnicity (HR 2.151; 95% CI:1.539–3.005), corticosteroids (≥10 mg/day) (HR 1.271; 95% CI: 1.034–1.561), immunosuppressors (HR 1.348; 95% CI:1.079–1.684), hospitalization by SLE (HR 2.567; 95% CI:1.905–3.459) , Katz severity index (HR 1.160; 95% CI:1.105–1.217), SLICC/ACR damage index (HR 1.069; 95% CI:1.031–1.108) and smoking (HR1.332; 95% CI:1.121–1.583). Duration of antimalarial use (months) proved protective (HR 0.998; 95% CI: 0.997–0.999). Conclusions Severe infection constitutes a predictor of poor prognosis in SLE patients, is more common in Latin Americans and is associated with age, previous infection and smoking. Antimalarials exerted a protective effect.
The purpose of this study was to assess the prevalence, associated factors, and impact on mortality of primary respiratory disease in a large systemic lupus erythematosus (SLE) retrospective cohort.
...All adult patients in the RELESSER-TRANS (Registry of Systemic Lupus Erythematosus Patients of the Spanish Society of Rheumatology SER, cross-sectional phase) registry were retrospectively investigated for the presence of primary pleuropulmonary manifestations.
In total 3215 patients were included. At least one pleuropulmonary manifestation was present in 31% of patients. The most common manifestation was pleural disease (21%), followed by lupus pneumonitis (3.6%), pulmonary thromboembolism (2.9%), primary pulmonary hypertension (2.4%), diffuse interstitial lung disease (2%), alveolar hemorrhage (0.8%), and shrinking lung syndrome (0.8%). In the multivariable analysis, the variables associated with the development of pleuropulmonary manifestation were older age at disease onset (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.02-1.04), higher SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) scores (OR 1.03, 95% CI 1.00-1.07), the presence of Raynaud's phenomenon (OR 1.41, 95% CI 1.09-1.84), secondary antiphospholipid syndrome (OR 2.20, 95% CI 1.63-2.97), and the previous or concomitant occurrence of severe lupus nephritis, (OR 1.48, 95% CI 1.12-1.95) neuropsychiatric manifestations (OR 1.49, 95% CI 1.11-2.02), non-ischemic cardiac disease (OR 2.91, 95% CI 1.90-4.15), vasculitis (OR 1.81, 95% CI 1.25-2.62), hematological manifestations (OR 1.31, 95% CI 1.00-1.71), and gastrointestinal manifestations, excluding hepatitis (OR 2.05, 95% CI 1.14-3.66). Anti-RNP positivity had a clear tendency to significance (OR 1.32, 95% CI 1.00-1.75; P = 0.054). The development of pleuropulmonary manifestations independently contributes to a diminished survival (hazard ratio of 3.13). However, not all complications will influence the prognosis in the same way. Whereas the occurrence of pleural disease or pulmonary thromboembolism has a minimal impact on the survival of these patients, the remaining manifestations have a major impact on mortality.
Except for pleural disease, the remaining respiratory manifestations are very uncommon in SLE (<4%). Pleuropulmonary manifestations independently contributed to a decreased survival in these patients.
In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of ...the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA.
In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool.
Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.
To analyze the gut microbiota of patients with rheumatoid arthritis (RA) according to disease activity.
An observational cross-sectional study of 110 patients with RA and 110 age- and sex-matched ...controls was performed. Patients were classified according to the disease activity (DAS28 ≥3.2 or DAS28 <3.2). Clinical and epidemiological variables were included. The gut microbiota was analyzed using 16S rRNA sequencing and bioinformatics analysis based on QIIME and PICRUSt. A multivariate analysis was performed to identify factors associated with inflammatory activity.
The mean DAS28 indicated remission/low inflammatory activity in 71 patients (64.5 %) and moderate/high activity in 39 (35.5 %) during follow-up. Alpha and beta diversity analysis revealed differences in gut microbiota between the 3 study groups. In the moderate/high activity RA, we observed a significant change in the abundance of genera compared with the other groups. The abundance of Collinsella and Bifidobacterium was increased in RA patients compared with controls. The metabolic profile of gut microbiota was characterized by differences in pathways related to Biosynthesis, Generation of Precursor Metabolites/Energy, and Degradation/Utilization/Assimilation between the 3 groups. The factors associated with cumulative inflammatory activity in RA were age (OR 95 % CI, 1.065 1.002–1.131), obesity (OR 95% CI, 3.829 1.064–8.785), HAQ score (OR 95% CI, 2.729 1.240–5.009), and expansion of the genus Collinsella (OR 95% CI, 3.000 1.754–9.940).
The composition of gut microbiota differed between patients with RA and moderate/high activity, patients with remission/low activity, and controls. The genus Collinsella, age, obesity, and physical function were associated with cumulative inflammatory burden in RA.
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•The intestinal microbiota is altered in patients with rheumatoid arthritis (RA), however it is important to clarify the association between gut dysbiosis and cumulative inflammatory burden in RA.•The genus Collinsella seems to play an important role in the cumulative inflammatory burden within established RA.•Likewise, other factors such as age, obesity, and physical function were associated with higher inflammatory activity in RA patients.•Therefore, future studies on the treatment of these factors for the control of cumulative inflammatory burden in RA are necessary.
Objective: In this study, we aimed to evaluate the worldwide incidence and prevalence of ANCA-associated vasculitis (AAV). Methods: A systematic search of Medline and Embase was conducted until June ...2020 for studies that analyzed the incidence and prevalence of patients aged >16 years diagnosed with AAV in different geographical areas. A meta-analysis was undertaken to estimate the pooled incidence per million person-years and prevalence per million persons in AAV overall and for each subtype of AAV: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The 95% confidence interval (CI) and I2 for heterogeneity were calculated. Results: The meta-analysis included 25 studies that met the inclusion criteria and covered a total of 4547 patients with AAV. Frequency increased over time. The global pooled incidence (95% CI) was 17.2 per million person-years (13.3−21.6) and the global pooled prevalence (95% CI) was 198.0 per million persons (187.0−210.0). The pooled incidence per million person-years for each AAV subtype varied from highest to lowest, as follows: GPA, 9.0; MPA, 5.9; and EGPA, 1.7. The individual pooled prevalence per million persons was, as follows: GPA, 96.8; MPA, 39.2; and EGPA, 15.6. AAV was more predominant in the northern hemisphere. By continent, a higher incidence in America and pooled prevalence of AAV was observed in America and Europe. Conclusion: The pooled incidence and prevalence of AAV seem to be increasing over time and are higher in the case of GPA. AAV was generally more frequent (incidence and prevalence) in the northern hemisphere.
Background
Studies in axial spondyloarthritis (AxSp) have shown that intensity of pain, anxiety, depression and inflammatory activity are associated with poor sleep quality.
Aim
To describe mood and ...sleep disorders and positive psychological factors in patients with AxSp and psoriatic arthritis (PsA) and to evaluate the psychological factors that are potentially involved in sleep disorders.
Design
Multicenter cross‐sectional observational study based on a series of patients with AxSp and PsA.
Participants
Participants were selected consecutively from patients aged ≥18 years with AxSp or PsA followed at the rheumatology department of 4 Spanish hospitals. Inclusion criteria: age ≥18 years, AxSp (ASAS criteria) or PsA (CASPAR criteria), ability to understand the study and prepared to complete the questionnaires.
Methods
Main outcomes: Oviedo Sleep Quality questionnaire result. Secondary outcomes: psychological status evaluated using the Hospital Anxiety and Depression Scale (HADS) questionnaire, health‐related quality of life evaluated using SF‐36, perception of pain evaluated using the short questionnaire for assessment of pain (BDU) and fatigue evaluated using the Fatigue Scale (FACIT) questionnaire. We performed a descriptive multivariate linear regression analysis to study factors that were independently associated with sleep disorders. The STROBE guidelines were adopted.
Results
We included 301 patients (152 50.5% with AxSp and 149 49.5% with PsA). The multivariate linear regression analysis for the whole sample showed that insomnia was inversely associated with emotional recovery and biologic disease‐modifying antirheumatic drugs and directly associated with depression in both groups. The analysis by disease (AxSp and PsA) showed that insomnia was independently associated with depression and emotional recovery.
Conclusions
Insomnia may be associated with other mood disorders, quality of life and inflammatory activity in the patients studied here.
Relevance to clinical practice
A nurse intervention can be carried out to prevent sleep disorders knowing the consequences and triggers of the problem.
Objective
To describe the incidence and fatality of coronavirus disease 2019 (COVID‐19) and identify risk factors to fatality in patients with inflammatory articular diseases (IAD).
Methods
This is a ...cross‐sectional observational study of IAD patients and COVID‐19 with controls matched for age, sex, and RT‐PCR. A control group was used to compare the cumulative incidence (CI) and case fatality rate (CFR). The main outcomes of the study were CI and CFR. Other variables included comorbidities, treatments, and characteristics of the COVID‐19. Multiple logistic regression analysis was performed to investigate risk factors for fatality in patients with IAD.
Results
Of the 1537 patients who fulfilled the inclusion criteria, 23/1537 (1.49%) had IAD 13 (0.8%) had rheumatoid arthritis (RA), 5 psoriatic arthritis (PsA) (0.3%) and 5 axial spondyloarthritis (0.3%). There were no significant differences in CI of COVID‐19 and CFR in patients with IAD compared with COVID‐19 patients without IAD. In RT‐PCR positive patients, the CI of COVID‐19 in PsA and AS was higher. Of the 23 IAD patients, 2 RA patients (8.6%) died. The patients did no show characteristics of the COVID‐19 disease different from the population. In multivariate analysis, the factor associated with fatality in patients with IAD was older age (OR 95% CI, 1.1 1.0‐1.2).
Conclusion
COVID‐19 CI, fatality rate and other features do not seem to be increased in IAD patients. Older age was associated with fatality in patients with IAD.
Objective
To compare the prevalence of the main comorbidities in 2 large cohorts of patients with primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), with a focus on ...cardiovascular (CV) diseases.
Methods
This was a cross‐sectional multicenter study where the prevalence of more relevant comorbidities in 2 cohorts was compared. Patients under followup from SJOGRENSER (Spanish Rheumatology Society Registry of Primary SS) and RELESSER (Spanish Rheumatology Society Registry of SLE), and who fulfilled the 2002 American–European Consensus Group and 1997 American College of Rheumatology classification criteria, respectively, were included. A binomial logistic regression analysis was carried out to explore potential differences, making general adjustments for age, sex, and disease duration and specific adjustments for each variable, including CV risk factors and treatments, when appropriate.
Results
A total of 437 primary SS patients (95% female) and 2,926 SLE patients (89% female) were included. The mean age was 58.6 years (interquartile range IQR 50.0–69.9 years) for primary SS patients and 45.1 years (IQR 36.4–56.3 years) for SLE patients (P < 0.001), and disease duration was 10.4 years (IQR 6.0–16.7 years) and 13.0 years (IQR 7.45–19.76 years), respectively (P < 0.001). Smoking, dyslipidemia, and arterial hypertension were associated less frequently with primary SS (odds ratio OR 0.36 95% confidence interval (95% CI) 0.28–0.48, 0.74 95% CI 0.58–0.94, and 0.50 95% CI 0.38–0.66, respectively) as were life‐threatening CV events (i.e., stroke or myocardial infarction; OR 0.57 95% CI 0.35–0.92). Conversely, lymphoma was associated more frequently with primary SS (OR 4.41 95% CI 1.35–14.43). The prevalence of severe infection was lower in primary SS than in SLE (10.1% versus 16.9%; OR 0.54 95% CI 0.39–0.76; P < 0.001).
Conclusion
Primary SS patients have a consistently less serious CV comorbidity burden and a lower prevalence of severe infection than those with SLE. In contrast, their risk of lymphoma is greater.
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