Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.[Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE19033.]Human monozygotic (MZ) twins exhibit variable degrees of concordance for complex diseases, such as cancer, cardiovascular diseases, or autoimmune disorders. Whereas concordance rates close to 100% in identical twins apply to coinheritance of mutant genes that are dominant and highly penetrant, most diseases or traits show a concordance in identical twins in the broad range of 5%-75% (Nance 1978). Most of the twin-based studies have focused on the concordance between siblings that has led to the identification of traitspecific genes (Hrubec and Robinette 1984), while less attention has been paid to the degree of discordance, which suggests the participation of factors other than pure genetic changes. Recently, interest has shifted toward exploring the molecular mechanisms involved in determining phenotypic differences. The increasing recognition of the influence of epigenetics in phenotypic outcomes continues to open up new lines of research involving twin studies. DNA methylation and histone modifications, the major sources of epigenetic information, regulate gene expression levels and provide an alternative mechanism for modulating gene function to those arising from genetic changes (Esteller 2008). Interestingly, epigenetic changes are

Objective. To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists.Methods. Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years.Results. Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (pre-OR) and 2 began treatment after the recommendations were issued (post-OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre-OR, the active TB rate in BIOBADASER patients was 20.9-fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6-and 6.2-fold higher than the background and EMECAR populations, respectively. Post-OR, 324 patients with a tuberculin skin test result >5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03-0.88; P ‫؍‬ 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02-8.2). There were no INH treatmentrelated hospitalizations or deaths.Conclusion. Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists.

EudraCT: 2010-021602-37; NCT01663116; Results.

Juvenile-onset SLE has more frequent neurological and renal manifestations than adult-onset SLE, but immunological markers are similar in both groups. These features suggest the most severe clinical manifestations in the juvenile-onset SLE group are not related with the presence of studied antibodies by different methods.

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Objective. To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA.Methods. Patients with active RA despite stable MTX (10–25 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 × 500 and 2 × 500 mg; 2 × 500 and 2 × 1000 mg (dose escalation); and 2 × 1000 and 2 × 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48.Results. At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 × 500 mg (n = 134) or dose escalation (n = 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 × 1000 mg group (n = 93) were consistently higher, with significantly more patients achieving EULAR responses (P = 0.0495). At Week 48, rituximab 2 × 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 × 500 to 2 × 1000 mg did not appear to be associated with improved outcomes compared with continual 2 × 500 mg. All RTX regimens demonstrated comparable safety.Conclusions. RTX 2 × 500 and 2 × 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 × 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48.Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00422383.

Objective. Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease that may not always be related to the presence of traditional cardiovascular risk factors. The aim of this study was to determine if anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with cardiovascular disease in patients with RA. Methods. Anti-CCP antibodies were determined by enzyme-linked immunosorbent assay in the earliest serum sample available from 937 patients with a diagnosis of RA. We studied the relationship between anti-CCP antibodies with traditional cardiovascular risk factors and cardiovascular events. Results. We found positive anti-CCP antibodies (>25 units/ml) in 672 patients (71.7%). There was no association between the anti-CCP antibodies and cardiovascular risk factors such as smoking, hypertension, dyslipidemia, being overweight, or diabetes mellitus. However, patients who had positive anti-CCP antibodies experienced more frequent ischemic heart disease (6.5% versus 2.6%; odds ratio [OR] 2.58, 95% confidence interval [95% CI] 1.17-5.65) and had higher mortality rates (11.2% versus 6.8%; OR 1.72, 95% CI 1.01-2.91). Similar results were obtained when we considered anti-CCP titers 20-fold higher (>500 units/ml). Multivariable analysis showed that ischemic heart disease is independently associated with positive anti-CCP antibodies (OR 2.8, 95% CI 1.19 -6.56; P ‫؍‬ 0.009). Conclusion. Anti-CCP antibodies in patients with RA are independently associated with the development of ischemic heart disease.

Rituximab can be an effective treatment option for patients who have refractory lupus with severe or life-threatening disease with an acceptable tolerance profile.