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To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as to investigate its mechanisms.Patients with primary Sjögren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression.Twelve female patients with primary Sjögren's syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature.In patients with primary Sjögren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.

Objective Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene–gene interactions in a number of known lupus susceptibility loci. Methods Eighteen single-nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2-step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. Results We detected and confirmed gene–gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10−5 [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10−45). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P = 0.0028 and P = 0.0047, respectively). Conclusion We provide evidence for gene–gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.

OBJECTIVE: Genetic association of the IL2/IL21 region at chromosome 4q27 has previously been reported in lupus and a number of autoimmune and inflammatory diseases. This study was undertaken to determine whether this genetic effect could be localized, using a very large cohort of lupus patients and controls. METHODS: We genotyped 45 tag single-nucleotide polymorphisms (SNPs) across the IL2/IL21 locus in 2 large independent lupus sample sets. We studied a set of subjects of European descent consisting of 4,248 lupus patients and 3,818 healthy controls, and an African American set of 1,569 patients and 1,893 healthy controls. Imputation in 3,004 additional controls from the Wellcome Trust Case Control Consortium was also performed. Genetic association between the genotyped markers was determined, and pairwise conditional analysis was performed to localize the independent genetic effect in the IL2/IL21 locus in lupus. RESULTS: We established and confirmed the genetic association between IL2/IL21 and lupus. Using conditional analysis and transethnic mapping, we localized the genetic effect in this locus to 2 SNPs in high linkage disequilibrium: rs907715 located within IL21 (odds ratio 1.16 [95% confidence interval 1.10-1.22], P=2.17×10(-8)) and rs6835457 located in the 3'-untranslated flanking region of IL21 (odds ratio 1.11 [95% confidence interval 1.05-1.17], P=9.35×10(-5)). CONCLUSION: Our findings establish the genetic association between lupus and IL2/IL21 with a genome-wide level of significance. Further, our findings indicate that this genetic association within the IL2/IL21 linkage disequilibrium block is localized to IL21. If other autoimmune IL2/IL21 genetic associations are similarly localized, then the IL21 risk alleles would be predicted to operate by a fundamental mechanism that influences the course of a number of autoimmune disease processes., Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibodies to nuclear and cell surface antigens. Although the etiology of SLE remains unknown, evidence for genetic susceptibility is well established. The HLA class II alleles DRB1*1501, *0301, and *0801 and the HLA class I alleles A*01 and B*08 in the major histocompatibility complex (MHC) region are consistently associated with SLE. HLA loci may also influence SLE through additional inherited or noninherited mechanisms. Differences in maternal and paternal transmission rates, or parent-of-origin effects, have not been previously examined in SLE. One potential mechanism influencing disease susceptibility is “genomic imprinting” due to epigenetic modification of the genome. This modification results in unequal transcription of parental alleles and subsequent allele expression, depending on whether alleles were transmitted from the mother or from the father. Increased HLA compatibility between a mother and her offspring is hypothesized to contribute to the risk of autoimmune disease. Maternal–offspring effects can present as excess HLA compatibility between the mother and affected offspring (Figure 1). In mice, HLA similarity between mother and fetus has been shown to promote the persistence of maternal cells in the offspring (maternal microchimerism) following pregnancy (1). Figure 1 Maternal–offspring HLA compatibility relationships. The developing immune system of the fetus is also directly exposed to noninherited maternal antigens (NIMAs) in utero (2). Exposure to NIMAs can have a lifelong influence on the immune system and has been theorized to tolerize or predispose to autoimmune reactions. A tolerogenic effect may explain the longer survival of renal transplants from sibling donors expressing NIMAs versus noninherited paternal HLA. Decreased B cell responses to HLA class I NIMAs in humans have been reported (3). Recent data suggest that fetuses may also develop T cell tolerance to NIMAs in utero through tolerogenic fetal regulatory T cells that are maintained throughout life (4). The aim of this study was to test the hypothesis that the DRB1 locus influences SLE through these novel biologic mechanisms in addition to genetic transmission of particular HLA risk alleles.

Objective Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. Methods Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case–control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. Results We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 × 10−25). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. Conclusion Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

Primary Sjogren’s syndrome (PSS) is a common systemic autoimmune disorder affecting approximately 0.09% of the adult population (1). Based on American European Consensus Criteria (AECG) criteria, prevalence among women ranges from 0.1 to 0.6 percent in US, UK and Greek cohorts (2). Patients present with constitutional symptoms, as well as a wide variety of neurologic disorders and systemic involvement, in addition to complaints of oral and ocular dryness. PSS can lead to vasculitis (3) and is associate with a 40 fold increased risk of lymphoma (4). However, fatigue and pain are the most common extra-glandular symptoms (5, 6). Abnormal fatigue is defined as enduring, generalized tiredness and can be characterized in terms of intensity, duration and effects upon daily function (7). In population-based studies, approximately 20% of healthy adults report persistent fatigue (8, 9). Among patients with autoimmune disease the prevalence of fatigue is much higher, in the range of 60–70% (10–12). Despite the impact that fatigue has on quality of life in rheumatic disorders, there is no consensus regarding the assessment of fatigue. There is very little data comparing different fatigue measures and the pathogenesis of clinically significant persistent fatigue is unknown. In the primary care setting, chronic fatigue is strongly associated with depression. In a general medical practice, 73% of patients presenting with a complaint of chronic fatigue had a psychiatric diagnosis (13). The relationship of fatigue to depression in PSS is less clear. Despite the importance of clinically significant fatigue in the majority of patients with PSS, only a few studies have examined the relationship of fatigue to other clinical variables (5, 14–19). The relative contribution of physiologic variables, behavioral and immune mediated factors to fatigue has not been well characterized. While previous studies of PSS have demonstrated an association of fatigue with depression (5), the relationship between fatigue and depression is complex and the effect of illness severity is unclear. A key unresolved issue is whether chronic fatigue experience by patients with systemic autoimmunity is mediated primarily by a disturbance in immune function or by factors such as sleep disorder and depression which are associated with fatigue in persons with non-autoimmune disorders. In order to better understand the determinants of fatigue in PSS, we concurrently evaluated the differential effect of behavioral, cognitive and clinical variables contributing to fatigue in PSS. We used multiple validated measures to assess fatigue and compared the factors predictive of fatigue using 3 instruments and a visual analog scale. We hypothesized that depression; pain and helplessness contribute to, but do not entirely account for, the variance in fatigue severity in patients with PSS.

Objective To distinguish familial differences from sex-related differences in the clinical manifestations of systemic lupus erythematosus (SLE). Methods A total of 372 affected individuals from 160 multiplex SLE pedigrees were analyzed. Twenty-five of these pedigrees contained at least 1 affected male relative. Comparisons of the presence of each of the 11 1982 American College of Rheumatology criteria for SLE were made between female family members with affected male relatives and those without affected male relatives, using Fisher's exact tests. Results The presence of renal disease was significantly increased in female family members with an affected male relative when compared with those with no affected male relative (68% and 43%, respectively; P = 0.002). This trend remained after stratifying by race and was most pronounced in European Americans. A familial basis for differences in hematologic and immunologic manifestations was also suggested, while arthritis and dermatologic features appeared to be most influenced by sex. Conclusios Our results demonstrate that the increased prevalence of renal disease previously reported in men with SLE is, in large part, a familial rather than sex-based difference, at least in multiplex SLE families. Distinguishing familial from sex-related differences may facilitate efforts to understand the genetic and hormonal factors that underlie this complex autoimmune disease.

To identify chromosomal regions containing genes involved in the susceptibility to human systemic lupus erythematosus (SLE)-related traits.In the context of a genome scan, we analyzed 101 SLE-affected sibpairs with respect to dermatologic, renal, immunologic, hematologic, neurologic, cardiopulmonary, and arthritic characteristics. Phenotypes were redefined in terms of principal components, which are synthetic variables composed of linear combinations of the original traits. Using 9 principal components obtained from these 7 traits plus age at SLE onset and race, we analyzed genome scan data with the multivariate version of the new Haseman-Elston regression model.The largest linkage for an individual trait was on chromosome 2 at 228 cM (immunologic; P = 0.00048). The most significant linkage to an individual principal component was on chromosome 4 at 208 cM (P = 0.00007). The largest multivariate linkage was on chromosome 7 at 69 cM (P = 0.0001). Of the individual organ systems, dermatologic involvement had the largest effect (P = 0.0083) at this peak at 7p13 on chromosome 7. Further analyses revealed that malar rash, a subtype of dermatologic involvement, was linked significantly (P = 0.00458) to this location.These results provide evidence of the presence and locations of genes that are involved in the genetic susceptibility to SLE-related traits in humans.

The possible molecular mimicry of the Epstein-Barr virus (EBV) peptide PPPGRRP by the peptide PPPGMRPP from Sm B'/B of the human spliceosome is consistent with the possibility that EBV infection is related to the origin of systemic lupus erythematosus (SLE) in some patients. Association of EBV exposure with SLE was therefore tested for and subsequently found in children and adolescents (odds ratio [OR] 49.9, 95% confidence interval [95% CI] 9.3-1,025, P10(-11)). These results were confirmed at the level of EBV DNA (OR10, 95% CI 2.53-infinity, P0.002). Much smaller seroconversion rate differences were found against 4 other herpes viruses. Herein, we extend these studies to adults and test the hypothesis that EBV infection is associated with adult SLE.We selected 196 antinuclear antibody-positive adult SLE patients (ageor =20 years) and 2 age-, race-, and sex-matched controls per patient. SLE patients and matched controls were tested for evidence of previous infection with EBV, cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), or varicella-zoster virus (VZV) by standardized enzyme-linked immunosorbent assays.Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45-infinity, P = 0.014). No differences were observed between SLE patients and controls in the seroconversion rate against CMV, HSV-2, or VZV.These new data from adults, along with the many suggestive features of EBV infection, are consistent with the contribution of this infection to the etiology of SLE.

Genetic susceptibility to systemic lupus erythematosus (SLE) is undoubtedly complex and, presumably, involves multiple loci. Linkage of SLE to D1S229 at chromosome 1q41 has been previously reported in a cohort of 52 affected sibpairs. The present study sought to confirm this reported linkage in an independent cohort of 127 extended multiplex SLE pedigrees containing 107 affected sibpairs.Genotype data were collected for D1S229 and 18 flanking microsatellite markers spanning chromosome 1q32-1q42. Analyses of genotype data included a model-based logarithm of odds (LOD) score approach, affected sibpair analyses, and transmission disequilibrium tests.A maximum LOD score of 1.46 was found with D1S229 in a subgroup of 78 European American pedigrees, with additional support from multiple markers clustered around D1S229. Increased allele sharing in affected siblings was most significant at D1S2616, particularly in European Americans (P = 0.0005), followed by D1S229 (P = 0.002), D1S490 (P = 0.028), and D1S1605 (P = 0.037). Although linkage in a subgroup of 40 African American pedigrees was not suggested by the analyses of any marker tested in the chromosomal region surrounding D1S229, a maximum LOD score of 3.03 was found with D1S3462, mapped 15 centimorgans distal to D1S229.Our linkage analysis results in European Americans at D1S229 are remarkably similar to those previously reported. That at least 1 genetic effect near this locus is important for susceptibility to lupus should now be generally accepted, and efforts to identify the gene are thereby justified.