Stratification of pedigrees multiplex for systemic lupus erythematosus and for self‐reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3

Objective

Arthritis is a common manifestation in systemic lupus erythematosus (SLE), appearing in ∼85% of patients. Often, the polyarthritis at presentation of SLE cannot be distinguished from rheumatoid arthritis (RA) by physical examination or history. Indeed, physicians initially tell many SLE patients that they have RA (one source of “self‐reported RA”), only to have SLE established later. In addition, RA aggregates in families with an SLE proband. We predicted that pedigrees multiplex for both SLE and for self‐reported RA would better isolate particular genetic effects. If this proved to be true, we would then use the increased genetic homogeneity to more easily reveal genetic linkage.

Methods

From a collection of 160 pedigrees multiplex for SLE, we selected 36 pedigrees that also contained ≥2 members with self‐reported RA (19 pedigrees were African American, 14 were European American, and 3 were of other ethnic origin). Data from a genome scan of 307 microsatellite markers were evaluated for SLE linkage by contemporary genetic epidemiologic techniques.

Results

The most significant evidence of linkage to SLE was obtained at 5p15.3 in the European American pedigrees by both parametric (logarithm of odds [LOD] score 6.2, P = 9.3 × 10⁻⁸) and nonparametric (LOD score 6.9, P = 1.7 × 10⁻⁸) methods. The best‐fitting model for this putative SLE gene in this region was a recessive gene with a population frequency of 5% and with 50% penetrance in females and 15% penetrance in males at virtually 100% homogeneity.

Conclusion

For a genetically complex disease phenotype, an unusually powerful linkage has been found with SLE at 5p15.3 in European American pedigrees multiplex for SLE and for self‐reported RA. This result predicts the presence of a gene at the top of chromosome 5 in this subset of patients that is important for the pathogenesis of SLE.

     

Linkage at 5q14.3-15 in multiplex systemic lupus erythematosus pedigrees stratified by autoimmune thyroid disease

OBJECTIVE: To identify genetic effects potentially shared between systemic lupus erythematosus (SLE) and autoimmune thyroiditis (AITD). METHODS: Families from the Lupus Multiplex Registry and Repository were studied in which there was at least 1 member who had both SLE and AITD (Graves' disease or Hashimoto thyroiditis). Genome scan genotyping findings in these pedigrees were evaluated for evidence of genetic linkage, by the maximum-likelihood parametric method. Nineteen pedigrees were used in the initial genome scan. Subsequently, an independent sample of 16 pedigrees was used to replicate findings. RESULTS: Studies of the first set of 19 pedigrees yielded a 2-point parametric logarithm of odds (LOD) of 4.97, which was independently confirmed in the replication sample of 16 pedigrees (LOD 2.89). For all 35 pedigrees together, the 2-point LOD was 7.86, under a dominant model used for screening with 90% penetrance and a disease allele frequency of 10%. The multipoint locus homogeneity LOD in the 35 pedigrees was 6.90 (alpha = 1.0) at 5q14.3-15 between D5S1725 and D5S1453, a 12-cM interval, with the peak at D5S1462 at 96.64 cM (nonparametric linkage P = 0.00002). Fine mapping further confirmed the genetic linkage effect and narrowed the region likely to contain the gene to approximately 5 Mb. CONCLUSION: These results suggest that stratifying SLE pedigrees by the presence of other autoimmune disorders may facilitate the discovery of genes related to SLE and that 5q14.3-15 harbors a susceptibility gene shared by SLE and AITD.     

Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia

Hemolytic anemia is a forme fruste of systemic lupus erythematosus (SLE), being observed months or even years before the onset of other clinical manifestations in some patients. We hypothesized that hemolytic anemia in those SLE-affected patients would identify a group of SLE pedigrees that share a high degree of genetic homogeneity. From 160 multiplex SLE pedigrees, we sought evidence for linkage in 35 (16 African-American, 17 European-American, and 2 Hispanic) who had at least one SLE-affected patient with hemolytic anemia. Significant linkage was present at 11q14 in the 16 African-American pedigrees, yielding a maximum two-point logarithm of odds (LOD) score of 4.5 at D11S2002. The segregation pattern of SLE in these African-American pedigrees suggested a dominant mode of inheritance and, when maximized across penetrance and disease allele frequencies, produced a multipoint LOD of 4.7. Multipoint analysis yielded a multipoint heterogeneity LOD score of 3.6 (alpha = 0.63), again with maximum LOD at D11S2002. Finally, markers typed 7 centimorgans to either side of D11S2002 achieved LOD scores of 3 or better by using the maximized model, supporting linkage to 11q14. Clearly, pedigree ascertainment based on select clinical manifestations is an important tool, capable of revealing otherwise cryptic genetic linkages in complex genetic diseases. Thus, we show strong evidence for an SLE susceptibility gene, SLEH1, near D11S2002 in African-American pedigrees multiplex for SLE that have at least one SLE-affected patient with hemolytic anemia.     

Confirmation of genetic linkage between human systemic lupus erythematosus and chromosome 1q41.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Linkage at 5q14.3–15 in multiplex systemic lupus erythematosus pedigrees stratified by autoimmune thyroid disease

Objective

To identify genetic effects potentially shared between systemic lupus erythematosus (SLE) and autoimmune thyroiditis (AITD).

Methods

Families from the Lupus Multiplex Registry and Repository were studied in which there was at least 1 member who had both SLE and AITD (Graves' disease or Hashimoto thyroiditis). Genome scan genotyping findings in these pedigrees were evaluated for evidence of genetic linkage, by the maximum‐likelihood parametric method. Nineteen pedigrees were used in the initial genome scan. Subsequently, an independent sample of 16 pedigrees was used to replicate findings.

Results

Studies of the first set of 19 pedigrees yielded a 2‐point parametric logarithm of odds (LOD) of 4.97, which was independently confirmed in the replication sample of 16 pedigrees (LOD 2.89). For all 35 pedigrees together, the 2‐point LOD was 7.86, under a dominant model used for screening with 90% penetrance and a disease allele frequency of 10%. The multipoint locus homogeneity LOD in the 35 pedigrees was 6.90 (α = 1.0) at 5q14.3–15 between D5S1725 and D5S1453, a 12‐cM interval, with the peak at D5S1462 at 96.64 cM (nonparametric linkage P = 0.00002). Fine mapping further confirmed the genetic linkage effect and narrowed the region likely to contain the gene to ∼5 Mb.

Conclusion

These results suggest that stratifying SLE pedigrees by the presence of other autoimmune disorders may facilitate the discovery of genes related to SLE and that 5q14.3–15 harbors a susceptibility gene shared by SLE and AITD.

     

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

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. CONCLUSION: 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.     

IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis

BACKGROUND: Recently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640-T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene. AIM: To test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA. PATIENTS AND METHODS: 100 French Caucasian trio families with RA were genotyped and analysed with the transmission disequilibrium test, the frequency comparison of the transmitted and untransmitted alleles, and the genotype relative risk. 97% power was available to detect at least a trend in favour of a factor similar to that reported for SLE. RESULTS: The analysis showed the absence of linkage and association globally and in "autoimmune" RA subsets, with a weak non-significant trend against the IRF5 rs20046470-T allele. Given the robustness of familial-based analysis, this slight negative trend provided strong evidence against even a weaker factor than that reported for SLE. CONCLUSION: Our results exclude the IRF5 rs2004640-T allele as a major genetic factor for RA in this French Caucasian population.     

Update on human systemic lupus erythematosus genetics

PURPOSE OF REVIEW: Susceptibility to systemic lupus erythematosus (SLE) has a genetic component. In recent years, nine complete genome scans using family collections that differ greatly in ethnic compositions and geographic locations have identified several strong, confirmed SLE susceptibility loci. Evidence implicating individual gene polymorphisms (or haplotypes) within some of the linked intervals has been reported. This review highlights recent findings that may lead to the identification of putative genes and new insights in the pathogenesis of SLE. RECENT FINDINGS: Eight of the best-supported SLE susceptibility loci are 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12p24, and 16q12. These are chromosomal regions exhibiting genome-wide significance for linkage in single studies and suggestive evidence for linkage in other samples. Linkage analyses conditioning on pedigrees in which one affected member manifesting a particular clinical condition have also yielded many chromosomal regions linked to SLE. The linked interval on chromosome 6p has been narrowed to 0.5 approximately 1.0 Mb (million basepairs) of 3 MHC class II containing risk haplotypes in white subjects. Cumulative results have shown that hereditary deficiencies of complement component C4A (a MHC class III gene) confer risk for SLE in almost all ethnic groups studied. The FcgammaR genes (located at 1q23) have been convincingly demonstrated to play an important role in susceptibility to SLE (and/or lupus nephritis). The evidence for the intronic single nucleotide polymorphism of program cell death gene 1 (PDCD1 at 2q37) to confer susceptibility is promising but not yet compelling. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. SUMMARY: Further replications of linkage and association are the immediate task. The respective contribution of each susceptibility gene, relationships between genotypes and phenotypes, and potential interactions between susceptibility gene products need to be elucidated. This line of investigation is now well poised to provide novel insights into how genetic variants can affect functional pathways leading to the development of SLE.     

Familial systemic lupus erythematosus in Finland

OBJECTIVE: To perform a cross sectional nation-wide clinical study of familial systemic lupus erythematosus (SLE) in Finland. METHODS: We sought to identify all Finnish families in which at least 2 members satisfied the classification criteria for SLE. About 1,200 patients with SLE (80-85% of all patients attending Finnish hospitals) were contacted. Personal and/or phone interviews and examination of medical records were used to verify the diagnoses. A comparison of clinical characteristics was made between familial cases of SLE and matched sporadic controls. RESULTS: We identified 53 multiplex families with 113 SLE patients. Forty-six families had 2 affected members and 7 families had 3 affected members. There were 3 pairs of monozygotic female twins and one pair of dizygotic twins of the opposite sex concordant for SLE. Eleven (9.7%) of the 113 familial cases of SLE were male. No differences were found in the clinical presentation of SLE between familial and sporadic cases (sex, age at onset, major clinical manifestations, and common laboratory tests). The incidence of familial SLE was approximately 4-5%. CONCLUSION: Our study shows that familial and sporadic SLE are not different disease entities; this means that we can extrapolate the results of future genetic analyses in multiplex SLE families to all patients with SLE.     

Thrombocytopenia identifies a severe familial phenotype of systemic lupus erythematosus and reveals genetic linkages at 1q22 and 11p13

Systemic lupus erythematosus (SLE) is a complicated autoimmune disease with a definite genetic predisposition. Thrombocytopenia predicts severe disease and death in SLE, making the identification of the related genetic risk factors especially important. We selected the 38 pedigrees that had an SLE patient with thrombocytopenia (platelets, < 10 x 10(9)/L [< 100,000/microL]) from a collection of 184 pedigrees multiplex for SLE. Linkages were established at 1q22-23 (maximum logarithm of odds [lod(max)] = 3.71) in the 38 pedigrees and at 11p13 (lod(max) = 5.72) in the 13 African American pedigrees. Nephritis, serositis, neuropsychiatric involvement, autoimmune hemolytic anemia, anti-double-stranded DNA, and antiphospholipid antibody were associated with thrombocytopenia. Other results show that SLE is more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient is considered. These results are consistent with thrombocytopenia being a component of a severe familial form of SLE and with genes at 1q22-23 and 11p13 contributing to this severe phenotype and to the subsequent high mortality associated with thrombocytopenia in SLE.     

Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus

OBJECTIVE: Although low-affinity alleles of human Fcgamma receptor types IIA and IIIA (FcgammaRIIA and FcgammaRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case-control studies, the relative contribution of these genes to SLE susceptibility has not been resolved. METHODS: We analyzed the distribution of alleles of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 126 multiplex-SLE pedigrees and FcgammaRIIA and FcgammaRIIIA in a case-control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE. RESULTS: We found evidence for linkage at both the FcgammaRIIIA (single-point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcgammaRIIA (single-point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcgammaRIIIB locus. Family-based tests of association demonstrated increased transmission of the low-affinity F176 allele at the FcgammaRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcgammaRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcgammaRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2- and 3-locus haplotype analysis of the extended Fcgamma receptor cluster did not reveal any significant association beyond that observed with FcgammaRIIIA alone. In a large case-control replication study of 438 patients with SLE and 219 controls, FcgammaRIIIA provided the strongest evidence of an FcgammaR-SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007). CONCLUSION: To our knowledge, these data are the first to demonstrate linkage and both family-based and case-control-based association of FcgammaRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcgammaRIIIA gene in the pathophysiology of this complex genetic disease.     

Association between systemic lupus erythematosus and Helicobacter pylori seronegativity

OBJECTIVE: Helicobacter pylori is a gram negative spiral bacterium that is clearly associated with a variety of gastrointestinal pathologies. A number of non-gastrointestinal diseases have also been associated with H. pylori. We investigated the prevalence of H. pylori seropositivity as part of a larger serologic survey in a group of 466 patients with systemic lupus erythematosus (SLE) and 466 controls. METHODS: We studied subjects for seropositivity against 5 antigens including mumps, measles, rubella, varicella zoster, and H. pylori. The 466 SLE patients were taken from a total of 290 pedigrees multiplex for SLE and matched to 466 controls for age (+/- 3 yrs), sex, and ethnicity to non-SLE affected individuals, taken mostly from the same collection of pedigrees multiplex for SLE. Assays for seropositivity were performed using a heterogeneous immunoassay technique. Pearson's chi-square was used to test for association of categorical variables and Student t-test for continuous variables. Logistic regression was used to compute the odds ratio for H. pylori seropositivity in patients and controls. RESULTS: There was a significant difference only in H. pylori seropositivity between SLE cases and their controls. The results were not altered by intrafamilial correlation. Subset analysis by race and sex showed that the differences between the African-American female patients with SLE and their matched controls were responsible for this association. Female African-American patients with SLE had a lower prevalence of H. pylori seropositivity compared to controls (38.1% vs 60.2%, OR 0.41, p = 0.0009, 95% CI 0.24-0.69). Of the 113 African-American female SLE patients in the study group, 43 were seropositive for H. pylori. The mean age of onset for SLE was older in the seropositive group (34.4 yrs) compared to the seronegative SLE patients (28.0 yrs) (t = 2.11, p = 0.039). CONCLUSION: Of 5 serologic tests performed, only the frequency of H. pylori seropositivity was different between SLE cases and their controls, and then only in African-Americans. We found an association between being seronegative for H. pylori and the development of SLE in African-American women, who also tend to be younger at the time of disease onset. These findings suggest that there is a possible protective role for H. pylori infection against the development of SLE or that immunoregulatory events leading to H. pylori seropositivity are inversely related to the risk of SLE.     

Update on genetic risk factors for systemic lupus erythematosus and rheumatoid arthritis

The results of twin and family studies clearly implicate an important role for genetic factors in the etiology of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, the complex nature of these diseases has hampered progress in defining the genetic determinants. Recent advances in molecular genetic and statistical methodology offer new hope to overcome these challenges. This review highlights recent efforts to identify genetic risk factors for SLE and RA using allele sharing and other linkage methods. In spite of striking differences between these studies, some agreement in terms of the regions providing evidence of linkage also exists. Thus, together these studies highlight regions of the genome that are likely to contain SLE and RA susceptibility genes. In addition, the results of these studies, in conjunction with progress in other complex human diseases, suggest several important considerations for future studies.     

Genome scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African-American pedigrees

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcγ receptors (FcγR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, λ_s > 10, purported linkage at 1q41–42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log₁₀ of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14–23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26–27, and 12p12–11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcγRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.     

Validation of self-report of rheumatoid arthritis and systemic lupus erythematosus: The Women's Health Initiative

OBJECTIVE: The Women's Health Initiative (WHI), initiated in 1993, enrolled 161,808 postmenopausal women aged 50-79 years and followed them with annual questionnaires for 8 years in order to study major causes of morbidity and mortality. Our objective was to determine the most effective and efficient means to validate self-reported rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in the WHI. METHODS: Data from 2 of 40 WHI clinical centers were used. Of these 7443 women, 643 self-reported RA and 106 self-reported SLE. Research coordinators contacted these women using mailers and telephone calls to obtain medical record releases and a Connective Tissue Screening Questionnaire (CSQ). Medical records were obtained on 286 self-reported RA and 34 self-reported SLE and reviewed by 3 rheumatologists blind to the self-reported diagnoses. Sensitivity, specificity, and the kappa statistic were computed to evaluate the level of agreement between self-report and chart review. RESULTS: Self-reported RA was accurate only 14.7% (42/286 cases) of the time. Coupling the self-report to medication data improved the positive predictive value (PPV; 62.2%) and kappa (0.53), suggesting a moderate agreement to chart review. Self-reported SLE was accurate only 11.8% (4/34 cases) of the time. Coupling the self-report to medication data improved the PPV (40.0%) and kappa (0.44), suggesting a moderate agreement to chart review. The CSQ was inferior to using medication data but was substantially better than self-report alone. CONCLUSION: The performance of disease self-report coupled with medication history in validating RA and SLE was very good and should obviate the need for time-consuming medical record reviews.     

Neuropsychiatric syndromes in patients with systemic lupus erythematosus and rheumatoid arthritis

OBJECTIVE: The cause of neurologic (N) and psychiatric (P) syndromes in patients with systemic lupus erythematosus (SLE) is mutifactorial and includes primary immunopathogenic mechanisms, nonspecific sequelae of chronic disease, and concurrent illnesses. We compared the prevalence, diversity, and clinical significance of NP syndromes in patients with SLE and rheumatoid arthritis (RA). METHODS: Fifty-three patients with SLE were matched by age and sex to 53 patients with RA attending ambulatory clinics in a single academic medical center. All fulfilled the American College of Rheumatology (ACR) classification criteria for either SLE or RA. Cumulative NP manifestations were determined using the ACR nomenclature and case definitions for 19 NP syndromes. Depression and anxiety were measured by the Hospital Anxiety and Depression Scales (HADS) and symptoms of cognitive dysfunction were assessed by the Cognitive Symptoms Inventory (CSI). Health related quality of life (HRQOL) was evaluated by the SF-36 and fatigue by a 10 point Likert scale. RESULTS: The patients were well matched with regard to age, sex, disease duration, and years of education. There were no significant differences in self-reported HRQOL, fatigue, anxiety, depression, and cognitive symptoms between the 2 groups. The proportion of patients with cumulative NP events was higher in RA than in SLE patients (47% vs 28%; p = 0.045), and of these the occurrence of multiple NP events in individual patients was comparable in both groups (SLE 53%; RA 48%; p = 0.75). Fifty-five percent and 66% of NP events occurred prior to the diagnosis of SLE and RA, respectively. NP events common to both SLE and RA patients were headaches, mood disorders, acute confusional states, anxiety, cerebrovascular disease, and cognitive dysfunction. Seizures and demyelinating syndrome occurred only in SLE patients, but were rare. Depression scores (HADS) were significantly higher in SLE patients with a history of cumulative NP events compared to RA patients with NP events (p = 0.02). Similarly, symptoms of cognitive dysfunction (CSI) were more common in SLE patients with a history of NP manifestations (p = 0.02). However, there were no significant differences in SF-36 subscale or fatigue scores between SLE and RA patients with cumulative NP events. CONCLUSION: NP syndromes, regardless of etiology, are common in both SLE and RA patients. SLE patients with NP syndromes report more symptoms of depression and cognitive dysfunction compared to RA patients with NP syndromes, but do not report significantly poorer HRQOL. These results emphasize the presence of non-disease-specific causes of NP manifestations in SLE patients, which should be acknowledged in future studies of pathogenesis and treatment.     

Mortality in systemic lupus erythematosus

OBJECTIVE: To examine mortality rates in the largest systemic lupus erythematosus (SLE) cohort ever assembled. METHODS: Our sample was a multisite international SLE cohort (23 centers, 9,547 patients). Deaths were ascertained by vital statistics registry linkage. Standardized mortality ratio (SMR; ratio of deaths observed to deaths expected) estimates were calculated for all deaths and by cause. The effects of sex, age, SLE duration, race, and calendar-year periods were determined. RESULTS: The overall SMR was 2.4 (95% confidence interval 2.3-2.5). Particularly high mortality was seen for circulatory disease, infections, renal disease, non-Hodgkin's lymphoma, and lung cancer. The highest SMR estimates were seen in patient groups characterized by female sex, younger age, SLE duration <1 year, or black/African American race. There was a dramatic decrease in total SMR estimates across calendar-year periods, which was demonstrable for specific causes including death due to infections and death due to renal disorders. However, the SMR due to circulatory diseases tended to increase slightly from the 1970s to the year 2001. CONCLUSION: Our data from a very large multicenter international cohort emphasize what has been demonstrated previously in smaller samples. These results highlight the increased mortality rate in SLE patients compared with the general population, and they suggest particular risk associated with female sex, younger age, shorter SLE duration, and black/African American race. The risk for certain types of deaths, primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths due to circulatory disease does not appear to have diminished.     

Genetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus

Objective

Although low‐affinity alleles of human Fcγ receptor types IIA and IIIA (FcγRIIA and FcγRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case–control studies, the relative contribution of these genes to SLE susceptibility has not been resolved.

Methods

We analyzed the distribution of alleles of FcγRIIA, FcγRIIIA, and FcγRIIIB in 126 multiplex‐SLE pedigrees and FcγRIIA and FcγRIIIA in a case–control replication study, using allele‐specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE.

Results

We found evidence for linkage at both the FcγRIIIA (single‐point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcγRIIA (single‐point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcγRIIIB locus. Family‐based tests of association demonstrated increased transmission of the low‐affinity F176 allele at the FcγRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcγRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcγRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2‐ and 3‐locus haplotype analysis of the extended Fcγ receptor cluster did not reveal any significant association beyond that observed with FcγRIIIA alone. In a large case–control replication study of 438 patients with SLE and 219 controls, FcγRIIIA provided the strongest evidence of an FcγR–SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007).

Conclusion

To our knowledge, these data are the first to demonstrate linkage and both family‐based and case–control–based association of FcγRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcγRIIIA gene in the pathophysiology of this complex genetic disease.

     

An update on genetic studies of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease. Genetic factors are thought to contribute to its pathogenesis. There have been numerous recent advances in the study of murine and human lupus genetics. In well-defined experimental transgenic or gene-knockout mouse models, the development of lupus-like disease has implicated specific genes and pathways in the disease pathogenesis. Linkage analyses have mapped multiple susceptibility loci and disease suppressive loci using inbred strains of mice that spontaneously develop lupus-like disease. Elegant genetic dissection and function studies have led to the recent identification of two murine candidate susceptibility genes, Ifi202 (encoding an interferon-inducible protein) and Cr2 (encoding complement receptors 1 and 2). In human lupus, casecontrol studies have established associations of SLE with certain major histocompatibility class II alleles, complement deficiencies, and polymorphisms of Fcψ receptor genes, a complement-related gene, and cytokine genes. During the past several years, linkage analyses using SLE multiplex families have provided many chromosomal regions for further exploration of susceptibility genes. Six regions exhibiting significant linkage to SLE are promising. Studies are underway to fine map these linked regions and to identify the genes in the susceptibility regions. An understanding of the genes involved in the development of lupus should provide targets for more focused therapy in lupus.     

Familial juvenile systemic lupus erythematosus in Arab children

Aim of this study is to analyze the demographic, clinical, and biochemical features, and survival of familial juvenile systemic lupus erythematosus (FJSLE) in Arab children. The medical records of children with FJSLE seen at three pediatric rheumatology clinics in Saudi Arabia and Oman were retrospectively reviewed. All included children have met the following criteria: Arab ethnicity, definite diagnosis of SLE using the revised 1982 American College of Rheumatology classification criteria and family history of more than one affected sibling with SLE. The collected data included: gender, age at diagnosis, clinical and laboratory features at diagnosis. Unusual co-morbidity and mortality associated with the disease were studied. There were 50 children with FJSLE belonging to 18 families; the frequency of FJSLE in our cohort was 20.8%. The mean age at onset of SLE was 86?months (range, 18–168?months), while the mean age at diagnosis was 95?months (range, 24–192?months), and the mean duration of follow-up was 60.9?months (range, 7–132?months). The proportion of girls was predominant (78%). Autosomal recessive mode of inheritance was strongly suggested in number of our families. Mucocutaneous manifestations, arthritis, and nephritis were the most frequent features. Thirty-five patients had renal lesions, 18 of them had class IV nephritis according WHO classification. All patients were treated with different doses of steroid and immunosuppressive drugs; 37 (74%) patients received cyclophosphamide, and 6 patients treated with Rituximab. There were 5 patients required dialysis due to ESRD and 8 deaths related to SLE during the period of follow-up. FJSLE is not uncommon in our society. These findings may be helpful in identifying SLE patients with a stronger genetic predisposition; hopefully, one or more additional risk loci can be identified in multiplex Arab families that are different from what has been reported in other ethnic populations.