A large Icelandic family with early osteoarthritis of the hip associated with a susceptibility locus on chromosome 16p

Objective

To describe a large kinship with inherited hip osteoarthritis (OA) and its associated susceptibility locus.

Methods

Four generations of a kinship with familial hip OA were identified and characterized by family history and by clinical, radiographic, and histopathologic examination. In the genome‐wide search for a susceptibility locus, OA cases were defined as those who had undergone total hip replacement associated with a clinical and radiographic diagnosis of hip OA. A genome‐wide scan was performed using a framework set of microsatellite markers with an average spacing of 10 cM.

Results

The hip OA of this family was indistinguishable from that of idiopathic, nonfamilial hip OA. There was no apparent evidence of spondyloepiphyseal dysplasia or other dysplasias usually associated with mutations in collagen genes. The genome‐wide scan revealed a locus on chromosome 16p between 28 cM and 47 cM from the telomere, and this locus met the criteria for suggestive linkage (multipoint allele‐sharing logarithm of odds [LOD] score 2.58, P = 1.6 × 10⁻⁴). Two additional regions with LOD scores of >1.5 were obtained.

Conclusion

We have identified and described the largest kinship with familial hip OA reported to date. Evidence for linkage in this family suggests that a gene for susceptibility to hip OA exists on chromosome 16p. This represents an independent identification of a susceptibility locus previously reported for hip OA in this geographic region.

     

Systemic lupus erythematosus genome scan: Support for linkage at 1q23, 2q33, 16q12–13, and 17q21–23 and novel evidence at 3p24, 10q23–24, 13q32, and 18q22–23

Objective

To identify chromosome regions likely to harbor genes that predispose to the development of systemic lupus erythematosus (SLE) by analyzing a full genome scan in nuclear families ascertained for siblings with SLE.

Methods

Approximately 400 multiallelic markers spaced an average of 10 cM apart were genotyped in a multiethnic panel of 238 individuals from 62 multiplex SLE families having 88 affected sibling pairs and 456 total sibling pairs. Findings were analyzed by 2 model‐free statistical linkage procedures.

Results

Evidence supporting linkage to 4 previously reported (1q23, 2q33, 16q12–13, and 17q21–23) and 4 novel (3p24, 10q23–24, 13q32, and 18q22–23) chromosome regions was revealed. Stratification by family ethnicity indicated that linkage to 3 regions, 2q33, 10q23–24, and 18q22–23, was derived primarily from the Caucasian families, while linkage to 17q21–23 was seen primarily in the non‐Caucasian families.

Conclusion

Linkage to the same chromosome regions in independent cohorts is a critical step in finding the genes that predispose to a complex disorder such as SLE. Four linked regions also seen in independent SLE cohorts lend credibility to the 4 novel regions identified by these analyses. Substantial linkage information was gleaned by genotyping and analyzing the unaffected siblings. These results provide additional evidence that the SLE clinical phenotype is genetically complex, multigenic, and heterogeneous.

     

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.

     

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.

     

Assessment of atherosclerotic risk factors and endothelial function in children and young adults with pediatric‐onset systemic lupus erythematosus

Objective

To characterize atherosclerotic risk factors and endothelial function in pediatric‐onset systemic lupus erythematosus (SLE).

Methods

Lipoproteins, oxidized state, and autoantibodies to oxidized low‐density lipoprotein (Ox‐LDL) were assessed. Endothelial function was evaluated using brachial artery reactivity.

Results

Thirty‐three SLE patients and 30 controls were studied. SLE subjects had significantly decreased mean high‐density lipoprotein (HDL) cholesterol (41 mg/dl versus 51 mg/dl; P = 0.002) and apolipoprotein A‐I (97 mg/dl versus 199 mg/dl; P = 0.0004). There was no difference between groups in markers of oxidized state (including nitric oxide metabolites, isoprostanes, and Ox‐LDL) or in endothelial function. However, SLE subjects had increased median anti‐Ox‐LDL IgG (2,480 relative light units [RLU] versus 1,567 RLU; P = 0.0007) and IgG immune complexes with LDL (4,222 RLU versus 2,868 RLU; P = 0.002).

Conclusion

Pediatric SLE patients had significantly decreased levels of HDL cholesterol and apolipoprotein A‐I and elevated titers of autoantibodies to Ox‐LDL. Despite these atherosclerotic risk factors, SLE patients had normal measures of oxidized state and endothelial function.

     

Whole‐genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom

Objective

To undertake a systematic whole‐genome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA).

Methods

Two hundred fifty‐two RA‐affected sibling pairs from 182 UK families were genotyped using 365 highly informative microsatellite markers. Microsatellite genotyping was performed using fluorescent polymerase chain reaction primers and semiautomated DNA sequencing technology. Linkage analysis was undertaken using MAPMAKER/SIBS for single‐point and multipoint analysis.

Results

Significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA–DRB1) was identified around the major histocompatibility complex (MHC) region on chromosome 6. Suggestive linkage (P < 7.4 × 10⁻⁴) was identified on chromosome 6q by single‐ and multipoint analysis. Ten other sites of nominal linkage (P < 0.05) were identified on chromosomes 3p, 4q, 7p, 2 regions of 10q, 2 regions of 14q, 16p, 21q, and Xq by single‐point analysis and on 3 sites (1q, 14q, and 14q) by multipoint analysis.

Conclusion

Linkage to the MHC region was confirmed. Eleven non‐HLA regions demonstrated evidence of suggestive or nominal linkage, but none reached the genome‐wide threshold for significant linkage (P = 2.2 × 10⁻⁵). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.

     

Linkage mapping of a novel susceptibility locus for Behçet's disease to chromosome 6p22‐23

Objective

The etiology of Behçet's disease is unknown; however, familial aggregation studies indicate a strong genetic background and a complex inheritance model. Association of HLA–B51 with Behçet's disease is regarded as being the strongest evidence of genetic contribution described to date. A low rate of recombination was observed within the telomeric end of the major histocompatibility complex up to the HFE gene, which causes hereditary hemochromatosis. We therefore hypothesized that the telomere of 6p may harbor a susceptibility gene for Behçet's disease.

Methods

A series of 28 multicase families of Turkish origin was ascertained, and 78 of the 183 available family members were diagnosed as having Behçet's disease. For the analysis of the telomeric region adjacent to HLA–B, we used a panel of 20 highly polymorphic microsatellite markers between D6S273 and D6S470, covering a region of ∼36 cM.

Results

Multipoint nonparametric linkage analysis using GeneHunter 2.0 software revealed a broad peak of linkage, with the highest Z score of 4.11 at position D6S285, which is ∼17 cM telomeric to HLA–B.

Conclusion

This significant linkage finding may indicate a second susceptibility locus in the telomere of chromosome 6p. Identification of this putative susceptibility gene could help to further understand the pathogenesis of Behçet's disease.

     

Haplotypes of the HRES‐1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus

Objective

Endogenous retroviral sequences represent a link between viral and genetic factors that may influence the development of systemic lupus erythematosus (SLE). The HRES‐1 human endogenous retroviral sequence is centrally located at the 1q42 chromosomal region relative to microsatellites previously associated with SLE. We therefore undertook the present study to determine the haplotypes of the HRES‐1 locus and their linkage to SLE.

Methods

One hundred six patients with SLE, 82 unrelated healthy Caucasian individuals, and 70 healthy members of 34 lupus families were examined. HRES‐1 was amplified by polymerase chain reaction (PCR) and analyzed by sequencing and restriction enzyme mapping. Microsatellites were analyzed by PCR. Haplotype construction and transmission disequilibrium testing (TDT) were performed in lupus families.

Results

Based on 4 single‐nucleotide polymorphisms (SNPs) within a 935‐base interval, we detected 6 HRES‐1 haplotypes that were differentially segregated in unrelated Caucasian patients and control subjects (χ² = 16.86, P = 0.0048) and were in linkage disequilibrium (LD) with the D1S225 microsatellite (P = 0.0002). The microsatellites D1S225, D1S235, and D1S2785 (but not D1S229) were linked to SLE by TDT. Interestingly, LD between HRES‐1 SNPs at bases 653 and 1259 was reduced in patients with SLE (P = 0.048). The HRES‐1 653C/1259C–harboring alleles were associated with the presence of renal disease (P = 0.0021) and with the absence of lung disease (P = 0.0323), while the 956A allele was associated with the antiphospholipid syndrome in patients with SLE (P = 0.0036).

Conclusion

The HRES‐1 locus represents a recombination hot spot at the 1q42 chromosomal region that influences the development and disease manifestations of SLE.

     

The Fibromyalgia Family Study: A Genome‐Wide Linkage Scan Study

Objective

Familial aggregation of fibromyalgia has been increasingly recognized. The goal of this study was to conduct a genome‐wide linkage scan to identify susceptibility loci for fibromyalgia.

Methods

We genotyped members of 116 families from the Fibromyalgia Family Study and performed a model‐free genome‐wide linkage analysis of fibromyalgia with 341 microsatellite markers, using the Haseman‐Elston regression approach.

Results

The estimated sibling recurrence risk ratio (λ_s) for fibromyalgia was 13.6 (95% confidence interval 10.0–18.5), based on a reported population prevalence of 2%. Genome‐wide suggestive evidence of linkage was observed at markers D17S2196 (empirical P [P_e] = 0.00030) and D17S1294 (P_e = 0.00035) on chromosome 17p11.2–q11.2.

Conclusion

The estimated sibling recurrence risk ratio (λ_s) observed in this study suggests a strong genetic component of fibromyalgia. This is the first report of genome‐wide suggestive linkage of fibromyalgia to the chromosome 17p11.2–q11.2 region. Further investigation of these multicase families from the Fibromyalgia Family Study is warranted to identify potential causal risk variants for fibromyalgia.

     

Effects of a stress‐reduction program on psychological function,pain, and physical function of systemic lupus erythematosus patients: A randomized controlled trial

Objective

To assess the effects of a stress‐reduction program on pain, psychological function, and physical function in persons with systemic lupus erythematosus (SLE) who experience pain.

Methods

Ninety‐two SLE patients were assigned randomly to receive either biofeedback‐assisted cognitive‐behavioral treatment (BF/CBT), a symptom‐monitoring support (SMS) intervention, or usual medical care (UC) alone.

Results

BF/CBT participants had significantly greater reductions in pain and psychological dysfunction compared with the SMS group (pain, P = 0.044; psychological functioning, P < 0.001) and the UC group (pain, P = 0.028; psychological functioning, P < 0.001). BF/CBT had significantly greater improvement in perceived physical function compared with UC (P = 0.035), and improvement relative to SMS was marginally significant (P = 0.097). At a 9‐month followup evaluation, BF/CBT continued to exhibit relative benefit compared with UC in psychological functioning (P = 0.023).

Conclusion

This study supports the utility of a brief stress management program for short‐term improvement in pain, psychological function, and perceived physical function among persons with SLE who experience pain.

     

Rheumatologists' quality of care for lupus: Comparison study between a university and county hospital

Objective

Quality of care received from physicians may impact health outcomes in systemic lupus erythematosus (SLE). We compared physician quality of care (P‐QOC), health‐related quality of life (HRQOL), and disease activity and damage between SLE patients receiving outpatient care at a university and a county rheumatology clinic.

Methods

Forty‐two university and 41 county clinic SLE patients provided data on 5 P‐QOC parameters and HRQOL health outcomes (Short Form 36 [SF‐36] health survey and EuroQol 5‐domain instrument [EQ‐5D]). Disease activity and damage were measured. Chi‐square analysis and Student's t‐tests were used for comparisons.

Results

Overall satisfaction with medical care was similar; however, university patients had higher P‐QOC scores than county patients in “perception of doctor's understanding of impact of SLE on patient's life” (P = 0.02) and “providing education/educational information to understand their disease” (P = 0.05). HRQOL, disease activity, and damage were similar in the 2 groups. Overall satisfaction with medical care was directly related SF‐36 general health (r = 0.34, P = 0.03) and EQ‐5D visual analog scale on state of health (r = 0.39, P = 0.01), and inversely related EQ‐5D pain (r = ?0.37, P = 0.02).

Conclusion

Patient perceptions of P‐QOC differed across the 2 centers despite similar demographics, clinical and HRQOL outcomes, and significant overlap in the physicians serving each clinic. Patients' overall satisfaction with medical care is associated with better HRQOL.

     

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.

     

Meta‐analysis of four rheumatoid arthritis genome‐wide linkage studies: Confirmation of a susceptibility locus on chromosome 16

Objective

Susceptibility to rheumatoid arthritis (RA) is likely to involve several genes of weak effect, and consequently, individual studies may have insufficient power to detect linkage. Four major RA genome‐wide linkage studies have been carried out, but apart from the well‐established HLA susceptibility locus, none of the reported significant regions of linkage has been replicated. We applied a genome‐search meta‐analysis to 4 RA genome searches to assess linkage across studies, using published results.

Methods

For each study, 120 genomic bins of ∼30 cM were defined and ranked according to the maximum evidence for linkage within each bin. Ranks were summed across studies and each bin was assessed empirically by the magnitude of summed rank, using a permutation test. A high summed rank indicated a region in which evidence for linkage was consistent across several studies.

Results

In addition to the HLA locus (P < 0.00002), the strongest evidence for an RA susceptibility locus was found on chromosome 16 (P = 0.004). This locus was not identified as statistically significant in any of the 4 individual RA genome searches. In total, 12 regions achieved a significant (P < 0.05) summed rank, compared with the 6 bins expected by random chance. Four of these regions (on chromosomes 6p, 16cen, 6q, and 12p) reached a significance value of P < 0.01, suggesting that a subset of these regions contains RA susceptibility loci.

Conclusion

Using a meta‐analysis approach, we have identified existing and novel putative RA susceptibility loci. These results can provide a basis for further positional and functional candidate‐gene studies, and may prove useful in other complex rheumatic diseases.

     

Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus

Objective

CXCR4 is a chemokine with multiple effects on the immune system. In murine lupus models, we demonstrated that monocytes, neutrophils, and B cells overexpressed CXCR4 and that its ligand, CXCL12, was up‐regulated in diseased kidneys. We undertook this study to determine whether CXCR4 expression was increased in peripheral blood leukocytes from patients with systemic lupus erythematosus (SLE) and whether CXCL12 expression was increased in kidneys from patients with SLE.

Methods

Peripheral blood leukocytes from 31 SLE patients, 8 normal controls, and 9 patients with rheumatoid arthritis were prospectively analyzed by flow cytometry for CXCR4 expression. Biopsy samples (n = 14) from patients with lupus nephritis (LN) were immunostained with anti‐CXCL12 antibody.

Results

CD19+ B cells and CD4+ T cells from SLE patients displayed a >2‐fold increase (P = 0.0001) and >3‐fold increase (P < 0.0001), respectively, in median CXCR4 expression compared with that in controls (n = 7–8). Moreover, CXCR4 expression on B cells was 1.61‐fold higher in patients with SLE Disease Activity Index (SLEDAI) scores >10 (n = 8) than in patients with SLEDAI scores ≤10 (n = 16) (P = 0.0008), 1.71‐fold higher in patients with class IV LN (n = 5) than in patients with other classes of LN (n = 7) (P = 0.02), and 1.40‐fold higher in patients with active neuropsychiatric SLE (NPSLE) (n = 6) than in patients with inactive NPSLE (n = 18) (P = 0.01). CXCL12 was significantly up‐regulated in the tubules and glomeruli of kidneys in patients with LN (n = 14), with the percentage of positive cells correlating positively with the severity of LN.

Conclusion

CXCR4 appears to be up‐regulated in multiple leukocyte subsets in SLE patients. The heightened expression of CXCR4 on B cells in active NPSLE and of CXCL12 in nephritic kidneys suggests that the CXCR4/CXCL12 axis might be a potential therapeutic target for SLE patients with kidney and/or central nervous system involvement.

     

Genetic analyses of interferon pathway–related genes reveal multiple new loci associated with systemic lupus erythematosus

Objective

The overexpression of interferon (IFN)–inducible genes is a prominent feature of systemic lupus erythematosus (SLE); it serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. This study was undertaken to investigate the genetic variations responsible for sustained activation of IFN‐responsive genes in SLE.

Methods

We systematically evaluated association of SLE with a total of 1,754 IFN pathway–related genes, including IFN‐inducible genes known to be differentially expressed in SLE patients and their direct regulators. We used a 3‐stage study design in which 2 cohorts (total of 939 SLE cases and 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons.

Results

A total of 15,166 single‐nucleotide polymorphisms (SNPs) passed all quality control filters; 305 of these SNPs demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including those for the transmembrane receptor CD44 (CD44 [rs507230]; P = 3.98 × 10⁻¹²), the cytokine pleiotrophin (PTN [rs919581]; P = 5.38 × 10⁻⁴), the heat‐shock protein DnaJ (DNAJA1 [rs10971259]; P = 6.31 × 10⁻³), and the nuclear import protein karyopherin α1 (KPNA [rs6810306]; P = 4.91 × 10⁻²).

Conclusion

This study expands the number of candidate genes that have been shown to be associated with SLE and highlights potential of pathway‐based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.

     

The −169C/T polymorphism in FCRL3 is not associated with susceptibility to rheumatoid arthritis or systemic lupus erythematosus in a case–control study of Koreans

Objective

In Japanese individuals, the −169C/T single‐nucleotide polymorphism (SNP) in FCRL3 has been reported to be associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroid diseases. The objective of this study was to test the association of this SNP with RA and SLE, in a case–control study of Korean individuals.

Methods

The −169C/T SNP in FCRL3 was genotyped in 1,060 patients with RA, 457 patients with SLE, and 697 unaffected control subjects, using the MassARRAY SNP genotyping system. Associations were tested by multivariate logistic regression, with adjustments for age and sex.

Results

No association was detected between the −169C/T SNP and RA (odds ratio [OR] 1.11, 95% confidence interval [95% CI] 0.83–1.48, P = 0.50) or SLE (OR 1.00, 95% CI 0.73–1.37, P = 0.99). This SNP was not associated with rheumatoid factor status, shared epitope status, radiographic severity in patients with RA, or disease manifestations in patients with SLE.

Conclusion

The association of the −169C/T SNP in FCRL3 with RA and SLE that was observed in Japanese patients was not replicated in a Korean population.

     

Urinary lipocalin‐2 is associated with renal disease activity in human lupus nephritis

Objective

Pathogenic monoclonal anti–double‐stranded DNA (anti‐dsDNA) antibodies up‐regulate the expression of lipocalin‐2 in glomerular mesangial cells. This study was undertaken to investigate whether polyclonal anti‐dsDNA antibodies promote the local secretion of lipocalin‐2 in the kidneys of patients with systemic lupus erythematosus (SLE), and whether urinary lipocalin‐2 represents a marker of kidney involvement in SLE.

Methods

Hispanic, African American, and white patients with SLE and normal healthy control subjects from affiliated hospitals of the Albert Einstein College of Medicine were recruited for this cross‐sectional study. Patients were classified based on the presence of active renal disease according to the SLE Disease Activity Index (SLEDAI). Correlations of clinical and laboratory data with urinary and serum levels of lipocalin‐2 were assessed.

Results

Among SLE patients, urinary lipocalin‐2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3–45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1–20.3; n = 38) (P = 0.023). Compared with the values in normal controls (median 4 ng/ml, IQR 0–11.1; n = 14), urinary levels of lipocalin‐2 in SLE patients were significantly higher (non‐normalized median 19.3 ng/ml, IQR 8–34.2) (P = 0.004). The presence of lipocalin‐2 in the urine of patients with LN correlated significantly with the renal SLEDAI score (r = 0.452, P = 0.009), but not with extrarenal disease activity.

Conclusion

The high prevalence of LN in SLE patients and the prognostic significance of kidney disease support the need for identifying early biomarkers to assess the risk of nephritis development and for following up patients with established disease. These findings indicate that urinary lipocalin‐2 is a potential marker of the presence and severity of renal involvement in adult patients with SLE.

     

Influence of coping skills on health‐related quality of life in patients with systemic lupus erythematosus

Objective

To identify coping strategies used by patients with systemic lupus erythematosus (SLE), and to assess the influence of main clinical and coping variables on health‐related quality of life (HRQOL).

Methods

We administered the Coping Orientation to Problems Experienced and the Short Form 36 questionnaire to a group of 144 patients with SLE and a group of 129 healthy controls. At the time of the psychological assessment, all patients underwent a complete clinical and laboratory evaluation.

Results

SLE patients had higher scores in acceptance (P < 0.001) and turning to religion (P = 0.05) and lower scores in planning (P = 0.001), suppression of competing activities (P = 0.010), restraint coping (P = 0.031), focusing on and venting of emotion (P = 0.009), and strategies focused on problem (P = 0.012) compared with controls. By means of linear regression analysis, HRQOL in SLE patients seemed to be influenced positively by restraint coping and positive reinterpretation and growth, and negatively by focusing on and venting of emotion, behavioral disengagement, and mental disengagement. When clinical variables were added to the multivariate analysis for coping strategies, more significant regression models that included joint pain were obtained.

Conclusion

In facing stressful situations, patients with SLE tend to use coping skills that are generally adopted for events perceived as nonmodifiable. Strategies that show a passive attitude and joint pain seem to impair these patients' HRQOL.

     

Expression of the markers BDCA‐2 and BDCA‐4 and production of interferon‐α by plasmacytoid dendritic cells in systemic lupus erythematosus

Objective

To study the expression of blood dendritic cell antigen 2 (BDCA‐2) and BDCA‐4 molecules by plasmacytoid dendritic cells (PDCs) in the blood of patients with systemic lupus erythematosus (SLE), and to study PDC production of interferon‐α (IFNα) and its inhibition by anti–BDCA‐2 and anti–BDCA‐4 antibodies.

Methods

Peripheral blood mononuclear cells (PBMCs) from SLE patients (SLE PBMCs) and from healthy controls were induced to produce IFNα in vitro by SLE serum containing an endogenous IFNα‐inducing factor (SLE‐IIF) or by herpes simplex virus type 1 (HSV‐1). The frequencies and numbers of BDCA‐2–, BDCA‐3–, and BDCA‐4–expressing cells were analyzed by flow cytometry, and the effects of anti–BDCA‐2 and anti–BDCA‐4 monoclonal antibodies (mAb) on IFNα production were investigated.

Results

IFNα production by SLE PBMCs induced by SLE‐IIF or HSV‐1 was decreased compared with that of healthy control PBMCs (P = 0.002 and P = 0.0007, respectively). The proportions of BDCA‐2– and BDCA‐3–expressing cells in SLE PBMCs were reduced compared with those in PBMCs from healthy controls (P = 0.01 and P = 0.004, respectively). IFNα producers in culture, especially among SLE PBMCs, displayed reduced BDCA‐2 expression and constituted only a minority of the BDCA‐2–positive cells, at least in healthy control PBMCs (median 18%). IFNα production by both SLE and healthy control PBMCs stimulated by SLE‐IIF or HSV‐1 was markedly reduced by anti–BDCA‐2 mAb (median 81–98% inhibition). Anti–BDCA‐4 mAb only partially inhibited SLE‐IIF–induced IFNα production.

Conclusion

SLE patients had a reduced number of BDCA‐2–expressing PDCs, also termed natural IFNα‐producing cells, and their IFNα production could be inhibited by anti–BDCA‐2/4 mAb. Such mAb may be a therapeutic option for inhibiting the ongoing IFNα production in SLE patients.