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Objective. To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE).Methods. TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes.Results. The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRB1*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation.Conclusion. TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.

Objective. To investigate the relationship between quantitative estimates of global brain damage based on magnetization transfer imaging (MTI) and cerebral functioning, as measured by neurologic, psychiatric, and cognitive assessments, as well as disease duration in patients with a history of neuropsychiatric systemic lupus erythematosus (NPSLE).Methods. In patients with systemic lupus erythematosus (SLE), neurologic, psychiatric, and psychological symptoms often occur. The frequency of nervous system involvement has been reported to range from 11% to 60% (1). Infection, drug side effects, hypertension, or metabolic derangements, as well as an intrinsic brain manifestation of SLE (i.e., neuropsychiatric SLE [NPSLE]), can cause such symptoms. The uncertain pathogenesis and the wide variety of manifestations of NPSLE complicate the development of a uniform diagnostic decision-making protocol and a uniform method of monitoring a patient with this type of SLE. Findings of routine brain imaging studies are often unremarkable in patients with NPSLE, or the studies reveal abnormalities, such as cerebral atrophy and white matter hyperintensities (on magnetic resonance imaging [MRI]), that can also be found in SLE patients without neuropsychiatric symptoms. Furthermore, no correlation has thus far been demonstrated between quantitative measures of such nonspecific abnormalities and measures of brain function (2-5).Recently, magnetization transfer ratio (MTR) histogram analysis, a quantitative MRI technique based on magnetization transfer imaging (MTI), was applied in patients with primary NPSLE but without abnormalities on MRI that could account for the clinical picture. With this technique, cerebral abnormalities were identified in these patients (6,7). Such abnormalities were found in SLE patients who had had episodes of neuropsychiatric symptoms in the past (chronic NPSLE) as well as in patients who were experiencing an active phase of neuropsychiatric symptoms (active NPSLE) (6,7). The

Objective-To investigate the association of interleukin 10 (IL10) promoter polymorphisms and neuropsychiatric manifestations of systemic lupus erythematosus (SLE). Methods-IL10 haplotypes of 11 healthy volunteers were cloned to confirm that in the Dutch population, only the three common haplotypes (-1082/-819/-592) GCC, ACC and ATA exist. The IL10 promoter polymorphisms of 92 SLE patients and 162 healthy controls were determined. The medical records of the SLE patients were screened for the presence of neuropsychiatric involvement. Results-All cloned haplotypes were either GCC, ACC or ATA. Forty two SLE patients had suVered from neuropsychiatric manifestations (NP-SLE). In NP-SLE patients, the frequency of the ATA haplotype is 30% versus 18% in the controls and 17% in the non-NP-SLE group (odds ratios 1.9, p=0.02, and 2.1, p=0.04, respectively), whereas the GCC haplotype frequency is lower in the NP-SLE group compared with controls and non-NP-SLE patients (40% versus 55% and 61%, odds ratios 0.6, p=0.02 and 0.4 p=0.006). The odds ratio for the presence of NP-SLE is inversely proportional to the number of GCC haplotypes per genotype when the NP-SLE group is compared with non-NP-SLE patients. Conclusions-The IL10 locus is associated with neuropsychiatric manifestations in SLE. This suggests that IL10 is implicated in the immunopathogenesis of neuropsychiatric manifestations in SLE. (Ann Rheum Dis 1999;58:85-89) Genetic factors play an important part in the aetiopathogenesis of systemic lupus erythematosus (SLE). This is illustrated by the 50-60% concordance rate of SLE beween monozygotic twins.1 Furthermore, several susceptibility loci have been identified, including HLA class I and II, C4A complement null alleles, tumour necrosis factor (TNF), and Fc--RIIIa polymorphisms. [2][3][4][5][6]

Objective. The clinical symptoms of neuropsychiatric systemic lupus erythematosus (NPSLE) are usually reversible, but whether the associated brain damage is also reversible is still a matter of debate. Since magnetization transfer imaging (MTI) is more sensitive than conventional magnetic resonance imaging (MRI) in demonstrating brain damage, it has become a useful tool in the detection and quantification of diffuse brain disorders such as multiple sclerosis. In this study, MTI was applied to investigate whether central nervous system (CNS) damage is present in patients with a history of NPSLE.Methods. Eleven female patients with a history of NPSLE and no previous or concurrent primary neurologic or psychiatric disease (ages 17-49 years), 11 female patients with SLE without a history of NPSLE (non-NPSLE; ages 15-51 years), and 10 healthy female controls (ages 17-47 years) underwent MTI. From these MTI scans, quantitative data on the uniformity of the brain parenchyma and atrophy were derived.Results. One NPSLE and 1 non-NPSLE patient were excluded from this study due to infarctions detected with conventional MRI. MTI measures normalized for intracranial volume, reflecting abnormalities of the brain parenchyma as well as atrophy, were lower (P < 0.001) in the NPSLE group than in both control groups. A higher (P < 0.005) mean ratio of cerebrospinal fluid to intracranial volume, indicative of atrophy, was present in the NPSLE group compared with either the non-NPSLE patients or healthy controls. Still, the MTI measures solely reflecting uniformity of the brain parenchyma (normalized for brain volume) were also significantly (P < 0.001) lower in the NPSLE patients than in both control groups.Conclusion. This study demonstrates that using MTI, CNS damage can be demonstrated in patients with a history of NPSLE. MTI might, therefore, be an alternative and sensitive tool to detect brain injury in NPSLE, and might also be useful in studying the natural history of the disease.The clinical symptoms of diffuse neuropsychiatric systemic lupus erythematosus (NPSLE) are usually reversible, but it is unknown whether the underlying brain disorder is also reversible. Although punctate areas of increased signal (PAIS) or atrophy can be found in NPSLE patients with the use of diagnostic imaging techniques, these characteristics are also demonstrated in SLE patients who do not have NPSLE (1). Still, functional imaging techniques have demonstrated a variety of abnormalities that are found strictly in NPSLE patients (2-10). Some of the results have suggested transient abnormalities, whereas others have indicated lasting damage.Magnetization transfer imaging (MTI) is a magnetic resonance imaging (MRI) technique that has 2 advantages over conventional MRI: it seems to be more sensitive to structural brain damage, and it permits easy and robust quantification of such structural damage (11). MTI has been applied as a method to detect and quantify diffuse diseases of the brain, such as multiple sclerosis (MS). In MS patients, MTI estimates...

Our results indicate that volumetric MTI analysis detects cerebral changes in the active phase of NPSLE. The abnormalities in the brain parenchyma of patients with chronic NPSLE produced MTI values that were the same as those in patients with inactive MS. MTI values in the active phase of NPSLE differed from those in the chronic phase, which might reflect the presence of inflammation. These preliminary results suggest that MTI might provide evidence for the presence of active NPSLE. MTI might also prove to be a valuable technique for monitoring treatment trials.

BackgroundSeveral studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication.Methodology and Principal Findings22 single nucleotide polymorphisms (SNPs) in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls). 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients) we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population.ConclusionWe conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.

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