Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis.

OBJECTIVE: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes. METHODS: 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc. RESULTS: The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1). CONCLUSION: The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.

Clinical presentations and molecular basis of complement C1r deficiency in a male African-American patient with systemic lupus erythematosus.

Homozygous deficiencies of early components for complement activation are among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). Eleven cases of C1r deficiency are documented but this is the first report on the molecular basis of C1r deficiency. The proband is an African-American male who developed SLE at 3 months of age. He had a discoid lupus rash and diffuse proliferative glomerulonephritis. Serum complement analysis of the patient showed zero CH50 activity, undetectable C1r, and reduced levels of C1s, but highly elevated levels of complement C4, C2, and C1-inhibitor. The coding regions of the mutant C1R gene with 11 exons located at chromosome 12p13 were polymerase chain reaction (PCR)-amplified and sequenced to completion. DNA sequencing revealed a homozygous C→T mutation at nucleotide-6392 in exon 10 of the C1R gene, resulting in a nonsense mutation from Arg-380 (R380X). The patient's clinically normal mother was heterozygous for this mutation. A sequence-specific primer (SSP) PCR coupled with StuI-restriction fragment length polymorphism (RFLP) was developed to detect the novel mutation. Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects.

Attenuation of expression of extracellular matrix genes with siRNAs to Sparc and Ctgf in skin fibroblasts of CTGF transgenic mice.

Transgenic mice that over-express connective tissue growth factor (CTGF) in fibroblasts under the control of an enhancer/promoter element of the Col1a2 gene (Col1a2-CTGF) recapitulate multiorgan fibrosis similar to fibrosis observed in Scleroderma (SSc). In this study we investigate the regulation of secreted protein acidic and rich in cysteine (Sparc) and Ctgf siRNAs on the expression of several extracellular matrix components in the fibroblasts derived from Col1a2-CTGF transgenic mice. Three fibroblast lines were obtained from each of wide type C57BL/6 and CTGF transgenic C57BL/6, and were transfected with Sparc siRNA or Ctgf siRNA. Real-time quantitative RT-PCR and Western blotting were used to examine the transcription and protein levels of type I collagen, CTGF and SPARC. Student's t-tests were used to determine the significance of the results. Our results showed that Col1a2 and Ctgf increased expression at both transcriptional and translational levels in the fibroblasts from the Col1a2-CTGF transgenic mice compared with those in the fibroblasts from their normal wild-type littermate. The treatment with Sparc siRNA or Ctgf siRNA attenuated the mRNA and/or protein expression of the Col1a2, Ctgf and Sparc in these fibroblasts. Sparc and Ctgf siRNAs also showed a reciprocal inhibition at transcript levels. Therefore, our results indicated that both SPARC and CTGF appeared to be involved in the same biological pathway, and they have the potential to serve as a therapeutic target for fibrotic diseases such as SSc.

BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians.

OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.

Gene interaction at HLA-DQ enhances autoantibody production in primary Sjögren's syndrome.

Primary Sjögren's syndrome is an autoimmune disorder characterized by dryness of the mouth and eyes. The human leukocyte antigen (HLA) locus DQ is related to the primary Sjögren's syndrome autoantibodies that bind the RNA proteins Ro/SSA and La/SSB. Both DQ1 and DQ2 alleles are associated with high concentrations of these autoantibodies. An analysis of all possible combinations at DQ has shown that the entire effect was due to heterozygotes expressing the DQ1 and DQ2 alleles. These data suggest that gene interaction between DQ1 and DQ2 (or alleles at associated loci), possibly from gene complementation of trans-associated surface molecules, influences the autoimmune response in primary Sjögren's syndrome.

Anti-KJ: a new antibody associated with the syndrome of polymyositis and interstitial lung disease.

Antibodies to aminoacyl-tRNA synthetases (anti-Jo-1, anti-PL-7, anti-PL-12) have been found in the serum of some patients with polymyositis (PM). Patients with these antibodies have an unusually high rate of interstitial lung disease (ILD) in association with their PM. Two patients (K.J. and B.T.) with severe ILD and PM were found to have antibodies to a cytoplasmic antigen, but tests to determine whether the antigen was an aminoacyl-tRNA synthetase were negative, including tests of KJ serum for inhibitory effects on the 20 synthetases. KJ immunoprecipitates did not contain tRNA, in contrast to antisynthetase sera. When IgG samples were added to a reticulocyte in vitro translation system at a concentration of 0.3 mg/ml, KJ IgG inhibited globin mRNA translation by 98%, while anti-Jo-1 IgG inhibited 62% and normal IgG had little effect. Thus, both anti-KJ and the antisynthetases are directed at antigens that are involved in translation and protein synthesis, and both are associated with the syndrome of lung disease and PM. This syndrome may be associated with antibodies to translation-related proteins in general, which may have implications for the link of PM and enteroviruses, which are mRNA viruses.

Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant.

Autoantibodies to phospholipids (APA) occur frequently in systemic lupus erythematosus (SLE) and other autoimmune disorders and predispose to intravascular thromboses. Major histocompatibility complex (MHC) class II alleles (HLA-DR and DQ) were determined by restriction fragment length polymorphisms (RFLP) in 20 patients with APA (lupus anticoagulant). HLA-DQw7 (DQB1*0301), linked to HLA-DR5 and -DR4 haplotypes, occurred in 70% and was significantly increased compared to 139 race-matched normal controls (P = 0.002, P corrected [pc] = 0.05, odds ratio [OR] = 5.1). Moreover, the frequency of HLA-DQw7 was significantly higher in SLE patients with APA as compared with patients without APA but with other autoantibodies, including anti-Ro and La (P = 0.0001, pc = 0.002, OR = 10.7), anti-Ro alone (P = 0.001, pc = 0.02, OR = 11.2), anti-dsDNA (P = 0.001, pc = 0.02, OR = 7.1), and possibly anti-Sm (P = 0.04, pc = NS, OR = 6.8) and anti-nRNP (U1-RNP) (P = 0.01, pc = NS, OR = 7.8). The DQB1*0301 allele of DQw7 showed the strongest association, while the frequencies of the DQA1*0301 (45%) and DQA1*0501 (50%) alleles did not differ from the controls. Among the HLA-DQB1*0301 (DQw7) negative patients, all possessed HLA-DQw8 (DQB1*0302) and/or HLA-DQw6 (DQB1*0602 or DQB1*0603) alleles. The HLA-DQB1*0301 chain shares an identical seven amino acid sequence with DQB1*0302, *0602, and *0603 chains in the third hypervariable region of the HLA-DQ molecule. This candidate "epitope" may play a role in mediating an autoimmune response to APA.

Association of polar amino acids at position 26 of the HLA-DQB1 first domain with the anticentromere autoantibody response in systemic sclerosis (scleroderma).

HLA class II alleles (detected by DNA typing) were determined in 116 Caucasians with systemic sclerosis positive and negative for anticentromere autoantibodies (ACA). Significantly increased frequencies of HLA-DR5(DRw11) (P = 0.009) and the Dw13(DRB1*0403, *0407) subtypes of DR4 (probability corrected, Pc = 0.005) were seen in ACA positive patients, and HLA-DR1 and DRw8 were also increased. These findings appeared to reflect linkage disequilibrium of DR5(DRw11) and many DR4(Dw13) haplotypes with HLA-DQw7 and DR1 with DQw5. In fact, the presence of a DQB1 allele having a polar glycine or tyrosine at position 26 of the DQB1 first domain versus a hydrophobic leucine accounted for 100% of ACA positive Caucasian systemic sclerosis patients compared to 69% of the ACA negative SS patients (P = 0.0008) and 71% of Caucasian controls (P = 0.0003) as well as all 7 ACA patients of non-Caucasian background. Furthermore, the genotype frequency of DQB1 alleles lacking leucine at position 26 was 73% in ACA positive SS patients, compared to 42% of ACA negative patients (P = 1.2 x 10(-5)) and 38% of controls (P = 5.8 x 10(-7)). These data, then, suggest that the second hypervariable region of the HLA-DQB1 chain may form the candidate epitope associated with the ACA response.

Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis).

Previous studies in Caucasians with progressive systemic sclerosis (PSS) have suggested associations of antitopoisomerase I (antitopo I) autoantibodies with either serologically defined HLA-DR2 or DR5. To better define class II HLA associations with the antitopo I response, 161 PSS patients (132 Caucasians and 29 American blacks) were studied for antitopo I autoantibodies by immunodiffusion and immunoblotting, and their HLA-DRB1, DRB3, DQA1, and DQB1 alleles were determined by restriction fragment length polymorphic analysis and DNA oligotyping. Among Caucasians with antitopo I, HLA-DR5(DRB1*1101-*1104), DRB3*0202 and DQw3 (DQw7,8,9) were significantly increased in frequency. In American blacks, however, only HLA-DQB1*0301(DQw7) was significantly increased. The presence of HLA-DQB1*0301(DQw7) and other HLA-DQB1 alleles bearing the uncharged polar amino acid residue tyrosine at position 30 of the outermost domain was found in all antitopo I-positive Caucasian PSS patients compared with 66% of antitopo I-negative PSS patients (pc = 0.007) and 70% of normal controls (pc = 0.008), as well as all antitopo I-positive black patients. The association with HLA-DQB1 was independent of HLA-DR5(DRB1*1101-*1104) or any other HLA-DRB1, DRB3, or DQA1 alleles. Alternative or additional candidate epitopes for this autoimmune response include alanine at position 38 and threonine at position 77 of these same DQB1 alleles. These data suggest that genetic predisposition to the antitopo I response in PSS is associated most closely with the HLA-DQB1 locus.

Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans.

Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.

PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by various autoantibodies that recognize autoantigens displayed on the surface of cells undergoing apoptosis. The genetic contribution to SLE susceptibility has been widely recognized. We previously reported evidence for linkage to SLE of the human chromosome 1q41-q42 region and have now narrowed it from 15 to 5 cM in an extended sample using multipoint linkage analysis. Candidate genes within this region include (a) PARP, poly(ADP-ribose) polymerase, encoding a zinc-finger DNA-binding protein that is involved in DNA repair and apoptosis; (b) TGFB2, encoding a transforming growth factor that regulates cellular interactions and responses; and (c) HLX1, encoding a homeobox protein that may regulate T-cell development. Using a multiallelic, transmission-disequilibrium test (TDT), we found overall skewing of transmission of PARP alleles to affected offspring in 124 families (P = 0.00008), preferential transmission of a PARP allele to affected offspring (P = 0.0003), and lack of transmission to unaffected offspring (P = 0.004). Similar TDT analyses of TGFB2 and HLX1 polymorphisms yielded no evidence for association with SLE. These results suggest that PARP may be (or is close to) the susceptibility gene within the chromosome 1q41-q42 region linked to SLE.

Sulfatides: targets for anti-phospholipid antibodies.

BACKGROUND: Sulfatides are sulfated glycosphingolipids expressed on the surface of erythrocytes, leukocytes, and platelets. Sulfatides interact with several cell adhesion molecules involved in hemostasis. Beta2-glycoprotein I is an anionic phospholipid-binding plasma protein, and the phospholipid-bound form is the target for most anti-phospholipid antibodies that are associated with recurrent thrombosis, miscarriages, and neurological symptoms. In this study, we examined whether beta2-glycoprotein I forms a complex with sulfatides and thereby becomes a target for anti-phospholipid antibodies. METHODS AND RESULTS: Beta2-glycoprotein I binds to surface-bound sulfatides but not to other glycolipids, such as ceramide, cerebrosides, sphingomyelin, or ganglioside. At a sulfatide coating density of 1 microg/well, beta2-glycoprotein I reaches half-maximal binding at 2.5 microg/mL, and the binding is saturated at 10 microg/mL. The binding of beta2-glycoprotein I also depends on the coating density of sulfatides in the well. At a constant beta2-glycoprotein I concentration of 5 microg/mL, maximal binding of beta2-glycoprotein I is observed at a coating density of 1 mug/well. The serum from 14 patients with anti-cardiolipin antibodies, a subset of anti-phospholipid antibodies, bound to sulfatide-bound beta2-glycoprotein I and previous absorption on cardiolipin-coated surfaces decreased the immunoreactivity toward sulfatide-beta2-glycoprotein I complex by >50% in 12 of 14 patients. Furthermore, immunoaffinity-purified anti-cardiolipin antibodies from 4 of 5 patients reacted with sulfatide-bound beta2-glycoprotein I. CONCLUSIONS: These results show that not only anionic phospholipids, as commonly known, but also sulfatides are targets for most anti-phospholipid antibodies. We therefore postulate that interactions of these antibodies with sulfatides may contribute to some of the clinical symptoms of the anti-phospholipid antibody syndrome.

A fatal case of Vibrio vulnificus presenting as septic arthritis.

Vibrio vulnificus is an invasive gram-negative bacillus that may cause necrotizing cellulitis, bacteremia, and/or sepsis. Although V vulnificus infection is uncommon, it is frequently fatal and is usually attributed to ingestion of raw shellfish or traumatic exposure to a marine environment; patients are also often found to have a hepatic disorder (cirrhosis, alcohol abuse, or hemochromatosis) or an immunocompromised health status, and most commonly present with septicemia or a wound infection. We describe a patient who presented with septic arthritis as the first clinical manifestation of a V vulnificus infection. The organism was subsequently identified in a synovial fluid aspirate.

An antigenic region of topoisomerase I in DNA polymerase chain reaction-generated fragments recognized by autoantibodies of scleroderma patients.

Topoisomerase cDNA and various fragments thereof generated by the DNA polymerase chain reaction were cloned into plasmid expression vectors (pET series) and the expressed polypeptides were probed with scleroderma sera from seven different patients immunoreactive with topoisomerase I. All sera reacted selectively with a region between amino acid residues 405 and 484 of human topoisomerase I. This conclusion is based on loss of reactivity when this region was omitted from larger pieces. Other portions of topoisomerase I were not reactive with these autoantibodies. At least two different epitopes appear to be recognized within this region by different sera based on differences in immunoreactivity of the 405-484 region when expressed as C-terminal, N-terminal or internally within a peptide.

Unique epitopes in RNA helicase II/Gu protein recognized by serum from a watermelon stomach patient.

RNA helicase II/Gu (RH II/Gu) is a nucleolar antigen originally identified using an autoimmune serum from a patient with watermelon stomach. A later report showed that anti-RH II/Gu autoantibodies were also present at low frequency in connective tissue disease (CTD) patients who did not show any symptoms suggestive of a watermelon stomach lesion. In an attempt to understand the relationship between watermelon stomach, also called gastric antral vascular ectasia (GAVE), and autoimmune disorder, we identified the antigenic sites recognized by these autoantibodies. Serum Gu uniquely recognized epitopes at amino acids 646-748 of RH II/Gu and all four CTD patient sera recognized antigenic sites within amino acids 1-173. Anti-RH II/Gu serum produced by immunizing rabbit with recombinant human RH II/Gu protein bound to the same antigenic sites recognized by the CTD patient sera, but it did not recognize the serum Gu epitopes. Results are also presented showing the use of these anti-RH II/Gu antibodies in the analysis of the evolutionary conservation of RH II/Gu in human, monkey and mouse.

Buschke-Ollendorff syndrome associated with elevated elastin production by affected skin fibroblasts in culture.

Buschke-Ollendorff syndrome (BOS; McKusick 16670) is an autosomal dominant connective-tissue disorder characterized by uneven osseous formation in bone (osteopoikilosis) and fibrous skin papules (dermatofibrosis lenticularis disseminata). We describe two patients in whom BOS occurred in an autosomal dominant inheritance pattern. The connective tissue of the skin lesions showed both collagen and elastin abnormalities by electron microscopy. Cultured fibroblasts from both patients produced 2-8 times more tropoelastin than normal skin fibroblasts in the presence of 10% calf serum. Involved skin fibroblasts of one patient produced up to eight times normal levels, whereas apparently uninvolved skin was also elevated more than threefold. In a second patient, whose involvement was nearly complete, elastin production was high in involved areas and less so in completely involved skin. Transforming growth factor-beta 1 (TGF beta 1), a powerful stimulus for elastin production, brought about similar relative increases in normal and BOS strains. Basic fibroblast growth factor, an antagonist of TGF beta 1-stimulated elastin production, was able to reduce elastin production in basal and TGF beta 1 stimulated BOS strains. Elastin mRNA levels were elevated in all patient strains, suggesting that Buschke-Ollendorff syndrome may result, at least in part, from abnormal regulation of extracellular matrix metabolism that leads to increased steady-state levels of elastin mRNA and elastin accumulation in the dermis.

Studies in familial systemic lupus erythematosus.

Although many examples of familial SLE have been reported, the relative importance of genetic and environmental factors remains unclear. In an effort to better understand these factors, eight such families were studied. These families, plus one deceased pair and 31 described in the literature consisted of 8 pairs of identical twins, one pair of non-identical twins, and 16 sibling and 15 parent-offspring combinations. Fifty-three cases in 25 families provided sufficient documentation for detailed analysis. Each familial case was compared to his affected relative utilizing 23 clinical and laboratory features of SLE. A control group of non-related SLE patients, each matched to a familial case for age, sex, race and disease duration, was similarly analyzed. Impressive concordance for disease expression was found between pairs of identical twins and between parent and offspring. No such concordance was found between siblings and controls. These findings support genetic influences in the expression of SLE in identical twins and parents and offspring pairs. Comparison of the frequencies of clinical and laboratory attributes in the familial group as opposed to non-familial groups showed no real differences. Thus, familial SLE is probably not a different disease entity from non-familial SLE. The finding of four father-offspring pairs lessens the possibility that SLE is transmitted during the perinatal period. The onset of SLE in each of identical twins occurred within an average of 2 years. In siblings, however, while the average difference in age at onset was 9 years, the average difference in time of onset (actual date) was only 3 years. Comparable figures for parents and offspring were 20 and 8 years, respectively. These data suggest environmental influences in the initiation of SLE, especially in siblings. Studies of 27 unaffected first-degree relatives in our eight families revealed two sisters with thyroid disease, persistent leukopenia and sedimentation rate elevation. They were daughters of a patient with SLE and Hashimoto's thyroiditis and sisters of a patient with SLE. The remaining 25 relatives were clinically, hematologically, biochemically, and serologically normal. While these studies suggest both genetic and environmental influences in the pathogenesis of SLE, further studies are necessary to elucidate the mechanisms.

Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease.

1. Among patients with SLE, 71 (51%) had significant neuropsychiatric problems during the course of the disease. In 52 (37%), the nervous system manifestations were secondary to SLE. 2. The most frequent manifestations were psychiatric dysfunction, seizures, long tract signs, cranial neuropathy, and peripheral neuropathy. 3. Psychiatric abnormalities secondary to SLE were characterized by organic features (present in 22 of 24) and by the association of neurologic lesions which were often diffuse or multifocal. 4. An abnormal cerebrospinal fluid was found in 32% of neuropsychiatric episodes in which specimens were obtained. The most frequently abnormal study was the electroencephalogram (71%), and the least frequent was the brain scan (8%). These studies did not correlate with specific clinical patterns. 5. In 63% of the patients, NP manifestations preceded the diagnosis of SLE or occurred within the first year of diagnosed disease, and in most episodes were associated with evidence of clinical and/or serologic activity of the underlying illness. 6. Only two clinical features showed significant and striking correlations with neuropsychiatric involvement, namely vasculitis and thrombocytopenia. The possible pathogenic implications have been discussed. 7. Only 2 of the 140 patients were felt to have steroid-induced psychoses. In approximately one-half of the NP episodes secondary to SLE, patients were receiving no corticosteriods on presentation. Of those developing while patients were on steroids, the majority occurred on low doses or after tapering from higher levels. 8. The immediate prognosis for improvement in neuropsychiatric function was good with 84% of episodes showing complete or partial resolution. Corticosteroids appeared to be of benefit in a substantial number of patients although their precise role is difficult to quantitate. 9. Five and 10 years survivals for the overall population were 94% and 82%, respectively. There were no significant differences in survival for patients with or without nervous system involvement.

Familial systemic lupus erythematosus: immunogenetic studies in eight families.

Familial SLE provides a unique opportunity to study the relationships of previously associated genetic factors (HLA and complement component deficiencies) to the occurrence of SLE, other immune disorders, and autoantibodies in families. Thus, eight families containing two or more affected members with SLE (n = 22) and their relatives (n = 40) were examined for HLA genotypes, complement components and autoantibodies. Among the 40 non-SLE relatives, 7 (18%) had other immune diseases, including thyroid disease in 2, rheumatoid arthritis in 2, ITP in 2, and Henoch-Schönlein purpura in one. This compared to 4 of the 22 SLE patients (also 18%) of whom 3 had thyroid disease and one PSS. Eleven non-SLE relatives (28%) had ANA, which was in high-titer in 5 (13%). Eleven (28%) had antibodies to ssDNA, and one had a BFP. Only the SLE patients had antidsDNA, Ro(SSA), Sm or nRNP. A heterozygous C2 deficiency (C2D) was found in only one of the seven kindreds studied, and followed an A25, B18 DR7 haplotype. Heterozygous C2D, however, was inherited by only one of three family members with SLE. HLA-DR2 occurred in 36% and DR3 in 36% of SLE patients, which was not significantly different from either non-SLE family members or unrelated local controls. Sib pair analysis of seven sets presented here and seven from two published reports, demonstrated only random distribution with SLE. Similarly, other immune disorders and autoantibodies followed no consistent HLA haplotypes or DR specificities. Interestingly, DR2 and/or DR3 were found in five of the six patients (83%) having anti-ro(SSA) antibodies (p = NS). These data strongly suggest that genetic factors (other than HLA and complement component deficiencies) and/or environmental factors are necessary for the expression of SLE and other immune abnormalities in lupus families.

Systemic lupus erythematosus: a review of clinico-laboratory features and immunogenetic markers in 150 patients with emphasis on demographic subsets.

Clinical and laboratory features as well as immunogenetic markers were analyzed in 150 patients with SLE to determine if demographic factors--age at diagnosis, sex and race--influenced the expression of disease. The overall series included 103 white females, 35 black females, 10 white males and 2 black males; the mean age at diagnosis was 32.5 years. Males had a significantly older mean age at diagnosis than females (40.4 versus 31.8 years) and a significantly higher frequency of peripheral neuropathy (50% versus 18.8%). No other differences in clinical or laboratory features or HLA-DR or DQ phenotype frequencies were noted. Blacks had a significant younger mean age at diagnosis than whites (26.9 versus 33.4 years) as well as significantly higher frequencies of nephritis, hypertension, acute lupus pneumonitis, discoid rash, hyperglobulinemia and hypocomplementemia. There were no differences in autoantibody frequencies between race-specific subgroups. HLA-DR2, DRw52 and DQ1 were significantly associated with SLE in whites compared to controls; no HLA-DR or DQ associations were found with SLE in blacks. In whites, HLA-DR2 was associated with the presence of anti-Ro(SS-A) antibody while HLA-DR3 was associated with the presence of both anti-Ro(SS-A) and anti-La(SS-B) antibody. In blacks, HLA-DR2 was associated with the presence of anti-nDNA antibody. In whites, patients with late-onset SLE (age at diagnosis greater than or equal to 50 years) had significantly lower frequencies of nephritis and mesenteric vasculitis but, on the other hand, a higher frequency of secondary Sjögren syndrome than patients with age at diagnosis less than or equal to 22 years. Similar findings were noted when blacks aged 35 and above were compared to those aged 17 and below at diagnosis. In whites, the frequency of both anti-Ro(SS-A) and La(SS-B) antibodies increased with increasing age as did that of HLA-DR3; HLA-DR2, however, was more frequent in those with younger age at diagnosis. These data suggest the existence of two serologic-genetic subsets of SLE with different age at diagnosis.