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 approximately 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 >or=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 x 10(-8)) and nonparametric (LOD score 6.9, P = 1.7 x 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.     

Rheumatoid arthritis in a United States Public Health Service Hospital in Oklahoma. Serologic manifestations in rheumatoid arthritis vary among tribal groups

Objective. To study the serologic manifestations of rheumatoid arthritis (RA) at a United States Public Health Service Hospital that serves numerous tribes in Oklahoma. Methods. Forty-five patients with RA were identified, and serologic studies for antinuclear antibody (ANA), rheumatoid factor, and antibodies to extractable nuclear antigens were performed. Extraarticular manifestions of RA were also evaluated. Results. Twelve of the 45 patients with RA were Kiowa. These patients were significantly more likely to have a positive ANA (75%) than the other patients with RA (28%). In addition, anti-Ro was significantly more common among Kiowa (33%) than among members of other tribes (3%). There was no difference in the extraarticular manifestions of the Kiowa compared with the other Native American tribes. Conclusion. RA can be distinctly characterized by serology among groups of American Indians living in the same geographic area.     

A distinctive autoantibody profile in black female patients with lupus nephritis

Objective. Lupus nephritis has often been associated with anti-DNA, but, based on the findings in eluate studies, it appears that other antigen–antibody reactions, such as those involving anti–Ro/SS-A, antinuclear RNP (anti-nRNP), and/or anti-Sm, may also contribute to the pathogenesis of nephritis. In the present investigation, we identified and further studied a distinctive precipitin profile present in black women with nephritis. Methods. Longitudinal clinical and serologic studies of a cohort of university-based systemic lupus erythematosus (SLE) patients (n = 120) were carried out over an 8-year period. Results. A subset of 20 black female patients was identified, of whom 8 had lupus nephritis (group I) and 12 did not (group II). Group I was characterized by a distinct precipitin profile consisting of anti–Ro/SS-A, anti-Sm, and anti-nRNP, but no anti–La/SS-B. SLE disease duration at presentation was significantly shorter in group I than in group II (mean 1.94 years versus 5.21 years; P = 0.02). The distinctive precipitin profile of anti–Ro/SS-A, anti-Sm, and anti-nRNP occurred exclusively in group I patients (6 of 8, versus 0 of 12 in group II; P < 0.001). In white lupus nephritis patients, this precipitin profile was not seen. Conclusion. While the mechanism responsible for the relationship of this distinctive serologic profile to the development of nephritis in black female lupus patients remains to be determined, its presence may be used as a marker for severe and progressive renal disease.     

Aminobisphosphonate inhibition of interleukin-1—induced bone resorption in mouse calvariae

Interleukin-1 (IL-1) is probably an important lymphokine mediator of inflammation and bone resorption. IL-1 derived from mononuclear cells, a melanoma cell line (MM96 cells), and recombinant human IL-1 (rHuIL-1β) increased in vitro bone resorption, as measured by the release of ⁴⁵Ca from cultured mouse calvariae. The 50% maximum active resorption was observed with 0.125 ng/ml or approximately 10⁻¹¹M rHuIL-1β. The resorptive action of IL-1 was not entirely dependent on prostaglandin mediation, since its effect was evident when prostaglandin synthesis was inhibited in the cultures by indomethacin. IL-1—induced resorption has been shown to be inhibited by 10⁻⁵M 3-amino-1-hydroxypropylidene-1-1-bisphosphonate (APD). This inhibition was partially reversed by increasing doses of IL-1. In vitro toxicity studies showed that at concentrations of 10⁻⁴M, APD inhibited the growth of cultured MM96, murine myelomonocytic P388D1, and rat osteosarcoma UMR 106 cells, but not other mast and lymphoid cell lines. These in vitro observations may have relevance to the use of APD in bone and joint diseases in which inflammation and bone resorption are prominent.