Niewold, Timothy B.

Objective Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end‐stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene ( APOL1 ) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. Methods APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN‐ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. Results Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN‐ESRD cases than in SLE non‐nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN‐ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE‐ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10 −9 ), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10 −6 ). The age‐, sex‐, and admixture‐adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes ( P = 0.01). Conclusion APOL1 G1/G2 alleles strongly impact the risk of LN‐ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN‐ESRD in African Americans.

Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF-α) levels. We explored circulating TNF-αlevels in SLE families to determine whether high levels of TNF-αwere clustered in a heritable pattern. We measured TNF-αin 242 SLE patients, 361 unaffected family members, 23 unaffected spouses of SLE patients, and 62 unrelated healthy controls. Familial correlations and relative recurrence risk rates for the high TNF-αtrait were assessed. SLE-affected individuals had the highest TNF-αlevels, and TNF-αwas significantly higher in unaffected first degree relatives than healthy unrelated subjects(P=0.0025). No Mendelian patterns were observed, but 28.4% of unaffected first degree relatives of SLE patients had high TNF-αlevels, resulting in a first degree relative recurrence risk of 4.48(P=2.9×10-5). Interestingly, the median TNF-αvalue in spouses was similar to that of the first degree relatives. Concordance of the TNF-αtrait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF-αin SLE pathogenesis, and TNF-αlevels may relate with heritable factors. The high degree of concordance in SLE patients and their spouses suggests that environmental factors may also play a role in the observed familial aggregation.

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

ObjectiveTo evaluate serum interferon‐α (IFNα) activity in the context of autoantibody profiles in patients with juvenile dermatomyositis (JDM).MethodsSera from 36 patients with JDM were analyzed. Autoantibody profiles were determined by probing microarrays, which were fabricated with ∼80 distinct autoantigens, with serum and a Cy3‐conjugated secondary antibody. Arrays were scanned and analyzed to determine antigen reactivity. Serum IFNα activity was measured using a functional reporter cell assay. Sera were assayed alone or in combination with cellular material released from necrotic U937 cells to stimulate peripheral blood mononuclear cells from healthy donors in vitro, and IFNα production in culture was measured by a dissociation‐enhanced lanthanide fluoroimmunoassay (DELFIA).ResultsReactivity against at least 1 of 41 autoantigens on the microarray, including Ro 52, Ro 60, La, Sm, and RNP, was observed in 75% of the serum samples from patients with JDM. IFNα activity was detected in 7 samples by reporter cell assay. The reporter cell assay showed a significant association of reactivity against Ro, La, Sm, and proliferating cell nuclear antigen with serum IFNα activity (P = 0.005). Significance Analysis of Microarrays (SAM) identified increased reactivity against Sm, RNP, Ro 52, U1‐C, and Mi‐2 in these sera. Sixteen samples induced IFNα production as measured by DELFIA, and there was a significant association of reactivity against Ro, La, Sm, and RNP with the induction of IFNα by serum and necrotic cell material (P = 0.034). SAM identified increased reactivity against Ro 60 in these sera.ConclusionThese data support the hypothesis that nucleic acid–associated autoantibodies, including the Ro/La and Sm/RNP complexes, may stimulate the production of active IFNα in children with JDM.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple genetic risk factors, high levels of interferon alpha (IFN- α ), and the production of autoantibodies against components of the cell nucleus. Interferon regulatory factor 5 (IRF5) is a transcription factor which induces the transcription of IFN- α and other cytokines, and genetic variants of IRF5 have been strongly linked to SLE pathogenesis. IRF5 functions downstream of Toll-like receptors and other microbial pattern-recognition receptors, and immune complexes made up of SLE-associated autoantibodies seem to function as a chronic endogenous stimulus to this pathway. In this paper, we discuss the physiologic role of IRF5 in immune defense and the ways in which IRF5 variants may contribute to the pathogenesis of human SLE. Recent data regarding the role of IRF5 in both serologic autoimmunity and the overproduction of IFN- α in human SLE are summarized. These data support a model in which SLE-risk variants of IRF5 participate in a “feed-forward” mechanism, predisposing to SLE-associated autoantibody formation, and subsequently facilitating IFN- α production downstream of Toll-like receptors stimulated by immune complexes composed of these autoantibodies.