Objective. Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment.Methods. In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed.Results. Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the lowdose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the Supported by the European League Against Rheumatism.

Background Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. Methods Using case–control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus–specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. Results A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion–deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. Conclusions A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.)

In the present study, we assessed the frequency and characteristics of the main causes of morbidity and mortality in systemic lupus erythematosus (SLE) during a 10-year period and compared the frequency of early manifestations with those that appeared later in the evolution of the disease. In 1990, we started a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 10 years (1990-2000).A total of 481 (48.1%) patients presented 1 or more episodes of arthritis at any time during the 10 years, 311 (31.1%) patients had malar rash, 279 (27.9%) active nephropathy, 194 (19.4%) neurologic involvement, 166 (16.6%) fever, 163 (16.3%) Raynaud phenomenon, 160 (16.0%) serositis (pleuritis and/or pericarditis), 134 (13.4%) thrombocytopenia, and 92 (9.2%) thrombosis. When the prevalences of the clinical manifestations during the initial 5 years of follow-up (1990-1995) were compared with those during the ensuing 5 years (1995-2000), most manifestations were found to be more frequent during the initial 5 years. Of the 1,000 patients, 360 (36%) presented infections, 169 (16.9%) hypertension, 121 (12.1%) osteoporosis, and 81 (8.1%) cytopenia due to immunosuppressive agents. Twenty-three (2.3%) patients developed malignancies; the most frequent primary localizations were the uterus and the breast.Sixty-eight (6.8%) patients died, and the most frequent causes of death were similarly divided between active SLE (26.5%), thromboses (26.5%), and infections (25%). A survival probability of 92% at 10 years was found. A lower survival probability was detected in those patients who presented at the beginning of the study with nephropathy (88% versus 94% in patients without nephropathy, p = 0.045). When the causes of death during the initial 5 years of follow-up (1990-1995) were compared with those during the ensuing 5 years (1995-2000), active SLE and infections (28.9% each) appeared to be the most common causes during the initial 5 years, while thromboses (26.1%) became the most common cause of death during the last 5 years.In conclusion, most of the SLE inflammatory manifestations appear to be less common after a long-term evolution of the disease, probably reflecting the effect of therapy as well as the progressive remission of the disease in many patients. Meanwhile, a more prominent role of thrombotic events is becoming evident, affecting both morbidity and mortality in SLE.