The B-cell activity factor (BAFF) acts as a positive regulator of B-cell function. To gain further insight into the understanding of B-cell hyperactivity in autoimmune diseases, the serum level of BAFF was determined in 43 systemic lupus erythematosus (SLE) patients, 58 primary Sjögren's syndrome (pSS) patients, 28 rheumatoid arthritis (RA) patients, and 68 normal control subjects using an in-house sandwich ELISA. A commercial kit was used to detect soluble CD23 (sCD23) reflecting B-cell activation. In-house assays for the detection of autoantibodies also were used. We found an increased level of BAFF in SLE, pSS, and RA sera compared with normal subjects (respectively, 10.6 +/- 8.5, 15.8 +/- 12.9, 9.7 +/- 1.5 ng/mL vs. 4.6 +/- 2.9 ng/mL, P < .001). sCD23 released on B-cell activation also was found to be elevated in SLE, pSS, and RA compared with normal sera. However, no correlation was found between the circulating BAFF and the level of sCD23. By contrast, we observed that high levels of BAFF were associated with the presence of autoantibodies (anti-double-stranded DNA antibodies in SLE, anti-SSA antibodies in pSS, and rheumatoid factors in RA). Our data suggest that BAFF is influential in driving antibody production rather than activation of the B lymphocytes in autoimmune diseases.

Objective. Continuous treatment with the antitumor necrosis factor ␣ (anti-TNF␣) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested.Methods. Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on-demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on-demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58.Results. Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P < 0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean ؎ SD 5.8 ؎ 2.2 versus 3.5 ؎ 2; P < 0.0001). Addition of MTX did not significantly affect the proporClinicalTrials.gov identifier: NCT00439283.

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Objective. Anti-double-stranded DNA (antidsDNA) antibodies may contribute to the pathogenesis of glomerulonephritis (GN) by cross-reacting with ␣-actinin in murine models and in some patients with systemic lupus erythematosus (SLE). We therefore sought to determine possible disease associations with serologic and clinical features and to characterize this new autoantibody specificity.Methods. One hundred patients with SLE were recruited into this multicenter study, as well as 100 rheumatic disease controls and 2,100 healthy blood donors. Clinical disease was evaluated by the SLE Disease Activity Index (SLEDAI; excluding the anti-DNA component). Anti-dsDNA antibodies were detected by conventional enzyme-linked immunosorbent assay (ELISA) and by a commercial enzyme immunoassay (EIA). Anti-␣-actinin antibodies were detected by ELISA, and their specificity was confirmed by Western blotting and by indirect immunofluorescence using rat kidney sections and mesangial cells as substrates. Highly positive sera were selected for absorption experiments and were affinity-purified for cross-reactivity studies and measurement of antibody avidity.Results. Sera from 62 of the SLE patients had anti-dsDNA antibodies; 21 of these sera also had anti-␣-actinin antibodies, as compared with 1 of the 38 sera without anti-dsDNA antibodies. Of the 22 patients with anti-␣-actinin antibodies, 10 had GN, as compared with 14 of the 78 without anti-␣-actinin antibodies (P < 0.01). In patients with GN, anti-␣-actinin, but not anti-dsDNA, antibodies correlated with the SLEDAI score (minus the anti-DNA component) and with treatment. The fraction of serum anti-dsDNA antibodies that cross-reacted with ␣-actinin exhibited high avidity for dsDNA, as determined using a commercial EIA for high-avidity anti-dsDNA antibodies and an in-house conventional ELISA.Conclusion. The ␣-actinin-binding antibodies are significantly associated with GN in SLE. Whether such autoantibodies may anticipate the development of this complication of SLE remains to be verified.

Systemic lupus erythematosus (SLE) disease is an autoimmune disease of unknown aetiology that affects predominantly women of child bearing age. Since previous studies, including ours, have demonstrated that CD4+ T cells and B cells from SLE patients are defective in their ability to methylate their DNA upon antigen stimulation, the aim of this study was to investigate whether DNA demethylation affects the transcription of HRES-1 in B cells. HRES-1 is the prototype of Human Endogenous Retrovirus (HERV) overexpressed in SLE. We have observed that SLE B cells were characterized by their incapacity to methylate the HRES-1 promoter, both in unstimulated and in anti-IgM stimulated B cells. In turn, HRES-1/p28 expression was increased in SLE B cells after B cell receptor engagement, but not in controls. In SLE B cells the Erk/DNMT1 pathway was defective. In addition, blocking the autocrine-loop of IL-6 in SLE B cells with an anti-IL-6 receptor monoclonal antibody restores DNA methylation and control of HRES-1/p28 expression became effective. As a consequence, a better understanding of HERV dysregulation in SLE reinforces our comprehension of the disease and opens new therapeutic perspectives.