IntroductionClinical trials revealed a high efficacy of mycophenolate mofetil (MMF) in inducing and maintaining remission in patients with class III-V-lupus nephritis. Also extrarenal manifestations respond to MMF treatment. However, few attempts have been undertaken to delineate its mechanism of action in systemic lupus erythematosus (SLE) a disease characterized by enhanced B cell activation.MethodsClinical and paraclinical parameters of 107 patients with SLE were recorded consecutively and analyzed retrospectively. Patients were divided into treatment groups (MMF: n = 39, azathioprine (AZA) n = 30 and controls without immunosuppressive therapy n = 38). To further delineate the effect of mycophenolic acid (MPA) on naive and memory B cells in vitro assays were performed.ResultsAlthough patients taking AZA flared more frequently than patients on MMF or controls, the analysis of clinical parameters did not reveal significant differences. However, profound differences in paraclinical parameters were found. B cell frequencies and numbers were significantly higher in patients taking MMF compared to those on AZA but lower numbers and frequencies of plasmablasts were detected compared to AZA-treated patients or controls. Notably, MMF treatment was associated with a significantly higher frequency and number of transitional B cells as well as naive B cells compared to AZA treatment. Differences in T cell subsets were not significant. MPA abrogated in vitro proliferation of purified B cells completely but had only moderate impact on B cell survival.ConclusionsThe thorough inhibition of B cell activation and plasma cell formation by MMF might explain the favorable outcomes of previous clinical trials in patients with SLE, since enhanced B cell proliferation is a hallmark of this disease.

IntroductionDisease activity and therapy show an impact on cellular and serological parameters in patients with systemic lupus erythematosus (SLE). This study was performed to compare the influence of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) therapy on these parameters in patients with flaring, organ-threatening disease.MethodsSLE patients currently receiving CYC (n = 20), MMF (n = 25) or no immunosuppressive drugs (n = 22) were compared using a cross-sectional design. Median disease activity and daily corticosteroid dose were similar in these treatment groups. Concurrent medication, organ manifestations, and disease activity were recorded, and cellular and serological parameters were determined by routine diagnostic tests or flow cytometric analysis. In addition follow-up data were obtained from different sets of patients (CYC n = 24; MMF n = 23).ResultsAlthough both drugs showed a significant effect on disease activity and circulating B cell subsets, only MMF reduced circulating plasmablasts and plasma cells as well as circulating free light chains within three months of induction therapy. Neither MMF nor CYC were able to reduce circulating memory B cells. MMF lowered IgA levels more markedly than CYC. We did not observe a significant difference in the reduction of IgG levels or anti-dsDNA antibodies comparing patients receiving MMF or CYC. In contrast to MMF, induction therapy with CYC was associated with a significant increase of circulating CD8+ effector T cells and plasmacytoid dendritic cells (PDCs) after three months.ConclusionsThe results indicate differences between MMF and CYC with regard to the mechanism of action. MMF, but not CYC, treatment leads to a fast and enduring reduction of surrogate markers of B cell activation, such as circulating plasmablasts, plasma cells and free light chains but a comparable rate of hypogammaglobulinemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0603-8) contains supplementary material, which is available to authorized users.

Macrophage migration inhibitory factor (MIF) is a central proinflammatory cytokine that regulates innate and adaptive immune responses. To evaluate its role in primary vasculitides, we determined MIF by enzyme-linked immunoassay in the sera of patients with Wegener's granulomatosis (WG; n=26), microscopic polyangiitis (MPA; n=10), polyarteritis nodosa (PAN; n=9) and giant cell arteritis (GCA; n=11). Healthy controls (n=26) and patients with sarcoidosis (n=14) were studied in parallel. Serum levels of MIF were significantly higher in patients with WG (median 41.1, range 3.2-120 ng/ml) than those in healthy controls (6.0, 0.015-36.5 ng/ml; P<0.001) and in patients with sarcoidosis (13.8, 0.015-67.1 ng/ml; P<0.05). MIF values were higher in MPA patients (29.5, 9.9-69.4 ng/ml; P<0.01) in comparison with those in healthy controls. In particular, increased levels of MIF were associated with active disease as assessed by the Birmingham Vasculitis Activity Score. Sequential studies showed decreased levels of MIF after initiation of immunosuppressive therapy, with clinical improvement in WG and MPA patients. In contrast, serum levels of MIF were not significantly elevated in patients with PAN and GCA. The results suggest that MIF contributes to the inflammatory process and correlates with disease activity in antineutrophil cytoplasmic antibody-associated vasculitides.

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An objective was to determine the frequency of GM-CSF secreting peripheral blood mononuclear cells (PBMC) in patients with active systemic lupus erythematosus (SLE) and their relation to other cytokine secreting PBMC, activation markers on lymphocytes/monocytes, clinical manifestations and anti-dsDNA antibodies. A second objective was to further investigate the influence of immunoadsorption (IA) therapy on these parameters. The number of GM-CSF, interleukin-1beta (IL-1beta), IL-6, interferon-gamma (INF-gamma) or tumour necrosis factor-alpha (TNF-alpha) secreting PBMC was assessed by ELISPOT assay in 10 patients with active SLE. Further, the expression of activation markers on lymphocytes and monocytes was determined by flow cytometry. Three courses of IA were performed in the patients. Seventeen healthy, age- and sex-matched volunteers served as controls. GM-CSF secreting PBMC were significantly increased whereas INF-gamma secreting cells were decreased in SLE patients. The expression of CD71 (transferrin receptor) on CD4+ T-cells and of the costimulatory molecule CD86 on B-lymphocytes was significantly increased in SLE patients. GM-CSF secreting PBMC and CD4+/CD71+ T-cells correlated with anti-dsDNA antibody titres and decreased towards levels of controls during IA. Disease activity and anti-dsDNA autoantibody titres were significantly reduced after the treatment. Our results demonstrate significant alterations of cellular and humoral immunity in SLE patients. The impaired immunity can be modulated by IA. Thus IA may prove an immunomodulatory therapeutic option in addition to the mere depletion of anti-dsDNA autoantibodies.