Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis

The objective of this study was to investigate the interaction between levels of BAFF (B-cell activation factor of the tumour necrosis factor [TNF] family) and APRIL (a proliferation-inducing ligand) and B-cell frequencies in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) treated with the B-cell-depleting agent rituximab. Ten patients with SLE were treated with rituximab in combination with cyclophosphamide and corticosteroids. They were followed longitudinally up to 6 months after B-cell repopulation. Nine patients with RA, resistant or intolerant to anti-TNF therapy, treated with rituximab plus methotrexate were investigated up to 6 months after treatment. The B-cell frequency was determined by flow cytometry, and serum levels of BAFF and APRIL were measured by enzyme-linked immunosorbent assays. BAFF levels rose significantly during B-cell depletion in both patient groups, and in patients with SLE the BAFF levels declined close to pre-treatment levels upon B-cell repopulation. Patients with SLE had normal levels of APRIL at baseline, and during depletion there was a significant decrease. In contrast, patients with RA had APRIL levels 10-fold higher than normal, which did not change during depletion. At baseline, correlations between levels of B cells and APRIL, and DAS28 (disease activity score using 28 joint counts) and BAFF were observed in patients with RA. In summary, increased BAFF levels were observed during absence of circulating B cells in our SLE and RA patient cohorts. In spite of the limited number of patients, our data suggest that BAFF and APRIL are differentially regulated in different autoimmune diseases and, in addition, differently affected by rituximab treatment

Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus

The role of inflammation in the development of atherosclerosis is now accepted and a focus of many studies because of its complex mechanisms. The risk of cardiovascular disease (CVD) and atherosclerosis is reported to be increased in systemic lupus erythematosus (SLE), especially in the group of young women. The introduction of statins in the 1990’s lowered considerably the morbidity and mortality in CVD. In the last decade, research efforts were concentrated on the immunological mechanisms of atherosclerosis and on the possibility to influence these mechanisms. Our group recently reported a negative association between natural IgM-antibodies against phosphorylcholine (IgM anti-PC) and CVD outcome in the general population. Potential mechanisms considered include anti-inflammatory properties and inhibition of uptake of oxidized low density lipoprotein (oxLDL) in macrophages. The objective herein was to study mechanisms of atherosclerosis in SLE and the relation to traditional and non-traditional risk factors in an SLE cohort, in comparison with an age and sex matched control group. As systemic endothelial dysfunction is one of the earliest signs of atherosclerosis in the general population, we also assessed skin microvascular endothelial function in SLE patients and controls. A total of 114 patients with SLE were compared with 122 age and sex-matched population-based controls. Common carotid intima-media thickness (IMT), calculated intima-media area (cIMa) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded according to echogenicity. Anti-PC was assessed by enzyme-linked immunosorbent assay (ELISA). Endothelial function in skin was tested with local application of acetylcholine (ACh) and any concomitant increase in skin perfusion was measured with Laser Doppler Fluxmetry (LDF) in 84 of the SLE-patients and 81 of the age- and sex-matched controls. Incidence of hypertension, presence of insulin resistance (determined by homeostasis model assessment of insulin resistance, HOMA-IR) and the levels of triglycerides and C-reactive protein (CRP) were increased in the SLE patients, while smoking, cholesterol and high density lipoprotein (HDL) did not differ from controls. Low levels of IgM anti-PC were more common in the SLE patients than in the controls. IMT and cIMa did not differ significantly between groups. However, plaques were more often found in the SLE patients. Age, LDL and IgM anti-PC were independently associated with plaque occurrence in the SLE patients. Furthermore, in the left carotid arteries echolucent plaques were more prevalent in SLE when compared to controls. There were no significant differences in skin microvascular endothelial function between SLE patients and controls. In the SLE group, endothelial function did not vary in relation to presence of skin manifestations, Raynaud’s phenomenon, nephritis or plaque occurrence. In SLE patients with CVD, however, endothelial function was impaired. Conclusion: Plaque occurrence in the carotid arteries was increased in SLE and was independently associated with age, LDL and low anti-PC levels. Vulnerable plaques were more common in SLE than in controls. Anti-PC could be a novel risk marker for atherosclerosis with therapeutic potential in SLE. Skin microvascular endothelial function was associated with CVD but not with early signs of atherosclerosis in SLE-patients. The endothelial function was not different in SLE-patients, as compared to controls

Endothelial cell interactions with neutrophils : studies of adhesion and effects of lipoxygenase metabolites and antirheumatic drugs

Inflammation is a process of vital importance in the defence and elimination of microorganisms as well as in the repair of the damaged tissue. However, inadequate or excessive inflammation leads to inflammatory diseases such as rheumatoid arthritis. Neutrophil polyntorphonuclear granulocytes (PMN) are important participators in inflammatory reactions. Endothelial cells (EC) are crucial for the regulation of inflammatory responses by their capacity to modulate their expression of adhesion molecules as well as activating molecules. Mechanisms of adhesion of PMN to human umbilical vein endothelial cells (HUVEC) were studied in vitro with emphasis on effects of leukotrienes, lipoxins, cytokines and antirheumatic agents. Lipoxin A4 (LXA4), but not LXB4, induced an increase in HUVEC binding of PMN. The kinetic of the adhesive response was intermediate to that of rapid (e.g. LTB4) and slow acting agonists (e.g. IL-1ß). The LXA4 response was partially blocked by the PAF-receptor antagonist WEB-2086, indicating the involvement of PAF in the activation process. The LXA4 induced adhesive response was resistant to pertussistoxin (PT), indicating that the activation process was independent of PT-sensitive G-proteins. Pre-treatment of EC with LXA4 prior to stimulation with LT134 reduced the adhesive responses conferred by LTB4. Thus, LXA4 seems not to be a pro- or anti-inflammatory agent but an inflammatory modulator. The peptido-leukotrienes C4 (LTC4) and LTD4 are potent inflammatory mediators involved in the pathophysiology of e.g. bronchial asthma. LTD4 induced rapid rises of intracellular Ca2+ in HUVEC as well as PMN, LTC4 only in HUVEC. LTC4 and LTD4, in contrast to LTB4, did not affect the adhesive responses of HUVEC or PMN. The intracellular release of Ca2+ was blocked by the peptido-leukotriene blocker SKF 104,353, indicating the presence and involvement of specific receptors on HUVEC as well as on PMN. Peroxisome proliferator-activating receptors (PPAR) are nuclear receptors that regulates transcription of e.g. enzymes involved in lipid metabolism but also involved in the regulation of inflammatory responses. PPAR[alpha] is expressed in EC. However, treatment of HUVEC with the PPAR[alpha] agonist WY 14,643 had no influence on adhesive interactions between HUVEC and PMN, indicating that the modulating capacity of PPAR is conferred at other steps than the adhesive interactions. Gold sodium thiornalat (GSTM) and auranofin (AF) interfered with adhesive interactions between PMN and HUVEC induced by IL-1ß. Likewise, GSTM reduced endothelial expression of E-selectin, AF interfered with expression of E- selectin as well as of ICAM-1. Prednisolone interfered with adhesive as well as cytotoxic interactions between PMN and HUVEC, by multiple effects on the PMN as well as on the HUVEC, including a hampering effect on cytokine induced E-selectin expression. Thus, adhesive interactions between EC and PMN (as well as other classes of leukocytes) are of pivotal importance in inflammatory reactions. Agents interfering with these interactions will offer more potent and selective treatments of inflammatory disorders

A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission.

Treatment with tumour necrosis factor (TNF) blockers, once started as therapy for rheumatoid arthritis (RA), is usually continued indefinitely. The aim of this trial was to assess the possibility of discontinuing treatment with adalimumab (ADA) while maintaining remission in patients with RA with established disease in stable remission on combination therapy with ADA and methotrexate (MTX)