Mikael Heimbürger

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

IntroductionThe risk of cardiovascular disease (CVD) and atherosclerosis is reported to be increased in systemic lupus erythematosus (SLE). We recently reported a negative association between natural IgM-antibodies against phosphorylcholine (anti-PC) in the general population, high anti-PC levels leading to decreased atherosclerosis development and low levels to increased risk of CVD. Potential mechanisms include anti-inflammatory properties and inhibition of uptake of oxidized low density lipoprotein (LDL) in macrophages. The objective herein was to study atherosclerosis in SLE in detail and in relation to traditional and non-traditional risk factors.MethodsA 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 as a surrogate measure of atherosclerosis. Plaques were graded according to echogenicity and grouped as 1 to 4, with 1 being echoluscent, and considered most vulnerable. Anti-PC was studied by ELISA.ResultsHypertension, triglycerides and insulin resistance (determined by homeostasis model assessment of insulin resistance) and C-reactive protein (CRP) were increased in SLE (P < 0.01) while smoking, LDL, high density lipoprotein (HDL) did not differ between groups. Low levels of anti-PC IgM (lowest tertile) were more common in SLE patients than in controls (P = 0.0022). IMT and cIMa did not differ significantly between groups. However, plaques were more often found in SLE patients (P = 0.029). Age, LDL and IgM anti-PC (lowest tertile) were independently associated with plaque occurrence in SLE. Further, in the left carotid arteries echoluscent plaques (grade 1) were more prevalent in SLE as compared to controls (P < 0.016).ConclusionsPlaque occurrence in the carotid arteries is increased in SLE and is independently associated with age, LDL and low anti-PC levels. Vulnerable plaques were more common in SLE. Anti-PC could be a novel risk marker also with a therapeutic potential in SLE.

Resistive Home Exercise in Patients with Recent-onset Polymyositis and Dermatomyositis — A Randomized Controlled Single-blinded Study with a 2-year Followup

Objective. To evaluate the outcome of resistive home exercise and its possible longterm influence on health, disability, and disease activity in patients with active polymyositis (PM) or dermatomyositis (DM). Methods. Nineteen patients with recent-onset PM/DM were included after introduction of high-dose prednisolone. They were assessed by independent assessors as to perceived health, muscle performance, aerobic capacity, and serum creatine phosphokinase (CPK) at baseline and after 24 weeks, including repeated muscle biopsies at 24 weeks (single-blinded randomized controlled study), and in an open-label followup at 52, 78, and 104 weeks. Patients were randomized to 12 weeks, 5 days/week resistive home exercise with telephone support and encouragement for another 12 weeks of twice-a-week home or gym exercise (EG, n = 10) or to 24 weeks, 5 days/week range of motion exercise (CG, n = 9). Patients in the CG group without inflammatory infiltrates in muscle biopsies at 24 weeks were invited to the 12-week resistive home exercises. Results. At baseline, the EG had poorer perceived health, but otherwise the groups were comparable. At 24 weeks, both groups improved in muscle performance and aerobic capacity (p < 0.001 to < 0.05) with no signs of increased inflammation assessed by CPK levels or muscle biopsies. Both groups improved in muscle performance and aerobic capacity up to 52 weeks (p < 0.05) lasting to 104 weeks in the EG (p < 0.05) and presented minor improvements in perceived health. Conclusion. Our study supports the safety of resistive exercise in patients with active PM/DM but did not reveal any between-group differences in exercise effects. An individually adapted physical therapist–supervised home exercise program might be recommended in early active PM/DM, with regular evaluation of muscle performance and health.

Minor salivary gland immunohistology in the diagnosis of primary Sjögren's syndrome.

BACKGROUND Focal lymphocytic infiltrates of minor salivary glands are considered target-organ related signs of Sjögrens syndrome. The percentages of plasma cells expressing IgA, IgG and IgM in minor salivary gland biopsies have also been suggested as useful in establishing a diagnosis of Sjögrens syndrome, and this study aimed at evaluating this method. METHODS All biopsies from patients under investigation for Sjögrens syndrome (n = 210) at our department during 4 years were analyzed for IgA, IgG and IgM producing cells by immunohistochemistry, and related to Sjögren classification parameters. RESULTS A focus score >or=1 was observed in 67/210 patients and the frequency of IgA producing cells was <70% in 42/210 patients. Sufficient clinical data for classification of disease were available for 57/210 patients. Patients were classified as having primary Sjögrens syndrome (pSS) (n = 9), secondary Sjögrens syndrome (sSS) (n = 12) or non-Sjögrens syndrome (non-SS) (n = 36). IgA expressing cells were significantly decreased (P < 0.01) and IgG expressing cells significantly increased (P < 0.02) in patients with pSS compared to non-SS. Also, increased numbers of salivary gland IgG producing plasma cells correlated with increased IgG serum levels (P < 0.001). However, there was no significant difference between sSS and non-SS with regard to IgA, IgG or IgM expressing cells in the glands. CONCLUSIONS Our results support previous reports indicating the relevance of quantitative evaluation of Ig isotype expression in plasma cells in the clinical investigation of Sjögrens syndrome and further indicate a difference in plasma cell populations between pSS and sSS.

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.

Objectives 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). Methods In a randomised, controlled, open-label pilot study of patients with RA in stable remission treated with ADA+MTX, patients were randomised in a 1:1 ratio to continue with ADA plus MTX (arm AM) or MTX monotherapy (arm M) for 52 weeks. Flare was defined as Disease Activity Score (DAS28) ≥2.6 or a change in DAS28 (ΔDAS28) of >1.2 from baseline at any time. Patients in arm M with a flare restarted ADA. The primary end point was the proportion of patients in remission at week 28. Results 31 patients were enrolled in the study and randomised to arm AM (n=16) or arm M (n=15). At 28 weeks, 15/16 patients (94%) and 5/15 patients (33%) in arms AM and M, respectively, were in remission (p=0.001). During the first 28 weeks, 50% (8/16) in the AM arm and 80% (12/15) in the M arm had a flare (p=0.08). The number of patients in the AM and M arms with ≥1 ΔDAS28 >1.2 during the first 28 weeks was 1/16 (6%) and 8/15 (53%), respectively (p=0.005). Conclusions In this study, remission was rarely maintained in patients with long-standing disease who discontinued ADA. Discontinuation may be feasible in only a minority of patients with established RA in stable clinical remission. Trial registration number NCT00808509.

Microcirculation as determined by iontophoresis in SLE-patients and controls

Background: The risk of cardiovascular disease (CVD), microangiopathy and prevalence of atherosclerotic plaques are increased in Systemic Lupus Erythematosus (SLE). As systemic endothelial dysfunction is one of the earliest signs of these vascular outcomes in the general population we assessed skin microvascular endothelial function in SLE patients. Methods: Endothelial function in skin was tested with local application of acetylcholine (inducing endothelium-dependent vasodilatation) and any concomitant increase in skin perfusion was measured with Laser Doppler Fluxmetry (LDF) in 84 SLE-patients (83% women, mean age 47 years) and 81 age and sex matched controls. Common carotid intima-media thickness (cIMT) and plaque occurrence were also determined using B-mode ultrasound. Results: 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 skin manifestations, Raynauds phenomenon, nephritis or plaque occurrence. In SLE patients with CVD, however, endothelial function was impaired. Conclusion: Skin microvascular endothelial function is associated with CVD but not with early signs of atherosclerosis in SLE-patients. The endothelial function is not different in SLE-patients as compared to controls.

Abberant Cytosolic Calcium Ion Mobilization in Chronic Granulomatous Disease Neutrophils

Beside the inability to produce superoxide ions, neutrophils (PMN) from chronic granulomatous disease (CGD) patients show other functional defects, e.g. abnormal membrane potential reactions. We observed that PMN from a female CGD carrier, with a discrete mutation in one allele of the pg91phox gene and exhibiting extreme lyonization, showed a consistently and remarkably delayed PMN cytosolic calcium response to the tripeptide fMLP or leukotriene B4 (LTB4). In keeping with results from other CGD patients, membrane potential changes were abnormal, whereas chemotaxis and adherence was normal. Since phospholipase D-generated metabolites are important for calcium transients we examined the generation of phosphatidic acid, but found that to be normal. A male CGD patient with pg91phox deficiency exhibited a trend toward prolongation of this calcium response, whereas two other CGD patients (one with p47 and one with 67phox deficiencies) had normal calcium transients. Thus, our finding points to a defect of the stimulus response coupling for fMLP and LTB4, which is supposed to be characteristic for this patient or a subset of CGD patients.