Anne Günther

Long-term experience with rituximab in anti-synthetase syndrome-related interstitial lung disease

OBJECTIVE To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD). METHODS Patients with severe ILD and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8). RESULTS Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%). CONCLUSION This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention.

Relation of coronary artery calcium score to premature coronary artery disease in survivors >15 years of Hodgkin's lymphoma.

Long-term survival in Hodgkin lymphoma (HL) survivors is complicated by an increased risk for coronary artery disease (CAD) due to radiation-induced endothelial damage. Our objective was to quantify total coronary artery calcium (CAC) in long-term HL survivors who had survived >or=15 years after treatment and relate it to the presence of verified CAD. Forty-seven HL survivors 50 +/- 7 years of age who had survived 22 +/- 3 years after mediastinal radiotherapy underwent CAC scoring (Agatston and volume scores) in a multidetector computed tomographic scanner. Total volume score was higher in 7 patients (15%) with verified CAD (median 439, range 8 to 2,057) compared to those without (median 68, 0 to 767, p = 0.022). Ten patients had CAC scores >200. Of these 10, 5 had undergone revascularization of coronary arteries. None of the 8 patients with a CAC score 0 had symptomatic CAD. In conclusion, postirradiation CAC can be quantified by CAC score and this may be a simple and suitable method to screen for CAD in long-term HL survivors. Patients with a CAC score >200 often have clinically significant CAD, and further investigation including angiography may be justified. Lower CAC scores, however, do not exclude CAD and further studies should be undertaken to define the best algorithm for follow-up of this patient group.

Systemic markers of inflammation are associated with cardiac allograft vasculopathy and an increased intimal inflammatory component.

We evaluated an extensive profile of clinical variables and immune markers to assess the inflammatory milieu associated with cardiac allograft vasculopathy (CAV) assessed by intravascular ultrasound (IVUS) and virtual histology (VH). In total, 101 heart transplant (HTx) recipients were included and underwent IVUS/VH examination and measurement of plasma C‐reactive protein (CRP), soluble tumor necrosis factor receptor‐1, interleukin‐6, osteoprotegerin, soluble gp130, von Willebrand factor, vascular cell adhesion molecule‐1 (VCAM‐1) and neopterin. Mean Maximal Intimal Thickness (MIT) was 0.61 ± 0.19 mm and mean fibrotic, fibrofatty, dense calcified and necrotic core components were 55 ± 15, 14 ± 10, 15 ± 13 and 17 ± 9%, respectively. In multivariate analysis, CRP > 1.5 mg/L (OR 4.6, p < 0.01), VCAM‐1 > 391 ng/mL (adjusted OR 3.2, p = 0.04) and neopterin > 7.7 nmol/L (OR 3.8, p = 0.02) were independently associated with MIT > 0.5 mm. Similarly, CRP > 1.5 mg/L (OR 3.7, p < 0.01) and VCAM‐1 > 391 (OR 2.7, p = 0.04) were independently associated with an increased intimal inflammatory component (dense calcified/necrotic core component > 30%). Advanced CAV is associated with elevated CRP, VCAM‐1 and neopterin and the two former biomarkers are also associated with an increased intimal inflammatory component. Forthcoming studies should clarify if routine measurements of these markers can accurately identify HTx recipients at risk of developing advanced CAV and vulnerable lesions.

Atherosclerotic lesions in lymphoma survivors treated with radiotherapy

BACKGROUND AND PURPOSE Radiotherapy causes premature atherosclerosis in Hodgkins lymphoma survivors (HLSs). We determined whether atherosclerosis within the radiation field was predicted by traditional risk factors independent of radiation and compared the extent of atherosclerosis in HLSs treated with mantle field radiotherapy with non-irradiated patients. MATERIAL AND METHODS Forty-three HLSs (median age 50 years, range 38-63) treated with mantle field radiotherapy were included. Cardiovascular risk factors were registered at first follow-up (FU-1) 5-13 years after treatment. A second follow-up (FU-2) occurred 18-27 years after treatment. At FU-2, in-field atherosclerosis was assessed by computed tomography with calculation of coronary artery calcium volume score (CACS) and pre-cranial artery atherosclerosis score (PAS). Peripheral endothelial dysfunction was assessed by ante-brachial strain-gauge plethysmography. CT angiography of pre-cranial vessels was also performed in 43 non-irradiated patients. RESULTS Multiple linear regression analyses showed that cholesterol at FU-1 was a predictor of CACS (β 308 (95% CI 213-403), p < 0.001), PAS (β 3.67 (95% CI 2.29-5.04), p < 0.001) and peripheral endothelial dysfunction (β 2.74 (95% CI 0.47-5.01), p = 0.02). There were more atherosclerotic lesions in HLSs (n = 141) than in non-irradiated patients (n = 73, p = 0.001). CONCLUSION Irradiated arteries are characterized by widespread atherosclerotic lesions aggravated by elevated levels of cholesterol.

Ultrasonographic evaluation of the rectus abdominis muscle after breast reconstruction with the DIEP flap

The aim of this study was to evaluate whether the dissection of the vascular pedicle of the deep inferior epigastric perforator (DIEP) flap could induce secondary muscle atrophy. Evaluation of the rectus abdominis muscle was performed using ultrasonography, and the muscle thickness was measured as an expression of muscle substance. This was performed at 4 levels: below the xiphoid process, at the umbilicus level, above the symphysis, and between the 2 last mentioned (central zone). The results were expressed as the ratio of the muscle thickness on the operated side where dissection of the vascular pedicle was performed to the thickness of the contralateral not operated muscle. Thirteen patients were included with a mean follow up of 20 months (range, 7–42months). The combined measurements showed that the thickness of the muscle as a whole was significantly reduced on the operated side compared with the opposite side. Broken down to the specific levels, the greatest reduction in thickness, approximately 10%, was found at the xiphoid process and above the symphysis. We conclude that performing the dissection of the vascular pedicle of the DIEP flap gives a small but significant degree of muscular atrophy.

Arterial haemodynamics and coronary artery calcification in adult patients with juvenile idiopathic arthritis

Objective To compare arterial haemodynamics in adults with long-term juvenile idiopathic arthritis (JIA) to that of healthy controls, and explore the influence of traditional cardiovascular risk factors and disease characteristics on arterial haemodynamics plus coronary artery calcification. Methods 87 JIA patients (median age 38.4 years) with persistently active disease at least 15 years after disease onset (registered by longitudinal follow-up), were re-examined after median 29 years and compared with 87 matched controls. Arterial haemodynamics were characterised by arterial stiffness and blood pressure. Sphygmocor was used to measure the arterial stiffness markers pulse wave velocity (PWV) and augmentation index (AIx). Coronary calcification was assessed by CT. Results Compared to controls, patients had significantly higher PWV (7.2 vs 6.9 m/s, p=0.035), and systolic and diastolic blood pressure (SBP, p=0.050 and DBP, p=0.029). AIx was numerically higher in the patients compared to the controls, but no statistically significant difference was found. Coronary calcification was present in 22 (26%) of the patients. Daily smoking was more frequent (p=0.043), and insulin resistance was higher (p=0.034) in patients than controls. In patients, DBP, but no disease variables were determinants of PWV. Disease variables as well as traditional cardiovascular risk factors were associated with higher AIx, DBP and the presence of coronary calcification. Conclusions JIA patients with long-term active disease had altered arterial haemodynamics compared with controls in our study. PWV was mainly determined by increased DBP, a parameter that again was associated with JIA disease and treatment variables.

Prevalence and risk factors for coronary artery calcification following kidney transplantation for systemic lupus erythematosus

OBJECTIVES Patients with SLE who undergo kidney transplantation are at increased risk of premature cardiovascular disease. The current study aimed to investigate the prevalence of coronary artery calcification in transplanted SLE patients without coronary symptoms and to explore risk factors associated with coronary atherosclerosis. METHODS This was a cross-sectional study in transplanted SLE patients with a functioning graft. Evaluation included laboratory tests, SLE disease activity indices, multi-slice CT for quantification of coronary calcification (Agatston score >400 = high calcification, <400 = mild to moderate calcification). Arterial and aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWV). RESULTS Thirty-nine patients were analysed, three of whom had a prior history of coronary events. Coronary artery calcification was present in 82% of patients (n = 32), with 36% (n = 14) with a high level of arterial calcification. Multivariate regression analysis showed the following factors to be independently associated with high coronary calcification: PWV (0.41, 95% CI 0.17, 0.66, P = 0.001), time since diagnosis of LN (0.66, 95% CI 0.43, 0.71, P < 0.001) and BMI (0.39, 95% CI 0.15, 0.63, P = 0.002). Immunosuppression regimen was not significantly different between groups. CONCLUSIONS Coronary artery calcification is widespread in transplanted SLE patients despite a normal profile of conventional cardiovascular risk factors. The risk of calcification increases with disease duration, BMI and PWV in this population.

Pulmonary Involvement in the Antisynthetase Syndrome: A Comparative Cross-sectional Study.

Objective. Interstitial lung disease (ILD) is a major component of the antisynthetase syndrome, but quantitative data on longterm pulmonary outcome in antisynthetase syndrome are limited. In this study, the main aims were to compare pulmonary function tests (PFT) and the 6-min walking distance (6MWD) between patients with antisynthetase syndrome and healthy sex- and age-matched controls, to evaluate the extent of ILD by lung high-resolution computed tomography (HRCT), and to assess correlations between PFT measures and ILD extent. Methods. Concurrent PFT and 6MWD were performed in 68 patients with antisynthetase syndrome and their individually matched controls. Additionally, in the patients, the extent of ILD was determined in 10 HRCT sections, expressed as percentage of total lung volumes. Results. Median disease duration in the antisynthetase syndrome cohort was 71 months. Compared with the matched controls, the patients with antisynthetase syndrome had mean 28%, 27%, and 53% lower absolute values of forced vital capacity (FVC), forced expiratory volume in 1 s, and DLCO (p < 0.001). Mean difference in 6MWD between patients and controls was 116 m (p < 0.001). Median extent of ILD by HRCT was 20% (range 0–73) and correlated with FVC and DLCO. Pulmonary outcome did not differ between Jo1 and non-Jo1 subsets. Conclusion. To our knowledge, this study is the first to demonstrate a highly significant difference in PFT between patients with antisynthetase syndrome with 6 years of followup and healthy controls. DLCO displayed the highest difference with mean 53% lower value in the patients. FVC and DLCO correlated significantly with ILD extent, indicating these variables as appropriate outcome measures in antisynthetase syndrome–associated ILD.

Increased peak systolic velocity in the renal artery of paediatric kidneys transplanted to adult recipients

BACKGROUND Paediatric kidneys transplanted to adult recipients increase in size after transplantation. It is unknown if the renal artery diameter increases concomitantly with the kidney. This study was performed to assess if peak systolic velocity (PSV) in the renal arteries of paediatric kidneys transplanted to adult recipients is comparable to PSV in the renal arteries of adult kidneys transplanted to adult recipients. Subjects and methods. Fifteen adult patients with paediatric renal transplants were examined with ultrasound Doppler and compared with a control group of adult recipients with adult transplants. MR angiography (MRA) or intra-arterial angiography (IA) was performed in patients with elevated PSV. MRA renal diameters of the paediatric transplants were compared with adult transplants. RESULTS The mean maximum PSV of the paediatric kidneys was 2.0 m/s (0.9-3.8), almost twice compared with the adult grafts transplanted to adult recipients, 1.1 m/s (0.7-1.6), P < 0.001. Seven paediatric transplants had a PSV >1.8 m/s, but only two had significant stenosis on MRA/IA. All patients had excellent blood pressure and renal function. The mean diameter of the paediatric renal arteries was 4.1 mm (3.4-6.0), whereas the mean for the adult renal arteries was 5.6 mm (4.8-6.9), P = 0.02. CONCLUSION Adult recipients of paediatric kidneys have significantly higher maximum PSV in the renal artery compared to adult recipients of adult grafts. The significantly smaller renal artery diameter might explain the high PSV. A PSV >1.8 m/s by itself does not necessarily indicate transplant renal artery stenosis in paediatric kidneys transplanted to adult recipients, but should be related to clinical findings.

Cardiac Assessment of Patients With Type 1 Diabetes Median 10 Years After Successful Simultaneous Pancreas and Kidney Transplantation Compared With Living Donor Kidney Transplantation.

Background In recipients with type 1 diabetes, we aimed to determine whether long-term normoglycemia achieved by successful simultaneous pancreas and kidney (SPK) transplantation could beneficially affect progression of coronary artery disease (CAD) when compared with transplantation of a kidney-alone from a living donor (LDK). Methods In 42 kidney transplant recipients with functioning grafts who had received either SPK (n = 25) or LDK (n = 17), we studied angiographic progression of CAD between baseline (pretransplant) and follow-up at 7 years or older. In addition, computed tomography scans for measures of coronary artery calcification and echocardiographic assessment of left ventricular systolic function were addressed at follow-up. Results During a median follow-up time of 10.1 years (interquartile range [IQR], 9.1-11.5) progression of CAD occurred at similar rates (10 of 21 cases in the SPK and 5 of 14 cases in the LDK group; P = 0.49). Median coronary artery calcification scores were high in both groups (1767 [IQR, 321-4035] for SPK and 1045 [IQR, 807-2643] for LDK patients; P = 0.59). Left ventricular systolic function did not differ between the 2 groups. The SPK and LDK recipients were similar in age (41.2 ± 6.9 years vs 40.5 ± 10.3 years; P = 0.80) and diabetes duration at engraftment but with significant different mean HbA1c levels of 5.5 ± 0.4% for SPK and 8.3 ± 1.5% for LDK patients (P < 0.001) during follow-up. Conclusions In patients with both type 1 diabetes and end-stage renal disease, SPK recipients had similar progression of CAD long-term compared with LDK recipients. Calcification of coronary arteries is a prominent feature in both groups long-term posttransplant.