Sten P. Willemsen

Disease Activity of Rheumatoid Arthritis During Pregnancy : Results From a Nationwide Prospective Study

OBJECTIVE According to common knowledge and retrospective studies, approximately 75-90% of patients with rheumatoid arthritis (RA) will improve during pregnancy. Prospective data on disease activity during pregnancy are limited. Therefore, this study aimed to prospectively determine the disease activity during pregnancy in RA patients treated in an era of new treatment options. METHODS For 84 RA patients (American College of Rheumatology criteria), a Disease Activity Score in 28 joints (DAS28) and medication use were obtained, before conception if possible, at each trimester of pregnancy and at 6, 12, and 26 weeks postpartum. Improvement and deterioration were determined by assessing changes in DAS28 and by applying the DAS28-derived European League Against Rheumatism (EULAR) response criteria. RESULTS Disease activity decreased with statistical significance (P = 0.035) during pregnancy and increased postpartum. In patients with at least moderate disease activity in the first trimester (n = 52), at least 48% had a moderate response during pregnancy according to EULAR-defined response criteria. In patients with low disease activity in the first trimester (n = 32), disease activity was stable during pregnancy. Thirty-nine percent of patients had at least a moderate flare postpartum according to reversed EULAR response criteria. Less medication was used during pregnancy compared with before conception and compared with postpartum. CONCLUSION This study demonstrates that patients achieve remission during pregnancy and deteriorate postpartum, although less frequently than previously described.

Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study

IntroductionImprovement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study.MethodsSerum from 148 RA cases and 32 healthy controls was collected at several time points before, during and after pregnancy. Improvement during pregnancy and postpartum flare were determined according to the European League Against Rheumatism (EULAR) response criteria. Galactosylation and sialylation of Immunoglobulin G (IgG) and the presence of bisecting N-acetylglucosamine (GlcNAc) were analyzed by matrix-assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS).ResultsIgG1 and IgG2 galactosylation of the cases and controls increased during pregnancy with a maximum in the third trimester. Galactosylation decreased directly postpartum. IgG galactosylation of controls was at a higher level than cases (P < 0.001 at all time points) and a similar pattern was observed for sialylation. Moreover, there was a good association between galactosylation and sialylation. The increase in galactosylation was significantly more pronounced for cases with improvement than cases without improvement during pregnancy. The reverse was true for deteriorators and non-deteriorators postpartum. The presence of bisecting GlcNAc was not significantly influenced by pregnancy or postpartum for cases and controls.ConclusionsThis large cohort study demonstrates the association of changes in galactosylation with both pregnancy-induced improvement and postpartum flare in RA-patients, suggesting a role for changes in glycosylation in the pregnancy-induced improvement of RA.

Association of Higher Rheumatoid Arthritis Disease Activity During Pregnancy With Lower Birth Weight Results of a National Prospective Study

OBJECTIVE To determine the outcome of pregnancy in women with rheumatoid arthritis (RA) in relation to disease activity and medication use during the pregnancy. METHODS In a prospective study, pregnant women with RA were evaluated before conception (when possible), during each trimester of the pregnancy, and postpartum. Clinical characteristics, disease activity, medication use, and pregnancy outcome were analyzed. To examine the independent influence of prednisone use and disease activity on birth weight, regression analyses were performed, with adjustments for gestational age of the child at delivery, the sex of the newborn, and the mothers smoking status, education level, parity, and use of an assisted reproduction technique. Kaplan-Meier curve analyses were performed to examine the association between medication use and gestational age at delivery. RESULTS Data from 152 Caucasian RA patients with singleton pregnancies were available. Both the mean +/- SD birth weight (3,379 +/- 564 gm) and the mean +/- SD birth weight standard deviation score (SDS; +0.1 +/- 1.1), which is the birth weight adjusted for the gestational age and sex of the newborn, were comparable with those in the general population. On multiple linear regression analyses of birth weight and birth weight SDS, both of which were adjusted for covariates, only disease activity was associated with lower birth weight (P = 0.025). The gestational age at delivery was significantly lower in women who were taking prednisone (38.8 versus 39.9 weeks; P = 0.001), and their delivery was more often premature (<37 weeks; P = 0.004). CONCLUSION Pregnancy outcome in women with well-controlled RA is comparable with that in the general population. The effect of prednisone on birth weight is mediated by a lower gestational age at delivery, whereas a higher level of disease activity independently influences birth weight negatively, suggesting an immune-mediated mechanism.

Supervised exercise therapy versus usual care for patellofemoral pain syndrome: an open label randomised controlled trial.

Objective To assess the effectiveness of supervised exercise therapy compared with usual care with respect to recovery, pain, and function in patients with patellofemoral pain syndrome. Design Open label randomised controlled trial. Setting General practice and sport physician practice. Participants Patients with a new episode of patellofemoral pain syndrome recruited by their general practitioner or sport physician. Interventions The intervention group received a standardised exercise programme for 6 weeks tailored to individual performance and supervised by a physical therapist, and were instructed to practise the tailored exercises at home for 3 months. The control group were assigned usual care, which comprised a “wait and see” approach of rest during periods of pain and refraining from pain provoking activities. Both the intervention group and the control group received written information about patellofemoral pain syndrome and general instructions for home exercises. Main outcome measures The primary outcomes were self reported recovery (7 point Likert scale), pain at rest and pain on activity (0-10 point numerical rating scale), and function (0-100 point Kujala patellofemoral score) at 3 months and 12 months follow-up. Results A total of 131 participants were included in the study: 65 in the intervention group and 66 in the control group. After 3 months, the intervention group showed better outcomes than the control group with regard to pain at rest (adjusted difference −1.07, 95% confidence interval −1.92 to −0.22; effect size 0.47), pain on activity (−1.00, −1.91 to −0.08; 0.45), and function (4.92, 0.14 to 9.72; 0.34). At 12 months, the intervention group continued to show better outcomes than the control group with regard to pain (adjusted difference in pain at rest −1.29, −2.16 to −0.42; effect size 0.56; pain on activity −1.19, −2.22 to −0.16; effect size 0.54), but not function (4.52, −0.73 to 9.76). A higher proportion of patients in the exercise group than in the control group reported recovery (41.9% v 35.0% at 3 months and 62.1% v 50.8% at 12 months), although the differences in self reported recovery between the two groups were not statistically significant. Predefined subgroup analyses revealed that patients recruited by sport physicians (n=30) did not benefit from the intervention, whereas those recruited by general practitioners (n=101) showed significant and clinically relevant differences in pain and function in favour of the intervention group. Conclusion Supervised exercise therapy resulted in less pain and better function at short term and long term follow-up compared with usual care in patients with patellofemoral pain syndrome in general practice. Exercise therapy did not produce a significant difference in the rate of self reported recovery. Trial registration ISRCTN83938749.

Effect of Glucosamine Sulfate on Hip Osteoarthritis: A Randomized Trial

Context Although many patients use glucosamine to treat osteoarthritis, available studies have reported inconsistent effects of glucosamine on symptoms and joint changes. In addition, previous studies have more often included patients with knee than with hip osteoarthritis. Contribution The investigators randomly assigned 222 patients with hip osteoarthritis to glucosamine, 1500 mg/d, or placebo. After 2 years of treatment, no clinically significant effect on pain, function, or joint space narrowing was found. Caution Twenty of the patients in the trial had joint replacement during the study. The Editors The effectiveness of glucosamine sulfate for treating osteoarthritis is controversial. A 2005 systematic review of 20 trials found evidence to be inconclusive (1). In the 15 trials comparing glucosamine with placebo, the overall effect on pain favored glucosamine, but 8 of the trials found no effect on pain. More recent trials (24) have also yielded inconclusive results. In the Netherlands and other countries, glucosamine is sold as an over-the-counter dietary supplement and is used by many patients, often on the advice of their physicians. Given the prevalent use of glucosamine, definitive evidence about its effectiveness is needed. Some studies suggest that glucosamine may provide greater benefit to patients with less severe radiographic osteoarthritis than to patients with more severe disease (5, 6). Most previous trials have studied only patients with knee osteoarthritis, with the exception of 3 early trials that included patients with other affected joints (79). Trials specifically testing glucosamine in patients with hip osteoarthritis have not been available. Although osteoarthritis of the knee is more common than hip osteoarthritis, hip osteoarthritis is common enough to warrant assessment of glucosamine for this condition. To date, only 2 trials have published data on the effects of glucosamine sulfate on joint structure (10, 11). Some expressed concern about the radiography protocol used in these trials (1214), and further study is needed to clarify these findings. To explore some of the uncertainties regarding the effectiveness of glucosamine sulfate, we conducted a 2-year, blinded, randomized, placebo-controlled trial to evaluate the effect of glucosamine sulfate on the symptomatic and radiographic progression of hip osteoarthritis in patients recruited from primary care settings. Methods Study Design In this trial, all outcome assessors, patients, data analysts, and researchers were blinded to group assignment. The Medical Ethics Committee of the Erasmus Medical Center, Rotterdam, the Netherlands, approved the study design, and patients provided written informed consent. We reported the detailed study protocol in 2005 (15) and summarize it here. Setting and Participants General practitioners in the Rotterdam area recruited study patients. Patients were eligible for inclusion if they met the American College of Rheumatology clinical criteria for hip osteoarthritis (16) during a screening examination at the research center. Patients who had undergone or were awaiting hip replacement surgery were not eligible. We excluded patients who had a Kellgren and Lawrence score of 4 (17), renal disease, liver disease, diabetes mellitus, or a disabling comorbid condition that would make visits to the research center impossible, as well as patients already receiving glucosamine and those unable to fill out Dutch questionnaires. We encouraged patients who violated study protocol and those who had total hip arthroplasty during the study to complete data collection to limit the loss to follow-up. Randomization and Intervention Eligible patients were randomly assigned to receive either 1500 mg of oral glucosamine sulfate (administered once daily as two 750-mg tablets) or placebo for 2 years. The glucosamine used in this study was provided by Numico Research BV (Wageningen, the Netherlands) but was manufactured by Nutricia Manufacturing USA (Greenville, South Carolina). It contained 2000 mg of D-glucosamine sulfate 2-potassium chloride, which results in a net content of 1500 mg of glucosamine sulfate per 2 pills. The placebo pills were identical in appearance, smell, and taste. We used a computer-generated, blinded randomization list provided by an independent researcher to randomly assign patients to glucosamine sulfate or placebo. This list, which was randomized per block of 6 numbers, stratified patients by radiologic findings (Kellgren and Lawrence score <2 vs. 2) and by local versus generalized osteoarthritis; patients received a number in chronological order (15). Assignment of patients to the right stratum of the random assignment list was done by the main researcher, who was blinded to therapy. To evaluate blinding, patients had to indicate in the last questionnaire to which treatment they thought they were randomly assigned. Outcomes and Follow-up Primary outcome measures were WOMAC 3.1 (5-point Likert format) pain and function over 24 months and joint space narrowing after 24 months (18, 19). Secondary outcome measures were WOMAC pain, function, and stiffness after 3, 12, and 24 months; overall WOMAC stiffness; a visual analogue scale (VAS) to measure pain in the past week; and pain medication use. The WOMAC subscales are presented as normalized scores (0 to 100, where 0 equals no symptoms). We recorded the use of pain medication; classified patients as never, occasional, or daily users; and then determined whether people increased, decreased, or did not change their use of pain medication from baseline. In the case of patients with bilateral hip symptoms, we asked patients to indicate their most affected hip for our analyses of joint space narrowing. For patients who were undecided, we used the hip with the highest Kellgren and Lawrence score or the smallest internal rotation during a physical examination. We used QBone Planner 5.4 (Medis, Leiden, the Netherlands) to measure joint space width on calibrated digital radiographs of the hip joints. We read radiographs from both time points (baseline and 24 months) side by side. One researcher measured joint space width manually on predefined lateral, superior, axial, and medial sites (20). In addition to these 4 points, we visually identified and measured the minimal joint space width on both the baseline and 24-month radiograph. We used the smallest of these 6 measurements as the actual minimum joint space width for analyses. A second observer also measured the joint space width in a random subset of 28 study patients, and we found high interobserver agreement (intraclass correlation coefficient of minimal joint space width, 0.98). We collected data for the primary and secondary outcome measures at different time points throughout the study. At baseline and after 24 months, patients came to the Erasmus Medical Center for radiography and to complete study questionnaires. Weight-bearing, anteroposterior digital radiography of the pelvis was performed according to a highly standardized protocol to allow reliable measurement of joint space narrowing (15). At baseline and then every 3 months through month 24, we asked patients to complete the WOMAC instrument, a VAS for pain in the past week (score range, 0 to 100; 0 equals no pain), and a checklist for specific adverse events and to answer questions regarding pain medication and adherence. We mailed the intermediate questionnaires to the patients for completion at home. A researcher visited patients every 6 months to deliver a new supply of study medication and evaluate adherence by using the Brief Medication Questionnaire (BMQ) (21) and a pill count. The BMQ monitors the amount of days per week that patients have taken their study medication. For overall effect, we considered patients to be adherent if they ingested more than 80% of the total study medication. Statistical Analysis We used the data from all nine 3-month questionnaires (at baseline and 3, 6, 9, 12, 15, 18, 21, and 24 months). We also report outcomes for measurements at 3, 12, and 24 months and a mean effect of the therapy over 24 months incorporating all scores. We performed the analyses by using SPSS 11.0.1 (SPSS, Chicago, Illinois) and SAS 8.2 (SAS Institute, Cary, North Carolina). We used linear mixed models to analyze the data, assuming that data were missing at random. We chose an unstructured covariance structure to model the covariance of repeated measures by patients, because this yielded the lowest Akaike information criterion. Fixed effects were time, time by therapy, and the covariates we adjusted for. For patients who had total hip arthroplasty during the trial, we included observed data before surgery in the analysis and assumed data after surgery to be missing. For patients who were lost to follow-up, we included all observed data in the analysis. We adjusted the WOMAC and VAS pain analyses for body mass index, sex, and agefactors that may have influenced symptoms (22, 23). We also adjusted analyses for pain medication use and Kellgren and Lawrence score. The analyses for joint space narrowing were adjusted for Kellgren and Lawrence score (24), age, and sex (25). We used ordinal regression analysis to assess the effect of glucosamine sulfate on pain medication use by using data from all patients who completed the study and did not have total hip arthroplasty. We performed additional analyses to assess the effect of adherence on the outcome. To explore the validity of the missing-at-random data assumption for patients who underwent total hip arthroplasty during the study, we did sensitivity analyses on the WOMAC pain data. In 5 scenarios, the missing data for patients who underwent total hip arthroplasty were imputed with extreme scores: mean of the 5 best scores for the glucosamine sulfate recipients and that of the 5 worst scores for the placebo recipients (traditional best case); mean of the best scores for placebo recipients and

Lack of Effect of Tai Chi Chuan in Preventing Falls in Elderly People Living at Home: A Randomized Clinical Trial

OBJECTIVES: To evaluate the effectiveness of Tai Chi Chuan in fall prevention in elderly people living at home with a high risk of falling.

Air Pollution Exposure During Pregnancy, Ultrasound Measures of Fetal Growth, and Adverse Birth Outcomes: A Prospective Cohort Study

Background: Air pollution exposure during pregnancy might have trimester-specific effects on fetal growth. Objective: We prospectively evaluated the associations of maternal air pollution exposure with fetal growth characteristics and adverse birth outcomes in 7,772 subjects in the Netherlands. Methods: Particulate matter with an aerodynamic diameter < 10 μm (PM10) and nitrogen dioxide (NO2) levels were estimated using dispersion modeling at the home address. Fetal head circumference, length, and weight were estimated in each trimester by ultrasound. Information on birth outcomes was obtained from medical records. Results: In cross-sectional analyses, NO2 levels were inversely associated with fetal femur length in the second and third trimester, and PM10 and NO2 levels both were associated with smaller fetal head circumference in the third trimester [–0.18 mm, 95% confidence interval (CI): –0.24, –0.12 mm; and –0.12 mm, 95% CI: –0.17, –0.06 mm per 1-μg/m3 increase in PM10 and NO2, respectively]. Average PM10 and NO2 levels during pregnancy were not associated with head circumference and length at birth or neonatally, but were inversely associated with birth weight (–3.6 g, 95% CI: –6.7, –0.4 g; and –3.4 g, 95% CI: –6.2, –0.6 g, respectively). Longitudinal analyses showed similar patterns for head circumference and weight, but no associations with length. The third and fourth quartiles of PM10 exposure were associated with preterm birth [odds ratio (OR) = 1.40, 95% CI: 1.03, 1.89; and OR = 1.32; 95% CI: 0.96, 1.79, relative to the first quartile]. The third quartile of PM10 exposure, but not the fourth, was associated with small size for gestational age at birth (SGA) (OR = 1.38; 95% CI: 1.00, 1.90). No consistent associations were observed for NO2 levels and adverse birth outcomes. Conclusions: Results suggest that maternal air pollution exposure is inversely associated with fetal growth during the second and third trimester and with weight at birth. PM10 exposure was positively associated with preterm birth and SGA.

Association between galactosylation of immunoglobulin G and improvement of rheumatoid arthritis during pregnancy is independent of sialylation

Rheumatoid arthritis (RA) is known to improve during pregnancy and to flare after delivery. Changes in the glycosylation of immunoglobulin G (IgG)s fragment crystallizable (Fc) have been suggested to play a role herein. Recent animal studies indicate that not galactosylation but mainly sialylation is important in this respect. We aim to find new associations between IgG-Fc N-glycosylation and improvement of RA during pregnancy and the flare after delivery. Sera of RA patients (n = 251 pregnancies) and healthy controls (n = 32), all participating in a prospective cohort study on RA and pregnancy (PARA study), were collected before conception, during pregnancy, and after delivery. Using a recently developed fast and robust nanoRP-HPLC-sheath-flow-ESI-MS method the glycosylation of IgG Fc-glycopeptides was measured in a subclass specific manner, with relative standard deviations of <4% for the 8 most abundant IgG Fc glycopeptides during the entire measurement period of over 3 weeks. In patients and controls, several glycosylation changes were observed during pregnancy. In depth analysis of the association of these glycosylation changes with disease activity revealed that galactosylation, independent of sialylation, is associated with improvement of RA during pregnancy. Functional studies in human cell systems should be performed to obtain more insight into this matter.

Parental smoking during pregnancy, early growth, and risk of obesity in preschool children: the Generation R Study

BACKGROUND Maternal smoking during pregnancy seems to be associated with obesity in offspring. Not much is known about the specific critical exposure periods or underlying mechanisms for this association. OBJECTIVE We assessed the associations of active maternal and paternal smoking during pregnancy with early growth characteristics and risks of overweight and obesity in preschool children. DESIGN This study was a population-based, prospective cohort study from early fetal life until the age of 4 y in 5342 mothers and fathers and their children. Growth characteristics [head circumference, length, weight, and body mass index (BMI; in kg/m(2))] and overweight and obesity were repeatedly measured at the ages of 1, 2, 3, and 4 y. RESULTS In comparison with children from nonsmoking mothers, children from mothers who continued smoking during pregnancy had persistently smaller head circumferences and heights until the age of 4 y, whereas their weights were lower only until the age of 3 mo. This smaller length and normal to higher weight led to an increased BMI [SD score difference: 0.11; 95% CI: 0.02, 0.20; P < 0.05)] and an increased risk of obesity (odds ratio: 1.61; 95% CI: 1.03, 2.53; P < 0.05) at the age of 4 y. In nonsmoking mothers, paternal smoking was not associated with postnatal growth characteristics or risk of obesity in offspring. Maternal smoking during pregnancy was associated with a higher BMI at the age of 4 y in children with a normal birth weight and in those who were small for gestational age at birth. CONCLUSION Our findings suggest that direct intrauterine exposure to smoke until late pregnancy leads to different height and weight growth adaptations and increased risks of overweight and obesity in preschool children.

Blood pressure tracking during pregnancy and the risk of gestational hypertensive disorders: The Generation R Study

AIMS Blood pressure tracking can be used to examine the predictability of future values by early measurements. In a population-based prospective cohort study, among 8482 pregnant women, we examined whether blood pressure in early pregnancy tracks to third trimester and whether this tracking is influenced by maternal characteristics and is associated with the risk of gestational hypertensive disorders. METHODS AND RESULTS Blood pressure was measured in each trimester of pregnancy. Information about doctor-diagnosed pregnancy-induced hypertension and preeclampsia was obtained from medical records. Correlation coefficients between first and third trimester for systolic and diastolic blood pressure were 0.47 and 0.46, respectively. The odds ratio for staying in the highest tertile from first to third trimester for systolic blood pressure was 3.09 [95% confidence interval (CI): 2.73, 3.50] and for diastolic blood pressure 3.28 (95% CI: 2.90, 3.69). Blood pressure tracking coefficients were lower in younger, shorter, and non-European women and in women with higher gestational weight gain. Systolic and diastolic blood pressure changes from second to third trimester, but not from first to second trimester, were positively associated with the risks of pregnancy-induced hypertension and preeclampsia. CONCLUSION Blood pressure tracks moderately during pregnancy and is influenced by maternal characteristics. Second to third trimester increases in systolic and diastolic blood pressure are associated with an increased risk of gestational hypertensive disorders.