Damini Jawaheer

Time to Pregnancy among Women with Rheumatoid Arthritis

OBJECTIVEnTo assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP).nnnMETHODSnThe study included pregnant women from across Denmark who enrolled in the Danish National Birth Cohort between 1996 and 2002 and had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data, including TTP, maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking, and alcohol consumption, were collected using a detailed computer-assisted telephone interview at ∼16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the abovementioned variables.nnnRESULTSnOverall, compared with women with no recorded RA (n=74,255), women with prevalent RA (onset prior to conception) (n=112) were slightly older (mean±SD age 30.8±4.3 years versus 29.7±4.1 years), were more likely to have been treated for infertility (9.8% versus 7.6%), and were more likely to have taken>12 months to conceive (25.0% versus 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (odds ratio 1.6 [95% confidence interval 1.0-2.4]). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy.nnnCONCLUSIONnWomen with RA onset prior to conception had a slightly longer TTP compared with those who did not have RA, indicating a slight reduction in fecundity.

Sex differences in response to anti-tumor necrosis factor therapy in early and established rheumatoid arthritis -- results from the DANBIO registry.

Objective. To investigate sex differences in response to anti-tumor necrosis factor-α (TNF-α) therapy over time in early versus established rheumatoid arthritis (RA). Methods. Patients with RA who initiated anti-TNF therapy between January 2003 and June 2008 in Denmark were selected from the DANBIO Registry. Sex differences in baseline disease features were examined using chi-square, Mann-Whitney U tests, and t tests. Using a generalized estimating equations (GEE) model for repeated measures, we examined European League Against Rheumatism (EULAR) responses in men and women over 48 months of followup, adjusting for baseline values of age, 28-joint Disease Activity Score (DAS28), disease duration, and anti-TNF, methotrexate, and prednisolone use. Results. At initiation of anti-TNF therapy (baseline), 328 women and 148 men had early RA (≤ 2 yrs), and 1245 women and 408 men had established RA (> 2 yrs). In both early and established RA, men and women had active disease with similar DAS28 scores (mean ± SD 5.2 ± 1.1), physician global scores, swollen joint counts, and radiographic changes. In early RA, men were significantly more likely to achieve a EULAR good/moderate response over 48 months compared to women (GEE; p = 0.003), and a significant interaction between sex and followup time (GEE; p < 0.0005) suggested that men achieved this response sooner than women. Conclusion. Better responses to anti-TNF therapy among men compared to women in early but not established RA suggest that disease duration at initiation of therapy may be an important factor to consider when investigating sex differences in treatment responses.

Fetal Growth and Preterm Birth in Children Exposed to Maternal or Paternal Rheumatoid Arthritis: A Nationwide Cohort Study

To assess indicators of fetal growth and risk of preterm birth in children of parents with rheumatoid arthritis (RA).

Disease Progression and Treatment Responses in a Prospective DMARD-naïve Seropositive Early Rheumatoid Arthritis Cohort: Does Gender Matter?

Objective. To assess gender differences in disease characteristics and treatment responses over time in a disease-modifying antirheumatic drug (DMARD)-naive seropositive early rheumatoid arthritis (RA) cohort. Methods. Patients with polyarticular disease who were DMARD-naive and had seropositive early RA (< 14 months) were recruited by the Western Consortium of Practicing Rheumatologists. Each patient was examined at study entry, after 6 and 12 months, and yearly thereafter. Clinical and demographic data were collected. We investigated gender differences in baseline disease characteristics and treatment using chi-squared, Mann-Whitney U, and t tests. We used generalized estimating equations (GEE) models for repeated measures to examine whether the rate of change of specific disease outcomes during the first 2 years after DMARD initiation was significantly influenced by gender. Results. At baseline, men (n = 67) and women (n = 225) had similar disease activity and radiographic damage; men, however, had significantly worse erosion, while women had worse joint space narrowing. Despite similar treatment, women had worse disease progression over the 2-year followup, as assessed by trends in Disease Activity Score 28/erythrocyte sedimentation rate (DAS28-ESR4), physician global scores, and tender joint counts. In the GEE model, gender was significantly associated with the rate of change of DAS28-ESR4 scores (p = 0.009), although not independently associated with disease activity. Self-reported measures (Health Assessment Questionnaire-Disability Index, patient global scores, fatigue, pain) were worse among women at baseline and throughout the study period. Men were more likely to achieve remission. Conclusion. At baseline, men and women had similar disease activity and joint damage. Responses to treatment over time were better among men in this prebiologic era; women had worse progression despite similar treatment.

Significance of sex in achieving sustained remission in the consortium of rheumatology researchers of North America cohort of rheumatoid arthritis patients.

To determine whether men with rheumatoid arthritis (RA) are more likely to achieve remission compared to women.

A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis.

BackgroundStudies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings have been inconsistent across studies. Among Japanese patients, onlyxa0a few SNPs have been investigated. We report here the first genome-wide association study (GWAS) to identify genetic biomarkers of anti-TNF response among Japanese RA patients, using response at 2 time-points for a more reliable clinical phenotype over time.MethodsDisease Activity Scores based on 28 joint counts (DAS28) were assessed at baseline (before initial therapy), and after 3 and 6xa0months in 487 Japanese RA patients starting anti-TNF therapy for the first time or switching to a new anti-TNF agent. A genome-wide panel of SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline at both 3 (ΔDAS-3) and 6xa0months (ΔDAS-6) as the response phenotype, a longitudinal genome-wide association analysis was conducted using generalized estimating equations (GEE) models, adjusting for baseline DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (ΔDAS-3 or ΔDAS-6) as phenotype; all other variables were the same as in the GEE models.ResultsIn the GEE models, borderline significant association was observed at 3 chromosomal regions (6q15: rs284515, pu2009=u20096.6x10−7; 6q27: rs75908454, pu2009=u20096.3x10−7 and 10q25.3: rs1679568, pu2009=u20098.1x10−7), extending to numerous SNPs in linkage disequilibrium (LD) across each region. Potential candidate genes in these regions include MAP3K7, BACH2 (6q15), GFRA1 (10q25.3), and WDR27 (6q27). The association at GFRA1 replicates a previous finding from a Caucasian dataset. In the cross-sectional analyses, ΔDAS-6 was significantly associated with the 6q15 locus (rs284511, pu2009=u20092.5x10−8). No other significant or borderline significant associations were identified.ConclusionThree genomic regions demonstrated significant or borderline significant associations with anti-TNF response in our dataset of Japanese RA patients, including a locus previously associated among Caucasians. Using repeated measures of response as phenotype enhanced the power to detect these associations.

Pregnancy-Induced Changes in Systemic Gene Expression among Healthy Women and Women with Rheumatoid Arthritis

Background Pregnancy induces drastic biological changes systemically, and has a beneficial effect on some autoimmune conditions such as rheumatoid arthritis (RA). However, specific systemic changes that occur as a result of pregnancy have not been thoroughly examined in healthy women or women with RA. The goal of this study was to identify genes with expression patterns associated with pregnancy, compared to pre-pregnancy as baseline and determine whether those associations are modified by presence of RA. Results In our RNA sequencing (RNA-seq) dataset from 5 healthy women and 20 women with RA, normalized expression levels of 4,710 genes were significantly associated with pregnancy status (pre-pregnancy, first, second and third trimesters) over time, irrespective of presence of RA (False Discovery Rate (FDR)-adjusted p value<0.05). These genes were enriched in pathways spanning multiple systems, as would be expected during pregnancy. A subset of these genes (n = 256) showed greater than two-fold change in expression during pregnancy compared to baseline levels, with distinct temporal trends through pregnancy. Another 98 genes involved in various biological processes including immune regulation exhibited expression patterns that were differentially associated with pregnancy in the presence or absence of RA. Conclusions Our findings support the hypothesis that the maternal immune system plays an active role during pregnancy, and also provide insight into other systemic changes that occur in the maternal transcriptome during pregnancy compared to the pre-pregnancy state. Only a small proportion of genes modulated by pregnancy were influenced by presence of RA in our data.

Parental rheumatoid arthritis and long-term child morbidity: a nationwide cohort study

OBJECTIVEnTo estimate the influence of parental rheumatoid arthritis (RA) on child morbidity.nnnDESIGNnNationwide cohort study.nnnSETTINGnIndividual linkage to nationwide Danish registries.nnnPARTICIPANTSnAll singletons born in Denmark during 1977-2008 (n=1u2005917u2005723) were followed for an average of 16u2005years.nnnMAIN OUTCOME MEASURESnAdjusted HRs for child morbidity; that is, 11 main diagnostic groups and specific autoimmune diseases within the International Classification of Diseases 8th and 10th versions.nnnRESULTSnCompared with unexposed children, children exposed to maternal RA (clinical and preclinical) (n=13u2005566) had up to 26% higher morbidity in 8 of 11 main diagnostic groups. Similar tendencies were found in children exposed to paternal RA (clinical and preclinical) (n=6330), with statistically significantly higher morbidity in 6 of 11 diagnostic groups. HRs were highest for autoimmune diseases with up to three times increased risk of juvenile idiopathic arthritis (HR, 95% CI 3.30, 2.71 to 4.03 and 2.97, 2.20 to 4.01) and increased risk of up to 40% of diabetes mellitus type 1 (HR, 95% CI 1.37, 1.12 to 1.66 and 1.44, 1.09 to 1.90) and up to 30% increased HR of asthma (HR, 95% CI 1.28, 1.20 to 1.36 and 1.15, 1.04 to 1.26). Conclusions were roughly similar for children exposed to maternal clinical RA and for children only followed up to 16u2005years of age.nnnCONCLUSIONnChildren of parents with RA had consistent excess morbidity. If the associations reflect biological mechanisms, genetic factors seem to play an important role. These findings call for attention given to children of parents with RA.

Parental rheumatoid arthritis and childhood epilepsy: A nationwide cohort study

Objective: To assess the influence of parental rheumatoid arthritis (RA) on risk of epilepsy. Methods: We performed a nationwide cohort study including all singletons born in Denmark from 1977 to 2008 (n = 1,917,723) through individual linkage to nationwide Danish registries. The children were followed for an average of 16 years. Main outcome measures were adjusted hazard ratios (HRs) for epilepsy with onset in early childhood (29 days–4 years), late childhood (5–15 years), adolescence/adulthood (≥15 years), and at any age until the end of follow-up (December 31, 2010). Results: Compared to unexposed children, children exposed to maternal RA had an increased risk of early and late childhood epilepsy (adjusted HRs 1.34 [95% confidence interval (CI) 1.13–1.60] and 1.26 [95% CI 1.13–1.41]), while children exposed to maternal RA had no increased risk of epilepsy in adolescence/adulthood (HR 1.15 [95% CI 0.92–1.45]). Paternal RA was not associated with an overall risk of epilepsy in the offspring (HR 0.96 [95% CI 0.81–1.15]) or at any age. Children exposed to maternal RA in utero had a more pronounced increased risk of early childhood epilepsy than children exposed to mothers who were diagnosed with RA after childbirth (HR 1.90 [95% CI 1.26–2.86] vs HR 1.26 [95% CI 1.03–1.52], respectively [p = 0.16]). Conclusions: Exposure to maternal RA was associated with an increased risk of childhood epilepsy, while exposure to paternal RA was not, which indicates that changes in the intrauterine environment may play a role.

Parental Rheumatoid Arthritis and Autism Spectrum Disorders in Offspring: A Danish Nationwide Cohort Study

OBJECTIVEnMaternal rheumatoid arthritis (RA) has been associated with an increased risk of autism spectrum disorder (ASD) in the offspring. We assessed the potential influence of both maternal and paternal RA on the risk of ASD in offspring to disentangle the influence of genetic inheritance from other conditions potentially leading to fetal programming.nnnMETHODnThe nationwide cohort study included all children born alive from 1977 to 2008 in Denmark (Nxa0= 1,917,723). Cox regression models were used to calculate hazard rate ratios (HR) of ASD in offspring exposed to maternal or paternal RA, compared to unexposed children.nnnRESULTSnMaternal RA was associated with an approximately 30% increased risk of ASD in the offspring (HRxa0= 1.31 and 95% CIxa0= 1.06-1.63). Also, paternal RA seemed to increase the risk of ASD by approximately 30% (HRxa0= 1.33, 95% CIxa0= 0.97-1.82).nnnCONCLUSIONnOur findings suggest maternal as well as paternal RA to be associated with an increased risk of ASD in the offspring, indicating that genetic factors associated with RA may also play a role in the etiology of ASD in children of parents with RA.