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Objective: To assess whether gene expression signatures associated with rheumatoid arthritis (RA) before pregnancy differ between women who improve or worsen during pregnancy, and to determine whether these expression signatures are altered during pregnancy when RA improves or worsens., Methods: Clinical data and blood samples were collected before pregnancy (T0) and at the third trimester (T3) from 11 women with RA and 5 healthy women. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI). At each timepoint, RA-associated gene expression signatures were identified using differential expression analysis of RNA sequencing profiles between women with RA and healthy women., Results: Of the women with RA, 6 improved by T3 (RA improved) , 3 worsened (RA worsened) ,and 2 were excluded. At T0, mean CDAI scores were similar in both groups (RA improved 11.2 ± 9.8; RA worsened 13.8 ± 6.7; Wilcoxon rank-sum test: P = 0.6). In the RA improved group, 89 genes were differentially expressed at T0 ( q < 0.05 and fold change ≥ 2) compared to healthy women. When RA improved at T3, 65 of 89 (73%) of these genes no longer displayed RA-associated expression. In the RA worsened group, a largely different RA gene expression signature (429 genes) was identified at T0. When RA disease activity worsened at T3, 207 of 429 (48%) genes lost their differential expression, while an additional 151 genes became newly differentially expressed., Conclusion: In our pilot dataset, pre-pregnancy RA expression signatures differed between women who subsequently improved or worsened during pregnancy, suggesting that inherent genomic differences may influence how pregnancy affects disease activity. Further, these RA signatures were altered during pregnancy as disease activity changed., (Copyright © 2021 by the Journal of Rheumatology.)

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.

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.

Objective: To confirm the reported strong association between the HLA-DRB1*0401/0404 genotype and susceptibility to rheumatoid arthritis (RA), and to investigate the influence of sex, age at disease onset, and variables of disease severity on the strength of this association., Methods: A case control design was adopted comparing the frequency of specific HLA-DRB1 genotypes between 201 Caucasian patients with RA and 139 controls. HLA typing was performed using a polymerase chain reaction based oligonucleotide approach with HLA-DR4 subtyping using an amplification refractory mutation system RFLP technique., Results: The risk of RA in those carrying a single shared epitope (SE) allele was 4 times, and in those carrying 2 SE alleles, 8 times that in the SE negative individuals. This increase was highest in individuals carrying 2 different SE alleles, with the risk in *0401/*0404 cases being 26 times higher. This genotype was associated with a 90-fold increased risk in men and this was more than doubled when age at disease onset was below 30. In all patients with RA, this genotype was associated with a substantially increased risk of being rheumatoid factor positive and having subcutaneous nodules and/or radiological erosion., Conclusion: Possession of the HLA-DRB1*0401/*0404 genotype carries a substantially high risk for RA development specifically in its more severe forms. The risks are particularly increased in young men.