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Objective: We investigated methotrexate safety and the influence of dose on efficacy outcomes in combination with three different biologic treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA). Methods: This post hoc analysis included 812 treatment‐naïve patients with early RA who were randomized (1:1:1:1) in the NORD‐STAR trial to receive methotrexate in combination with ACT, certolizumab‐pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24 weeks of treatment. Results: Compared with ACT, the prevalence of methotrexate‐associated side effects was higher when methotrexate was combined with tocilizumab (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.20–1.84) but not with certolizumab‐pegol (HR 0.99, 95% CI 0.79–1.23) or with abatacept (HR 0.93, 95% CI 0.75–1.16). With ACT as the reference, the methotrexate dose was significantly lower when used in combination with tocilizumab (β −4.65, 95% CI −5.83 to −3.46; P < 0.001) or abatacept (β −1.15, 95% CI −2.27 to −0.03; P = 0.04), and it was numerically lower in combination with certolizumab‐pegol (β −1.07, 95% CI −2.21 to 0.07; P = 0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations. Conclusion: Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/wk, and these were more frequent in combination with tocilizumab versus ACT. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24 weeks. [ABSTRACT FROM AUTHOR]

Objective: The high prevalence of osteoporosis in rheumatoid arthritis (RA) is due to inflammation that stimulates differentiation of osteoclasts, a process involving circulating monocytes and T cell-derived factors. The aim of this study was to evaluate relations between circulating monocytes, T cell subsets, and changes in bone characteristics before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in RA., Methods: Thirty patients with untreated early RA who met the American College of Rheumatology/EULAR 2010 criteria were included. Data were collected before and 48 weeks after treatment with methotrexate (MTX) together with one of three bDMARDs (abatacept, tocilizumab, or certolizumab pegol). Disease activity was measured using the Clinical Disease Activity Index, swollen or tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates. Proportions of monocyte and CD4 + T cell subsets in blood samples were analyzed by flow cytometry. Bone densitometry was performed using high-resolution peripheral quantitative computed tomography (HR-pQCT)., Results: HR-pQCT revealed an overall decrease in cortical (P = 0.009) and trabecular (P = 0.034) bone mineral density, although a subset of patients showed no bone loss after 48 weeks of treatment. The overall bone loss was not associated with age, body mass index, sex, intraarticular glucocorticoid injections, or baseline disease activity. Loss of trabecular bone volume fraction correlated with high proportions of circulating CXCR3 + Th2 cells (r = -0.38, P = 0.04) and CXCR3 + Th17 cells (r = -0.36, P = 0.05) at baseline. Similarly, no loss of trabecular bone volume fraction correlated with high proportions of regulatory T cells (r = 0.4, P = 0.03) at baseline. However, the associations were not significant when corrected for confounders and multiple testing., Conclusion: MTX together with bDMARDs efficiently reduce disease activity but only prevent bone loss in a subset of patients with RA after 48 weeks of treatment. The correlations of circulating baseline T helper cell and regulatory T cell populations with trabecular bone changes suggest a potential novel role for these cells in systemic bone homeostasis during early RA., (© 2024 The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT)., Methods: Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking., Results: In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks., Conclusions: Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice., Trial Registration Number: EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815., Competing Interests: Competing interests: LP reports institutional support for the present manuscript from Amsterdam University Medical Centers. MLH reports institutional grants from AbbVie, Bristol Myers Squibb, Eli Lilly, MSD, Pfizer, Sandoz, Novartis, Nordforsk and UCB; speaker honoraria from Medac, Novartis, Pfizer, Sandoz and UCB; institutional data safety monitoring board or advisory board fees from AbbVie. MLH has chaired the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies. MLH co-chairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondyloarthritis based on secondary data and is partly funded by Novartis and UCB. DCN reports research grant from MSD; consulting fees from Bristol Myers Squibb, Lilly, Novartis, Pfizer, and UCB; speaker honoraria from Pfizer and UCB; participation on a data safety monitoring board or advisory board fees from UCB. MØ reports institutional grants from AbbVie, Amgen, Bristol Myers Squibb, Merck, Celgene, Eli Lilly Novartis and UCB; personal speaker honoraria from AbbVie, Bristol Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB; participation on a data safety monitoring board or advisory board personal fees from AbbVie, Bristol Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB. EAH reports institutional grant from research council of Norway; personal speaker honoraria from Pfizer, UCB and Novartis; and participation on a data safety monitoring board or advisory board fees from AbbVie, Pfizer and Eli Lilly. TU reports personal speaker honoraria from Lilly, Pfizer, UCB and Galapagos. TR reports a patent application (TR is the inventor) based on the use of bioengineered IgG targets for the characterisation of rheumatoid factor reactivity patterns. RFvV reports institutional support for the present manuscript from Bristol Myers Squibb; institutional grants for research or education from Alfasigma, AstraZeneca, Bristol Myers Squibb, Galapagos, MSD, Novartis, Pfizer, Roche, Sanofi and UCB; consulting fees from AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb, Galapagos, GSK, Janssen, Pfizer, RemeGen and UCB; speaker honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Janssen, Pfizer and UCB; and participation on a data safety monitoring board or advisory board fees from AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb, Galapagos, GSK, Janssen, Pfizer, RemeGen and UCB. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: The objective of this study was to determine if baseline adiponectin, leptin, and resistin levels are associated with response to antirheumatic treatment in early rheumatoid arthritis (RA)., Methods: This study included 341 participants of the Nordic Rheumatic Diseases Strategy Trials and Registries trial with untreated early RA, randomized at baseline into four treatment arms: methotrexate combined with (1) prednisolone, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Follow-up was up to 48 weeks. Adipokines were measured in plasma at baseline with enzyme-linked immunosorbent assay. The primary outcome for this report was the difference in remission (Clinical Disease Activity Index [CDAI] ≤2.8) over 48 weeks stratified by median adipokine levels., Results: At baseline, levels of adiponectin and leptin were not associated with markers of RA activity, whereas participants with higher resistin levels had higher C-reactive protein (CRP) levels, swollen joint count, and Disease Activity Score in 28 joints based on CRP compared to participants with lower resistin. Overall, participants with baseline adipokine levels above the median and those with adipokine levels below the median had similar mean CDAI and changes in CDAI throughout follow-up for up to 48 weeks. Adjusted Cox proportional hazards models did not show any effect of baseline adiponectin, leptin, and resistin levels on the likelihood of achieving CDAI remission (adiponectin: hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.80-1.45, P = 0.62; leptin: HR 0.89, 95% CI 0.64-1.26, P = 0.52; resistin: HR 0.86, 95% CI 0.65-1.13, P = 0.26)., Conclusion: Baseline adiponectin, leptin, and resistin levels are not associated with the likelihood of achieving CDAI remission over 48 weeks of treatment in a large cohort of people with untreated early RA., (© 2024 The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA)., Methods: This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI ≥30 kg/m 2 . All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI., Results: Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms., Conclusion: In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received., Trial Registration Number: NCT01491815., Competing Interests: Competing interests: MLH reports research grants from AbbVie, iogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V., Lundbeck Foundation, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Nordforsk to institution; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Medac, Sandoz paid to institution; participation on a Data Safety Monitoring Board or Advisory Board from AbbVie paid to institution; MLH has chaired the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies; MLH co-chairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondylarthritis based on secondary data and is partly funded by Novartis. DN reports personal consultancy fees from BMS, Lilly, MSD, Novartis, Pfizer and UCB, and personal study grant from MSD, outside current work. BG reports consulting fee from Novartis and Lectures fees from Novartis and Nordic Pharma. MØ reports grants from Amgen, BMS, Merck, Celgene and Novartis to institution; consulting fees from Galapagos, Gilead, Hospira, Janssen, Merck, Novartis, Pfizer, UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, BMS, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, UCB; support for attending meetings and/or travel from UCB; participation on a Data Safety Monitoring Board or Advisory Board from Galapagos, Gilead, Hospira, Janssen, Merck, Novartis, Pfizer, UCB. TS-I reports research grant from Amgen paid to the institution, honoraria from Nordic Pharma. TU reports personal fees from Galapagos, Lilly, Pfizer, UCB outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action., Methods: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025)., Results: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%., Conclusions: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments., Trial Registration Number: NCT01491815., Competing Interests: Competing interests: MØ received the study drug from BMS and UCB; research grants from Abbvie, BMS, Merck, Novartis and UCB; speaker fees from Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, MEDAC, Merck, Novartis, Pfizer, Sandoz, and UCB; and consultancy fees from Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, MEDAC, Merck, Novartis, Pfizer, Sandoz and UCB. RFvV received the study drug from BMS and UCB; research grants from BMS, GSK, UCB and AstraZeneca; consulting fees from AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer and UCB; expert fees from AbbVie, Galapagos, GSK, Janssen, Pfizer, R-Pharma and UCB; and advisory board fees from AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer and UCB. MLH received research grants from AbbVie, Biogen, BMS, Celtrion, Eli Lily, Janssen Biologics B.V., Lundbeck Foundation, MSD, Pfizer, Roche, Samsung Biopies, Sandoz and Novartis; and institution pay from Pfizer, Medac, AbbVie and Sandoz; chaired the steering committee of the Danish Rheumatology Quality Registry (DANBIO), which receives public funding from the hospital owners and funding from pharmaceutical companies; cochairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondylorthritis based on secondary data and is partly funded by Novartis. DCN received consulting fees from AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB' meeting support from Pfizer; advisory board participation fee from Novartis; and other service fee by BMS. MTN received research grants from AbbVie, BMS, Pfizer, Galapagos, Amgen and Eli Lily. BG received consulting fee from Novartis and honorary lecture payment from Novartis and Nordic-Pharma. IG received royalty fee for book authorship and support for attending meetings by EULAR. DG received advisory board fee from Eli Lily and AbbVie and speakers fee from Eli Lily. A-BA received speakers fee from AbbVie, Eli Lily, Novartis and Pfizer. CG received the study drug from BMS and UCB. MKL received advisory board fee from AbbVie. AS received advisory board fee from GSK (institution pay). LU received speakers fee from Janssen and support for meeting/travel from AbbVie and Eli Lily. DJS received honorarium fee from UCB (not a part of this, unrelated medication). GB received consultancy fee from UCB. ICO received research grants from EU Horizon 2020 and EU Horizon Europe, advisory board participation from IMPRESS-Norway, ALPHA2PREVENT, FLECAPRO and EVOLVD, and meeting/travel support from European Clinical Research Infrastructure Network. The remaining authors declared no disclosures., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

In the nematode worm Caenorhabditis elegans and several other animal species, many ciliary genes are regulated by RFX (Regulatory Factor binding to the X-box) transcription factors (TFs), which bind to X-box promoter motifs and thereby directly activate ciliary gene expression. This setup (RFX TF/X-box/ciliary gene) makes it possible to search for novel ciliary gene candidates genome-wide by using the X-box promoter motif as a search parameter. We present a computational approach that (i) identifies and extracts from whole genomes genes and the corresponding promoter sequences and annotations; (ii) searches through promoters for regulatory sequence elements (like promoter motifs) by using training sets of known instances of these elements; (iii) scores (evaluates) and sorts all positive hits in a database; and (iv) outputs a list of candidate genes and promoters with a given regulatory sequence element. Evolutionary conservation across species (orthology) of genes, promoters, or regulatory sequence elements is used as an important strengthening feature during the overall search approach. Our computational approach is set up in a modular fashion: not every part needs to be used for a particular search effort. In principle, our approach has broad applications. It applies to any group of genes that share common (conserved) regulation through common (conserved) regulatory sequence elements., (Copyright © 2013 Elsevier Inc. All rights reserved.)