This paper reviews the clinical effects on bone of 10 mg of prednisone daily in early rheumatoid arthritis, given for 2 years in the Utrecht Study and in the second CAMERA (Computer- Assisted Management in Early Rheumatoid Arthritis) Study, and addresses the question whether there were joint-sparing effects and whether these were offset by adverse effects, especially osteoporosis. We conclude that a 2-year adjunct treatment with 10 mg of prednisone daily increases the benefits of disease-modifying antirheumatic drug therapy and has joint-sparing properties, even if added to the tight control methotrexate-based strategy aiming for remission. Importantly, with good control of inflammation and adequate use of calcium, vitamin D and bisphosphonates - according to national or international guidelines - steroid-induced osteoporosis is rare over 2 years.
BackgroundRapidly reducing disease activity is of major importance in the management of newly diagnosed rheumatoid arthritis (RA) patients as early response strongly correlates with long-term clinical outcomes. To select patients for whom it would be favourable to initiate a biological drug from start of therapy, it is crucial to study biological pathways and biomarkers involved in treatment response.ObjectivesTo identify biological networks and signature genes among disease modifying anti-rheumatic drug (DMARD)-naïve early RA patients achieving sustained drug-free remission (sDFR) after initiating treatment with tocilizumab (TCZ).MethodsData was used from DMARD-naïve early RA patients in the U-Act-Early trial who had been randomized to initiate TCZ therapy. The study design and details have previously been described.[1] Briefly, TCZ (8 mg/kg) was given every 4 weeks and if remission was not achieved, methotrexate (oral) was added. When the target was achieved, therapy was tapered and subsequently discontinued provided remission persisted. sDFR was reached when patients remained ≥3 months in remission while being drug-free until the end of the two-year study period. Before the first dose of medication, whole blood samples were collected and RNA was isolated from CD4 cells and analyzed using RNA sequencing. The DESeq2 package was used to identify differentially expressed genes (DEGs) between responders (achieving sDFR, n=13) and non-responders (not able to taper medication, n=11). Subsequently, weighted gene co-expression network analysis (WGCNA) was used to study clusters (modules) within the 1000 most relevant DEGs.ResultsIn total, eight modules with varying sizes (10–470 genes) were identified. The module best correlated (Pearson correlation coefficient 0.52, p=0.009) with achieving sDFR included 26 genes and was used for further functional analysis. Within this module, we found three significantly enriched pathways in the Kyoto Encyclopaedia of Genes and Genomes (KEGG) database. These were calcium signalling pathway (p=5.81E-04), carbohydrate digestion & absorption (p=4.46E-02), and neuroactive ligand-receptor interaction (p=2.61E-02). In addition, we identified 83 overrepresented Gene Ontology (GO) terms of which granulocyte migration (p=2.70E-04), myeloid leukocyte migration (p=8.95E-04) and G-protein coupled amine receptor activity (p=1.25E-03) were most significant. The genes in the module of interest showing the highest connectivity were the upregulated testis expressed 22 (TEX22), doublecortin lie kinase 2 (DCLK2), and the downregulated Williams Beuren syndrome chromosome region 27 (WBSCR27) gene (Fig. 1).ConclusionsWhen performing network analyses of the DEGs between responders and non-responders, TEX22 and DCLK2 were identified as signature genes for treatment response to TCZ therapy. WBSCR27 was found to be associated with less chance of achieving sDFR.References
Bijlsma JW, Welsing PM, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-E...
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