AB0087 Cytotoxicity and Genotoxicity in Rheumatoid Arthritis: A Dual Effect of Disease and Drugs:

Abstract

BackgroundStudies about cytotoxicity and genotoxicity in rheumatoid arthritis (RA) are limited and the toxicity of Disease Modifying Anti-Rheumatic Drugs (DMARDs) commonly used in treatment is still a concern.Objectivesto assess cytotoxicity and genotoxicity in RA and the possible cyto and genotoxic effects of some DMARDs used in treatment.MethodsThe study included 30 female RA patients divided according to treatment into three groups and ten healthy controls. Two groups received DMARDs for at least 3 months period: methotrexate (MTX) only group (n=12 patients), MTX with SSZ (sulphasalazine) group (n=8) and ten DMARDs naieve RA who received only Non Steroidal Anti-Inflammatory Drugs (NSAIDs). The MTX dose was 15–20 mg/wk, SSZ dose was 1.5–2 gm daily. All RA on DMARDs received concomitant daily folic acid dose of 0.5 mg.Peripheral blood samples were taken to assess the cytotoxicity by chromosomal analysis (karyotyping) using solid Giemsa stain and GTG-banding according to the International System for Human Chromosome Nomenclature. Genotoxicity and DNA damage was assessed by the miconucleustest usin g cytochalasin –B.ResultsCompared to controls, RA patients had significantly higher chromosomal aberrations (CAs) in the form of breaks, satellite association, endoreduplication, aneuploidy, double minute, and other aberrations. There was also a statistically significant increase in the markers of genotoxicity in RA patients compared to controls: micronuclei (MN), nucleoplasmic bridges (NPB) and necrotic and/or apoptotic cells (Table1). CAs were found in all RA groups, those receiving DMARDs as well as the DMARD naieve group. CAs were significantly higher in MTX and in MTX-SSZ group when compared to RA on NSAIDs only. Meanwhile, there was no significant difference between the CAs in the MTX and the MTX-SSZ groups. In addition, the number of binucleated (BN) cells with MN, NPB, and the necrotic and/or apoptotic cells was statistically higher in MTX-RA and MTX-SSZ-RA compared to the NSAIDs group. Whereas, no statistical difference was found between the two DMARDs groups.RA patients who were on DMARDs for a longer duration (>5 years) showed a statistically significant increase in all cytotoxicity and genotoxicity markers than those for shorter duration (<5 years).Markers of cyto/genotoxicityControl (n=10)Total RA (n=30)PMean ± SDMean ± SDBreaks0.6±1.0714.77±11.58<0.001*Satellite association6.2±6.4938.16 ±14.77<0.05*Double minute0.0±0.02.03±4.77<0.05*Endo- reduplication0.0±0.09.7±8.31<0.05*Aneuploidy0.0±0.05.3±4.5<0.05*Other aberrations0.0±0.00.70±0.51<0.05*BN cells with MN1.5±1.221.73±12.38<0.01*BN cells with NPB0.8±1.013.27±9.96<0.01*Necrotic and/or apoptotic cells2.3±1.829.93±12.10<0.001**P is significant at values ≤0.05.ConclusionsRA patients show significantly increased markers of cytotoxicity and genotoxicity, regardless the type of medications received, sugggesting them to represent underestimated disease features which could provide new insights into its pathogenesis. MTX further aggrevates the cyto- and genotoxicity...

A systematic overview of the spermatotoxic and genotoxic effects of methotrexate, ganciclovir and mycophenolate mofetil

“…Overall, eight of these studies investigated MTX in immunosuppressive dose ranges. A recent prospective cohort study by Soliman et al (2016) 24 investigated the genotoxic effect of weekly doses of 15–20 mg MTX for at least 3 months among 12 women with rheumatoid arthritis. Compared with nonsteroidal anti‐inflammatory drug‐treated rheumatoid arthritis patients, MTX caused increased satellite associations, endoreduplications and aneuploidies.…”