Serum and synovial survivin in rheumatoid arthritis: Relation to disease activity and severity

Abstract

BackgroundRheumatoid arthritis (RA) is a progressive debilitating autoimmune disease, affecting 1% of the world population, leading to cartilage and bone destruction caused by insufficient apoptosis in the inflamed RA synovium. Survivin is a proto-oncogene biomarker known for its anti-apoptotic and cell cycle-regulating properties. Overexpression of survivin in non-cancerous processes has been linked to inflammation, presumably contributing to the decreased apoptosis in the T cells of the cerebrospinal fluid in multiple sclerosis, in skin lesions of patients with psoriasis and in synovial tissue of patients with RA.Aim of the workThe aim of this study is to measure the serum and synovial levels of survivin and clarify their relations to disease activity, functional capacity, and radiographic damage in patients with RA.Patients and methodsThis study was carried outon50patients with RA who hada mean ageof46.4±10.94 years.Theywere39femalesand11males.Thecontrolgroupwasofmatchedageand sex,withameanageof46.03±10.53yearsandfemale:maleratioof23:7.Allpatients were subjected to full history taking, thorough clinical examination, assessment of disease activity by disease activity score 28 activity score, and assessment of functional capacity and disability using Health Assessment Questionnaire. Plain radiographs of both hands of feet were done, scored and graded by Larsen score. Serum survivin from all the studied participants and survivin levelsinthe synovial fluid aspirated from 18 patients with RA who presented with knee effusion at the time of examination were measuredbyenzyme-linked immunosorbent assay, usingapair of matched anti bodies (R&D systems, Abingdon, Uk).ResultsThe mean serum survivin level was highly statistically significantly elevated (P<0.001) in the sera of patients with RA than in the controls, being 239.1 ±115.15 and 77.03±30.20 pg/ml, respectively. Synovial survivin levels ranged between 420 and 575 pg/ml, with a mean of 479.61±52.68 pg/ml, which was statistically significantly higher than the mean serum survivin level in patients with RA (P<0.001). Patients were divided into survivin -ve group, which included 21 (42%) of 50 patients with serum survivin less than 167.63 pg/ml, and survivin +ve group, which included 29 (58%) of 50 patients with RA with serum survivin more than or equal to 167.63 pg/ml. Survivin +ve RA patients group had significantly longer mean disease duration (P<0.001), Higher Health Assessment Questionnaire SCORE, and higher mean Larsen score (P<0.001) than survivin -ve RA patients group. Overall, nine (69.2%) of 13 RA patients with Sjogren’s syndrome, eight (80%) of 10 of the patients with pleural effusion, three (50%) of six patients with Raynaud’s phenomenon, and all patients with SC nodules (five, 100%), episcleritis (two, 100%), and vasculitis (one, 100%) were survivin +ve. Larsen score in the patients with RA ranged from 0 to 65, with a mean of 23.6 ±18.98. Patients with RA who had Larsen score grading more than or equal to 2 (27/ 50, 52%) were considered to have an erosive RA disease. There were no statistically significant differences between patients with RA according to the presence of erosion regarding age, sex, visual analog scale values, disease activity score values, the presence of rheumatoid factor antibodies or anti-cyclic citrullinated peptides antibodies, the mean of hemoglobin %, white blood cells count, platelets count, erythrocyte sedimentation rate first hour value, or the C-reactive protein level. All patients with RA with erosive disease were survivin +ve and had statistically significantly elevated mean serum and synovial survivin levels than those patients with non erosive disease (337.37±55.19 vs. 126.78±24.33 pg/ ml and 422.5±3.53 vs. 486.75±51.52 pg/ml, respectively).ConclusionsHigh levels of survivin are detected in the sera and synovial fluid of patients with RA and are associated with erosive joint damage and poor functional outcomes. Our findings support the role of survivin in the pathogenesis of RA. Further studies are needed on a larger group of RA patients follow-up to ascertain the erosive effect of survivin. Conduction of studies on survivin antagonist to evaluate their effect on ameliorating RA disease progression is recommended.