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Rheumatoid arthritis (RA) is a canonical autoimmune disease that shares numerous risk factors with diabetes mellitus (DM). The production of autoantibodies is a characteristic feature in both diseases. To determine the frequency and specificity of DM-related antibodies (DMab) in RA patients and to study whether DMab associates with new DM cases in RA patients, we measured DMab defined as IgG against glutamic acid decarboxylase (GADA), tyrosine phosphatase (IA2-ab), and zinc transporter (ZnT8-ab) in a cohort of 290 RA patients (215 women and 75 men, median disease duration 11 years). Of those, 21 had a DM diagnosis at baseline. The development of new DM cases and mortality were traced in a 10-year prospective follow-up. Predictive analyses for DM and mortality were carried out by the Mantel–Cox regression. We found that 27 of the patients (9.3%) had DMab, equally often men and women. The presence of DMab was more frequent in patients with DM (p = 0.027. OR 4.01, 95%CI [1.20; 11.97]), suggesting their specificity for the disease. Men had more prevalent incidental DM at the baseline (12% vs. 5%, p = 0.030) and among the new DM cases (p = 0.012. HR 6.08, 95%CI [1.57; 25]). New DM developed equally frequently in DMab-positive and DMab-negative patients. DM, but not DMab, significantly increased the estimated mortality rate in RA patients (p = 0.021, OR 4.38 [1.2; 13.52]). Taken together, we conclude that DMab are associated with DM in RA patients, but they are not solely enough to predict disease development or mortality in those patients.

Osteoporosis is a major cause of age-related fractures. Healing complications in osteoporotic patients are often associated with increased mortality and morbidity. Stimulation of the implant-adjacent bone could be beneficial in terms of the surgical outcome. Over the past decade, numerous investigations have implicated insulin in normal bone growth, and recent studies have described the advantages of administering insulin locally to increase bone formation. Therefore, we hypothesized that insulin-coated titanium implants would increase bone formation in osteoporotic animals. The aim of this study was to evaluate the effects of insulin delivered from an implant surface on bone-related gene expression and bone formation in osteoporotic rats. Characterizations of the surfaces of insulin-coated and control implants were performed using ellipsometry and interferometry. Forty ovariectomized and four healthy Sprague Dawley rats were used and implants were inserted in the tibias. The systemic effect of insulin was assessed by measuring the blood glucose levels and total body weight. The animals were sacrificed either 1 day or 3 weeks postimplantation. Implant-adherent cells were analyzed by quantitative real-time PCR, and the bone adjacent to the implants was examined by microcomputed tomography and histomorphometry. The insulin-coated implants had no systemic effects. The insulin-coated samples demonstrated significantly lower expression of the gene for interleukin 1β (p = 0.019) at 1 day, and significantly exhibited more periosteal callus (p = 0.029) at 3 weeks. Locally delivered insulin has potential for promoting bone formation and it exerts potentially anti-inflammatory effects in osteoporotic rats. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2472-2480, 2018.

The aim of this study was to validate the use of survivin for preclinical recognition of rheumatoid arthritis (RA) among patients with unexplained arthralgia.Serum levels of survivin and the arthritis-specific autoantibodies RF and ACPA were measured in total of 5046 patients with musculoskeletal complains during 12 consecutive months in Gothenburg and in Umeå. Among them, 303 arthralgia patients were identified and prospectively followed.After 48 months, 12.2% of the arthralgia patients developed RA. Most of RA cases had high serum survivin, which increased the relative risk for RA (RR = 5.90, p = 3 × 10This study shows that measurement of survivin in serum improves estimation of RA risk and prospectively predicts RA development in patients with arthralgia. Survivin may indicate a phase preceding autoantibody production.

Background Permanent joint dysfunction due to bone destruction occurs in up to 50% of patients with septic arthritis. Recently, imaging technologies such as micro computed tomography (μCT) scan have been widely used for preclinical models of autoimmune joint disorders. However, the radiological features of septic arthritis in mice are still largely unknown. Methods NMRI mice were intravenously or intra-articularly inoculated with S. aureus Newman or LS-1 strain. The radiological and clinical signs of septic arthritis were followed for 10 days using μCT. We assessed the correlations between joint radiological changes and clinical signs, histological changes, and serum levels of cytokines. Results On days 5–7 after intravenous infection, bone destruction verified by μCT became evident in most of the infected joints. Radiological signs of bone destruction were dependent on the bacterial dose. The site most commonly affected by septic arthritis was the distal femur in knees. The bone destruction detected by μCT was positively correlated with histological changes in both local and hematogenous septic arthritis. The serum levels of IL-6 were significantly correlated with the severity of joint destruction. Conclusion μCT is a sensitive method for monitoring disease progression and determining the severity of bone destruction in a mouse model of septic arthritis. IL-6 may be used as a biomarker for bone destruction in septic arthritis.

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MicroRNAs (miRs) represent a part of epigenetic control of autoimmunity gaining increasing attention in rheumatoid arthritis (RA). Since cigarette smoking plays important role in RA pathogenesis and reprograms transcriptional profile of miRNAs, we ask if the onco-protein survivin, a novel biomarker of RA, may provide a link between smoking and miRNA. Studying survivin expression in leukocytes of 144 female RA patients we observed that smoking patients had higher survivin transcription and a remarkable spreading of survivin isoforms. This was associated with restricted pattern and low production of miRs. Additionally, miRNA processing enzymes Dicer and DGRC8 were decreased in the patients with survivin isoform spreading. The direct contribution of survivin in miRs biogenesis was confirmed by a massive increase of miRs production following inhibition of survivin in leukocyte cultures. Dicer is shown to mediate these effects of survivin. Chromatin immunoprecipitation analysis demonstrated binding of survivin to the Dicer promoter region. Dicer expression increased 5-folds following survivin inhibition. Taken together, this study presents experimental evidence of a novel cellular function of survivin, control of miRs biogenesis. Up-regulation of survivin in smokers suggests its role as effector of the adverse epigenetic control in RA.

Human resistin has proinflammatory properties that activate NF-κB-dependent pathways, whereas its murine counterpart is associated with insulin resistance. The aim of this study was to examine potential cross-talk between resistin and insulin/insulin-like growth factor (IGF) signaling in rheumatoid arthritis (RA).Levels of IGF-1, IGF binding protein 3, and resistin were measured in the blood and synovial fluid of 60 patients with RA and 39 healthy control subjects. Human RA synovium was implanted subcutaneously into SCID mice, and the mice were treated with resistin-targeting small interfering RNA. Primary synovial fibroblasts from patients with RA, as well as those from patients with osteoarthritis, and the human fibroblast cell line MRC-5 were stimulated with resistin. Changes in the IGF-1 receptor (IGF-1R) signaling pathway were evaluated using histologic analysis, immunohistochemistry, and reverse transcription-polymerase chain reaction.Resistin and IGF-1R showed different expression profiles in RA synovia. Low levels of IGF-1 in RA synovial fluid were associated with systemic inflammation and inversely related to the levels of resistin. Stimulation of synovial fibroblasts with resistin induced phosphorylation of IGF-1R to a degree similar to that with insulin, and also induced phosphorylation of transcription factor Akt. This was followed by gene expression of GLUT1, IRS1, GSK3B, and the Akt inhibitors PTPN and PTEN. Abrogation of resistin expression in vivo reduced the expression of IGF-1R, the phosphorylation of Akt, and the expression of PTPN and PTEN messenger RNA in RA synovium implanted into SCID mice.Resistin utilizes the IGF-1R pathway in RA synovia. Abrogation of resistin synthesis in the RA synovium in vivo leads to reductions in the expression of IGF-1R and level of phosphorylation of Akt.