Osteopenia/osteoporosis develops in the early phase of disease in patients with idiopathic inflammatory myopathies.

Objective: To study the relationship between different disease-related variables and bone mineral density (BMD) in patients with idiopathic inflammatory myopathies (IIMs).Method: Demographic and clinical data were retrospectively collected from the medical records of all patients diagnosed with IIMs during 2003-2018 in the Rheumatology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. BMD measurements by dual-energy X-ray absorptiometry (DXA) were compared among three patient groups categorized according to the time when DXA was performed in relation to the diagnosis: during the first month, 2-6 months, and 7-24 months after diagnosis.Results: In total, 48 patients were included in the study. BMD correlated positively with body mass index and the presence of myositis-specific autoantibodies. As expected, age and diseases duration had negative associations with BMD. Importantly, osteopenia and osteoporosis were significantly more common in patients who underwent DXA at later time-points of the disease than in those who underwent DXA during the first month after diagnosis.Conclusions: Reduced BMD is common in patients with IIMs. The development of osteopenia/osteoporosis starts in the early phase of myositis (within 6 months), and immediate osteoporosis prophylaxis at diagnosis is necessary.

Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension.

The aim of our study was to assess the levels of growth factors and interleukin (IL)-6 across the pulmonary circulation in patients with pulmonary arterial hypertension (PAH) and correlate them with clinical and haemodynamic data and outcome. Simultaneous arterial and pulmonary arterial blood samples in patients with PAH (n = 44) and controls (n = 20) were obtained during right heart catheterisation. Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta1 and IL-6 were measured using ELISA. Arterial median (interquartile range) values for VEGF, PDGF-BB, TGF-beta1 and IL-6 were significantly higher in patients (377 (218-588) versus 9.0 pg.mL(-1); 1,955 (1,371-2,519) versus 306 (131-502) pg.mL(-1); 26.42 (11.3-41.1) versus 7.0 (1.8-18.4) ng.mL(-1); and 3.98 (0.7-8.1) versus 0.7 pg.mL(-1), respectively; p<0.001 for all variables). There was a consistent step-up of VEGF, PDGF-BB and TGF-beta1 across the lungs in PAH patients (p<0.001, p = 0.002 and p<0.001, respectively), whereas in controls, arterial and pulmonary arterial serum levels of IL-6 and growth factors were similar (statistically nonsignificant). In multivariate analysis, increased IL-6 levels predicted mortality (hazard ratio 1.08 (95% confidence interval 1.02-1.15); p = 0.012). Our findings indicate increased release and/or decreased clearance of growth factors at the lung vascular level, which may contribute to vascular remodelling in PAH.

Model systems: modeling human staphylococcal arthritis and sepsis in the mouse.

The staphylococci have been recognized as serious pathogens for over a century and are the etiological agent of a variety of diseases ranging from mild cutaneous infections to often fatal forms of septic arthritis, endocarditis, toxic shock syndrome and sepsis. Despite intensive efforts to halt their spread, they remain the most common cause of community- and nosocomially acquired bacteremia. Murine models of Staphylocococus aureus-mediated arthritis and sepsis exist and are being used to gain a better understanding of the host-bacterium relationship as well to develop better methods of prevention and treatment.

Interaction with complement receptor 1 (CD35) leads to amelioration of sepsis-triggered mortality but aggravation of arthritis during Staphylococcus aureus infection.

The aim of this study was to assess the importance of complement receptor 1 (CR1, CD35) in Staphylococcus aureus arthritis and sepsis. The murine model of haematogenously acquired septic arthritis was used, injecting toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus LS-1 intravenously. CR1 was blocked using immunoglobulin G (IgG) rat antimouse CR1 monoclonal antibody (MoAb) (8C12). Evaluation of arthritis was performed clinically and histopathologically. In addition, the effect of blocking CR1 was assessed on the phagocytic activity of leucocytes and on T-cell dependent and independent inflammation. Seven days after inoculation with bacteria, 96% of CR1 MoAb-treated mice had clinical symptoms of arthritis compared with 58% of the control animals (P < 0.01). The severity of arthritis, expressed as mean arthritic index, was 2.9 +/- 0.5 and 1.4 +/- 0.5, respectively (P = 0.004). Fifteen days after bacterial inoculation, all CR1 MoAb-treated mice had severe arthritis (mean arthritic index 6.3 +/- 0.6), while only 77% of controls were affected (mean arthritic index 2.9 +/- 0.6; P = 0.002). The potential explanation of these findings is that treatment with CR1 MoAb significantly increases the polymorphonuclear cell-dependent inflammatory response as a result of enhanced vasodilatation in treated animals. We conclude that treatment with CR1 MoAb leads to amelioration of sepsis-induced mortality during S. aureus infection, possibly as a result of the increased phagocytic activity of peripheral phagocytes.

Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis.

OBJECTIVE: To evaluate the combined effect of systemic corticosteroid and antibiotic therapy on the course of septic arthritis. METHODS: The murine model of hematogenously acquired Staphylococcus aureus arthritis was used. Mice were treated with corticosteroids and antibiotics, and were followed up individually. Arthritis was evaluated clinically and histopathologically. Serum samples and bacterial isolates were also analyzed. RESULTS: The prevalence of arthritis 14 days after the onset of the disease was 22% in the corticosteroid and antibiotic-treated group, as compared with 81% in the control (nontreated) group and 48% in the antibiotic-treated group. The severity of arthritis also decreased in the corticosteroid and antibiotic-treated group, as did the mortality rate. Immunohistochemical analysis revealed a dramatic decrease in T cells and macrophages in the synovium of mice that took the combined therapy. The mechanisms leading to this outcome include the inhibitory effect of corticosteroids on T cell and B cell proliferation and differentiation, such as suppression of interferon-gamma (IFN gamma) production. Serum levels of IFN gamma were decreased 4-fold in the antibiotic-treated group compared with the controls; a 15-fold decrease was observed in the corticosteroid and antibiotic-treated animals. In addition, serum NO3- was significantly decreased in mice treated with antibiotics (P < or = 0.05), as well as in mice treated with corticosteroids and antibiotics (P < or = 0.001). CONCLUSION: Systemic corticosteroid administration along with antibiotic therapy had beneficial effects on the course and outcome of S aureus arthritis.

Beneficial effect of glucocorticoids on the course of haematogenously acquired Staphylococcus aureus nephritis.

The effect of combined antibiotic and corticosteroid treatment on the course of haematogenously acquired Staphylococcus aureus nephritis was studied. Mice were given a single injection of S. aureus producing toxic shock syndrome toxin-1 in a dose capable of inducing a high frequency of inflammatory kidney lesions and divided into three groups according to a treatment regimen. In all untreated animals inflammatory infiltrates were seen in kidney cortex and medulla with high frequencies of glomerular (90%) and tubular damage (50%) as well as fibrotic changes (50%). The treatment with antibiotics alone reduced significantly only the occurrence of focal inflammatory infiltrates. In contrast, the mice treated with a combination of antibiotics and corticosteroids displayed in 64% of cases normal histological kidney appearance and a significant decrease in occurrence of glomerular (P<0.01) and tubular (P<0.05) lesions. Immunohistochemically, the combined treatment resulted in a more pronounced decrease in numbers of CD4, IL-2R (four to fivefold) and CD8 positive cells in kidney inflammatory lesions compared to antibiotics only treated group. Thus, glucocorticoids in association with antibiotics are shown to improve the outcome of septic murine nephritis, possibly due to suppression of kidney infiltrating T cells.

Inhibition of nitric oxide synthase (NOS) aggravates Staphylococcus aureus septicaemia and septic arthritis.

The aim of this study was to assess the role of NO and its metabolites in bacterial arthritis. The murine model of haematogenously acquired septic arthritis was used. Swiss mice treated with NOS inhibitors (N(G)-monomethyl-L-arginine or N(omega)-nitro-L-arginine methyl ester) were injected intravenously with toxic shock syndrome toxin-1 (TSST-1) producing Staphylococcus aureus LS-1. Arthritis was evaluated clinically and histopathologically. Serum cytokine levels, bacterial isolates and intracellular capacity of macrophages to kill bacteria were also analysed. The frequency of arthritis in mice treated with NOS inhibitors was three to four-fold higher than that in non-treated controls (75% versus 20%). The severity of arthritis, expressed as mean arthritic index, was 1.4 and 0.4, respectively. Cartilage and/or bone destruction occurred in 63% of NOS inhibitor-treated mice, but only in 10% of controls. Also, the cumulative septicaemia-induced mortality was clearly higher in mice treated with NOS inhibitors compared with non-treated controls. Intracellular killing capacity of the peritoneal macrophages, treated in vitro with NOS inhibitors, was decreased. Thus, 24 h after bacterial inoculation peritoneal macrophages pretreated with NOS inhibitors killed more than 10 times less bacteria than the control ones (P<0.01). We conclude that NOS inhibitors aggravate S. aureus arthritis, possibly by inducing impairment of the intracellular killing capacity of macrophages.

Complement depletion aggravates Staphylococcus aureus septicaemia and septic arthritis.

The aim of the study was to assess the role of the complement system in Staphylococcus aureus arthritis and septicaemia. The murine model of haematogenously acquired septic arthritis was used, injecting intravenously toxic shock syndrome toxin-1 (TSST-1), producing S. aureus LS-1. Complement was depleted using cobra venom factor (CVF). Evaluation of arthritis was performed clinically and histopathologically. In addition, the effect of complement depletion on the phagocytic activity of leucocytes was assessed in vivo and in vitro. Six days after inoculation of S. aureus the prevalence of arthritis in decomplemented mice was three-fold higher than that in controls (91% versus 25%). The clinical severity of arthritis at the end of the experiment, expressed as arthritic index, was 7.3 and 1.9, respectively. These findings were confirmed by histological index of synovitis as well as of cartilage and/or bone destruction being significantly higher in decomplemented mice than in controls (9.8 +/- 1.7 versus 4.9 +/- 1.2, P < 0.05; and 7.9 +/- 1.7 versus 3.0 +/- 0.9, P < 0.05, respectively). Also, the septicaemia-induced mortality was clearly higher in decomplemented mice compared with the controls. CVF treatment significantly reduced in vivo polymorphonuclear cell-dependent inflammation induced by subcutaneous injection of olive oil and mirroring the capacity of polymorphonuclear cells (PMNC) to migrate and/or extravasate. Besides, the decomplementation procedure significantly impaired phagocytic activity of peripheral blood leucocytes in vitro, since the number of phagocytes being able to ingest bacteria decreased by 50% when the cells were maintained in decomplemented serum compared with those in intact serum. The conclusion is that complement depletion aggravates the clinical course of S. aureus arthritis and septicaemia, possibly by a combination of decreased migration/extravasation of PMNC and an impairment of phagocytosis.