A. Carletto

Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension.

BACKGROUND Lower activity of 11 beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) classically induces hypertension by leading to an altered tetrahydrocortisol- versus tetrahydrocortisone-metabolites (THFs/THE) shuttle. Recent cell culture and animal studies suggest a role for promoter methylation, a major epigenetic feature of DNA, in regulation of HSD11B2 expression. Little is known, however, of human HSD11B2 epigenetic control and its relationship with the onset of hypertension. OBJECTIVE To explore the possible relevance of HSD11B2 promoter methylation, by examining human peripheral blood mononuclear cell (PBMC) DNA and urinary THFs/THE ratio as a biochemical indicator of 11beta-HSD2 activity, in blood pressure control. METHODS Twenty-five essential hypertensives and 32 subjects on prednisone therapy were analyzed, the latter to investigate 11beta-HSD2 function in the development of hypertension. RESULTS Elevated HSD11B2 promoter methylation was associated with hypertension developing in glucocorticoid-treated patients in parallel with a higher urinary THFs/THE ratio. Essential hypertensives with elevated urinary THFs/THE ratio also showed higher HSD11B2 promoter methylation. CONCLUSIONS These results show a clear link between the epigenetic regulation through repression of HSD11B2 in PBMC DNA and hypertension.

Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: Comparison of adalimumab, etanercept and infliximab in the GISEA registry

OBJECTIVE To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

Obesity and reduction of the response rate to anti–tumor necrosis factor α in rheumatoid arthritis: An approach to a personalized medicine

Obesity is a mild, long‐lasting inflammatory disease and, as such, could increase the inflammatory burden of rheumatoid arthritis (RA). The study aim was to determine whether obesity represents a risk factor for a poor remission rate in RA patients requiring anti–tumor necrosis factor α (anti‐TNFα) therapy for progressive and active disease despite treatment with methotrexate or other disease‐modifying antirheumatic drugs.

Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis

TNF-like cytokine (TL1A) is a newly identified member of the TNF superfamily of ligands that is important for T cell costimulation and Th1 polarization. However, despite increasing information about its functions, very little is known about expression of TL1A in normal or pathological states. In this study, we report that mononuclear phagocytes appear to be a major source of TL1A in rheumatoid arthritis (RA), as revealed by their strong TL1A expression in either synovial fluids or synovial tissue of rheumatoid factor (RF)-seropositive RA patients, but not RF−/RA patients. Accordingly, in vitro experiments revealed that human monocytes express and release significant amounts of soluble TL1A when stimulated with insoluble immune complexes (IC), polyethylene glycol precipitates from the serum of RF+/RA patients, or with insoluble ICs purified from RA synovial fluids. Monocyte-derived soluble TL1A was biologically active as determined by its capacity to induce apoptosis of the human erythroleukemic cell line TF-1, as well as to cooperate with IL-12 and IL-18 in inducing the production of IFN-γ by CD4+ T cells. Because RA is a chronic inflammatory disease with autoimmune etiology, in which ICs, autoantibodies (including RF), and various cytokines contribute to its pathology, our data suggest that TL1A could be involved in its pathogenesis and contribute to the severity of RA disease that is typical of RF+/RA patients.

Efficacy of methotrexate in the treatment of ankylosing spondylitis: a three-year open study.

Abstract: The aim of the study was to evaluate the efficacy of methotrexate treatment in patients with ankylosing spondylitis in a 3-year open trial. Seventeen patients, 14 men and three women (mean age 32.7 ± 8.9 years), suffering from ankylosing spondylitis and non-responders to treatment with sulphasalazine, were enrolled in our study. Sixteen of them were evaluable at the end of the study. Methotrexate (7.5–10 mg/week) was administered for 3 years. Efficacy was evaluated on the basis of clinical and laboratory variables, radiographic signs of disease progression and daily dosage of indomethacin. We obtained a good and relatively prompt clinical response except for peripheral arthritis and iridocyclitis; in fact, after 3 months of methotrexate treatment a significant amelioration of the following parameters was observed: visual analogue scale for the evaluation of both night pain and general well-being, Shober’s test, occiput-wall distance, fingertip to floor, erythrocyte sedimentation rate, C-reactive protein level and daily dose of indomethacin. A further improvement was obtained during the subsequent period. Radiographs of the spine and sacroiliac joints did not show any signs of disease progression. Side-effects were a transitory elevation of transaminases (four cases) and slight hypogammaglobulinaemia (one case). Methotrexate treatment may be useful in ankylosing spondylitis, but a combined treatment might be indicated for patients with peripheral arthritis.

Neutrophil migration, oxidative metabolism, and adhesion in elderly and young subjects

Objective. To evaluate neutrophil functions in the elderly.Methods. We investigated the PMN migration in vivo and PMN superoxide production and adhesion in response to a variety of compounds; PMN have been isolated both from blood and from a skin experimental exudate (obtained by Senns skin window technique) of 25 normal elderly and of 25 normal young control subjects.Results. No difference was found in PMN migration in vivo (62.9±21.3×106 and 65.5±9.1×106 PMN/cm2/24 hours in elderly and young subjects respectively), neither were different the adhesion under basal condition and after some stimuli and the superoxide production in basal condition and in response to STZ and PMA in two groups. In elderly subjects superoxide production, in response to fMLP, markedly resulted lower than in young controls both by circulating PMNs (3.6±2.7 and 9.3±3.3 nMOLES O2−/106 PMN respectively, p<0.0001) and by exudate PMNs (13.6±4.3 and 19.4±6 nMOLES O2−106 PMNs respectively, p<0.005).Conclusion. Many PMN functions in the elderly do not differ from young people, suggesting that the overall defense function of these cells is not affected by aging. The only parameter that we have found to be different between the two groups is the poor superoxide production after fMLP stimulus of PMNs. The stimulus- and function-specificity of this defect in PMNs from elderly subjects indicates the existence of a dysregulation of the signal transduction pathway distal to fMLP receptor and proximal to NADPH oxidase activation.

The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis

Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR≥50 criteria, while the IL-6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile.

Neutrophil Functions and IL-8 in Psoriatic Arthritis and in Cutaneous Psoriasis

The aim of this study is to determine some functions of neutrophil in patients affected by psoriatic arthritis and to compare them to those of patients affected by cutaneous psoriasis and to normal controls. We used a model of experimental cutaneous inflammation allowing to separate a cluster of purified and viable PMN cells. Then we analyzed, within the three groups, the IL-8 concentration in serum and in the supernatant obtained from the inflammatory site to gather data on the possible pathogenic role played by this cytokine in psoriatic arthritis. We studied neutrophil functions in patients with cutaneous psoriasis and psoriatic arthritis, in acute phase, in comparison with healthy control subjects. We investigated in vivo neutrophil migration by Senns skin window technique and measured adhesion assay and superoxide production in circulating and migrating neutrophils after different stimuli. We also measured IL-8 concentration in serum and in the supernatant obtained from the inflammatory site, artificially created through the skin window scrape. Neutrophil migration in vivo was significantly higher in both groups of patients than in controls. In the presence of fMLP, blood cells showed a burst of superoxide release, which was significantly more pronounced in patients when compared to healthy controls. Neutrophils from skin window scrape showed a much higher response to fMLP as compared to blood cells of all subject groups, but no differences were observed between patients and controls. No correlation was found between the three groups in adhesion ability under basal condition or in response to different stimuli by circulating and migrating neutrophils. Our results also show a great increase of IL-8 in the exudate from patients compared to controls. Our study shows that there is no difference in neutrophil functions between patients with psoriatic arthritis and cutaneous psoriasis; moreover we suggest that the source of high IL-8 levels are neutrophils rather than the keratinocytes.

Mucosa-associated lymphoid tissue lymphoma of the salivary glands occurring in patients affected by Sjögren's syndrome: report of 6 cases.

Objective: Mucosa-associated lymphoid tissue (MALT) lymphoma of the salivary glands occurring in 6 patients affected by primary Sjögren’s syndrome is reported. Methods: Clinical findings, histologic type, stage, treatment and outcome of the 6 patients have been revised. Results: In all 6 cases the lymphoma was of the MALT type. Four patients had stage IE disease, 1 patient had stage IIE disease and 1 patient had stage IV disease. The patients received different treatments resulting in all cases in prolonged remission. After 7 years of complete remission 1 patient developed a diffuse large B-cell lymphoma. Conclusion: MALT lymphoma of the salivary glands is an indolent disease. Though the best therapy of this lymphoproliferative disorder remains to be established, prolonged remission has been obtained in our cases with different therapeutic approaches. We review the literature regarding the relationship between Sjögren’s syndrome and MALT lymphomas and study the mechanisms which may be involved in the transformation from a lymphoepithelial lesion into a neoplastic disorder.

Three clinical reports of Kikuchi's lymphadenitis combined with systemic lupus erythematosus

SummaryThe authors describe three cases of systemic lupus erythematosus (SLE) associated with Kikuchis histiocitic necrotizing lymphadenitis (HNL). Two patients presented a cytomegalovirus infection concomitantly with Kikuchis lymphadenitis; in one of them the onsets of SLE and HNL were simultaneous. In the third case an inguinal HNL was concomitant with vaginitis of unknown aetiology.