Piersandro Riboldi

Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients.

OBJECTIVE The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. METHODS Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. RESULTS An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. CONCLUSION Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.

Severe chronic urticaria is associated with elevated plasma levels of D‐dimer

Background:  Patients with chronic urticaria (CU) frequently show signs of thrombin generation as a result of the activation of the extrinsic pathway of coagulation and signs of fibrinolysis as shown by slightly increased mean D‐dimer plasma levels. Here, we studied patients with severe CU to see whether the activation of coagulation and fibrinolysis parallels the severity of the disease.

Pathogenic mechanisms mediating antiphospholipid syndrome.

Antiphospholipid antibodies are the marker for antiphospholipid syndrome. There is evidence that these autoantibodies lead to both thrombotic diathesis and obstetrical manifestations. Besides the known interaction with soluble coagulation factors, in vitro and in vivo experimental models and studies in humans recently have shown the ability of antiphospholipid antibodies to modulate functions of cells involved in coagulation homeostasis. These findings support a new hypothesis to explain the paradox of the prolongation of coagulation assays in vitro and the association with thrombophilic diathesis in vivo. Obstetrical manifestations have been linked to a direct antibody effect on the trophoblast leading to defective placentation that is not necessarily associated with thrombotic phenomena. Phospholipid binding proteins such as beta 2 -glycoprotein I appear to behave as a bridge between circulating antiphospholipid antibodies and cellular targets.

Anti-DNA antibodies: a diagnostic and prognostic tool for systemic lupus erythematosus?

The clinical impact of anti-DNA antibodies lies on their diagnostic power for systemic lupus erythematosus (SLE), being a formal classification criterion. In spite of such a disease association, low-avidity anti-DNA antibodies might also be part of the natural autoantibody repertoire. Their switch to pathogenic high-avidity autoantibodies is the result of the autoimmune process leading to SLE. Anti-DNA antibodies were shown to play a role in SLE pathogenesis and particularly in kidney damage. Accordingly, antibody titres might fluctuate in relation to disease activity, but their prognostic value for flares is still debated. Several methods for anti-DNA detection were described and there is evidence that the assays identify different antibodies with different prognostic value. The results of a multicenter study on four different routine tests for anti-dsDNA antibody detection showed that: (i) Farr assay displays the best diagnostic specificity/sensitivity for SLE, followed by Crithidia luciliae method (CLIFT), (ii) the new generation of solid phase assay (EliA) shows an increased sensibility versus the classical enzyme linked immune assay (ELISA) but a decreased specificity. Antibody titre detected by EliA and Farr assay correlated with disease activity. These findings would suggest that more than one assay should be useful for SLE diagnosis and monitoring.

Patients with antiphospholipid syndrome display endothelial perturbation

BACKGROUND There is strong evidence that antiphospholipid antibodies (aPL) perturb endothelium both in vitro and in experimental animal models. by inducing a vasculopathy and an endothelial pro-inflammatory/coagulant phenotype. However, few contrasting studies raised the issue about the possibility to detect a comparable endothelial perturbation in anti-phospholipid syndrome (APS) patients. The aim of this observational case-control study was to evaluate several parameters of endothelial perturbation in patients with APS and without any other atherosclerosis risk factor. PATIENTS AND METHODS We investigated plasma levels of soluble adhesion molecules (s-ICAM-1, s-VCAM-1, s-E-selectin), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays in 40 selected APS patients and 40 age- and sex-matched healthy subjects. In addition, we evaluated circulating endothelial cells by flow cytometry and brachial artery flow-mediated vasodilation. Patients and controls were free of conditions known to affect both the biological and the functional endothelial parameters. RESULTS Plasma levels of sTM, s-E-selectin and s-VCAM-1 did not differ from controls, while a significant increase in s-ICAM-1 (P = 0.029), t-PA (P = 0.003) and vWF titres (P = 0.002) was found. Circulating mature endothelial cells were also significantly higher in patients than in controls (P = 0.05) and decreased during both vitamin K antagonists (P = 0.001) and antiplatelet (P = 0.032) treatments. Mean brachial artery flow-mediated vasodilation responses were significantly impaired compared to healthy subjects (P = 0.0001). CONCLUSIONS As a whole these findings indicate that APS patients display an endothelial perturbation in the absence of other detectable traditional risk factors for atherosclerosis.

Role of the Interferon-Inducible Gene IFI16 in the Etiopathogenesis of Systemic Autoimmune Disorders

Abstract:  Interferons (IFNs) are now known to exert a multitude of immunological functions on both the innate and adaptive immunity. Given their pleiotropic effects on the immune system, it is conceivable that excess type I IFN or aberrant regulation of its signaling could contribute to autoimmunity. Several lines of evidence link IFNs to autoimmune disorders, in particular to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Expression of a spectrum of genes that constitutes an “IFN signature” is the most significant observation indicating that IFNs may be dominant among the pathogenic mediators involved in some autoimmune diseases. A family of IFN‐inducible genes, designated HIN‐200 in the human and IFI‐200 in the murine species, encodes evolutionary related human (IFI16, MNDA, AIM2, IFIX) and murine proteins (Ifi202 a, Ifi202b, Ifi203, Ifi204, Ifi205/D3). Physiological IFI16 expression was found in cells of the immune system, in endothelial cells, and in stratified squamous epithelia, such as skin. The presence of anti‐IFI16 antibodies was reported in SLE and primary/secondary Sjögrens syndrome. More recently, we reported that anti‐IFI16 autoantibodies differentiate limited cutaneous systemic sclerosis (lcSSc) from diffuse systemic sclerosis (dcSSc). Molecular studies performed in primary endothelial cells overexpressing IFI16 demonstrated that it may be involved in the early steps of inflammation by modulating endothelial cell function, such as expression of adhesion molecules and chemokine production, cell growth, and apoptosis. Moreover, here we report that IFI16 expression is induced by proinflammatory cytokines. In this article the role of the IFI16 protein and its corresponding autoantibodies in the etiopathogenesis of systemic autoimmune diseases, in which chronic inflammation is involved, are discussed.

Mast cells are critically involved in serum‐mediated vascular leakage in chronic urticaria beyond high‐affinity IgE receptor stimulation

To cite this article: Bossi F, Frossi B, Radillo O, Cugno M, Tedeschi A, Riboldi P, Asero R, Tedesco F, Pucillo C. Mast cells are critically involved in serum‐mediated vascular leakage in chronic urticaria beyond high‐affinity IgE receptor stimulation. Allergy 2011; 66: 1538–1545.

Endothelium as a target for antiphospholipid antibodies.

Several, and not necessarily alternative, pathogenic mechanisms have been suggested to sustain the thrombophilic diathesis of the anti-phospholipid syndrome. Among them, interference of anti-phospholipid antibodies with cell acting in the coagulation cascade likely plays a major role. Anti-phospholipid antibodies have been shown to react with endothelial cells mainly by reacting with beta 2 glycoprotein I expressed on the cell membrane surface. Beta 2 glycoprotein I can adhere to endothelial cell surface through the Annexin II receptor and through negatively charged structures (heparin-like molecules) that are bound by the phospholipid-binding site of the molecule. The autoantibody binding involves a yet unknown receptor that activates a signalling pathway able to translocate NFkappaB from the cytoplasm to the nucleus and to activate genes for adhesion molecule, pro-inflammatory cytokine and Tissue Factor up-regulation. The ultimate effect is the induction of a pro-inflammatory and a pro-coagulant endothelial phenotype that has been reproduced both in vitro and in vivo experimental models. Additional effects of anti-phospholipid-mediated endothelial cell activation are the interference with the protein C/S system, with the Annexin V binding, the up-regulation of endothelin I synthesis and the induction of apoptosis. Altogether these effects cooperate in switching endothelium from an anti-coagulant to a pro-coagulant surface.

Chronic urticaria: A disease at a crossroad between autoimmunity and coagulation

Chronic urticaria (CU), defined as recurrence of wheals with or without angioedema for more than 6 weeks, is a quite common disease that may severely worsen the quality of life. Studies carried out during the last 2 decades have demonstrated an autoimmune pathogenesis mediated by functionally active autoantibodies to the high affinity IgE receptor (FcepsilonRI) or to IgE which are able to induce histamine release from basophils and mast cells. However, such mechanism can be detected in less than 50% of patients only. The present article reviews recent findings showing an additional pathogenic mechanisms in CU patients: activation of the coagulation cascade resulting in thrombin production. Thrombin is a serine protease which may play a key role in urticaria, being able to induce edema through an increase in vascular permeability, mast cell activation and degranulation, and to induce the production of the anaphylotoxin C5a. Such mechanism seems to be active in the majority of CU patients, however their relationship with anti-FcepsilonRI or anti-IgE autoantibodies is still matter of research.

Cardiac involvement in systemic autoimmune diseases

The heart and the vascular system are frequent and characteristic targets of several systemic autoimmune diseases, in particular Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc). In this chapter we review the classic cardiac abnormalities and the more recent data about cardiovascular involvement as part of a major disease complication determining a substantial morbidity and mortality.In addition to the classic cardiac abnormalities involving the heart structures, acute and chronic ischemic heart disease and cerebrovascular accidents are threatening clinical manifestations of SLE and RA associated to an early accelerated atherosclerosis. Immune-mediated inflammation is now recognized as an important factor involved in the pathogenesis of atherosclerosis.Ongoing clinical studies are being devised to find specific risk factors associated with systemic autoimmune diseases and/or treatment regimens. Hopefully, prophylactic measures should be available within the next few years.