Histamine release positive test associates with disease remission in chronic spontaneous urticaria: a proof-of-concept study.

SUMMARY: Background. Histamine release (HR) test has previously been shown to predict the presence of endogenous histamine-releasing factors in chronic spontaneous urticaria (CSU). Objectives and methods. Twenty CSU patients unresponsive to antihistamine treatment were enrolled in order to evaluate the correlations between HR test results and demographic features, quality of life, disease activity, clinical course, and autologous serum and plasma skin tests (ASST and APST). Results. All patients with positive HR test (9/9, 100%) had a more severe disease activity at onset (urticaria activity score, UAS > 2) when compared to negative HR test patients (5/11; p = 0.04). Quality of life questionnaire's results were not substantially different between HR positive and negative subgroups at baseline (p > 0.05), and results of HR test and ASST/APST did not co-segregate (p > 0.05). After 12 months, patients with a positive HR test had a significant reduction of disease activity (p = 0.003) whereas patients with a negative HR test did not (p > 0.05), leading to disease remission and antihistamine treatment withdrawal in 67% (6/9) of positive HR test patients versus 18% (2/11) of negative HR test patients (p = 0.027). Conclusions. Positive HR test may predict spontaneous CSU remission at 12 months.

IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients.

OBJECTIVES: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre. METHOD: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as 'definite' or 'possible' according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI). RESULTS: Forty-one patients (15 females, 26 males) were included in this study: 26 with 'definite' IgG4-RD and 15 with 'possible' IgG4-RD. The median age at diagnosis was 62 years. The median follow-up was 36 months (IQR 24-51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1 month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking. CONCLUSIONS: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Patients with breakthrough reactions to iodinated contrast media have low incidence of positive skin tests.

BACKGROUND: The term "breakthrough reactions" designates repeated hypersensitivity reactions to iodinated contrast media (ICM) despite premedication with glucocorticoids and antihistamines. We aimed to retrospectively evaluate the rate of positive skin test (STs) in our cohort of patients with previous breakthrough reactions to different ICMs. METHODS: A series of 35 patients, who experienced at least one breakthrough reaction to ICM and who underwent STs within 6 months from the reaction were studied, and results were compared to a control group of patients with a first hypersensitivity reaction occurred without premedication. Skin prick tests (SPT), intradermal tests (IDT) and patch tests (PT) at different dilutions, with a set of three to four ICM were performed. RESULTS: Of the 35 patients with prior breakthrough reactions, 57% had an immediate reaction (IR) and 43% had a non-immediate reaction (NIR). Patients who experienced the first hypersensitivity IR or NIR, later had one or more breakthrough IR or NIR, respectively. Overall, 29% (10/35) of patients with prior breakthrough reactions resulted positive to STs compared to 57% (16/28) of the control group (p < 0.05). No significant difference in allergy history, age, sex, other clinical / demographic features nor chronic use of ACE-inhibitor, beta-blockers or NSAIDs was observed. CONCLUSION: This preliminary finding suggests that patients with prior breakthrough reactions have significantly lower immunologically proven ICM reactions (positive STs) if compared to non-breakthrough patients. According to that, a considerable number of breakthrough reactions seems to be non-allergic hypersensitivity reactions or reactions which could be mostly prevented by a proper, well-timed skin testing. Larger prospective studies are needed to confirm these results, with a more careful analysis of patients' risk factors, a laboratory assessment that includes an in vitro allergy diagnostics, and hopefully a drug provocation test for selected cases.

Efficacy and safety of biological agents in adult-onset Still's disease.

OBJECTIVES: To describe the efficacy and safety of different biological agents in a large cohort of 20 patients with adult-onset Still's disease (AOSD). METHOD: We retrospectively evaluated 20 patients with severe or refractory AOSD treated with at least one biological agent (anakinra, etanercept, tocilizumab, and adalimumab), followed up for at least 12 months at our Institution. We collected and analysed data on the disease course, treatment outcome, and adverse effects, and compared our data with other published series. RESULTS: The median duration of follow-up was 5 years. In 12 patients a single biological drug induced a clinical response. In eight patients the biological agent that was first administered proved ineffective, and a switch to a different biologic was necessary. In three patients a third biologic was necessary to achieve disease control. The biologics eventually determined a clinical response in all patients. Patients with systemic disease showed better responses than patients with chronic articular disease (p < 0.05). Biological agents allowed either the withdrawal or the tapering of corticosteroid therapy (p < 0.0001) and of disease-modifying anti-rheumatic agents (DMARDs; p < 0.05). Three patients experienced herpes zoster reactivation. CONCLUSIONS: This is the longest follow-up of a cohort of AOSD patients treated with biological agents. Our data show that biologics are safe and generally effective in the long-term management of AOSD, particularly in cases with systemic disease, and suggest that a clinical response can be obtained in almost all AOSD patients, although a switch to drugs with a different mechanism of action may be necessary.

Pancreatic involvement in Legionella pneumonia.

Legionella-associated pancreatitis has been rarely reported. Since this condition is very rarely suspected and investigated in patients with Legionella pneumonia, its incidence is probably underestimated. Here we report a case of Legionella pneumonia-associated pancreatitis and review the relevant related literature.

Proposal of a skin tests based approach for the prevention of recurrent hypersensitivity reactions to iodinated contrast media.

The purpose of the present work is to evaluate the efficacy of an approach that combines clinical history, skin tests results, and premedication, in preventing recurrent hypersensitivity reactions to iodinated contrast media (ICM). Skin Prick tests, Intradermal tests, and Patch tests were performed in 36 patients with a previous reaction to ICM. All patients underwent a second contrast enhanced radiological procedure with an alternative ICM selected on the basis of the proposed approach. After alternative ICM re-injection, only one patient presented a mild NIR. The proposed algorithm, validated in clinical settings where repeated radiological exams are needed, offers a safe and practical approach for protecting patients from recurrent hypersensitivity reactions to ICM.

Intravascular immunity as a key to systemic vasculitis: a work in progress, gaining momentum.

Vascular inflammation contributes to the defence against invading microbes and to the repair of injured tissues. In most cases it resolves before becoming apparent. Vasculitis comprises heterogeneous clinical entities that are characterized by the persistence of vascular inflammation after it has served its homeostatic function. Most underlying mechanisms have so far remained elusive. Intravascular immunity refers to the surveillance of the vasculature by leucocytes that sense microbial or sterile threats to vessel integrity and initiate protective responses that entail most events that determine the clinical manifestations of vasculitis, such as end-organ ischaemia, neutrophil extracellular traps generation and thrombosis, leucocyte extravasation and degranulation. Understanding how the resolution of vascular inflammation goes awry in patients with systemic vasculitis will facilitate the identification of novel pharmacological targets and bring us a step closer in each patient to the selection of more effective and less toxic treatments.

Cardiometabolic and immune factors associated with increased common carotid artery intima-media thickness and cardiovascular disease in patients with systemic lupus erythematosus.

BACKGROUND AND AIM: Patients with systemic lupus erythematosus (SLE) have a higher prevalence of subclinical atherosclerosis and higher risk of cardiovascular (CV) events compared to the general population. The relative contribution of CV-, immune- and disease-related risk factors to accelerated atherogenesis in SLE is unclear. METHODS AND RESULTS: Fifty SLE patients with long-lasting disease (mean age 44 ± 10 years, 86% female) and 50 sex- and age-matched control subjects were studied. Common carotid artery intima-media thickness (CCA-IMT) was used as a surrogate marker of atherosclerosis. We evaluated traditional and immune- and disease-related factors, assessed multiple T-cell subsets by 10-parameter-eight-colour polychromatic flow cytometry and addressed the effect of pharmacological therapies on CCA-IMT. In SLE patients, among several cardiometabolic risk factors, only high-density lipoprotein levels (HDL) and their adenosine triphosphate-binding cassette transporter 1 (ABCA-1)-dependent cholesterol efflux capacity were markedly reduced (p < 0.01), whereas the CCA-IMT was significantly increased (p = 0.03) compared to controls. CCA-IMT correlated with systolic blood pressure, low-density lipoprotein (LDL) cholesterol and body mass index (BMI), but not with disease activity and duration. The activated CD4(+)HLA-DR(+) and CCR5(+) T-cell subsets were expanded in SLE patients. Patients under hydroxychloroquine (HCQ) therapy showed lower CCA-IMT (0.62 ± 0.08 vs. 0.68 ± 0.10 mm; p = 0.03) and better risk-factor profile and presented reduced circulating pro-atherogenic effector memory T-cell subsets and a parallel increased percentage of naïve T-cell subsets. CONCLUSION: HDL represents the main metabolic parameter altered in SLE patients. The increased CCA-IMT in SLE patients may represent the net result of a process in which 'classic' CV risk factors give a continuous contribution, together with immunological factors (CD4(+)HLA-DR(+) T cells) which, on the contrary, could contribute through flares of activity of various degrees over time. Patients under HCQ therapy present a modified metabolic profile, a reduced T-cell activation associated with decreased subclinical atherosclerosis.

Hypertension negatively affects the pregnancy outcome in patients with antiphospholipid syndrome.

The impact of hypertension in the pregnancies from autoimmune patients is not unequivocally defined. We have prospectively followed 168 pregnancies from 135 patients from four Italian centres to verify the potential impact of hypertension in the antiphospholipid syndrome (APS). The rate of preeclampsia, mean neonatal weight and gestational age at delivery were significantly lower in patients with both APS and hypertension than in patients with hypertension or APS alone. This information may be relevant for counselling and care of these patients.

Adult onset Still's disease: clinical presentation in a large cohort of Italian patients.

OBJECTIVES: To characterise the clinical phenotype of Italian patients with adult-onset Still's disease (AOSD). METHODS: Sixty-six subjects who received a definite diagnosis of AOSD were seen and followed-up at our institution from 1991 to 2009. The diagnosis was made by a senior rheumatologist and confirmed by Yamaguchi's criteria for AOSD. Data regarding clinical manifestations, laboratory and radiographic features, and disease course were collected and compared with those reported in other published series of different ethnicity. RESULTS: The most frequent features were: articular pain (100%), acute phase reactants elevation (100%), elevated serum ferritin (97%), high fever (95%), negative RF and ANA (92%), neutrophilia (82%), skin rash (79%), and overt arthritis (79%). Forty-percent of patients showed a chronic articular disease. Five subjects (8%) experienced severe, life-threatening complications, and 1 patient died. As compared to other North American, North European, Middle Eastern, and Far Eastern cohorts, Italian patients showed significant differences in several epidemiologic, clinical and laboratory features. CONCLUSIONS: Our data show that AOSD is rare in the Italian population, and that its clinical presentation appears to be significantly influenced by the ethnicity of the affected patients. Given its broad differential diagnosis, early recognition of this condition is challenging, but it could become crucial in the setting of severe complications. Beyond the protean manifestations of this disease, a clinical picture of seronegative febrile arthritis and skin rash, concurrent with a marked elevation in serum ferritin should always be mindful of AOSD.

Translational mini-review series on immunology of vascular disease: mechanisms of vascular inflammation and remodelling in systemic vasculitis.

Vessel walls are the primary inflammatory sites in systemic vasculitides. In most cases the initiating event is unknown, and a self-sustaining circuit attracts and activates inflammatory leucocytes in the wall of vessels of various size and anatomical characteristics. Recent studies have revealed homeostatic roles of vascular inflammation and have identified the action of humoral innate immunity, in particular injury-associated signals and acute phase proteins, on the activation of circulating leucocytes, platelets and endothelial cells. These advances have provided clues to the molecular mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue injury.

Multiple drug hypersensivity: insight into the underlying mechanism and correlation with autoimmune diseases.

BACKGROUND: Subjects with drug hypersensitivity are sometimes simultaneously reactive to several drugs. This nosological entity is defined as multiple drug hypersensivity (MDH). Urticaria and angioedema are the commonest clinical manifestations of hypersensitivity drug reactions (HDR). These clinical signs are also pathognomonic of chronic idiopathic urticaria (CIU), whose pathogenetic mechanisms are still largely unknown. The diagnostic algorithm of CIU includes autologous serum skin test (ASST) and autologous plasma skin test (APST), which demonstrated a high positive and negative predictive value, in multiple nonsteroidal anti-inflammatory drugs (NSAIDs) intolerance. OBJECTIVE: to explore the underlying mechanism of MDH and to assess the correlation between such tests and autoimmune diseases (AD). METHODS: Twenty eight subjects with MDH referred to our Allergy/Immunology Unit were enrolled from May 2006 to May 2007. Eight healthy subjects served as controls. In addition to common diagnostic tools used in the diagnostic algorithm of MDH, enrolled subjects also underwent ASST and APST. RESULTS: Patients were predominantly female (23 female vs. 5 male; mean age 52.2 years). In 61% of cases MDH was associated with either CIU or AD. NSAIDs and antibiotics were the major causes of HIDR, both implied in 54% of subjects. The proportions of MDH-subjects with positive ASST and APST were 46.4% and 28.6%, respectively. All patients with MDH+AD+CIU (4/4) presented apositive ASST. CONCLUSIONS: In patients with MDH, ASST proved to be frequently positive, as previously described for multiple NSAIDs intolerance. In ASST-positive subjects, the activity of several drugs appears to add up FceRI-specific autoantibodies in the induction of the release of allergic mediators.

Risk factors for Sjögren's syndrome: a case-control study.

OBJECTIVE: The aim of this study was to investigate potential risk factors for Sjögren's syndrome (SS) by means of a multi-centre case-control study, focusing in particular on familial and environmental risk factors. 140 female SS patients and 109 female controls with orthopaedic problems were consecutively enrolled in seven university hospitals in Italy. METHODS: Information regarding the patient's lifestyle, her medical, menstrual and pregnancy history, and any family history of autoimmune diseases (AD) was obtained through a detailed structured questionnaire. The odds ratio (OR) and 95% confidence interval (95%CI) were calculated using unconditional logistic regression, adjusting for age and family size. The probability of first-degree relatives developing an autoimmune disease was also investigated. RESULTS: A positive family history of AD was significantly associated with SS. Subjects with a first-degree relative (FDR) with AD showed a seven-fold increase in the risk for SS compared to controls (OR=7.4, 95%CI 2.8-20.1); the strength of this association increased with the number of relatives affected. Similarly, the FDR of SS patients had a higher risk of AD in comparison to subjects without FDR affected by SS. Women with one or more pregnancies had an increased risk of SS (OR=2.1, 95%CI 1.0-4.3). CONCLUSION: This study suggests that a family history of AD is associated with SS.

Meningeal involvement in Wegener's granulomatosis is associated with localized disease.

Meningeal involvement is a rare occurrence in Wegener's Granulomatosis (WG). A Medline search uncovered only 48 previously reported cases. Here we describe the clinical features of meningeal involvement in WG and to evaluate the association with systemic disease extension. Through a systematic literature review of papers concerning meningeal involvement in WG, we collected and analysed data about sex, age, disease extension, symptoms, cerebrospinal fluid examination, imaging, ANCA and histology about previously reported patients. Headache is almost always the first symptom of meningeal involvement in WG. Later in the course of the disease other abnormalities may develop. Among them cranial nerve palsy, seizures and encephalopathy are the most frequent. Diagnosis is obtained by neuroimaging, which may disclose two distinct patterns of meningeal thickening: diffuse or focal. 62.9% of patients tests positive for ANCA. Histology typically shows necrotizing granulomatosis. Meningeal involvement is by far more frequent in the setting of localized WG. Meningitis is a rare complication of WG. It usually develops in patients with localized disease who are more likely to have destructive lesions of the upper airways. It may be recognized by a constellation of clinical and radiological findings and by histological signs of necrotizing granulomatosis, with little or no vasculitis.

The immunogenicity of experimental tumors is strongly biased by the expression of dominant viral cytotoxic T-lymphocyte epitopes.

The immunogenic Friend-Moloney-Rauscher (FMR) virus-induced tumors have been used extensively to clarify the cellular and molecular mechanisms responsible for tumor rejection and to develop immunotherapeutic strategies. We characterize here the trimolecular complex MHC class I-antigenic determinant-T cell receptor involved in the induction of a protective CTL response against the RMA thymoma. This complex is mainly composed by the D(b) molecule interacting with a Rauscher virus antigen (Ag) determinant and the Vbeta5+ T cell receptor. We also show that the chemically induced EL-4 thymoma acquires the susceptibility to recognition by anti-RMA CTLs and the ability to elicit a protective anti-RMA CTL response only upon infection by a virus of the FMR family and that RMA and FMR virus infected EL-4 cells share tumor-associated Ag. The data strongly support the hypothesis that the high immunogenicity of virus-induced or infected tumors is determined by the expression of immunodominant virus-encoded Ag. The demonstration of a different outcome in the immune responses elicited in the presence or in the absence of viral Ag further open the contention of the molecular requirements for immunogenicity and should stimulate a more careful revision of unexpected cross-reactivity among tumors.

Delayed clearance of apoptotic lymphoma cells allows cross-presentation of intracellular antigens by mature dendritic cells.

Single cells are deleted from the midst of living tissue during normal turnover and embryogenesis. This event is not associated with inflammation or autoimmunity. Little is known of the clearance of apoptotic cells during dangerous situations, accompanied by extensive cell death and tissue damage: when macrophages are overwhelmed by apoptotic cells, other phagocytes, including immature dendritic cells (DCs), may become involved. DCs efficiently present antigens derived from the processing of internalized apoptotic bodies to class I- and class II-restricted T cells. Antigen presentation results either in T cell activation or in their functional blockade. The outcome is influenced by pro-inflammatory maturative signals: efficient T cell cross-priming requires fully mature DCs. Here we discuss in vitro data suggesting that the number of apoptotic cells that die at a given time influences DC maturation and therefore their ability to uptake antigens from apoptotic cells and cross-activate T lymphocytes.

[Wegener's granulomatosis: an analysis of 50 patients]. / Granulomatosi di Wegener: descrizione di una casistica di 50 pazienti.

OBJECTIVES: To evaluate the rate of different organs involvement in 50 patients with Wegener's Granulomatosis (GW), and to describe their clinical manifestations and their response to treatment. METHODS: We evaluated 50 consecutive patients with GW, come to our attention from January 1987 to May 2003. 43 patients met the 1990 American College of Rheumatology (ACR) criteria for classification of GW; 7 patients the 1993 ELK criteria. RESULTS: 82% of patients presented Ear/Nose/Throat (ENT) involvement, which is the most common site of inflammation. 22% of our patients had ENT-restricted disease; in 78% of cases disease extended to other organs. Lungs were involved in 72% of cases; kidney in 36%; eye in 24%; nervous system (NS) in 14% (central NS in 10% and peripheral NS in 4%); skin in 10%; heart in 8%; testis in 4%. Arthritis was present in 10% of patients. We discuss treatment of all patients and response to therapy of those 28 whose follow-up is available. CONCLUSIONS: Involvement of airways and kidney is by far the most common in GW, though potentially any other organ or system may be affected. The total rate of other organs involvement is 70%.

Anti-beta2 glycoprotein I antibodies cause inflammation and recruit dendritic cells in platelet clearance.

Scavenger phagocytes are mostly responsible for the in vivo clearance of activated or senescent platelets. In contrast to other particulate substrates, the phagocytosis of platelets does not incite proinflammatory responses in vivo. This study assessed the contribution of macrophages and dendritic cells (DCs) to the clearance of activated platelets. Furthermore, we verified whether antibodies against the beta2 Glycoprotein I (beta2GPI), which bind to activated platelets, influence the phenomenon. DCs did not per se intemalise activated platelets. In contrast, macrophages efficiently phagocytosed platelets. In agreement with the uneventful nature of the clearance of platelets in vivo, phagocytosing macrophages did not release IL-1beta, TNF-alpha, or IL-10, beta2GPI bound to activated platelets and was required for their recognition by anti-beta2GPI antibodies. DCs internalised platelets opsonised by anti-beta2GPI antibodies. The phagocytosis of opsonised platelets determined the release of TNF-alpha and IL-1beta by DCs and macrophages. Phagocytosing macrophages, but not DCs, secreted the antiinflammatory cytokine IL-10. We conclude that anti-beta2GPI antibodies cause inflammation during platelet clearance and shuttle platelet antigens to antigen presenting DCs.

Adenosine induced production of a soluble factor affecting lymphocyte activation.

We show that a brief exposure of human peripheral blood mononuclear cells (PBMC) to adenosine or to theophylline results in a mitomycin C resistant regulatory activity. Adenosine induced suppression is also detectable in a lymphocyte subpopulation (T4+ enriched, originally described as helper inducer) resistant to the theophylline induced loss of capacity to form spontaneous rosettes with sheep erythrocytes (TTR). This activity is apparently dependent on the production of a soluble factor(s) since supernatants from adenosine treated TTR (SnA) exert a significant inhibition on the proliferative response of resting lymphocytes. On the contrary SnA increases the concanavalin A (ConA) preactivated lymphocytes proliferation. Similar results are detectable on the proliferative response in the mixed lymphocyte reaction (MLR). Perhaps these effects are related to different Interleukin 2 (Il 2) receptor expression on the cell surface of the resting and preactivated populations. A slow moving band corresponding to a protein of Mr of 64,500 and isoelectric point 7.6 is present in SnA. Only a slight Il 2 activity is detectable either in SnA and in control supernatant (SnC). These findings suggest that SnA may be a dynamic regulator of the early stages of lymphocyte activation.