ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE.

IntroductionHereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE type I) or dysfunction (C1-INH-HAE type II) is a rare disease characterized by recurrent episodes of edema with an estimated frequency of 1:50,000 in the global population without racial or gender differences. In this study we present the results of a nationwide survey of C1-INH-HAE patients referring to 17 Italian centers, the Italian network for C1-INH-HAE, ITACA.MethodsItalian patients diagnosed with C1-INH-HAE from 1973 to 2013 were included in the study. Diagnosis of C1-INH-HAE was based on family and/or personal history of recurrent angioedema without urticaria and on antigenic and/or functional C1-INH deficiency.Results983 patients (53% female) from 376 unrelated families were included in this survey. Since 1973, 63 (6%) patients diagnosed with C1-INH-HAE died and data from 3 patients were missing when analysis was performed. Accordingly, the minimum prevalence of HAE in Italy in 2013 is 920:59,394,000 inhabitants, equivalent to 1:64,935. Compared to the general population, patients are less represented in the early and late decades of life: men start reducing after the 5th decade and women after the 6th. Median age of patients is 45 (IQ 28-57), median age at diagnosis is 26 years (IQ 13-41). C1-INH-HAE type 1 are 87%, with median age at diagnosis of 25 (13-40); type 2 are 13% with median age at diagnosis of 31 (IQ 16-49). Functional C1INH is ≤50% in 99% of patients. Antigen C1INH is ≤50% in 99% of type 1. C4 is ≤50% in 96% of patients. The chance of having C1-INH-HAE with C4 plasma levels >50% is < 0.05.ConclusionThis nationwide survey of C1-INH-HAE provides for Italy a prevalence of 1:64,935. C1-INH-HAE patients listed in our database have a shorter life expectancy than the general population. An increased awareness of the disease is needed to reduce this discrepancy. Measurement of C4 antigen can exclude diagnosis of C1-INH-HAE with an accuracy > 95%. This parameter should be therefore considered for initial screening in differential diagnosis of angioedema.

To assess whether the immune derangement previously observed in SAPHO syndrome could be linked to variations in blood TH1, TH2 or TH17 lymphocytes frequency. Seven SAPHO patients with a protracted course of the disease were studied ex-vivo for intracellular cytokines production by means of flow-cytometry and compared with matched groups of Psoriatic Arthritis patients and healthy controls. The Kruskal-Wallis test on the median of the three categories showed that there is a significant association between the TH17 levels and the category (p value = 0.02474). The mean and variance for the proportion of IL-17 producing CD4+ cells were compared between groups showing significant differences between SAPHO versus PsA subgroup (p = 0.05) and SAPHO versus healthy controls (p = 0.008). Interestingly, activation of TH17 axis, but not of TH1 and TH2, has been found, and can be observed both in patients with different activity of the disease or treated with different drugs. The TH17 increase in peripheral blood of our SAPHO subjects resembles the one recently found in patients with different AIDs. Novel therapeutic options in these patients may therefore include IL-17 blockade.

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We here describe the case of a 43-year-old White woman who was diagnosed with rheumatoid arthritis treated with anti-tumour necrosis factor drugs that caused an adverse drug reaction. The objective of this study was to describe the outcome of a pregnancy under baricitinib, a JAK-inhibitor drug, in a woman affected by rheumatoid arthritis. Scant data are available about the safety of JAK inhibitors during pregnancy. A case report and review of literature about JAK-inhibitor exposure during pregnancy were conducted. After the failure of biologic disease-modifying antirheumatic drugs due to a loss of efficacy and adverse drug reaction, the patient was started on baricitinib when it was marketed. During the fifth month of this treatment, she reported missing her period and a pregnancy was confirmed, despite a previous recommendation of adequate contraception. Thus, she had been exposed to baricitinib for several weeks before conception and during the whole first-trimester until the 17th week of gestation. The treatment with baricitinib was promptly discontinued and she was regularly examined. Foetal growth was normal throughout pregnancy and ultrasound examination did not detect any macroscopic abnormality. This is the first report of exposure to baricitinib during pregnancy outside the drug registration study program. We report the positive pregnancy outcome of a continuous exposure to baricitinib during the first 17 weeks of pregnancy. Small molecules, such as JAK inhibitors, are increasingly being used in clinical practice in rheumatoid arthritis and in other diseases. Hence, more broad and focused studies are required to have an insight of safety for this drug class in the case of accidental exposure before or during pregnancy.

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Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular manifestations. Since the identification of the syndrome many immunosuppressive drugs have been used for the management of SAPHO, with variable results. The use of anti- TNF-α agents as a therapeutic option for SAPHO cases unresponsive or refractory to conventional drugs, demonstrated their efficacy for bone, skin and joints manifestations. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β , IL-6 and IL-8, involved in inflammation, acute-phase response induction and chemotaxis. IL-1 inhibition strategies with Anakinra have proven their efficacy as first and second line treatment. We herein review the literature concerning the use of biological drugs in patients with SAPHO syndrome. In addition, we describe for the first time the use of Ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and Anakinra. This anti-IL12/IL23 agent could be a promising therapeutic option, also considering the opportunity to interfere with the IL23/TH17 pathway, which we recently found disturbed. Furthermore, a rationale emerges for the use of the new anti-IL-1 antagonists or the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.

A b s t r a c t Introduction: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE)or with normal C1-INH is characterized by recurrent swellings due to uncontrolled production of vasoactive mediators, among which bradykinin (BK) is crucial. Through the binding and activation of the two human BK-receptors, kinins may have dual beneficial and deleterious effects in vascular and inflammation physiopathology by inducing oxidative stress. We aimed to assess the serum concentrations of advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) in patients affected by HAE. Material and methods: Blood samples were collected to measure the serum concentrations of AGEs and AOPPs by spectrofluorimetric and spectrophotometric methods in patients affected by C1-INH-HAE and FXII-HAE during the remission state. Results: We showed that the circulating levels of AOPPs observed on control group (0.94 (0.36) nmol/ mg) were significantly lower than those observed on the C1-INH-HAE group (1.68 (0.47) nmol/mg; p = 0.002) and FXII-HAE (1.50 (0.27) nmol/mg; p = 0.001). Moreover, the circulating levels of AGEs were significantly higher in C1- ) AU/g; p = 0.02) than the FXII group (141.48 (89.59) AU/g), thus demonstrating a state of heightened oxidative stress. Conclusions: Our observations show additional underlying events involved in HAE and are of central importance for further investigations of differences in bradykinin receptors signaling among the two disease subgroups.