Background
Hereditary angioedema (HAE) due to C1‐inhibitor deficiency (C1‐INH‐HAE) is a rare, potentially fatal, bradykinin‐mediated disease. Icatibant is a bradykinin B2 receptor antagonist ...originally approved in 2008 in the European Union and 2011 in the United States as an acute therapy option for HAE attacks in adults.
Objective
To compare demographics, disease characteristics and treatment outcomes of icatibant‐treated HAE attacks in patients with C1‐INH‐HAE enrolled in the Icatibant Outcome Survey across six European countries: Austria, France, Germany, Italy, Spain and the UK.
Methods
The Icatibant Outcome Survey IOS; Shire, Zug, Switzerland (NCT01034969) is an international observational study monitoring the safety and effectiveness of icatibant. Descriptive, retrospective analyses compared IOS country data derived during July 2009–April 2015.
Results
Overall, 481 patients with C1‐INH‐HAE provided demographic data. A significant difference across countries in age at onset (P = 0.003) and baseline attack frequency (P < 0.001) was found although no significant differences were found with respect to gender (majority female; P = 0.109), age at diagnosis (P = 0.182) or delay in diagnosis (P = 0.059). Icatibant was used to treat 1893 attacks in 325 patients with majority self‐administration in all countries. Overall, significant differences (all P < 0.001) were found across countries in time to treatment median 1.8 h; median range: 0.0 (Germany–Austria) to 4.4 (France) h, time to resolution median 6.5 h; median range: 3 (Germany–Austria) to 12 (France) h and attack duration median 10.5 h; median range: 3.1 (Germany–Austria) to 18.5 (France) h.
Conclusion
These data form the first European cross‐country comparison of disease characteristics and icatibant use in patients with C1‐INH‐HAE who are enrolled in IOS. International variation in icatibant practice and treatment outcomes across the six European countries assessed highlight the need to further investigate the range of country‐specific parameters driving regional variations in icatibant use.
SUMMARY
In this study we have evaluated the modifications of matrix metalloproteinases (MMPs) in malignant pleural fluids taken from patients suffering from lung cancer and treated with intrapleural ...talc instillation to induce pleurodesis. Furthermore, we have analysed the variations of some inflammatory mediators (C‐reactive protein, α‐1 antitrypsin) and of a protein (plasminogen) involved in MMP activation. In all patients the clinical improvement after talc pleurodesis was followed by a reduction in MMP‐1, TIMP‐1, C‐reactive protein, α‐1 antitrypsin and plasminogen activity. Furthermore, MMP‐9 levels were variable; in fact, in some patients they were high at the beginning of treatment, in others they increased a few days after pleurodesis induction. These inhibitory effects of talc on MMP‐1 and inflammatory mediators associated with the reduction of pleural effusion could constitute an effective means to evaluate the evolution of the treatment.
Phase 3 icatibant trials showed that most hereditary angioedema (HAE) (C1 inhibitor deficiency) acute attacks were treated successfully with one injection of icatibant, a selective bradykinin B2 ...receptor antagonist. We conducted a post hoc analysis of icatibant reinjection for HAE type I and II attacks in a real-world setting by using data from the Icatibant Outcome Survey, an ongoing observational study that monitors the safety and effectiveness of icatibant treatment.
Descriptive retrospective analyses of icatibant reinjection were performed on Icatibant Outcome Survey data (February 2008 to December 2012). New attacks were defined as the onset of new symptoms after full resolution of the previous attack. Potential associations between the patient and attack characteristics and reinjection were explored by using logistic regression analysis.
Icatibant was administered for 652 attacks in 170 patients with HAE type I or II. Most attacks (89.1%) were treated with a single icatibant injection. For attacks that required two or three injections, the second injection was given a median of 11.0 hours after the first injection, with 90.4% of second injections administered ≥6 hours after the first injection. Time to resolution and attack duration were significantly longer for two or three injections versus one icatibant injection (p < 0.0001 and p < 0.05, respectively). Multivariate logistic regression analysis identified sex, attack severity, and laryngeal attacks as significantly correlated with reinjection (all p ≤ 0.05). These factors did not remain predictors for reinjection when two outlier patients with distinct patterns of icatibant use were excluded.
In this real-world setting, most HAE attacks resolved with one icatibant injection. There was no distinct profile for patients or attacks that required reinjection when outliers with substantially different patterns of use were excluded. Because new attacks were not distinguished from the recurrence of symptoms, reinjection rates may be slightly higher than shown here. Clinical trial identifier: NCT01034969.
Icatibant was efficacious and generally well tolerated for type I or II hereditary angioedema (HAE) attacks in adults in the phase III, randomized, placebo-controlled For Angioedema Subcutaneous ...Treatment (FAST)-3 trial. The Icatibant Outcome Survey (IOS) is an international, observational study assessing icatibant treatment of HAE attacks. We conducted a posthoc analysis to compare for the first time the treatment of HAE type I or II attacks in patients prescribed icatibant in real-world (IOS) versus controlled trial settings (FAST-3). In FAST-3, patients received icatibant administered by health care professionals (HCPs). In IOS, patients self-administered icatibant or were treated by HCPs. Median time to treatment, time to resolution (almost complete resolution FAST-3 or complete resolution IOS), and attack duration in patients who were treated by an HCP were compared between IOS and FAST-3. Descriptive statistical methods compared nonlaryngeal attacks treated less than 12 hours from attack onset. Analysis included 102 patients (376 attacks) from IOS and 43 patients (43 attacks) from FAST-3 (controlled phase). All endpoints were significantly longer for patients in FAST-3 (HCP administration) versus IOS (HCP administration) (p < .001; all comparisons). For FAST-3 (HCP administered) versus IOS (HCP administered), median time from attack onset to treatment was 6.5 versus 2.0 hours, median time to symptom resolution was 8.0 versus 3.5 hours, and median attack duration was 16.9 versus 7.3 hours, respectively. For combined HCP and self-administration in IOS, these endpoints were 1.6, 4.4, and 7.8 hours, respectively. This posthoc analysis showed for the first time that type I and II HAE attacks were treated earlier with icatibant in a real-world versus a phase III setting, with a shortened time to symptom resolution and attack duration. ClinicalTrials.gov NCT00912093 (FAST-3); NCT01034969 (IOS).
Patients with hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) experience recurrent attacks of cutaneous or submucosal edema that may be frequent and severe; prophylactic ...treatments can be prescribed to prevent attacks. However, despite the use of long-term prophylaxis (LTP), breakthrough attacks are known to occur. We used data from the Icatibant Outcome Survey (IOS) to evaluate the characteristics of breakthrough attacks and the effectiveness of icatibant as a treatment option.
Data on LTP use, attacks, and treatments were recorded. Attack characteristics, treatment characteristics, and outcomes (time to treatment, time to resolution, and duration of attack) were compared for attacks that occurred with versus without LTP.
Data on 3228 icatibant-treated attacks from 448 patients with C1-INH-HAE were analyzed; 30.1% of attacks occurred while patients were using LTP. Attack rate, attack severity, and the distribution of attack sites were similar across all types of LTP used, and were comparable to the results found in patients who did not receive LTP. Attacks were successfully treated with icatibant; 82.5% of all breakthrough attacks were treated with a single icatibant injection without C1-INH rescue medication. Treatment outcomes were comparable for breakthrough attacks across all LTP types, and for attacks without LTP.
Patients who use LTP should be aware that breakthrough attacks can occur, and such attacks can be severe. Thus, patients with C1-INH-HAE using LTP should have emergency treatment readily available. Data from IOS show that icatibant is effective for the treatment of breakthrough attacks.
NCT01034969.
Background
Hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) is characterized by recurrent swelling in subcutaneous or submucosal tissues. Symptoms often begin by age 5–11 years and ...worsen during puberty, but attacks can occur at any age and recur throughout life. Disease course in elderly patients is rarely reported.
Methods
The Icatibant Outcome Survey (IOS) is an observational study evaluating the safety, tolerability, and efficacy of icatibant. We conducted descriptive analyses in younger (age < 65 years) versus elderly patients (age ≥ 65 years). Here, we report patient characteristics and safety‐related findings.
Results
As of February 2018, 872 patients with C1‐INH‐HAE type I/II were enrolled, of whom 100 (11.5%) were ≥ 65 years old. Significant differences between elderly versus younger patients, respectively, were noted for median age at symptom onset (17.0 vs 12.0 years), age at diagnosis (41.0 vs 19.4 years), and delay between symptom onset and diagnosis (23.9 vs 4.8 years) (P ≤ 0.0001 for all). Median age at diagnosis was significantly higher in elderly patients regardless of family history (P < 0.0001). Throughout the study, icatibant was used to treat 6798 attacks in 574 patients, with 63 elderly patients reporting 715 (10.5%) of the icatibant‐treated attacks. No serious adverse events (SAEs) in elderly patients were judged to be possibly related to icatibant, whereas two younger patients reported three possibly related SAEs. Excluding off‐label use and pregnancy (evaluated for regulatory purposes), the percentage of patients with at least one possibly/probably related AE was similar for elderly (2.0%) versus younger patients (2.7%). No deaths linked to icatibant treatment were identified. All related events in elderly patients were attributed to general disorders/administration site conditions, whereas related events in younger patients occurred across various system organ class designations.
Conclusions
Elderly patients with C1‐INH‐HAE were significantly older at diagnosis and had greater delay in diagnosis than younger patients. Elderly patients contributed to approximately 10% of the icatibant‐treated attacks. Our analysis found similar AE rates (overall and possibly/probably related) in icatibant‐treated elderly versus younger patients, despite the fact that elderly patients had significantly more comorbidities and were receiving a greater number of concomitant medications. Our analysis did not identify any new or unexpected safety concerns.
Cytokines are part of a family of molecules involved in the initiation, control and termination of the events that occurs in wound healing process. Aim of this study was to evaluate the production of ...some cytokines interleukin (IL)-6, IL-10, IL-1alpha, IL-1ra, interferon (IFN)-gamma in the drainage wound fluid from patients undergoing incisional hernia repair.
Ten female patients with abdominal midline incisional hernia undergoing to surgical repair were included in this study. In all cases a closed suction drain was placed in the wound below the fascia and it was removed on the 4th postoperative day. Wound fluid was collected on the 1st, 2nd, 3rd and 4th day and its amount in each time was recorded. The production of IL-6, IL-10, IL-1alpha, IL-1ra and IFN-gamma were evaluated as quantity produced in 24 hour.
In all patients the amount of drain fluid from surgical wound was highest on the 1st day after surgery, afterwards there is a significant reduction. The production of all cytokines evaluated was highest on the 1st day decreasing on the 2nd day except for IL-1alpha that not show any modification. The produciton of IL-1ra, IL-6, IL-1alpha and IL-10 was significantly reduced on the 3rd and 4th postoperative day in comparison with the respectively values recorded on the 1st day, whereas IFN-gamma levels were similar.
The dosage of cytokines in the drain fluid led us to better evaluated the events that follow surgical wound and their analysis offers further information in the role of cytokines in healing process, with the goal to get supportive treatments to promote the best evolution.
Interferon (IFN)-γ, interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-α were significantly increased in sera from Sicilian patients with acute boutonneuse fever (BF) compared with those of ...healthy controls. IFN-γ levels dropped sharply within the second week after infection. IL-6, IL-10, and TNF-α levels gradually declined; in convalescent patients only were they in the normal range. In contrast, peripheral blood mononuclear cells (PBMC) stimulated in vitro with phytohemagglutinin (PHA) produced low levelsof IL-10 and IFN-γ in acute BF that were compatible with the reduction in the levels of CD4+, CD4+/CD45RO+, and CD4+ICD45RA+ cells. In vitro production of TNF-α and IL-6 from PBMC stimulated with PHA was not significantly modified during the various phases of the infection compared with control PBMC, which could be due to the persistence of high levels of CD14+ monocytes compensating for the decrease in CD20+ B cells.
The ability of three modified tetrapeptides, representing fragments of the C‐reactive protein (CRP) sequence and stabilized in the first peptide bond by retro‐inverso modification, to affect the ...secretion of nitric oxide (NO) was studied in macrophages of BALB/c mice.
These tetrapeptides, resembling the aminoacid sequence of tuftsin (CRP I, H‐gThr‐(R,S)mLys‐Pro‐Leu‐OH, ITF 1192; CRP II, H‐gGly‐(R, S)mLys‐Pro‐Arg‐OH, ITF 1127; CRP III, H‐gThr‐(R,S)mLys‐Pro‐Gln‐OH, ITF 1193), were able to induce NO synthesis by peritoneal macrophages in a dose‐dependent manner; the most stimulating dose was 1000 ng ml−1 for CRP II and 100 ng ml−1 for CRP I and CRP III. NO synthesis was not strictly dependent on lipopolysaccharide (LPS) activation.
The enhanced effect of retro‐inverso CRP‐related analogues on the expression of iNOS (inducible NO synthase) was confirmed by higher levels of iNOS activity in the cytosol and by the increase in iNOS protein, as evaluated by Western blot analysis, in macrophages stimulated by CPR compared with untreated ones.
The production of NO by retro‐inverso CRP‐peptide analogues was significantly inhibited by dexamethasone (20 μm), NG‐monomethyl‐l‐arginine (l‐NMMA) (500 μm) and pyrrolidine dithiocarbamate (PDTC) (100 μm).
Retro‐inverso CRP‐peptide analogues stimulated macrophages to produce high levels of interleukin‐1 (IL‐1) and tumour necrosis factor‐α (TNF‐α) in the presence of LPS.
Retro‐inverso CRP‐peptide analogues stimulated NO synthesis by the enhancement of endogenously produced IL‐1 and TNF‐α, as the treatment of peritoneal macrophages with LPS in the presence of neutralizing anti‐IL‐1 and anti‐TNF monoclonal antibodies (mAbs) reduced retro‐inverso analogue‐induced NO secretion. Data indicate a predominant role for IL‐1α in the induction of NO secretion by retro‐inverso analogues.
These results suggest that retro‐inverso CRP derived analogues act as costimulators of NO and cytokine synthesis in macrophages. The mechanisms by which they cause iNOS induction appear to be strongly dependent on the activation of nuclear factor‐κB (NF‐κB).
British Journal of Pharmacology (1997) 120, 1383–1389; doi:10.1038/sj.bjp.0701050
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