Publications by authors named "Massimo Cugno"

113 Publications

The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells.

J Allergy Clin Immunol Pract 2021 Apr 3. Epub 2021 Apr 3.

Divison of Pulmonary and Critical Care Medicine and Allergy and Immunology, Dept. Medicine, The Medical University of South Carolina, Charleston, SC.

Chronic spontaneous urticaria is characterized by a perivascular non-necrotizing cellular infiltrate around small venules of the skin. It consists primarily of CD4(+) lymphocytes, a prominence of the Th-2 subtype but also Th-1 cells, with Th 17 cell derived cytokines elevated in plasma. There are also neutrophils, eosinophils, basophils, and monocytes. Chemokines derived from mast cells and activated endothelial cells drive the process. While the role of the cellular infiltrate has not previously been addressed, each constituent contributes to the overall pathogenesis and responsiveness to steroid, in particular, focus attention on its importance since short-term steroids do not affect autoimmunity or degranulation of mast cells, and act on margination of cells along the endothelium and chemotaxis to enter the surrounding dermis. In this review we address each cells contribution to the overall inflammatory response, as it is currently understood, with a view toward development of therapeutic options that impede the function of critical cells and/or their secretory products.
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http://dx.doi.org/10.1016/j.jaip.2021.03.033DOI Listing
April 2021

Mortality in Patients with COVID-19 on Renin Angiotensin System Inhibitor Long-Term Treatment: An Observational Study Showing that Things Are Not Always as They Seem.

Adv Ther 2021 Apr 1. Epub 2021 Apr 1.

Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Milan, Italy.

Introduction: At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, controversial data were reported concerning angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) that induced a number of physicians to stop using them in patients with COVID-19. Although large-scale studies have ruled out this concern, it is common experience that patients with COVID-19 taking ACE inhibitors or ARBs are at increased risk of death. The aim of this study was to investigate the reasons for this apparently high mortality rate.

Methods: During the first wave of the pandemic, we conducted a field study of 427 consecutive patients with COVID-19 upon their admission to the emergency department of a hospital in one of the most severely hit cities in northern Italy, and 30 days later. The disease was defined as being mild, moderate or severe on the basis of clinical, laboratory and imaging data, and a multivariate model was used to analyse the determinants of mortality.

Results: Within 30 days of admission, 31.6% of the patients treated with ACE inhibitors or ARBs and 15.2% of those not treated with these drugs had died. Multivariate analysis showed that the determinants of mortality were age (p = 0.0001), hypertension (p = 0.0120) and diabetes (p = 0.0129), whereas ACE inhibitors or ARBs had no effect on mortality. There was no significant difference between the patients treated with ACE inhibitors and those treated with ARBs.

Conclusion: The apparently increased mortality of patients with COVID-19 receiving long-term treatment with ACE inhibitors or ARBs is not due to the drugs themselves, but to the conditions associated with their use.
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http://dx.doi.org/10.1007/s12325-021-01704-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012518PMC
April 2021

IgM Autoantibodies to Complement Factor H in Atypical Hemolytic Uremic Syndrome.

J Am Soc Nephrol 2021 Mar 12. Epub 2021 Mar 12.

Center for Hemolytic Uremic Syndrome Prevention, Control and Management, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Background: Atypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class.

Methods: In 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein.

Results: We detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving . A significantly higher proportion of patients with bone marrow transplant-related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b.

Conclusions: Detectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H's active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.
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http://dx.doi.org/10.1681/ASN.2020081224DOI Listing
March 2021

Biomarkers of chronic spontaneous urticaria and their clinical implications.

Expert Rev Clin Immunol 2021 Mar 12;17(3):247-254. Epub 2021 Feb 12.

Medicina Interna, Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti, Università degli Studi di Milano, Milano, Italy.

: Chronic spontaneous urticaria (CSU) is a frequent disorder in which activation of effector cells and histamine release can be induced via several distinct pathogenetic mechanisms. Much work has been carried out to identify biomarkers useful for classifying CSU patients, and to predict their response to currently available treatments.: The recent literature dealing with CSU biomarkers was screened in PubMed and Google Scholar using 'chronic spontaneous urticaria', 'biomarker', 'diagnosis', 'therapy' and 'treatment response' as key words. The characteristics found in relevant papers were divided into clinical and serological biomarkers of (a) clinical severity/disease activity, and (b) response to treatments.: A diagnostic biomarker for CSU is still missing. Most biomarkers described so far do not seem to possess sufficient specificity for this disease. Basopenia and the activation of the coagulation cascade might be biomarkers of disease activity and severity, but information available so far is insufficient to consider their routine use. Markers suggesting IgG-mediated autoimmunity (autologous serum skin test, basophil activation/histamine release assays, low total IgE) seem to identify patients less prone to respond to omalizumab but responsive to cyclosporine. In contrast, 'autoallergy' (i.e. the presence of IgE to autoallergens), which is often associated with elevated IgE levels seems to identify patients who will respond to omalizumab.
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http://dx.doi.org/10.1080/1744666X.2021.1882304DOI Listing
March 2021

Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19.

J Autoimmun 2021 02 9;117:102595. Epub 2021 Jan 9.

Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy. Electronic address:

Background: Genetic variation at a multigene cluster at chromosome 3p21.31 and the ABO blood group have been associated with the risk of developing severe COVID-19, but the mechanism remains unclear. Complement activation has been associated with COVID-19 severity.

Objective: The aim of this study was to examine whether chromosome 3p21.31 and the ABO variants are linked to the activation of the complement cascade in COVID-19 patients.

Methods: We considered 72 unrelated European hospitalized patients with genetic data and evaluation of circulating C5a and soluble terminal complement complex C5b-9 (SC5b-9). Twenty-six (36.1%) patients carried the rs11385942 G>GA variant and 44 (66.1%) non-O blood group associated with increased risk of severe COVID-19.

Results: C5a and SC5-b9 plasma levels were higher in rs11385949 GA carriers than in non-carriers (P = 0.041 and P = 0.012, respectively), while C5a levels were higher in non-O group than in O group patients (P = 0.019). The association between rs11385949 and SC5b-9 remained significant after adjustment for ABO and disease severity (P = 0.004) and further correction for C5a (P = 0.018). There was a direct relationship between upper airways viral load and SC5b-9 in carriers of the rs11385949 risk allele (P = 0.032), which was not observed in non-carriers.

Conclusions: The rs11385949 G>GA variant, tagging the chromosome 3 gene cluster variation and predisposing to severe COVID-19, is associated with enhanced complement activation, both with C5a and terminal complement complex, while non-O blood group with C5a levels. These findings provide a link between genetic susceptibility to more severe COVID-19 and complement activation.
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http://dx.doi.org/10.1016/j.jaut.2021.102595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796659PMC
February 2021

Relationship between thrombin generation parameters and prothrombin fragment 1 + 2 plasma levels.

Int J Lab Hematol 2021 Jan 12. Epub 2021 Jan 12.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1111/ijlh.13462DOI Listing
January 2021

Complement activation and endothelial perturbation parallel COVID-19 severity and activity.

J Autoimmun 2021 01 29;116:102560. Epub 2020 Oct 29.

Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.

Background: Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet.

Objective: To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients.

Methods: In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma.

Results: The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels.

Conclusions: Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.
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http://dx.doi.org/10.1016/j.jaut.2020.102560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598768PMC
January 2021

Genetic and molecular evidence for complement dysregulation in patients with HELLP syndrome.

Thromb Res 2020 12 27;196:167-174. Epub 2020 Aug 27.

Internal Medicine, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy. Electronic address:

Background: HELLP (Hemolysis, elevated liver enzymes and low platelets) syndrome is a severe and acute pregnancy-related disorder that occurs in approximately 2.5 per 1000 deliveries and represents a major cause of maternal and perinatal morbidity and mortality. This syndrome has been suggested to be a microangiopathy and delivery is the only effective treatment.

Objectives: The aim of this study was to investigate the pathophysiology of HELLP syndrome by simultaneously exploring complement, haemostasis, autoimmunity and inflammation in relation to the clinical outcome.

Methods: We investigated 19 HELLP patients at the time of diagnosis and 3 months after delivery, for complement function, haemostasis and inflammation with immunoenzymatic methods. Complement-related gene variants were also analyzed by next generation sequencing and multiplex ligation-dependent probe amplification. Nineteen age-matched healthy pregnant women served as controls.

Results: At diagnosis, HELLP patients, compared to controls, showed significantly higher plasma levels of SC5b-9 (median 710 ng/ml [range 216-1499] vs 253 ng/ml [19-371], P < 0.0001) and of C5a (20.8 ng/ml [5.6-27.5] vs 12.7 ng/ml [3.2-24.6]; P = 0.004), which decreased three months after delivery (SC5b9: 190 ng/ml [83-446] vs 160 ng/ml [107-219]; C5a: 9.28 ng/ml [2.3-21.6] vs 10.7 ng/ml [2.5-21.2]). A significantly higher frequency of genetic variants involving complement regulatory genes was also observed (52.6% vs 15.8%; P = 0.016). Moreover, at HELLP diagnosis, patients showed increased coagulation markers (fragment F1 + 2 and D-dimer; P = 0.0001) while both patients and controls had high thrombin-generation potential that decreased after delivery.

Conclusions: In the pathophysiology of HELLP syndrome, complement dysregulation, in addition to coagulation activation, is involved and may represent a potential target for treatment with the aim of delaying delivery.
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http://dx.doi.org/10.1016/j.thromres.2020.08.038DOI Listing
December 2020

Complement activation in patients with COVID-19: A novel therapeutic target.

J Allergy Clin Immunol 2020 Jul 14;146(1):215-217. Epub 2020 May 14.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.

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http://dx.doi.org/10.1016/j.jaci.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224678PMC
July 2020

Autochthonous ST405 NDM-5 producing Escherichia coli causing fatal sepsis in Northern Italy.

Int J Antimicrob Agents 2020 May 11;55(5):105953. Epub 2020 Apr 11.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Infectious Diseases Unit, Department of Internal Medicine, Milan, Italy; Centre for Multidisciplinary Research in Health Science, Milan, Italy.

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http://dx.doi.org/10.1016/j.ijantimicag.2020.105953DOI Listing
May 2020

Hereditary Deficiency of the Second Component of Complement: Early Diagnosis and 21-Year Follow-Up of a Family.

Medicina (Kaunas) 2020 Mar 10;56(3). Epub 2020 Mar 10.

Internal Medicine, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Complement deficiencies are rare and often underdiagnosed primary immunodeficiencies that may be associated with invasive bacterial diseases. Serious infections with encapsulated organisms (mainly Streptococcus pneumoniae, but also Neisseria meningitides and Haemophilus influenzae type B) are frequent in patients with a deficiency of the second component of complement (C2), but no data are available on long-term follow-up. This study aimed to evaluate the long-term clinical outcome and the importance of an early diagnosis and subsequent infection prophylaxis in C2 deficiency. Here, we report the 21-year follow-up of a whole family which was tested for complement parameters, genetic analysis and biochemical measurements, due to recurrent pneumococcal meningitis in the elder brother. The two sons were diagnosed with homozygous type 1 C2 deficiency, while their parents were heterozygous with normal complement parameters. For the two brothers, a recommended vaccination program and antibiotic prophylaxis were prescribed. During the long-term follow-up, no severe/invasive infections were observed in either patient. At the age of 16, the younger brother developed progressive hypogammaglobulinemia of all three classes, IgA, IgM and IgG. A next generation sequencing panel excluded the presence of gene defects related to primary antibody deficiencies. Our data show that early diagnosis, use of vaccinations and antibiotic prophylaxis may allow a normal life in hereditary C2 deficiency, which can be characterized using functional and genetic methods. Moreover, a periodical check of immunoglobulin serum levels could be useful to detect a possible hypogammaglobulinemia.
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http://dx.doi.org/10.3390/medicina56030120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143546PMC
March 2020

Tocilizumab Effects on Coagulation Factor XIII in Patients with Rheumatoid Arthritis.

Adv Ther 2019 12 25;36(12):3494-3502. Epub 2019 Oct 25.

Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Ospedale Maggiore Policlinico, IRCCS Fondazione Ca' Granda Milano, Università degli Studi di Milano, Milan, Italy.

Introduction: Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease associated with a prothrombotic state. Tocilizumab, an interleukin-6 receptor inhibitor, is highly effective in controlling disease activity and thrombotic risk. Factor XIII (FXIII), involved in thrombotic complications, has been reported to be reduced in RA patients during maintenance treatment with tocilizumab, but no data are available before and after the drug administration. Thus, we investigated the effects of tocilizumab on FXIII, thrombin generation and inflammation in patients with RA naïve for the drug.

Methods: We studied 15 consecutive adult patients with RA at baseline and 4 weeks after the onset of parenteral administration of tocilizumab, measuring disease activity and plasma levels of C-reactive protein (CRP), FXIII, and prothrombin fragments F1+2 by immunoenzymatic methods. Fifteen healthy subjects, sex-and age-matched with patients, served as normal controls for laboratory measurements.

Results: At baseline, patients with established RA had a median DAS28 of 4.8 (3.2-8.3) and, compared to healthy controls, had higher plasma levels of CRP (p < 0.0001), FXIII (p = 0.017) and F1+2 (p < 0.0001). Four weeks after starting treatment with tocilizumab, based on the EULAR response criteria, eight patients were classifiable as responders and seven as non-responders. In responders, we observed a statistically significant reduction not only of the values of DAS28 and CRP (p = 0.012 for both), ut also of plasma levels of FXIII (p = 0.05) and F1+2 (p = 0.025). In non-responders, all the studied parameters were unchanged.

Conclusion: The decrease of FXIII and F1+2 levels after tocilizumab treatment observed only in those patients who responded to the drug indicates that the effect of tocilizumab on the prothrombotic state is linked to the control of inflammation and disease activity and not to a direct effect of the drug, thus contributing to the reduction of the cardiovascular risk.
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http://dx.doi.org/10.1007/s12325-019-01118-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860466PMC
December 2019

Editorial: Neutrophil-Mediated Skin Diseases: Immunology and Genetics.

Front Immunol 2019 9;10:2377. Epub 2019 Oct 9.

Department of Physiopathology and Transplantation, Università Degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.3389/fimmu.2019.02377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794441PMC
October 2020

New Insights Into the Pathogenesis of Bullous Pemphigoid: 2019 Update.

Front Immunol 2019 2;10:1506. Epub 2019 Jul 2.

Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are hallmarked by the production of autoantibodies directed against the hemidesmosomal anchoring proteins BP180 and BP230. In contrast to the robustness of the latter assumption, the multifaceted complexity of upstream and downstream mechanisms implied in the pathogenesis of BP remains an area of intense speculation. So far, an imbalance between T regulatory cells and autoreactive T helper (Th) cells has been regarded as the main pathogenic factor triggering the autoimmune response in BP patients. However, the contributory role of signaling pathways fostering the B cell stimulation, such as Toll-like receptor activation, as well as that of ancillary inflammatory mechanisms responsible for blister formation, such as Th17 axis stimulation and the activation of the coagulation cascade, are still a matter of debate. In the same way, the pathomechanisms implied in the loss of dermal-epidermal adhesion secondary to autoantibodies binding are not fully understood. Herein, we review in detail the current concepts and controversies on the complex pathogenesis of BP, shedding light on the most recent theories emerging from the literature.
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http://dx.doi.org/10.3389/fimmu.2019.01506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614376PMC
July 2020

Coagulation and Skin Autoimmunity.

Front Immunol 2019 20;10:1407. Epub 2019 Jun 20.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.

Several lines of evidence indicate that the immune system, inflammation, and coagulation are simultaneously activated in autoimmune and immune-mediated skin diseases. Pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha induce the expression of the main initiator of coagulation, i.e., tissue factor. The proteases of coagulation in turn act on protease-activated receptors inducing the expression of various pro-inflammatory cytokines triggering inflammation. The cross-talk among immune system, inflammation, and coagulation amplifies and maintains the activation of all three pathways. This review focuses on three skin disorders as chronic spontaneous urticaria (CSU), angioedema, and bullous pemphigoid (BP), in which the relationships among the three systems have been investigated or their clinical consequences are relevant. Markers of thrombin generation, fibrinolysis, and inflammation have been reported to be increased in the plasma during flares of CSU and angioedema, as well as in the active phase of BP, with the marker levels reverting to normal during remission. The coagulation activation seems to be important only at local level in CSU and angioedema while both at local and systemic levels in BP which is the only condition associated with an increased thrombotic risk. The prothrombotic state in autoimmune skin diseases raises the question of the indication of anticoagulant treatment, particularly in the presence of other cardiovascular risk factors.
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http://dx.doi.org/10.3389/fimmu.2019.01407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596352PMC
October 2020

Validation of the Predictive Model of the European Society of Cardiology for Early Mortality in Acute Pulmonary Embolism.

TH Open 2018 Jul 6;2(3):e265-e271. Epub 2018 Sep 6.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

 Acute pulmonary embolism (PE) is burdened by high mortality, especially within 30 days from the diagnosis. The development and the validation of predictive models for the risk of early mortality allow to differentiate patients who can undergo home treatment from those who need admission into intensive care units.  To validate the prognostic model for early mortality after PE diagnosis proposed by the European Society of Cardiology (ESC) in 2014, we analyzed data of a cohort of 272 consecutive patients with acute PE, observed in our hospital during a 10-year period. Moreover, we evaluated the additional contribution of D-dimer, measured at PE diagnosis, in improving the prognostic ability of the model. All cases of PE were objectively diagnosed by angiography chest CT scan or perfusion lung scan.  The overall mortality rate within 30 days from PE diagnosis was 10% (95% confidence interval [CI]: 6.4-13.5%). According to the ESC prognostic model, the risk of death increased 3.23 times in the intermediate-low-risk category, 5.55 times in the intermediate-high-risk category, and 23.78 times in the high-risk category, as compared with the low-risk category. The receiver operating characteristic analysis showed a good discriminatory power of the model (area under the curve [AUC] = 0.77 [95% CI: 0.67-0.87]), which further increased when D-dimer was added (AUC = 0.85 [95% CI: 0.73-0.96]).  This study represents a good validation of the ESC predictive model whose performance can be further improved by adding D-dimer plasma levels measured at PE diagnosis.
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http://dx.doi.org/10.1055/s-0038-1669427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524882PMC
July 2018

A 5-month history of fever and dry cough in a 67-year-old man.

Intern Emerg Med 2020 09 18;15(6):1057-1060. Epub 2019 Jun 18.

Medicina Interna, Dipartimento Di Fisiopatologia Medico-Chirurgica E Dei Trapianti, Università Degli Studi Di Milano, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Via Pace, 9, 20122, Milano, Italy.

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http://dx.doi.org/10.1007/s11739-019-02132-1DOI Listing
September 2020

Baseline D-dimer plasma levels correlate with disease activity but not with the response to omalizumab in chronic spontaneous urticaria.

Allergy 2019 12 26;74(12):2538. Epub 2019 Jun 26.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1111/all.13936DOI Listing
December 2019

Mechanisms of Inflammation in Neutrophil-Mediated Skin Diseases.

Front Immunol 2019 8;10:1059. Epub 2019 May 8.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.

Neutrophil-mediated skin diseases, originally named neutrophilic dermatoses (NDs), are a group of conditions due to an altered neutrophil recruitment and activation, characterized by polymorphic cutaneous manifestations with possible internal organ involvement. Although a number of diseases are included in this setting, the two prototypic forms are pyoderma gangrenosum (PG) and Sweet's syndrome (SS) which usually present with skin ulcers and plaque-type lesions, respectively. They have central features significantly overlapping with autoinflammatory conditions which manifest as repeated episodes of tissue inflammation. However, in contrast to appropriate inflammatory responses to insults or to autoimmune disease, there is an absence of identifiable pathogens, autoantibodies, or autoreactive lymphocytes. The recognition of monogenic autoinflammatory diseases which can present with NDs has led to study several genes involved in autoinflammation in NDs. Based on discovering of a number of mutations involving different autoinflammatory genes, neutrophil-mediated skin diseases are nowadays regarded as a spectrum of polygenic autoinflammatory conditions. Although disease mechanisms have not yet been completely elucidated, NDs are recognized as diseases involving dysfunctional cellular signaling mediated by pathways mainly related to inflammasome and IL-1 with the contributory role of IL-17 and other effector molecules. The precise elucidation of the above-mentioned pathologic mechanisms may pave the way to tailored treatments for patients with different neutrophil-mediated skin diseases.
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http://dx.doi.org/10.3389/fimmu.2019.01059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519315PMC
June 2020

Paradoxical Skin Reactions to Biologics in Patients With Rheumatologic Disorders.

Front Pharmacol 2019 26;10:282. Epub 2019 Mar 26.

UOC Dermatologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Targeted immune-modulating treatment with biological agents has revolutionized the management of immune-mediated inflammatory diseases, including rheumatologic conditions. The efficacy and tolerability of biological agents, from the initial tumour necrosis factor (TNF)-α inhibitors to the new anti-cytokine monoclonal antibodies, have dramatically changed the natural history of debilitating conditions such as rheumatoid arthritis and seronegative spondyloarthropathies. The widening use of biologics across several rheumatologic diseases has been associated with a new class of adverse events, the so-called paradoxical reactions. These events are inflammatory immune-mediated tissue reactions, developing paradoxically during treatment of rheumatologic conditions with targeted biologics that are commonly used for treating the idiopathic counterparts of these drug-induced reactions. The skin is frequently involved, and, even if considered rare to uncommon, these cutaneous manifestations are an important cause of biologic agent discontinuation. TNF-α antagonist-induced psoriasis, which can manifest or as exacerbation of a pre-existing form, is the prototypic and most frequent paradoxical skin reaction to biologics while other reactions, such as eczematous and lichenoid eruptions, hidradenitis suppurativa, pyoderma gangrenosum, Sweet's syndrome and granulomatous skin diseases, occur much more rarely. Management of these reactions consists of topical or systemic skin-directed therapies, depending on the severity and extension of the cutaneous picture, and it is generally associated with switching over to other disease-modifying regimens for treating the underlying rheumatologic condition. Here, we review in detail the current concepts and controversies on classification, pathogenesis and clinical management of this new class of cutaneous adverse events induced by biologics in rheumatologic patients.
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http://dx.doi.org/10.3389/fphar.2019.00282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443901PMC
March 2019

Total IgE and atopic status in patients with severe chronic spontaneous urticaria unresponsive to omalizumab treatment.

Allergy 2019 08 11;74(8):1561-1563. Epub 2019 Mar 11.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1111/all.13754DOI Listing
August 2019

Main Oral Manifestations in Immune-Mediated and Inflammatory Rheumatic Diseases.

J Clin Med 2018 Dec 25;8(1). Epub 2018 Dec 25.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Internal Medicine, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy.

Oral manifestations are frequent in patients with rheumatic diseases. The aim of this review is to offer readers practical advice concerning the onset, diagnosis and treatment of the main oral manifestations encountered in rheumatological and dental clinics. Signs and symptoms such as oral hyposalivation, xerostomia, temporomandibular joint disorders, periodontal disease, and dysphagia may be the first expression of a number of rheumatic diseases. Some of these manifestations are aspecific and very frequent, such as oral aphthosis, which can be the first manifestation in patients with systemic lupus erythematosus; some are potentially dangerous, such as jaw claudication during the course of giant cell arteritis; and some are very rare but peculiar, such as strawberry-like gingivitis in patients with granulomatosis with polyangiitis. Other oral manifestations are due to adverse reactions to disease-modifying anti-rheumatic drugs. Oral alterations in rheumatic diseases are frequently overlooked in clinical practice, but their prompt recognition not only allows the local lesions to be appropriately treated, but also makes it possible to identify an underlying systemic disease.
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http://dx.doi.org/10.3390/jcm8010021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351952PMC
December 2018

Haploidentical Hematopoietic Stem Cell Transplant Complicated by Atypical Hemolytic Uremic Syndrome and Kidney Transplant From the Same Donor With No Immunosuppression but C5 Inhibition.

Transplantation 2019 02;103(2):e48-e51

Hematology and Bone Marrow Transplantation Unit, IRCCS S. Raffaele Scientific Institution, Milan, Italy.

Background: Atypical hemolytic uremic syndrome (aHUS) is life-threatening condition particularly when complicating allograft hematopoietic stem cell transplant (HSCT). In the past, the outcome was very poor with the majority of patients reaching end-stage renal disease or dying with little or no chances of kidney transplant (KTx) due to the high risk of relapse. The availability of C5 inhibition has opened up significant therapeutic opportunities and has improved the outcome particularly if complement dysregulation (CD) is the underlying pathogenetic mechanism.

Methods: We describe a peculiar case of a girl with aHUS complicating HSCT and her subsequent successful KTx received from the same donor thus performed without immunosuppression but anti-C5 inhibition.

Results: Soon after HSCT performed for acute lymphoblastic leukemia, the patient developed a TMA due to CD and reached end-stage renal disease. After 2 years on dialysis, the patient received a KTx from her father who was already the HSCT donor. Given the full chimerism, no immunosuppressive agent was prescribed except a short (2 days) course of steroids and eculizumab to prevent aHUS relapse. Nine months after the KTx, the patient is well with normal renal function, no immunosuppression and continues eculizumab prevention of aHUS (1 infusion every 21 days).

Conclusions: All patients with transplant-associated thrombotic microangiopathy should be screened for the causes of CD. C5 inhibition with eculizumab is an important therapeutic resource to manage this complication. When KTx is necessary, immunosuppression can be safely withhold in case of same donor for both grafts and documented full chimerism.
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http://dx.doi.org/10.1097/TP.0000000000002505DOI Listing
February 2019

Angioedema and emergency medicine: From pathophysiology to diagnosis and treatment.

Eur J Intern Med 2019 01 13;59:8-13. Epub 2018 Sep 13.

Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milano, Italy. Electronic address:

Angioedema is a self-limiting edema of the subcutaneous or submucosal tissues due to localised increase of microvascular permeability whose mediator may be histamine or bradykinin. Patients present to emergency department when angioedema involves oral cavity and larynx (life-threatening conditions) or gut (mimicking an acute abdomen). After initial evaluation of consciousness and vital signs to manage breathing and to support circulation if necessary, a simple approach can be applied for a correct diagnosis and treatment. Forms of edema such as anasarca, myxedema, superior vena cava syndrome and acute dermatitis should be ruled out. Then, effort should be done to differentiate histaminergic from non-histaminergic angioedema. Concomitant urticaria and pruritus suggest a histaminergic origin. Exposure to allergens and drugs (mainly ACE inhibitors and non steroidal anti-inflammatory drugs) should be investigated as well as a family history of similar symptoms. Allergic histaminergic angioedema has a rapid course (minutes) whereas non histaminergic angioedema is slower (hours). Since frequently the intervention needs to be immediate, the initial diagnosis is only clinical. However, laboratory tests can be subsequently confirmatory. Allergic angioedema is sensitive to standard therapies such as epinephrine, glucocorticoids and antihistamines whereas non histaminergic angioedema is often resistant to these drugs. Therapeutic options for angioedema due C1-inhibitor deficiencies are C1-inhibitor concentrates, icatibant and ecallantide. If these drugs are not available, fresh frozen plasma can be considered. All these medications have been used also in ACE inhibitor-induced angioedema with variable results thus they are not currently recommended whereas experts agree on the discontinuation of the causative drug.
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http://dx.doi.org/10.1016/j.ejim.2018.09.004DOI Listing
January 2019

Elevated IgE to tissue factor and thyroglobulin are abated by omalizumab in chronic spontaneous urticaria.

Allergy 2018 12 29;73(12):2408-2411. Epub 2018 Aug 29.

UOC Dermatologia, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milano, Italy.

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http://dx.doi.org/10.1111/all.13587DOI Listing
December 2018

An unusual diagnosis in a 31-year-old man with abdominal pain and hyponatremia.

Intern Emerg Med 2018 Dec 17;13(8):1233-1238. Epub 2018 Mar 17.

Medicina Interna, Dipartimento di Scienze Cliniche e Comunità, Università degli Studi di Milano, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milan, Italy.

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http://dx.doi.org/10.1007/s11739-018-1826-xDOI Listing
December 2018

gene mutation in a patient with overlapping neutrophilic disease (pyoderma gangrenosum and aseptic abscess syndrome).

JAAD Case Rep 2018 Mar 16;4(2):120-122. Epub 2018 Jan 16.

Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milan, Italy.

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http://dx.doi.org/10.1016/j.jdcr.2017.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789524PMC
March 2018

Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome: an update.

Pediatr Nephrol 2018 03 18;33(3):457-461. Epub 2017 Oct 18.

Center for HUS Prevention, Control, and Management at Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.

Background: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by platelet consumption, hemolysis, and organ damage. Eculizumab (ECU), a humanized antibody that blocks complement activity, has been successfully used in aHUS, but the best treatment schedule is not yet clear.

Methods: Here, we report our experience with ECU maintenance treatment and the interval between subsequent doses being extended based on global classical complement pathway (CCP) activity aimed at <30% for maintaining aHUS into remission.

Results: We report on 38 patients with aHUS, 13 children, 21 female, with a median age of 25.0 years (range 0.5-60) at disease onset treated with ECU standard schedule for a median of 2.6 months (range 0.4-24.6). Once stable TMA remission was obtained, the interval between ECU doses was extended based on complement function, with a target CCP activity of <30%. With this approach, 22 patients regularly receive ECU infusion every 28 days and 16 every 21. During a median observation period on ECU, an extended interval of 26.9 months (range 0.8-80.9), with a cumulative observation period of 1,208 months, none of the patients relapsed.

Conclusion: Monitoring complement activity allows a safe reduction in the frequency of ECU administration in aHUS while keeping the disease in remission.
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http://dx.doi.org/10.1007/s00467-017-3813-2DOI Listing
March 2018

Elevated baseline D-dimer plasma levels are associated with a prompt response to omalizumab in patients with severe CSU.

J Allergy Clin Immunol Pract 2017 Nov - Dec;5(6):1740-1742. Epub 2017 Aug 31.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Medicina Interna, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milano, Italy.

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http://dx.doi.org/10.1016/j.jaip.2017.07.009DOI Listing
August 2019

Response.

Biol Blood Marrow Transplant 2017 11 15;23(11):2014-2015. Epub 2017 Aug 15.

Medicina Interna, Dipartimento di Fisiopatologia Medico Chirurgica, Università degli Studi di Milano, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.

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http://dx.doi.org/10.1016/j.bbmt.2017.07.017DOI Listing
November 2017