New insights into the pathogenesis of bullous pemphigoid: 2019 update

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

Acquired angioedema

Acquired angioedema (AAE) is characterized by acquired deficiency of C1 inhibitor (C1-INH), hyperactivation of the classical pathway of human complement and angioedema symptoms mediated by bradykinin released by inappropriate activation of the contact-kinin system. Angioedema recurs at unpredictable intervals, lasts from two to five days and presents with edema of the skin (face, limbs, genitals), severe abdominal pain with edema of the gastrointestinal mucosa, life-threateing edema of the upper respiratory tract and edema of the oral mucosa and of the tongue. AAE recurs in association with various conditions and particularly with different forms of lymphoproliferative disorders. Neutralizing autoantibodies to C1-INH are present in the majority of patients. The therapeutic approach to a patient with AAE should first be aimed to avoid fatalities due to angioedema and then to avoid the disability caused be angioedema recurrences. Acute attacks can be treated with plasma-derived C1-INH, but some patients become non-responsive and in these patients the kallikrein inhibitor ecallantide and the bradykinin receptor antagonist icatibant can be effective. Angioedema prophylaxis is performed using antifibrinolytic agents and attenuated androgens with antifibrinolytic agents providing somewhat better results. Treatment of the associated disease can resolve AAE in some patients

Mechanisms of Inflammation in Neutrophil-Mediated Skin Diseases

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

Mechanisms of Inflammation in Neutrophil-Mediated Skin Diseases

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

Paradoxical Skin Reactions to Biologics in Patients With Rheumatologic Disorders

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)-\u3b1 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-\u3b1 antagonist-induced psoriasis, which can manifest de novo 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

Complement activation predicts negative outcomes in COVID-19: The experience from Northen Italian patients

Coronavirus disease 19 (COVID-19) may present as a multi-organ disease with a hyperinflammatory and prothrombotic response (immunothrombosis) in addition to upper and lower airway involvement. Previous data showed that complement activation plays a role in immunothrombosis mainly in severe forms. The study aimed to investigate whether complement involvement is present in the early phases of the disease and can be predictive of a negative outcome. We enrolled 97 symptomatic patients with a positive RT-PCR for SARS-CoV-2 presenting to the emergency room. The patients with mild symptoms/lung involvement at CT-scan were discharged and the remaining were hospitalized. All the patients were evaluated after a 4-week follow-up and classified as mild (n. 54), moderate (n. 17) or severe COVID-19 (n. 26). Blood samples collected before starting any anti-inflammatory/immunosuppressive therapy were assessed for soluble C5b-9 (sC5b-9) and C5a plasma levels by ELISA, and for the following serum mediators by ELLA: IL-1β, IL-6, IL-8, TNFα, IL-4, IL-10, IL-12p70, IFNγ, IFNα, VEGF-A, VEGF-B, GM-CSF, IL-2, IL-17A, VEGFR2, BLyS. Additional routine laboratory parameters were measured (fibrin fragment D-dimer, C-reactive protein, ferritin, white blood cells, neutrophils, lymphocytes, monocytes, platelets, prothrombin time, activated partial thromboplastin time, and fibrinogen). Fifty age and sex-matched healthy controls were also evaluated. SC5b-9 and C5a plasma levels were significantly increased in the hospitalized patients (moderate and severe) in comparison with the non-hospitalized mild group. SC5b9 and C5a plasma levels were predictive of the disease severity evaluated one month later. IL-6, IL-8, TNFα, IL-10 and complement split products were higher in moderate/severe versus non-hospitalized mild COVID-19 patients and healthy controls but with a huge heterogeneity. SC5b-9 and C5a plasma levels correlated positively with CRP, ferritin values and the neutrophil/lymphocyte ratio. Complement can be activated in the very early phases of the disease, even in mild non-hospitalized patients. Complement activation can be observed even when pro-inflammatory cytokines are not increased, and predicts a negative outcome

Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin

Angioedema (AE) is a rare but potentially life-threatening side effect of therapy with inhibitors of angiotensin-converting enzyme (ACE), the main bradykinin (BK)- inactivating metallopeptidase in humans. The pathogenesis of ACE inhibitor (ACEi)- associated AE (AE+) is presently unknown, although there is increasing evidence of a kinin role. We analyzed the metabolism of endogenous BK (B(2) receptor agonist) and its active metabolite, des-Arg(9)-BK (B(1) receptor agonist), in the presence of an ACEi during in vitro contact activation of plasma from hypertensive patients (n = 39) who presented AE+. Kinetic parameters were compared with those measured in a control group (AE-) of hypertensive patients (n = 39) who never manifested any acute or chronic side effects while treated with an ACEi. The different kinetic parameters were analyzed using a mathematical model (y = k t(alpha) e(-beta t)) previously applied to a normal, healthy population. The slope of BK degradation, but not its formation from high-molecular-weight kininogen, was lower in AE+ patients when compared with the AE- controls. des-Arg(9)-BK accumulation during the kinetic measurements was significantly higher in AE+ plasma. This accumulation of the B(1) agonist in AE+ patients paralleled its half-life of degradation. In conclusion, our results show, for the first time, that an abnormality of endogenous des-Arg(9)-BK degradation exists in the plasma of patients with ACEi-associated AE, suggesting that its pathogenetic mechanism lies in the catabolic site of kinin metabolis

ISPY – NaCo imaging survey for planets around young stars : a young companion candidate embedded in the R CrA cloud

Context Within the NaCo-ISPY exoplanet imaging program, we aim at detecting and characterizing the population of low-mass companions at wide separations (≳10 AU), focusing in particular on young stars either hosting a known protoplanetary disk or a debris disk. Aims R CrA is one of the youngest (1-3 Myr) and most promising objects in our sample because of two previous studies that suggested the presence of a close companion. Our aim is to directly image and characterize the companion for the first time. Methods We observed R CrA twice with the NaCo instrument at the Very Large Telescope (VLT) in the L' filter with a one year time baseline in between. The high-contrast imaging data were reduced and analyzed and the companion candidate was detected in both datasets. We used artificial negative signals to determine the position and brightness of the companion and the related uncertainties. Results The companion is detected at a separation of 196.8 ± 4.5/196.6 ± 5.9 mas (18.7 ± 1.3/18.7 ± 1.4 AU) and position angle of 134.7 ± 0.5 ° /133.7 ± 0.7° in the first/second epoch observation. We measure a contrast of 7.29 ± 0.18/6.70 ± 0.15 mag with respect to the primary. A study of the stellar proper motion rejects the hypothesis that the signal is a background object. The companion candidate orbits in the clockwise direction and, if on a face-on circular orbit, its period is ˜43 - 47 yr. This value disagrees with the estimated orbital motion and therefore a face-on circular orbit may be excluded. Depending on the assumed age, extinction, and brightness of the primary, the stellar companion has a mass between 0.10 ± 0.02 M⊙ and 1.03-0.18+0.20 M⊙ range, if no contribution from circumsecondary material is taken into account. Conclusions As already hypothesized by previous studies, we directly detected a low-mass stellar companion orbiting the young Herbig Ae/Be star R CrA. Depending on the age assumptions, the companion is among the youngest forming companions imaged to date, and its presence needs to be taken into account when analyzing the complex circumstellar environment of R CrA