Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

Benralizumab for eosinophilic granulomatosis with polyangiitis: a retrospective, multicentre, cohort study.

BACKGROUND: Interleukin-5 (IL-5) inhibitors represent novel therapies for eosinophilic granulomatosis with polyangiitis (EGPA). This study assessed the effectiveness and safety of the IL-5 receptor inhibitor benralizumab in a European cohort of patients with EGPA. METHODS: This retrospective cohort study included patients with EGPA from 28 European referral centres of the European EGPA Study Group across six countries (Italy, France, UK, Russia, Spain, and Switzerland) who received benralizumab as any line of treatment between Jan 1, 2019, and Sep 30, 2022. We assessed the rates of complete response, defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] of 0) and a prednisone dose of up to 4 mg/day, in contrast to partial response, defined as a BVAS of 0 and a prednisone dose greater than 4 mg/day. Active disease manifestations, pulmonary function, variation in glucocorticoid dose, and safety outcomes were also assessed over a 12-month follow-up. FINDINGS: 121 patients with relapsing-refractory EGPA treated with benralizumab at the dose approved for eosinophilic asthma were included (64 [53%] women and 57 [47%] men; median age at the time of beginning benralizumab treatment 54·1 years [IQR 44·2-62·2]). Complete response was reported in 15 (12·4%, 95% CI 7·1-19·6) of 121 patients at month 3, 25 (28·7%, 19·5-39·4) of 87 patients at month 6, and 32 (46·4%, 34·3-58·8) of 69 patients at month 12; partial response was observed in an additional 43 (35·5%, 27·0-44·8) patients at month 3, 23 (26·4%, 17·6-37·0) at month 6, and 13 (18·8%, 10·4-30·1) at month 12. BVAS dropped from 3·0 (IQR 2·0-8·0) at baseline to 0·0 (0·0-2·0) at months 3 and 6, and to 0·0 (0·0-1·0) at month 12. The proportion of patients with systemic manifestations, active peripheral neurological disease, ear, nose, and throat involvement, and pulmonary involvement decreased, with an improvement in lung function tests. Six patients relapsed after having a complete response. The oral prednisone (or equivalent) dose decreased from 10·0 mg/day (5·0-12·5) at baseline to 5·0 mg/day (3·6-8·5) at month 3 (p<0·01), to 5·0 mg/day (2·5-6·3) at month 6, and to 2·5 mg/day (0·0-5·0) at month 12 (p<0·0001). 19 (16%) of 121 patients had adverse events and 16 (13%) discontinued benralizumab. INTERPRETATION: These data suggest that benralizumab could be an effective treatment for EGPA in real-life clinical practice. Further clinical trials are required to confirm the efficacy of benralizumab in patients with a higher baseline disease activity. FUNDING: None.

Autoinflammatory manifestations in adult patients.

Autoinflammatory diseases represent a family of immune-mediated conditions characterized by the unchecked activation of innate immunity. These conditions share common clinical features such as recurrent fever, inflammatory arthritis, and elevation of acute phase reactants, in the absence of an identified infectious etiology, generally without detectable serum autoantibodies, with variable response to glucocorticoids and in some cases colchicine, which represented the mainstay of treatment until cytokine blockade therapies became available. The first autoinflammatory diseases to be described were monogenic disorders caused by missense mutations in inflammasome components and were recognized predominantly during childhood or early adulthood. However, the progress of genetic analyses and a more detailed immunological phenotyping capacity led to the discovery a wide spectrum of diseases, often becoming manifest or being diagnosed in the adult population. The beneficial role of targeting hyperinflammation via interleukin 1 in complex non-immune-mediated diseases is a field of growing clinical interest. We provide an overview of the autoinflammatory diseases of interest to physicians treating adult patients and to analyze the contribution of hyperinflammation in non-immune-mediated diseases; the result is intended to provide a roadmap to orient scientists and clinicians in this broad area.

Serum ANCA as Disease Biomarkers: Clinical Implications Beyond Vasculitis.

Usually associated with autoimmune diseases, anti-neutrophil cytoplasmic antibodies are also detected in other conditions, such as infections, malignancies, and after intake of certain drugs. Even if the mechanisms of production and their pathogenic role have not been fully elucidated yet, ANCA are widely recognized as a clinically alarming finding due to their association with various disorders. While ANCA target several autoantigens, proteinase-3, and myeloperoxidase are the ones proved to be most frequently related to chronic inflammation and tissue damage in murine models. Albeit these autoantibodies could be present as an isolated observation without any implications, ANCA are frequently used in clinical practice to guide the diagnosis in a suspect of small vessel vasculitis. Conditions that should prompt the clinician to test ANCA status range from various forms of lung disease to renal or peripheral nervous system impairment. ANCA positivity in the presence of an autoimmune disease, especially rheumatoid arthritis, or connective tissue diseases, is frequently correlated with more clinical complications and treatment inefficacy, even in the absence of signs of vasculitis. For this reason, it has been postulated that ANCA could represent the final expression of an immune dysregulation rather than a pathogenic event responsible for organs damage. Recently, it has also been proposed that ANCA specificity (PR3 or MPO) could possibly define ANCA-associated vasculitides better than clinical phenotype. This review aims at summarizing the latest advancements in the field of ANCA study and clinical interpretation.

Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: A European Multicenter Observational Study.

OBJECTIVE: Mepolizumab proved to be an efficacious treatment for eosinophilic granulomatosis with polyangiitis (EGPA) at a dose of 300 mg every 4 weeks in the randomized, controlled MIRRA trial. In a few recently reported studies, successful real-life experiences with the approved dose for treating severe eosinophilic asthma (100 mg every 4 weeks) were observed. We undertook this study to assess the effectiveness and safety of mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks in a large European EGPA cohort. METHODS: We included all patients with EGPA treated with mepolizumab at the recruiting centers in 2015-2020. Treatment response was evaluated from 3 months to 24 months after initiation of mepolizumab. Complete response to treatment was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a prednisolone or prednisone dose (or equivalent) of ≤4 mg/day. Respiratory outcomes included asthma and ear, nose, and throat (ENT) exacerbations. RESULTS: Two hundred three patients, of whom 191 received a stable dose of mepolizumab (158 received 100 mg every 4 weeks and 33 received 300 mg every 4 weeks) were included. Twenty-five patients (12.3%) had a complete response to treatment at 3 months. Complete response rates increased to 30.4% and 35.7% at 12 months and 24 months, respectively, and rates were comparable between mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks. Mepolizumab led to a significant reduction in BVAS score, prednisone dose, and eosinophil counts from 3 months to 24 months, with no significant differences observed between 100 mg every 4 weeks and 300 mg every 4 weeks. Eighty-two patients (40.4%) experienced asthma exacerbations (57 of 158 [36%] who received 100 mg every 4 weeks; 17 of 33 [52%] who received 300 mg every 4 weeks), and 31 patients (15.3%) experienced ENT exacerbations. Forty-four patients (21.7%) experienced adverse events (AEs), most of which were nonserious AEs (38 of 44). CONCLUSION: Mepolizumab at both 100 mg every 4 weeks and 300 mg every 4 weeks is effective for the treatment of EGPA. The 2 doses should be compared in the setting of a controlled trial.

Serum ANCA and Overall Mortality: A 10-Year Retrospective Cohort Study on 1,024 Italian Subjects.

Background: Antineutrophil cytoplasmic antibodies (ANCA) are primarily involved in the pathogenesis of ANCA-associated vasculitides (AAV). However, ANCA may also be present in healthy subjects and in patients with autoimmune disorders different from AAV. We hypothesized that serum ANCA are associated with a worse prognosis in disorders other than AAV. Objective: We investigated the association between the overall survival and the presence of serum ANCA in 1,024 Italian subjects with various testing indications in a 10-year interval. Methods: In this retrospective cohort study, a population of 6,285 patients (many of whom were subsequently excluded due to our criteria) who tested for ANCA at a single center in 10 years was considered, and life status and comorbidities of subjects were collected. We compared the overall survival of ANCA-positive and ANCA-negative patients by means of Kaplan-Meier curves, while a multivariable adjusted Cox regression was used to evaluate the association between the ANCA status and the outcome (death) in terms of hazard ratios (HR) with 95% confidence intervals (CI). Results: The positivity of perinuclear ANCA (pANCA) increased significantly mortality (HR, 1.60; 95% CI, 1.10-2.32), while cytoplasmic ANCA (cANCA) positivity failed to show a significant association (HR, 1.43; 95% CI, 0.77-2.68). The increased mortality rate was observed for both pANCA and cANCA in patients suffering from rheumatic disorders. No association was found between mortality and anti-MPO (HR, 0.63; 95% CI, 0.20-2.00) or anti-PR3 (HR, 0.98; 95% CI, 0.24-3.96) after adjusting for confounders. Conclusions: Serum pANCA and cANCA are independent negative prognostic factors in patients with concurrent autoimmune diseases.

Eosinophils as Major Player in Type 2 Inflammation: Autoimmunity and Beyond.

Eosinophils are a subset of differentiated granulocytes which circulate in peripheral blood and home in several body tissues. Along with their traditional relevance in helminth immunity and allergy, eosinophils have been progressively attributed important roles in a number of homeostatic and pathologic situations. This review aims at summarizing available evidence about eosinophils functions in homeostasis, infections, allergic and autoimmune disorders, and solid and hematological cancers.Their structural and biological features have been described, along with their physiological behavior. This includes their chemokines, cytokines, granular contents, and extracellular traps. Besides, pathogenic- and eosinophilic-mediated disorders have also been addressed, with the aim of highlighting their role in Th2-driven inflammation. In allergy, eosinophils are implicated in the pathogenesis of atopic dermatitis, allergic rhinitis, and asthma. They are also fundamentally involved in autoimmune disorders such as eosinophilic esophagitis, eosinophilic gastroenteritis, acute and chronic eosinophilic pneumonia, and eosinophilic granulomatosis with polyangiitis. In infections, eosinophils are involved in protection not only from parasites but also from fungi, viruses, and bacteria. In solid cancers, local eosinophilic infiltration is variably associated with an improved or worsened prognosis, depending on the histotype. In hematologic neoplasms, eosinophilia can be the consequence of a dysregulated cytokine production or the result of mutations affecting the myeloid lineage.Recent experimental evidence was thoroughly reviewed, with findings which elicit a complex role for eosinophils, in a tight balance between host defense and tissue damage. Eventually, emerging evidence about eosinophils in COVID-19 infection was also discussed.

A Comprehensive Approach to Urticaria: From Clinical Presentation to Modern Biological Treatments Through Pathogenesis.

Urticaria is characterized by the cutaneous presence of wheals (hives), angioedema or both. Acute and chronic urticaria are distinguished based on a duration of less or more than 6 weeks. Chronic urticaria can be further classified into a spontaneous form and several inducible types triggered by specific external stimuli. Lifetime prevalence of urticaria may be up to 20%, with the acute form being way more common than the chronic one. Exacerbating factors (e.g. infections, drugs, food) and immune system alterations have been investigated as main triggers of mast cell activation, which in turn leads to increased vascular permeability and extravasation of inflammatory cells. While diagnostic workup is focused upon history taking, several emerging biomarkers correlate with severity and/or prognosis of the disease and can be necessary to differentiate chronic spontaneous urticaria from other disorders, such as vasculitis and autoinflammatory diseases. Treatment of acute urticaria is based upon H1 antihistamines and short courses of steroids. While H1 antihistamines are also used in chronic spontaneous urticaria, omalizumab is the standard of care in patients who are unresponsive to these. Recently, several new drugs have entered clinical trials to offer a therapeutic possibility for patients unresponsive to omalizumab. Numerous target molecules, such as mediators of mast cells activation, are under investigation. Amongst these, new anti-IgE therapies and possibly IL-5 pathway blockade seem to have reached enough data to move to advanced clinical trials.

The biology, pathogenetic role, clinical implications, and open issues of serum anti-neutrophil cytoplasmic antibodies.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.

Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19.

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.

Biomarkers and Diagnostic Testing for Renal Disease in Sjogren's Syndrome.

Primary Sjogren's syndrome (pSS) is an autoimmune disorder in which lymphocytic infiltration leads to lacrimal and salivary glands dysfunction, which results in symptoms of dryness (xerophthalmia and xerostomia). Extraglandular features are common and may affect several organs. Renal involvement has long been known as one of the systemic complications of pSS. The most classical lesion observed in pSS is tubulointerstitial nephritis (TIN) and less frequently membranoproliferative glomerulonephritis (MPGN), which is related to cryoglobulinemia. In some cases, renal biopsy is necessary for the definitive diagnosis of kidney involvement. Patients may present with proximal renal tubular acidosis, distal renal tubular acidosis and chronic kidney disease. Response to treatment is usually favorable. However, occasionally severe and rarely lethal outcomes have been described. Recently, several case series and cross-sectional studies have been published which investigated the factors associated with renal involvement in pSS and the most accurate screening tests for early detection. The presence of xerophthalmia, anti-SSA and rheumatoid factor positivity, low C3 levels and other features have all shown either positive or inverse associations with the development of renal complications. Serum creatinine, alpha-1-microglobulin, cystatin-C have been evaluated as early detection biomarkers with variable accuracy. More advanced techniques may be necessary to confirm proximal and distal renal tubular acidosis, along with nephrogenic diabetes insipidus. The aim of the current paper is to summarize and critically examine these findings in order to provide updated guidance on serum biomarkers and further testing for kidney involvement in pSS.

Interleukin-6 receptor blocking with intravenous tocilizumab in COVID-19 severe acute respiratory distress syndrome: A retrospective case-control survival analysis of 128 patients.

In cases of COVID-19 acute respiratory distress syndrome, an excessive host inflammatory response has been reported, with elevated serum interleukin-6 levels. In this multicenter retrospective cohort study we included adult patients with COVID-19, need of respiratory support, and elevated C-reactive protein who received intravenous tocilizumab in addition to standard of care. Control patients not receiving tocilizumab were matched for sex, age and respiratory support. We selected survival as the primary endpoint, along with need for invasive ventilation, thrombosis, hemorrhage, and infections as secondary endpoints at 30 days. We included 64 patients with COVID-19 in the tocilizumab group and 64 matched controls. At baseline the tocilizumab group had longer symptom duration (13 ± 5 vs. 9 ± 5 days) and received hydroxychloroquine more often than controls (100% vs. 81%). The mortality rate was similar between groups (27% with tocilizumab vs. 38%) and at multivariable analysis risk of death was not significantly influenced by tocilizumab (hazard ratio 0.61, 95% confidence interval 0.33-1.15), while being associated with the use at baseline of non invasive mechanical or invasive ventilation, and the presence of comorbidities. Among secondary outcomes, tocilizumab was associated with a lower probability of requiring invasive ventilation (hazard ratio 0.36, 95% confidence interval 0.16-0.83; P = 0.017) but not with the risk of thrombosis, bleeding, or infections. The use of intravenous tocilizumab was not associated with changes in 30-day mortality in patients with COVID-19 severe respiratory impairment. Among the secondary outcomes there was less use of invasive ventilation in the tocilizumab group.

Early Predictors of Clinical Deterioration in a Cohort of 239 Patients Hospitalized for Covid-19 Infection in Lombardy, Italy.

We described features of hospitalized Covid-19 patients and identified predictors of clinical deterioration. We included patients consecutively admitted at Humanitas Research Hospital (Rozzano, Milan, Italy); retrospectively extracted demographic; clinical; laboratory and imaging findings at admission; used survival methods to identify factors associated with clinical deterioration (defined as intensive care unit (ICU) transfer or death), and developed a prognostic index. Overall; we analyzed 239 patients (29.3% females) with a mean age of 63.9 (standard deviation [SD]; 14.0) years. Clinical deterioration occurred in 70 patients (29.3%), including 41 (17.2%) ICU transfers and 36 (15.1%) deaths. The most common symptoms and signs at admission were cough (77.8%) and elevated respiratory rate (34.1%), while 66.5% of patients had at least one coexisting medical condition. Imaging frequently revealed ground-glass opacity (68.9%) and consolidation (23.8%). Age; increased respiratory rate; abnormal blood gas parameters and imaging findings; coexisting coronary heart disease; leukocytosis; lymphocytopenia; and several laboratory parameters (elevated procalcitonin; interleukin-6; serum ferritin; C-reactive protein; aspartate aminotransferase; lactate dehydrogenase; creatinine; fibrinogen; troponin-I; and D-dimer) were significant predictors of clinical deterioration. We suggested a prognostic index to assist risk-stratification (C-statistic; 0.845; 95% CI; 0.802‒0.887). These results could aid early identification and management of patients at risk, who should therefore receive additional monitoring and aggressive supportive care.

Autonomic Abnormalities in Patients With Primary Sjogren's Syndrome - Preliminary Results.

Primary Sjögren's syndrome (pSS) is an autoimmune disease affecting exocrine glands and extra-glandular organs. There are conflicting reports on the presence of autonomic dysfunction in pSS and no data are available on the functional status of sympathetic outflow to the vessels and baroreceptor [baroreflex sensitivity (BRS)] control mechanisms. We investigated the cardiac (cBRS) and sympathetic (sBRS) baroreceptor modulation in both time and frequency domains and the cardiovascular autonomic profile in pSS patients compared to healthy controls. Autonomic symptoms were quantified by the Composite Autonomic Symptom Scale (COMPASS31) three-item questionnaire. The EULAR Sjogren's syndrome patient reported index (ESSPRI) questionnaire evaluated the magnitude of pSS clinical symptoms, i.e., fatigue, pain, and sicca symptoms. Electrocardiogram, beat-by-beat arterial pressure (AP) and respiratory activity were continuously recorded in 17 pSS patients and 16 healthy controls, while supine and during 75° head-up tilt. In seven patients and seven controls, muscle sympathetic nerve activity (MSNA) was measured. Spectrum analysis of RR variability provided markers of cardiac vagal modulation (HFRR nu) and sympatho-vagal balance [low frequency (LF)/high frequency (HF)]. The power of LF (0.1 Hz) oscillations of systolic arterial pressure (SAP) variability (LFSAP) evaluated the vasomotor response to sympathetic stimulation. Compared to controls, pSS patients scored higher in total COMPASS31 (p < 0.0001) and all ESSPRI subdomains (fatigue, p = 0.005; pain, p = 0.0057; dryness, p < 0.0001). Abnormal scialometry (<1.5 ml/15 min) and Schirmer tests (<5 mm/5 min) were found in pSS patients and salivary flow rate was negatively associated with ESSPRI dryness (p = 0.0014). While supine, pSS patients had lower SEQcBRS index of cardiac baroreceptor sensitivity, higher HFRRnu (p = 0.021), lower LF/HF (p = 0.007), and greater MSNA (p = 0.038) than controls. No differences were observed in LFSAP between groups. During orthostatic challenge, although LFSAP increased similarly in both groups, MSNA was greater in pSS patients (p = 0.003). At rest pSS patients showed lower cBR control and greater parasympathetic modulation. Furthermore, greater sympathetic nerve activity was observed in pSS patients while supine and in response to gravitational challenge. We hypothesized that such enhanced sympathetic vasoconstrictor activity might reflect an attempt to maintain blood pressure in a setting of likely reduced vascular responsiveness.

Anti-Neutrophil Cytoplasmic Antibodies Positivity and Anti-Leukotrienes in Eosinophilic Granulomatosis with Polyangiitis: A Retrospective Monocentric Study on 134 Italian Patients.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis associated with asthma, anti-neutrophil cytoplasmic antibodies (ANCA) positivity, and tissue eosinophilia. OBJECTIVE: To describe the presenting clinical features, significant biochemical alterations, and also potential pathogenic factors in adult patients diagnosed in our Center over a period of >20 years. METHOD: A retrospective study of EGPA patients diagnosed from 1994 to 2019 at ASST Grande Ospedale Metropolitano Niguarda Ca' Granda, Milan (Italy), which was performed according to the 1990 American College of Rheumatology criteria and Chapel Hill Consensus Conference definition. A dataset was compiled, registering demographic and clinical features, biochemical analysis at onset, and also the therapies received 3 months prior to EGPA diagnose. Statistical analyses were subsequently conducted dividing patients in 2 groups based on ANCA positivity and comparing them. RESULTS: Two groups were clearly identified by ANCA serology and specific organ involvement in accordance with literature reports; however, our data underline for the first time the association between anti-leukotriene receptor antagonists (LTRAs) and ANCA positivity. The group of previously treated patients presents an OR of 6.42 to be ANCA positive. This finding could be attributed to an imbalanced stimulation of leukotriene receptors, inducing both mast cells activation and an increased neutrophil extracellular traps release from neutrophils. CONCLUSION: Despite the limitations of this retrospective study, the association between LTRAs and ANCA antibodies elucidates the mechanism by which innate immunity is directly involved in tolerance breakdown and autoantibodies production. Validation of our results with targeted studies could clarify the differences between ANCA-positive and ANCA-negative patients with important consequences on the use of some drug classes in the treatment of EGPA and asthmatic subjects.

ANCA-Associated Vasculitides and Hematologic Malignancies: Lessons from the Past and Future Perspectives.

The purpose of this paper is to collect and summarize all evidences relating to an association between ANCA-associated vasculitides (AAVs) and hematologic malignancies, in the form of either a paraneoplastic vasculitis or leukemias and lymphomas developing on a preexisting vasculitis. Additionally, the role of cyclophosphamide in vasculitis treatment has been assessed and compared to rituximab. Paraneoplastic AAV seems to be an uncommon presentation of hemopathies. Hematologic malignancy risk in AAV is more likely to be increased by cyclophosphamide, although not yet definitely proven. Furthermore, the pathogenesis of ANCA-associated vasculitis has been reviewed with particular emphasis on the role of proteinase 3 (PR3) in fuelling granulomatosis with polyangiitis (GPA) inflammation. PR3 is a bactericidal protein expressed by neutrophilic granules and on their plasma membrane. Derangements in its expression and function have been linked to leukemias and GPA alike. PR3-derived PR1 peptide is being studied as an immunotherapy target in leukemia and multiple myeloma. This study is aimed at bringing together various evidences from the field of immunological and hematological research, at exposing contradictions, and at revealing novel insights on the association between ANCA-associated vasculitis and hematologic malignancies.

Cutting Edge: Biomarkers for Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is defined by the appearance of wheals and a variable presence of angioedema which persists for at least 6 weeks. It represents the most common subtype of chronic urticaria and is gaining importance in civil society because of its association with impaired quality of life. Moreover, CSU has a growing impact on national health systems representing a great burden due to its variable rate of response to the approved therapies. In this scenario, the identification of clinical and molecular biomarkers is of pivotal importance. Some groups are trying to detect molecules which would be able to help clinicians in reaching a proper diagnosis; additionally, the opportunity to describe disease severity which leads to cluster patients in different groups could fill the gap in the numerous unmet clinical needs. Several biomarkers are currently being studied with the purpose to predict the response to a defined therapy; unfortunately, none of them are ready to be translated from bench to bedside.

Omalizumab for Idiopathic Nonhistaminergic Angioedema: Evidence for Efficacy in 2 Patients.

Presently, there is inconclusive evidence regarding the most effective treatment for idiopathic nonhistaminergic acquired angioedema (InH-AAE). Omalizumab may, however, prove to be a promising option. This case report describes two patients who presented with recurrent angioedema attacks, which was refractory to antihistamine therapy. Hence, they were treated with 300 mg omalizumab, every 4 weeks, for a period of 6 months. Both patients had shown a rapid response to the treatment and achieved complete resolution of symptoms without further AE attacks throughout the entire duration of the treatment period. After omalizumab's suspension, one patient remained symptom free for the following 6 months and the other patient had recurrence of symptoms after 2 months for which he was retreated with omalizumab and once again became symptom free. Although omalizumab seems to be effective as a prophylactic treatment for InH-AAE, the determining factors leading to the differences in time-to-relapse between patients after its suspension remain unclear. Further studies are needed in order to better determine the potential therapeutic application of omalizumab and its role in maintenance therapy.

Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.