Presentation and progression of MPO-ANCA interstitial lung disease.

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

"Patient remodeling" as a consequence of uncontrolled and prolonged OCS use in severe asthma: how biologic therapy can reverse a dangerous trend.

INTRODUCTION: Asthma is a chronic inflammatory disease that can lead to airways remodeling. Despite their well-known side-effects, oral corticosteroids (OCS) continue to be used to reduce exacerbations and control asthma symptoms in many patients. CASE STUDY: We describe two cases of uncontrolled severe asthma characterized by systemic clinical consequences of prolonged OCS use, such as diabetes, weight gain, and osteoporosis. RESULTS: Both patients were treated with Dupilumab. During follow-up both patients showed an improvement in asthma control and were able to gradually taper the OCS dose, thus reducing the clinical burden associated with hypercortisolism. CONCLUSION: Dupilumab was able to control both the inflammatory-induced "airway remodeling" as well as the OCS-induced "patient remodeling".

Blood CD62Llow inflammatory eosinophils are related to the severity of asthma and reduced by mepolizumab.

BACKGROUND: Eosinophils have been divided into different subpopulations with distinct phenotypes based on CD62L expression. No data are available regarding the correlation between eosinophils subphenotypes and clinical severity of asthma, as well as the effect of anti-IL-5 therapy on these cells. The study investigates the correlation between blood CD62Llow inflammatory eosinophils (iEos) and clinical severity of severe eosinophilic asthma (SEA) and evaluates the impact of mepolizumab on iEos. METHODS: 112 patients were screened and were divided in two groups: biological-naive (n = 51) and biological-treated patients (n = 61). The Biological-naive patients were analyzed before treatment (Group A) and 19 out of 51 patients, were longitudinally analyzed before and after treatment with mepolizumab 100 mg s.c/4 weeks (Group B); 32 patients were excluded because they were being treated with other biological therapies. Blood eosinophils were analyzed by FACS and correlated with clinical scores. In vitro effect of IL-5 and mepolizumab on CD62L expression was assessed. RESULTS: A significant correlation between blood CD62Llow cells and clinical scores of asthma and nasal polyps, as well as the number of asthma exacerbations in the last year was shown in untreated patients. In longitudinally studied patients we observed a marked reduction of CD62Llow cells paralleled by an increase in the proportion of CD62Lbright cells, associated with clinical improvement of asthma control. In vitro, CD62L expression on eosinophils is modulated by IL-5 and anti-IL-5. CONCLUSION: A positive correlation between CD62Llow iEos and the baseline clinical features of SEA with CRSwNP was shown. Furthermore mepolizumab restores the healthy balance among eosinophils sub-phenotypes in SEA patients.

EGPA Phenotyping: Not Only ANCA, but Also Eosinophils.

BACKGROUND: Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a small-vessel necrotizing vasculitis. The anti-neutrophil cytoplasmic antibodies' (ANCA) role in defining clinical EGPA phenotypes is well established. Although the role of eosinophils in disease pathogenesis has been clearly demonstrated, the value of blood eosinophil count (BEC) as a biomarker of disease phenotypes is currently uncertain. METHODS: We retrospectively analyzed EGPA patients referred to our Immunology Clinic. Demographic, laboratory and clinical features were retrieved from clinical records, and a Logistic Regression was fitted to evaluate the predictive power of all baseline clinical and laboratory features to define EGPA phenotypes. RESULTS: 168 patients were recruited. BEC ≤ 1500 cells/mL was predictive of a clinical involvement characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and lung opacities (OR 0.18, 95% CI 0.07-0.43; respiratory-limited phenotype); BEC > 3500/mL was predictive of extrapulmonary organ involvement (OR 3.5, 95% CI 1.7-7.1; systemic phenotype). BEC was also predictive of peripheral nervous system (PNS) involvement, with a positive trend with increasing BEC (<1500/mL: OR 0.17, 95%CI, 0.06-0.47; >3500/mL: OR 2.8, 95% CI, 1.5-5.28). ANCA positivity was also predictive of extrapulmonary involvement (OR 4.7, 95% CI 1.9-11.99). CONCLUSIONS: according to BEC and irrespective of the ANCA status, two EGPA phenotypes could be identified, named systemic and respiratory-limited phenotypes, with different organ involvement and possibly different prognoses.

Anti-RuvBL1/2 Autoantibodies Detection in a Patient with Overlap Systemic Sclerosis and Polymyositis.

Anti-RuvBL1/2 autoantibodies have recently been detected in patients with systemic sclerosis (SSc) and scleromyositis overlap syndromes. These autoantibodies exhibit a distinct speckled pattern in an indirect immunofluorescent assay on Hep-2 cells. We report the case of a 48 year old man with facial changes, Raynaud's phenomenon, puffy fingers, and muscle pain. A speckled pattern on Hep-2 cells was identified, but the conventional antibody testing was negative. Based on the clinical suspicion and the ANA pattern, further testing was sought demonstrating anti-RuvBL1/2 autoantibodies. Hence, a review of the English literature was performed to define this newly emerging clinical-serological syndrome. With the one here reported, a total of 52 cases have been described to date (December 2022). Anti-RuvBL1/2 autoantibodies are highly specific for SSc and are associated with SSc/PM overlaps. Apart from myopathy, gastrointestinal and pulmonary involvement are frequently observed in these patients (94% and 88%, respectively).

Effectiveness of tocilizumab in hospitalized moderate-to-severe COVID-19 patients: a real-life study.

BACKGROUND: To assess the clinical effectiveness of Tocilizumab (TCZ) in moderate-to-severe hospitalized COVID-19 patients and factors associated with clinical response. METHODS: Five hundred eight inpatients with moderate-to-severe SARS-CoV-2 infection were enrolled. TCZ effect in addition to standard medical therapy was evaluated in terms of death during hospital stay. Unadjusted and adjusted risk of mortality for TCZ treated patients versus TCZ untreated ones was estimated using robust Cox regression model. We considered the combination of TCZ and ICU as time-dependent exposure and created a model using duplication method to assess the TCZ effect in very severe COVID-19 patients. RESULTS: TCZ reduced death during hospital stay in the unadjusted model (HR 0.54, 95%CI 0.33-0.88) and also in the adjusted model, although with loss of statistical significance (HR 0.72, 0.43-1.20). Better effectiveness was observed in patients with low SpO2/FiO2 ratio (HR 0.35, 0.21-0.61 vs. 1.61, 0.54-4.82, P<0.05), and, without statistical significance, in patients with high CRP (HR 0.51, 0.30-0.87 vs. 0.41, 0.12-1.37, P=NS) and high IL-6 (HR 0.49, 0.29-0.82 vs. 1.00, 0.28-3.55, P=NS). TCZ was effective in patients not admitted to ICU, both in the unadjusted (HR 0.33, 0.14-0.74) and in the adjusted (HR 0.39, 0.17-0.91) model but no benefit was observed in critical ICU-admitted patients both in the unadjusted (HR 0.66, 0.37-1.15) and in the adjusted model (HR 0.95, 0.54-1.68). CONCLUSIONS: Our real-life study suggests clinical efficacy of TCZ in moderate-to-severe COVID-19 patients but not in end-stage disease. Thus, to enhance TCZ effectiveness, patients should be selected before grave compromise of clinical conditions.

High proportion of inflammatory CD62Llow eosinophils in blood and nasal polyps of severe asthma patients.

BACKGROUND: In mice models, eosinophils have been divided into different subpopulations with distinct phenotypes and functions, based on CD62L and CD101 patterns of membrane expression. Limited data are available in humans. OBJECTIVE: To investigate eosinophils subpopulations in peripheral blood (PB) and nasal polyp tissue (NP) from severe eosinophilic asthma (SEA) patients plus concomitant chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: We recruited 23 SEA patients (14 with CRSwNP); as controls, we enrolled 15 non-severe asthma patients, 15 allergic rhinitis patients without asthma and 15 healthy donors. Eosinophils were isolated from PB and NP and analysed by FACS. Eotaxin-3 and eotaxin-1 mRNA expression in NP tissue was also evaluated. RESULTS: A significantly higher percentage of circulating CD62Llow cells was observed in SEA, as compared with controls, expressing higher levels of CCR3, CD69 and lower levels of CD125 (IL-5R), CRTH2, CD86 and CD28 in comparison with CD62Lbright cells. In NP, eosinophils showed a high proportion of CD62Llow phenotype, significantly greater than that observed in PB. Surface expression of IL-3R, IL-5R, CD69 and CD86 was significantly higher in CD62Llow eosinophils from NP than in those from blood. Moreover, eotaxin-3 mRNA expression positively correlated with the percentage of CD62Llow cells in NP. CONCLUSION: Two different eosinophil subphenotypes can be identified in blood and NP of SEA patients, with a preferential accumulation of CD62Llow inflammatory cells in NP.

Long-term retention rate of mepolizumab treatment in severe asthma: a 36-months real-life experience.

Objective: Mepolizumab is an anti-IL-5 monoclonal antibody that has shown, in different trials, the capacity to induce a reduction of exacerbations, an improvement of asthma control and a significant oral corticosteroid (OCS)-sparing effect. At present, there is limited real-life data about its long-term effects. The aim of the study was to evaluate the long-term effects of mepolizumab in real-life.Methods: We conducted a 36-months single-center retrospective study in 51 patients suffering from severe eosinophilic asthma treated with mepolizumab 100 mg/4 weeks. Clinical outcomes (symptoms, annual asthma exacerbation rates) were monitored. Additionally, we estimated annualized OCS dosage before and after mepolizumab treatment. Mepolizumab retention rate in the follow-up period was also evaluated.Results: A significant decrease of the annual rate of asthma exacerbations in association with significant changes in asthma control was observed. Specifically, the exacerbation rate significantly fell from 5.1 ± 4 per person/year in the pre-mepolizumab treatment period to 0.8 ± 1.2 per person/year in the 12-follow-up. The clinical benefit was maintained throughout the study follow up period of 36 months. Mepolizumab treatment induced significant changes in both ACT and ACQ5 scores. The majority of patients (65.2%) experienced a more pronounced improvement of 50% or more in SNOT-22. A mean cumulative OCS exposure reduction of 5365.5 mg over a 3-year period for patients receiving mepolizumab was estimated. The drug retention rate was: 96% at 12 months; 93.7% at 18 months, 88.9% at 24 months and 82.3% at 36 months.Conclusions: Our real-life results confirm that mepolizumab treatment allows to control asthma symptoms, reduce exacerbations and OCS exposure in a significant and sustained manner.

Primary antibody deficiencies represent an underestimated comorbidity in asthma patients: efficacy of immunoglobulin replacement therapy in asthma control.

OBJECTIVE: Primary antibody deficiencies (PAD) are an underestimated comorbidity in asthma and its treatment could improve disease control. METHODS: a retrospective cohort of asthmatics, affected by IgG subclass deficiency or unclassified antibody deficiency and treated with low-dose intravenous immunoglobulin replacement therapy (IRT) was recruited. Demographic and clinical data, chest CT scan, blood eosinophils, atopy, chronic oral corticosteroid (OCS) therapy were evaluated at baseline. Asthma exacerbations, lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI) and asthma-related hospitalizations were assessed after one and two years of IRT. RESULTS: 57 moderate-to-severe asthmatics were enrolled, mostly affected by T2 low asthma (39/57, 68.4%). After one year, IRT was effective in improving, irrespective of bronchiectasis, atopy, eosinophils and PAD type: 1) trough IgG (826.9 ± 221.3 vs 942.2 ± 195.1 mg/dl; p < 0.0001) and IgG subclasses (IgG1 355.4 ± 88.4 vs 466.7 ± 122.3, p < 0.0001; IgG2 300.1 ± 130.1 vs 347.6 ± 117.3, p < 0.0005) serum levels. 2) asthma exacerbations (6.4 ± 4.1 vs 2.4 ± 1.9, p < 0.0001), LRTI (4.3 ± 3.9 vs 1.3 ± 1.5, p < 0.0001) and hospitalization rate (0.26 ± 0.7 vs 0.05 ± 0.2, p < 0.01). These results persisted after 2 years of therapy. Estimated mean cumulative OCS exposure was reduced by 4500 mg over the 2-year period. CONCLUSIONS: low-dose IRT is effective in improving asthma control and lessening OCS burden in asthmatics affected by PAD.

Baseline Eosinophil Count as a Potential Clinical Biomarker for Clinical Complexity in EGPA: A Real-Life Experience.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-vessel necrotizing vasculitis with multiple organ involvement. Despite improvements in clinical management, biomarkers for organ involvement and disease prognosis are still an unmet need. Methods: EGPA patients referred to our immunology clinic were retrospectively reviewed. Demographic/clinical features, eosinophils, ANCA status, eosinophil cationic protein (ECP) and total serum IgE were evaluated at the baseline. Eosinophils, total serum IgE, ECP and ANCA were studied as possible biomarkers for lung and extrapulmonary disease. Results: In total, 167 EGPA patients were recruited for our study. A positive association between eosinophils and peripheral nervous system (PNS) involvement was demonstrated (p <0.001; chi-squared test). Receiver operating characteristic (ROC) curves using the eosinophil count or percentage as predictors of PNS involvement yielded AUC values of 0.75 and 0.67, respectively. ANCA positivity was associated with PNS involvement, while no correlations with clinical parameters were found for ECP and total serum IgE. Patients without extrapulmonary involvement had lower eosinophils (eosinophils: 2844.7 ± 1698 vs. 6373 ± 5468, p < 0.001; eosinophil percentage: 24.6 ± 10% vs. 36.2 ± 15.8, p < 0.001) and were less likely to be ANCA+ (p < 0.001, chi-squared test). Conclusion: Eosinophils in EGPA are an important biomarker and are associated with extrapulmonary involvement. These findings could strengthen the role of anti-eosinophilic drugs in improving extrapulmonary disease.

The anti-IgE monoclonal antibody omalizumab as adjuvant treatment in desensitization to carboplatin in patients with ovarian cancer.

•Ovarian cancer is the most lethal among gynecological cancers.•Carboplatin-based chemotherapy identifies as the main systemic treatment for ovarian cancer patients.•Almost one every three patients treated with carboplatin experiences hypersensitivity reactions.•Patients may experience breakthrough reactions during drug desensitization.•Omalizumab represents a promising new treatment to overcome carboplatin hypersensitivity.

How to Prevent and Mitigate Hypersensitivity Reactions to Biologicals Induced by Anti-Drug Antibodies?

Biologicals are widely used therapeutic agents for rheumatologic diseases, cancers, and other chronic inflammatory diseases. They are characterized by complex structures and content of variable amounts of foreign regions, which may lead to anti-drug antibodies (ADA) development. ADA onset may limit the clinical usage of biologicals because they may decrease their safety. In fact they are mainly associated with immediate hypersensitivity reactions (HSRs). Development of ADAs is reduced by concomitant immunosuppressive treatment, while it is increased by longer intervals between drug administrations; thus, regular infusion regimens should be preferred to reduce HSRs. Once ADAs have formed, some procedures can be implemented to reduce the risk of HSRs. ADAs may belong to different isotype; the detection of IgE ADA is advisable to be assessed when high and early ADAs are detected, in order to reduce the risk of severe HRs. In patients who need to reintroduce the biological culprit, as alternative therapies are not available, drug desensitization (DD) may be applied. Desensitization should be conceptually dedicated to patients with an IgE-mediated HSR; however, it can be performed also in patients who had developed non-IgE-mediated HSRs. Although the underlying mechanisms behind successful DD has not been fully clarified, the DD procedure is associated with the inhibition of mast cell degranulation and cytokine production. Additionally, some data are emerging about the inhibition of drug-specific immune responses during DD.

Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors.

Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial asthma can be distinguished into type 2 (eosinophilic) or nontype 2 (noneosinophilic) endotypes. In type 2 asthma endotype, the pathogenic mechanism is sustained by an inflammatory process driven by Th2 cells, type 2 innate lymphoid cells (ILC2) and type 2 cytokines, which include interleukin (IL)-4, IL-5, IL-9 and IL-13. The definition of asthma and chronic rhinusinusitis phenotype/endotype is crucial, taking into account the availability of novel biologic agents, such as monoclonal antibodies targeting the classical type 2 cytokines. Recently, new therapeutic strategies have been proposed and analyzed in preliminary clinical trials. Among them Janus kinase (JAK) inhibitors, now largely used for the treatment of other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, is receiving great relevance. The rationale of this strategy derives from the data that JAK is a tyrosine kinase involved in the signaling of T cell receptor and of several cytokines that play a role in allergic respiratory disease, such as IL-2, IL-4 and IL-9. In this review, we discuss whether treatment with biological agents and JAK inhibitors may be equally effective in controlling type 2 inflammatory process in both asthma and CRS.

Drug-specific Treg cells are induced during desensitization procedure for rituximab and tocilizumab in patients with anaphylaxis.

Biologic agents (BA) are able to induce an adaptive immune response in a proportion of exposed patients with the onset of anti-drug antibodies (ADA), which are usually responsible for hypersensitivity reactions (HR). Drug desensitization (DD) for BA allows transient clinical tolerance to the drug in reactive patients. The paper aimed to analyse the modification of drug-specific immune responses along DD in two patients with previous ADA-mediated HR (anaphylaxis) to rituximab and tocilizumab. The in vivo and in vitro assays of humoral and cellular response to drugs were carried out in a longitudinal manner throughout the DD cycles. We observed a progressive decrease of the pre-procedure ADA titer with negativization during the DD cycles in both patients. The monitoring of the drug-specific effector cell response showed the decrease in the BA-induced proliferation, while T cell response to unrelated antigens resulted unmodified along the DD cycles. Lastly, the increase of circulating drug-specific Treg cells mainly producing IL-35 were shown during the DD treatment. This study provides evidence that DD treatment to two BA inhibits humoral and cellular anti-drug response by increasing regulatory T cells and cytokines in an antigen-restricted manner. These modifications could contribute to the safety of the procedure.

Effectiveness of low-dose intravenous immunoglobulin therapy in minor primary antibody deficiencies: A 2-year real-life experience.

Primary antibody deficiencies (PAD) are the most prevalent group of primary immunodeficiencies (PID) in adults and immunoglobulin replacement therapy (IRT) is the mainstay therapy to improve clinical outcomes. IRT is, however, expensive and, in minor PAD, clear recommendations concerning IRT are lacking. We conducted a retrospective real-life study to assess the effectiveness of low-dose IRT in minor PAD on 143 patients fulfilling European Society for Immunodeficiencies (ESID) diagnostic criteria for immunoglobulin (Ig)G subclass deficiency (IgGSD) or unclassified antibody deficiency (UAD). All patients were treated with intravenous low-dose IRT (0.14 ± 0.06 g/kg/month). Immunoglobulin (Ig) classes and IgG subclasses were measured at baseline and after 1 year of IRT. The annual rate of total infections, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI) and hospitalizations was measured at baseline and after 1 and 2 years of IRT. After 1 year of IRT significant improvement was demonstrated in: (a) serum IgG (787.9 ± 229.3 versus 929.1 ± 206.7 mg/dl; p < 0.0001); (b) serum IgG subclasses (IgG1 = 351.4 ± 109.9 versus 464.3 ± 124.1, p < 0.0001; IgG2 = 259.1 ± 140 versus 330.6 ± 124.9, p < 0.0001; IgG3 = 50.2 ± 26.7 versus 55.6 ± 28.9 mg/dl, p < 0.002); (c) annual rate of total infections (5.75 ± 3.87 versus 2.13 ± 1.74, p < 0.0001), URTI (1.48 ± 3.15 versus 0.69 ± 1.27; p < 0.005), LRTI (3.89 ± 3.52 versus 1.29 ± 1.37; p < 0.0001) and hospitalizations (0.37 ± 0.77 versus 0.15 ± 0.5; p < 0.0002). The improvement persisted after 2 years of IRT. No significant improvement in URTI annual rate was noted in UAD and in patients with bronchiectasis. In conclusion, low-dose IRT can improve clinical outcomes in UAD and IgGSD patients, providing a potential economical advantage over the standard IRT dose.

Asthma and Chronic Rhinosinusitis: How Similar Are They in Pathogenesis and Treatment Responses?

Severe asthma and rhinosinusitis represent frequent comorbidities, complicating the overall management of the disease. Both asthma and chronic rhinosinusitis (CRS) can be differentiated into endotypes: those with type 2 eosinophilic inflammation and those with a non-type 2 inflammation. A correct definition of phenotype/endotype for these diseases is crucial, taking into account the availability of novel biological therapies. Even though patients suffering from type 2 severe asthma-with or without CRS with nasal polyps-significantly benefit from treatment with biologics, the existence of different levels of patient response has been clearly demonstrated. In fact, in clinical practice, it is a common experience that patients reach a good clinical response for asthma symptoms, but not for CRS. At first glance, a reason for this could be that although asthma and CRS can coexist in the same patient, they can manifest with different degrees of severity; therefore, efficacy may not be equally achieved. Many questions regarding responders and nonresponders, predictors of response, and residual disease after blocking type 2 pathways are still unanswered. In this review, we discuss whether treatment with biological agents is equally effective in controlling both asthma and sinonasal symptoms in patients in which asthma and chronic rhinosinusitis with nasal polyps coexist.

Immunogenicity-unwanted immune responses to biological drugs - can we predict them?

INTRODUCTION: Biological agents (BAs) target molecules involved in disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse, or serious adverse events such as infusion hypersensitivity reactions. The production of ADAs is the result of a specific adaptive immune response in which T and B cells are involved. AREAS COVERED: Factors conditioning the immunogenicity of BAs, including drug-, treatment- and patient-related factors are currently the subject of many studies. Among them, a lot of attention is dedicated to define the impact of BAs structure, the effect of targeting (soluble or membrane) molecules, the impact of interruption of therapy as well as the role of genetic (HLA and non-HLA) predisposing factors and disease activity. EXPERT OPINION: Knowledge of factors capable of influencing the immunogenicity of BAs may help to understand, in a predictive manner and at the single patient level, the presence of risk factors influencing the production of ADAs and their impact on clinical outcomes.