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.

Potential clinical and serological predictors of chronic spontaneous urticaria relapse in patients under omalizumab treatment.

Background: Omalizumab is not considered a disease-modifying drug and, accordingly, a large proportion of patients experience a relapse following withdrawal from treatment. Patients & methods: A total of 42 patients who underwent at least one cycle of treatment with omalizumab were enrolled. Two groups of relapsed and not-relapsed subjects were compared. Then, patients were divided into subgroups. Results: Female patients relapse more frequently than male subjects. Patients who relapsed complained a long duration of disease, while patients who did not relapse had short a history of disease. Very early responders are thought to have a high recurrence rate. Basal IgE levels were increased in early responders and cholesterol levels were high in very early responders, who relapse following withdrawal from omalizumab. High D-dimer levels were observed in late responders. Conclusion: The identification of clinical and serological predictors will play a pivotal role in the future management of patients treated with omalizumab.

Low-Dose Mepolizumab Effectiveness in Patients Suffering From Eosinophilic Granulomatosis With Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by multisystemic manifestations including asthma. Mepolizumab (300 mg/4 weeks) has recently been approved for EGPA. However, real-life data are scarce and report experiences with high doses of mepolizumab intravenously administered (750 mg/4 weeks). The aim of our study was to investigate in a real-life setting whether mepolizumab in EGPA patients at low doses would enable us 1) to control asthma symptoms, 2) to obtain oral corticosteroids (OCS) and/or immunosuppressors tapering and 3) to maintain clinical remission and avoid disease relapses. Mepolizumab (100 mg/4 weeks) was subcutaneously administered for 12 months in 18 EGPA patients with uncontrolled severe asthma. Symptoms, annual asthma exacerbation rates, OCS-sparing effects, lung function and eosinophil activation markers were monitored. The proportion of patients with clinical remission or relapse was also evaluated in month 12. A significant decrease in the annual rate of asthma exacerbations in association with significant changes in asthma control were observed. Specifically, 66.6% of the patients experienced no exacerbations during the mepolizumab treatment. Most patients (77.7%) were able to reduce the daily OCS dose by at least 50%. Four patients also stopped cyclosporine A during the study period. No EGPA relapse was observed and a large majority of the patients achieved clinical remission (94.3%). Clinical benefits were paralleled by reduction in blood eosinophils and serum levels of eosinophil activation markers. Low-dose mepolizumab showed clinically relevant benefits in exacerbation rates, asthma symptoms, OCS and immunosuppressive use in EGPA patients. These effects occurred without any EGPA relapse for extrapulmonary manifestations.

Rapid clinical improvement of atopic dermatitis in an Omalizumab treated patient.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disorder, whose symptoms and severity grossly depend on individual trigger factors. The majority of patients are satisfactorily treated with emollients together with topical and systemic therapies. However, treatment failure or long-term side effects with conventional treatment options can be a significant clinical problem. Recently, novel therapeutic approaches focus on targeting skewed immune responses providing a more effective, and less harmful approach. Among them, variable success has been reported using Omalizumab, when used in combination with classic therapies. This report describes an interesting case of severe adult onset difficult-to-treat atopic dermatitis dramatically improved in response to treatment with Omalizumab. CASE PRESENTATION: We present a case of an adult male with severe allergic atopic dermatitis, with concomitant involvement of the face, neckline, trunk and forearms and systemic symptoms such as diarrhoea with important decrease of his daily quality of life. The patient had been prescribed oral steroids in addition to anti-histamines to no avail. Due to lack of response to classic therapies, strict diet, as well as to treatment with intravenous corticosteroids, an off-label treatment with Omalizumab based on patient weight and total IgE value was proposed. Clear clinical results were observed after only a few weeks with regards to systemic symptoms, and just after 2 months of treatment in regards to skin involvement. CONCLUSIONS: In the majority of treated patients the clinical improvement of cutaneous manifestations is expected after several months of treatment, as skin manifestations are the consequence of a chronic inflammatory process. The outstanding rapid response observed in this case as well as the persistence of the clinical remission suggests that the block of the IgE pathways modulate functions of cells involved in the pathogenic mechanisms of chronic skin inflammation but also in the acute phases observed in the flare-ups of the disease.

Efficacy and Safety of Mepolizumab (Anti-Interleukin-5) Treatment in Gleich's Syndrome.

Gleich's syndrome (GS) is characterized by recurrent episodes of angioedema, increase in body weight, fever, hypereosinophilia, and elevated serum IgM. The exact etiology remains unclear. Currently, the only treatment strategy is the administration of high dose of steroids during the acute phases. We report the case of a 37-year-old man suffering from GS with recurrent episodes of angioedema, fever, hypereosinophilia [6,000/mm3 (45%)], and high eosinophil cationic protein (ECP) (>200 µg/l), treated with oral steroids during the acute phase (prednisone 50-75 mg/day), the dose of maintenance being 25 mg/day. No monoclonal components were identified, and genetic tests exclude mutations including Bcr/Abl, JAK2 V617F, c-KIT D816V, and FIP1L1-PDGFRA. Using Luminex technology, we observed higher serum levels of interleukin (IL)-5, CCL2, and CCL11 during the acute exacerbations in comparison with the clinical remission phases though CCL11 did not achieve statistical significance. The flow-cytometric analysis identified a CD3+ CD8- lymphocyte population with high frequency of IL-4-, IL-5-, and IL-13-producing cells. No clinical benefit was observed after therapeutic strategies with imatinib, interferon-α, cyclosporine-A, and azathioprine. Due to high IL-5 serum levels, an intravenous treatment with anti-IL-5 monoclonal antibody mepolizumab (750 mg every 4 weeks) was started. A reduction in the rate of exacerbation phases/year (10 ± 3 vs 2 ± 1; p < 0.005), in the eosinophils count both in percentage (28.8 ± 12.8 vs 9.8 ± 3.9; p < 0.001) and absolute value (2,737 ± 1,946 vs 782 ± 333; p < 0.001) were observed as well as the ECP serum levels (132.7 ± 62.7 vs 21 ± 14.2 µg/l; p < 0.05). The daily dose of prednisone was significantly reduced (25 vs 7.5 mg). Any adverse effects were recorded. To the best of our knowledge, this case is the first report of the disease successfully treated with mepolizumab, and it could represent a novel therapeutic strategy in GS.

Short article: Safety of targeted prophylaxis strategy in patients with resolved hepatitis B virus infection receiving rituximab for immune-mediated diseases.

OBJECTIVES: Rituximab (RTX) is a monoclonal antibody that is widely used in hematologic malignancies and immune-mediated diseases (IMID) and has been associated with the risk of hepatitis B virus reactivation (HBVr). Thus, antiviral prophylaxis is recommended before RTX treatment in all patients with chronic hepatitis B virus (HBV) infection and those with resolved infection affected by onco-hematological conditions. By contrast, the correct management of HBsAg-negative/HbcAb-positive patients candidates for RTX-containing regimens for IMID is still debated, owing to few data currently available in this setting. PATIENTS AND METHODS: We retrospectively evaluated the risk of HBVr in patients with IMID with resolved HBV infection, referred to the Infectious and Tropical Diseases Unit Outpatients Service, Careggi Hospital, Florence, Italy, between September 2013 and September 2017, undergoing RTX without antiviral prophylaxis and followed up by serial serum HBV-DNA monitoring. RESULTS: Overall, 20 patients with IMID were identified (70% female, with median age of 57 years) and followed up for a median period of 19 months (range: 2-36 months). A single HBVr case, detected in preclinical stage, was observed (1/20, 5%), and targeted prophylaxis was promptly introduced. CONCLUSION: The results supported the low to moderate risk of HBVr in HBsAg-negative/HBcAb-positive patients with IMID undergoing RTX, in contrast to what is observed in onco-hematological settings. The targeted prophylaxis strategy, based on serum HBV-DNA serial monitoring, seems a safe option in these patients.

T Cell Response to Infliximab in Exposed Patients: A Longitudinal Analysis.

This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression in vitro. The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.

LATEX sensitization in elderly: allergological study and diagnostic protocol.

BACKGROUND: The prevalence of latex allergy varies according to the population studied from 3% to 64%. No data exist in the present literature about elderly people because they were not considered among populations at risk. We report a retrospective observational study of 88 elderly patients of our centre of Dermatology and Allergology at Policlinico Umberto I, University of Rome, Sapienza. RESULTS: First and second level diagnostic tests showed latex positivity in 11,4% of patients studied for latex allergy in the elderly population. CONCLUSIONS: Our study demonstrates a prevalence of elderly-latex sensitization of 11,4%, showing that allergy to latex is a growing disease that can occur at any age. So, we propose these patients as an additional risk category for latex allergy.