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Background: IBD management has been significantly affected during the COVID-19 lockdown with potential clinical issues. Aims: The aim of this study was to analyse the impact of COVID-19 pandemic on the Italian paediatric IBD cohort. Methods: This was a multicentre, retrospective, cohort investigation including 21 different Italian IBD referral centres. An electronic data collection was performed among the participating centres including: clinical characteristics of IBD patients, number of COVID-19 cases and clinical outcomes, disease management during the lockdown and the previous 9 weeks. Results: 2291 children affected by IBD were enrolled. We experienced a significant reduction of the hospital admissions [604/2291 (26.3%) vs 1281/2291 (55.9%); p < 0.001]. More specifically, we observed a reduction of hospitalizations for new diagnosis (from n = 44 to n = 27) and endoscopic re-evaluations (from n = 46 to n = 8). Hospitalization for relapses and surgical procedures remained substantially unchanged. Biologic infusions did not significantly vary [393/2291 (17.1%) vs 368/2291 (16%); p = 0.3]. Telemedicine services for children with IBD were activated in 52.3% of the centres. In 42/2291(1.8%) children immunosuppressive therapies were adapted due to the concurrent COVID-19 pandemic. Conclusion: Due to the several limitations of the lockdown, cares for children with IBD have been kept to minimal standards, giving priorities to the urgencies and to biologics’ infusions and implementing telemedicine services.

Highlights • Lymphopenia and eosinopenia are associated with the severe form of COVID-19. • Increased levels of D-dimer, procalcitonin, and C reactive protein are prognostic biomarkers predicting coagulopathy. • Corticosteroids resulted the best therapy for the immune dysregulation in severe form of COVID-19. • Anticoagulative therapy is associated with reduced in-hospital mortality for COVID-19., Clinical symptoms of COVID-19 include fever, cough, and fatigue which may progress to acute respiratory distress syndrome (ARDS). The main hematological laboratory findings associated with the severe form of disease are represented by lymphopenia and eosinopenia which mostly occur in the elderly population characterized by cardiovascular comorbidities and immunosenescence. Besides, increased levels of D-dimer, procalcitonin, and C reactive protein (CRP) seem to be powerful prognostic biomarkers helping to predict the onset of coagulopathy. The host immune response to SARS-CoV-2 can lead to an aberrant inflammatory response or “cytokine storm” which contributes to the severity of illness. At immunological level, patients affected by a severe form of COVID-19 show poor clinical trajectories characterized by differential “immunotypes” for which T cell response seems to play a critical role in understanding pathogenic mechanisms of disease. Also, patients with mild to severe COVID-19 displayed macrophage activation syndrome (MAS), very low human leukocyte antigen D related (HLA-DR) expression with a parallel reduction of CD04+ lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Corticosteroids resulted the best therapy for the immune dysregulation whereas repurposing of tocilizumab (IL-6 receptor antagonist) appears to have mixed results in patients with COVID-19. Besides, anticoagulative therapy was associated with reduced in-hospital mortality and need of intubation among COVID-19 patients. Furthermore, the beneficial use of intravenous immunoglobulin (IVIG) and passive immunotherapy with convalescent plasma needs to be validated in large controlled clinical trials. In this review, we summarize the main hematological parameters with a prognostic value in COVID-19 and the basis of immunological reactivity during COVID-19, with a focus on ongoing clinical trials evaluating immune targets as possible therapeutic strategies.

Background Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) with a consistent safety profile in clinical trials. We report three cases of multiple teeth loss during teriflunomide treatment. Case reports Case 1: a 39 year-old woman started teriflunomide for RRMS, switching from interferon beta. Four months later she complained about mandibular pain followed by the sudden loss of 4 teeth, in the absence of bleeding or trauma. Suspecting a causal role, we discontinued teriflunomide and started the accelerated elimination procedure with cholestyramine. Orthopantomography and a subsequent dental CT scan showed diffuse alveolar atrophy and periapical bone loss in several residual roots. Investigating retrospectively the patient's dental history, and revising previous orthopantomographies dating from 2009, we highlighted a chronic and progressive dental pathology with several cavities and teeth loss. Case 2: A 52-year-old woman affected by multiple sclerosis (MS) since 1988, switched from interferon beta to teriflunomide treatment due to poor tolerability. One year later she experienced the sudden loss of five teeth in the absence of traumatic events. Dental assessment and orthopantomography confirmed moderate chronic periodontitis. Teriflunomide was discontinued and the accelerated elimination procedure with cholestyramine was performed. Case 3: A 56-year-old woman affected by MS for thirty years. She switched from interferon beta to teriflunomide due to injection site reactions. After eighteen months she experienced hypermobility of several teeth without gum inflammation or pain, followed by sudden loss of twelve teeth. No dental examination is available. Teriflunomide was discontinued without accelerated elimination procedure. Discussion Odontogenic infections (periodontal disease and dental caries) are common and can cause teeth loss if left untreated as in case 1. It is conceivable that local infections favoured by teriflunomide accelerated pulpitis, endodontic infections and periapical reactions followed by teeth loss in predisposed subjects. Poor oral hygiene is common in MS patients and might favour dental infections. Conclusions We underline the importance to assess concomitant teeth morbidity and to recommend accurate oral hygiene before and during teriflunomide treatment.

Multiple sclerosis (MS) is a chronic central nervous system (CNS) autoimmune disease. Studies of cancer risk in MS patients have shown inconsistent findings. A pubmed search of the literature on cancer risk in patients with MS was conducted and found published relative studies. The majority of these studies concluded that there was overall either reduced or no increased risk of developing malignancies between patients with MS compared to the general population. However, several studies suggested that patients with MS may have reduced risk in specific cancers such as of the digestive and respiratory organs, prostate, ovary, or increased risk in breast, brain and bladder tumors. At present it is uncertain if the immunologic profile of MS patients may be related to the increased or reduced frequency of some cancers and warrants further investigation. © 2015 Elsevier Ireland Ltd. 98 29 34

[Background] Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear., [Objective] We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations., [Methods] Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR., [Results] Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor–related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients’ Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor–related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells., [Conclusions] Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

Objective: To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD). Methods: We performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years]. Results: Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2±0.5 vs 1.7±2.4 before the use of anti-TNF, p

This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with

The association of cancer and pregnancy is increasingly encountered nowadays in clinical practice. Due to the relative rarity of the situation, it lacks a systematized approach. Different systemic therapies are used in managing cancer with uncertainty regarding the potential hazards they could pose on the pregnancy and/or the fetus. We have performed a systematic review of literature to identify all reports addressing cancer patients who were exposed to any of the known systemic therapies during the course of the pregnancy. The results were discussed in two parts; part I addresses pregnant patients with solid tumors while part I for those with hematological malignancies. In part I, we identified different solid tumors diagnosed and treated during the course of pregnancy. Breast cancer was the most commonly treated followed by ovarian cancer. Other tumors were treated as well including lung cancer, cervical cancer, sarcoma and melanomas. It is important to acknowledge the intent of therapy (palliative vs. curative) and the patients has to be properly counseled to reach an informed decision. We aim to provide a more robust consensus on how to approach these cases and provide a higher degree of evidence to support the safety of applying certain management strategies over the other.

Churg-Strauss angiitis or syndrome (CSA) is defined as an eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotising vasculitis affecting small- to medium-sized vessels, and is associated with asthma and eosinophilia. It is usually classified among the so-called anti-neutrophil antibody (ANCA)-associated systemic vasculitides (AASVs) because of its clinical and pathological features that overlap with those of the other AASVs. However, two recent studies on large cohorts of patients have found that ANCAs, usually P-ANCAs/MPO-ANCAs, were present in only 38% of patients. Moreover, the ANCA status was shown to segregate with clinical phenotype. ANCA-positive patients were significantly more likely to have disease manifestations associated with small-vessel vasculitis, including necrotising glomerulonephritis, mononeuritis and purpura, whereas ANCA-negative cases were significantly more likely to have cardiac and lung involvement. Vasculitis was documented less frequently in histological specimens from ANCA-negative patients in comparison with ANCA-positive ones. These findings have led to postulate the predominance of distinct pathogenetic mechanisms in the two subsets of patients: an ANCA-mediated process in ANCA-positive patients and tissue infiltration by eosinophils with subsequent release of toxic product in ANCA-negative cases. Preliminary results suggest that ANCA-positive and ANCA-negative patients also might have a different genetic background. Corticosteroids remain the cornerstone of the initial treatment of CSA. The addition of cyclophosphamide is indicated in treatment of patients with poor-prognosis factors or in patients without poor-prognosis factors but those that are prone to relapses. The length of the maintenance therapy remains to be established. However, the vast majority of patients require long-term corticosteroids treatment to control asthma. © 2009 Elsevier Ltd. All rights reserved

Highly active antiretroviral therapy (HAART) has been able to improve the immune system function and survival of HIV patients with a consequent increase in the number of HIV patients affected by end-stage liver disease (ESLD). Between June 2003 and October 2006, 10 HIV-positive patients underwent liver transplantations in our center.All patients were treated with HAART before transplantation; treatment was interrupted on transplantation day and was restarted once the patients' conditions stabilized. Five patients were hepatitis C virus (HCV)-positive, 3 were hepatitis B virus (HBV)-positive, and 2 were HBV-HCV coinfected. HIV viral load before transplantation was50 copies/mL in all cases. CD4+ cell count before transplantation ranged between 144 and 530 c/microL. Immunosuppression was based on Cyclosporine (CyA) and steroid weaning for 8 patients, and on Tacrolimus and steroid weaning for 2 patients.Five patients were cytomegalovirus (CMV)-positive pp65 antigenemia posttransplantation, and 1 patient was EBV-positive; 2 patients had a coinfection with HHV6. Four patients suffered from a cholestatic HCV recurrent hepatitis treated with antiviral therapy (peginterferon and Ribavirin). Three patients died after transplantation.The outcome of liver transplantation in HIV patients was influenced by infections (HCV, CMV, and EBV) and Kaposi's Sarcoma. HCV recurrence was more aggressive, showing a faster progression in this patient population. Drug interaction between HAART and immunosuppressants occurs; longer follow-up and better experience may improve the management of these drug interactions.

Background: Information regarding Clostridium difficile-associated diarrhea (CDAD) after solid-organ transplantation (SOT) is scarce, particularly after heart transplantation (HT). Although host immune response to C difficile plays a substantial role in the outcome of this infection, the responsibility of hypogammaglobulinemia (HGG) as a predisposing condition for CDAD has not been studied in SOT. We analyzed the incidence, clinical presentation, outcome and risk factors, including HGG, of CDAD after HT. Methods: Two hundred thirty-five patients who underwent HT (1993 to 2005) were included. Transplantation procedure and immunosuppression were standard. From January 1999 HGG was systematically searched and corrected when IgG levels were

Pixantrone is an immunesuppressor similar to mitoxantrone but with lower cardiotoxicity. We evaluated the effect of pixantrone on B cells and lymphomononuclear cells in the course of acute EAE. Pixantrone reduced the number of B cells and suppressed myelin basic protein (MBP) specific IgG production. In vitro, pixantrone induced apoptosis of rat B lymphocytes in a way similar to mitoxantrone. In addition, pixantrone inhibited antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-γ production, during EAE. These findings suggest a similar mechanism of action for pixantrone and mitoxantrone on the effector function of lymphomonocyte B and T cells.

SummaryIdiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease leading to death within a few years of diagnosis despite medical therapy. On the basis of methodologies of the Cochrane collaboration, this overview discusses the evidence for IPF therapy. Good-quality studies on oral corticosteroids, the most common medical therapy in use for IPF, are lacking. A few small studies have been carried out on the efficacy of many non-steroid immunosuppressive agents, and the results have been generally disappointing. The most extensively studied medical therapy, gamma interferon, showed a significant effect in a small randomized study, but its efficacy was not confirmed in a larger randomized-controlled trial. The long-awaited good news for patients affected by this deadly disease, and for their physicians, could come in the near future from large randomized-controlled trials with gamma interferon or other immunomodulatory agents.

In a recent epidemiological study, 15-20% of the population in Japan was estimated to have allergic conjunctivitis. Allergic conjunctival diseases (ACD) have a wide spectrum of clinical severity and the treatment strategy depends on the severity and duration of the disease. Most cases of the non-proliferative type of ACD, such as seasonal or perennial allergic conjunctivitis, can be treated with topical anti-allergic drugs. Of the ACD, vernal keratoconjunctivitis (VKC) is characterized by typical proliferative lesions, such as giant papillae and severe corneal lesions. Corticosteroid eye drops should be used in combination with anti-allergic eye drops when an anti-allergic drug is insufficient in cases of VKC and atopic keratoconjunctivitis with proliferative lesions. In spite of the high effectiveness of corticosteroid eye drops, they have important side-effects, such as elevation of intraocular pressure leading to glaucoma. Immunosuppressive agents and non-steroidal anti-inflammatory drugs (NSAIDs) are alternative topical agents to corticosteroids. Topically administered immunosuppressive agents, such as ciclosporin and tacrolimus, have antifibroblastic actions by inhibiting remodeling-inducing cells and act as a controller in the treatment of ACD. Non-steroidal antiinflammatory drug eye drops can be used to inhibit remodeling in ACD because of their excellent antiinflammatory and antifibroblastic effects, next to corticosteroids and immunosuppressive agents. Substitution of the topical treatment with corticosteroids by these agents in ACD not only spares the use of corticosteroids and decreases the risk of side-effects, but also brings about a more favorable effect in the long-term control of proliferative-type ACD.

Adequate dosage forms are essential for achieving successful pharmacotherapy. Innovative dosage forms or delivery systems may direct a drug to its specific site of action, optimize the timing of the drug release, or increase comfort or convenience for the patient. Thus, such innovations may improve efficacy and tolerability and lead to improvements in health-related quality of life. Specialized dosage forms (e.g., depot injections, extended-release formulations) of several psychiatric agents have been extensively used. The latest addition is an orally disintegrating formulation of the antidepressant mirtazapine. This dosage form dissolves rapidly in the mouth and is convenient for the large proportion of patients who have difficulty in swallowing tablets. © 2003 Elsevier B.V./ECNP. All rights reserved.

In order to evaluate the pharmacokinetics of cyclosporine A comparing the traditional (CsA-SCG) with the microemulsion formulation (CsA-ME), 20 clinically stable heart-transplant patients were enrolled in the study. All patients were on a thrice-daily dosage regimen (mean single dose 1.14±0.4 mg kg-1 body weight) of CsA-SCG. The steady-state area under the concentration-time curve during a dosage interval was calculated during three sequential periods: (1) the first after the morning oral dose of CsA-SCG; (2) the second (8 days later) after 2 hours intravenous infusion of cyclosporine; (3) the third after the CsA-ME morning oral dose (30 days after the milligram-to-milligram dose conversion). After switching from standard formulation CsA-SCG to CsA-ME, significant changes were observed in Cmax/ss (732 ± 178 vs 935 ± 250 ng ml-1, P < 0.001) and tmax (2.63 ± 1.21 vs 1.36 ± 0.49 h, P < 0.001). The CsA-ME mean bioavailability was higher than CsA-SCG (75 ± 19 vs 66 ± 16%; P < 0.001). The main CsA pharmacokinetic parameters of both formulations in clinically stable heart-transplant patients presented evident differences from data obtained in other transplant-patient populations. © 2001 Academic Press.