Guido Granata

Posterior reversible encephalopathy syndrome--Insight into pathogenesis, clinical variants and treatment approaches.

Posterior reversible encephalopathy syndrome is a rare clinicoradiological entity characterized by typical MRI findings located in the occipital and parietal lobes, caused by subcortical vasogenic edema. It was first described as a distinctive syndrome by Hinchey in 1996. Etiopathogenesis is not clear, although it is known that it is an endotheliopathy of the posterior cerebral vasculature leading to failed cerebral autoregulation, posterior edema and encephalopathy. A possible pathological activation of the immune system has been recently hypothesized in its pathogenesis. At clinical onset, the most common manifestations are seizures, headache and visual changes. Besides, tinnitus and acute vertigo have been frequently reported. Symptoms can be reversible but cerebral hemorrhage or ischemia may occur. Diagnosis is based on magnetic resonance imaging, in the presence of acute development of clinical neurologic symptoms and signs and arterial hypertension and/or toxic associated conditions with possible endotheliotoxic effects. Mainstay on the treatment is removal of the underlying cause. Further investigation and developments in endothelial cell function and in neuroimaging of cerebral blood flow are needed and will help to increase our understanding of pathophysiology, possibly suggesting novel therapies.

Vitiligo: Pathogenesis, clinical variants and treatment approaches ☆

Vitiligo is a common chronic acquired disease of pigmentation whose etiology is unknown, which usually occurs with asymptomatic whitish patch or macule. Although several hypotheses have been proposed in the literature, the leading theory is still the auto-immune etiology linked to specific genetic mutations. Vitiligo can also be associated with several autoimmune diseases, including autoimmune thyroid diseases, alopecia areata, and halo nevi. Sensorineural hearing loss was reported in several vitiligo patients due to a reduction in the number of melanocytes contained in the membranous labyrinth of the inner ear. Because of its complexity, several therapeutic options are available to treat this systemic disease.

On the Dark Side of Therapies with Immunoglobulin Concentrates: The Adverse Events

Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.

Longitudinal study on health-related quality of life in a cohort of 96 patients with common variable immune deficiencies.

Health-related quality of life (HRQoL) in common variable immunodeficiency diseases (CVID) was evaluated by different tools, which were mainly used to compare different schedules of immunoglobulins administration in cross-sectional or short-term longitudinal studies. We assessed the HRQoL and psychological status of CVID patients in a longitudinal study over a 6-year period by a generic, non-disease-specific instrument (SF-36), and by a General Health Questionnaire (GHQ-12) for the risk of depression/anxiety. At baseline, 96 patients were enrolled. After 1 year, a second assessment was performed on 92 patients and, after 6 years, a third assessment was performed on 66 patients. Eighteen patients died during the study time. HRQoL was low, with mental health scales less affected than physical scales. A decline in the score on SF-36 scales was observed between the first and the third assessment for the Physical Functioning, Body Pain, General Health, Social Functioning, and Role-Emotional scales. The General Health scale showed a lower score in these patients, when compared to patients with other chronic diseases. Approximately one-third of the patients were at risk of anxiety/depression at all observation times, a percentage that reached two thirds of the patients, considering only the group of females. Over the 6 years of the study, the health condition of 11/66 patients worsened, passing from “GHQ-negative” to “GHQ-positive”; their score on SF-36 scales also decreased. A decrement of one point in each of the Physical Functioning, Vitality, Social Functioning, and Mental Health SF-36 scales increased the risk of developing anxiety/depression from three to five percent. A negative variation of the Physical Functioning score increased the risk of psychological distress. In a survival analysis with dichotomized variables, Physical Functioning scores <50 were associated with a relative risk (RR) of 4.4, whereas Social Functioning scores <37.5 were associated with a RR of 10.0. In our study, it was the clinical condition, as opposed to the different treatment strategies with immunoglobulins, which had a major role on the deterioration of HRQoL. Moreover, in a quality-of-life evaluation, disorders such as anxiety/depression should be assessed, as they yet often go unrecognized. Our results might be helpful in the interpretation of currently available data on quality of life in CVID patients.

Hemolysis in patients with antibody deficiencies on immunoglobulin replacement treatment

Immunoglobulin (Ig)G replacement with intravenous or subcutaneous immunoglobulins is a lifelong substitutive therapy in patients with primary antibody deficiencies (PADs). Hemolysis after immunoglobulin therapy was described in patients receiving high immunoglobulin dosages. The issue of hemolysis after immunoglobulin administration at replacement doses has been considered of little clinical significance.

Lung Magnetic Resonance Imaging with Diffusion Weighted Imaging Provides Regional Structural as well as Functional Information Without Radiation Exposure in Primary Antibody Deficiencies

PurposePrimary antibody deficiency patients suffer from infectious and non-infectious pulmonary complications leading over time to chronic lung disease. The complexity of this pulmonary involvement poses significant challenge in differential diagnosis in patients with long life disease and increased radio sensitivity. We planned to verify the utility of chest Magnetic Resolution Imaging with Diffusion-Weighted Imaging as a radiation free technique.MethodsProspective evaluation of 18 patients with Common Variable Immunodeficiency and X-linked Agammaglobulinemia. On the same day, patients underwent Magnetic Resonance Imaging with Diffusion Weighted Imaging sequences, High Resolution Computerized Tomography and Pulmonary Function Tests, including diffusing capacity factor for carbon monoxide. Images were scored using a modified version of the Bhalla scoring system.ResultsMagnetic Resonance Imaging was non-inferior to High Resolution Computerized Tomography in the capacity to identify bronchial and parenchymal abnormalities. HRCT had a higher capacity to identify peripheral airways abnormalities, defined as an involvement of bronchial generation up to the fifth and distal (scores 2–3). Bronchial scores negatively related to pulmonary function tests. One third of consolidations and nodules had Diffusion Weighted Imaging restrictions associated with systemic granulomatous disease and systemic lymphadenopathy. Lung Magnetic Resolution Imaging detected an improvement of bronchial and parenchymal abnormalities, in recently diagnosed patients soon after starting Ig replacement.ConclusionsMagnetic Resonance Imaging with Diffusion Weighted Imaging was a reliable technique to detect lung alterations in patients with Primary Antibody Deficiencies.

The case for cost-effectively treating cryoglobulinemic vasculitis with interferon-free anti–hepatitis C virus therapy

Mixed cryoglobulinemia (MC) vasculitis affects approximately 5% of individuals with chronic hepatitis C virus (HCV) infection and ranges from mild to life-threatening. Sustained virological response leads to remission of vasculitis and reduced mortality, but the response rate to interferon-based regimens is low for frequent intolerance and ineligibility. Interferon-ineligible/intolerant/nonresponder patients with severe organ damage require salvage treatments with rituximab (RTX) or plasma exchange; however, these treatments are expensive and provide only temporary benefit. Both the American Association for the Study of Liver Diseases (http://www.hcvguidelines.org/full-report/when-and-whom-initiatehcv-therapy) and the European Association for the Study of the Liver (http://www.easl.eu/_newsroom/latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014) recommend prioritizing anti-HCV treatment in patients with MC vasculitis, but the impact of the severity of vasculitis on indication for early treatment is not thoroughly addressed. We performed a retrospective chart review of 58 patients with HCV-associated MC vasculitis followed at our institution (Supporting Methods). Interferon-based therapy led to sustained virological response in 11 patients (19%) (Supporting Fig. S1). Vasculitis was stratified into mild/moderate (purpura, peripheral neuropathy) and severe (nephropathy, chronic skin ulcers). Thirty interferon-ineligible/intolerant/nonresponder patients with chronic hepatitis, stable through follow-up, were selected; eight of them had severe vasculitis and 22 mild/moderate vasculitis (Supporting Fig. S1). The healthcare history, costs, and outcomes were compared in these two groups (Table 1); only hospitalizations and treatments related to complications of vasculitis were considered. Patients with severe vasculitis stayed in hospital a mean of 16.59 days/year and were all treated with RTX, plasma exchange, or both. Two of eight patients with severe vasculitis died from its complications, one from intestinal vasculitis and one from endstage renal disease and systemic infection resulting from infected skin ulcers. Patients with mild/moderate vasculitis stayed in hospital 0.66 days/year; only two of 22 were treated with RTX, and none died. Thus, healthcare cost overall and risk of death were higher in patients with severe MC compared to those with mild/moderate disease. Furthermore, there did not appear to be an association of use of either plasma exchange or RTX with cost (Supporting Table S1), which may have been related more to severity of illness than to response to treatment. Hagan et al. surmise a 12-week treatment with sofosbuvir/simeprevir, at a drug cost of

Macrophage Activation Syndrome as Onset of Systemic Lupus Erythematosus: A Case Report and a Review of the Literature.

150,000, as the state-of-the-art, most costeffective therapy for interferon-ineligible/intolerant HCV-infected individuals. Given the relatively high cost of care and the poor response/ high risk of death in patients with severe MC, prioritization of these patients for treatment with interferon-free therapy should be considered; and studies to determine tolerability and efficacy are warranted.

Paraneoplastic pemphigus: Insight into the autoimmune pathogenesis, clinical features and therapy

Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosis group of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication of several systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Stills disease. Several treatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, and cyclosporine. Here we report a case of 42-year-old woman in whom MAS occurred as onset of systemic lupus erythematosus.

Evaluation of estimated glomerular filtration rate and clinical variables in systemic sclerosis patients.

Paraneoplastic pemphigus is a rare autoimmune skin disease that is always associated with a neoplasm. Usually, oral, skin, and mucosal lesions are the earliest manifestations shown by paraneoplastic pemphigus patients. The pathogenesis of paraneoplastic pemphigus is not yet completely understood, although some immunological aspects have been recently clarified. Because of its rarity, several diagnostic criteria have been proposed. Besides, several diagnostic procedures have been used for the diagnosis, including indirect immunofluorescence, direct immunofluorescence, and ELISA. We reviewed the most recent literature, searching on PubMed “paraneoplastic pemphigus”. We included also papers in French, German, and Spanish. We found 613 papers for “paraneoplastic pemphigus”. Among them, 169 were review papers. Because of its varying clinical features, paraneoplastic pemphigus still represents a challenge for clinicians. Furthermore, diagnosis and management of paraneoplastic pemphigus requires close collaboration between physicians, including dermatologist, oncologist, and otorhinolaryngologist.