Pharmacogenetics of autoimmune diseases: Research issues in the case of Multiple Sclerosis and the role of IFN-beta

Pharmacogenetics of auto-immune diseases is a complex field of application for this relatively new discipline, since we still have a partial knowledge of the biological mechanisms of the disease and of the drugs currently used to treat it. We address a few key issues that emerge when planning a pharmacogenetic investigation in Multiple Sclerosis and that relate to the complexities existing at the biological-genetic level and at the phenotypic characterization. In fact, we think that a clearer characterization of the clinical phenotype representing the end-point of the investigation together with a critical appraisal of the multi-faceted dimension of the genetic component of either the disease and the pharmacogenetic profile of the drug investigated, will help to design more thorough study and to achieve deeper understanding of the practical results. We will primarily focus our research considerations on the role of Interferon Beta (IFN-beta) as a prototypal therapeutic agent in Multiple Sclerosis

Autologous hematopoietic cell transplantation in multiple sclerosis.

INTRODUCTION: Autologous haematopoietic cell transplantation (AHCT) is an evolving treatment avenue in multiple sclerosis (MS), which may be highly effective in controlling disease activity and improving disability. However, AHCT is associated with intrinsic toxicities and risks compared with conventional therapies. With growing experience in patient selection and treatment delivery, AHCT is increasingly considered an option in patients with aggressive disease that's responding poorly to disease modifying therapy. AREAS COVERED: This article provides an introduction to AHCT and looks at its development as a treatment for MS over the last 20 years. It also highlights potential mechanisms of action, patient selection, and future trends for this treatment approach. EXPERT OPINION: Currently published data suggest that AHCT's use is associated with significant reduction in MS disease activity and marked improvement in disability when used in patients with highly active relapsing remitting disease. Its long term safety and efficacy have not been fully evaluated but as increasing clinical trial data are published, its use is likely to grow. Further randomised controlled studies are needed to compare AHCT with standard disease modifying therapies and to optimise transplant regimens. Mechanistic studies may provide potential markers for response and a better understanding of disease pathogenesis

Long-term management of natalizumab discontinuation in a large monocentric cohort of multiple sclerosis patients

Background Pivotal and post-marketing studies demonstrated the impressive efficacy and the good tolerability profile of natalizumab in Multiple Sclerosis patients. On the other hand long-term safety of natalizumab therapy is burdened by the risk of progressive multifocal leukoencephalopathy, especially in anti-JCV seropositive patients treated for more than two years. Some of these patients must stop the drug at the risk of disease reactivation. Objectives To evaluate the effects of natalizumab discontinuation in a monocentric cohort of multiple sclerosis patients followed for a mean time of 22.4 months. Methods One hundred and ten patients, who stopped therapy after at least 12 infusions, were followed with periodic clinical and magnetic resonance imaging evaluations. One hundred patients started either immunomodulant therapy (n=90) or fingolimod (n=10) while 10 remained without any drug. Results "Disease-activity free" patients were 25% at one year after discontinuation and annualized relapse rate significantly increased from 0.06 to 0.84 (p<0.0001). We found that the risk of reactivation peaked despite alternative treatments between the second and the eighth month after suspension, a so-called "high risk period". During this period the majority of patients showed a return to pre-natalizumab disease activity while 10% of patients presented a "rebound activity". A higher pre-natalizumab disease activity was correlated with an increased risk of reactivation (p=0.004). Conclusions Our data suggest that disease reactivation peaked during a "high risk period" between the second and the eighth month since stopping the drug. During this period no alternative treatments seemed to provide an adequate protection from disease reactivation. Though transient, this phase could be potentially dangerous, therefore we need to develop more effective strategies to deal with this challenge

Robot assisted laparoscopic excision of a paraganglioma: new therapeutic approach

The Paraganglioma is the most common extra-adrenal pheochromocytoma arising from neural crest (1) (It will better to write: The paraganglioma is an extra-adrenal pheocromocytoma arising from the neural crest. 10% of pheocromocytomas are extra-adrenal and can arise form chromaffin tissue derived from primitive neuroectoderm). Minimally invasive techniques allow surgeons to perform the procedure without wide exposure and mobilization of intra abdominal organs. To our knowledge we present the third case of robotic excision of a retroperitoneal paraganglioma (2,3)

A Second Case of Gobello Nevus Syndrome

An uncommon type of epidermal nevus characterized by hyperpigmented hyperkeratotic bands following a Blaschko-linear pattern and generalized follicular hyperkeratosis were observed in a 17-year-old male patient who additionally showed tufted hair folliculitis on the scalp and clinodactyly of the fifth finger of both hands. The combination of epidermal nevus with skeletal abnormalities was first described by Gobello et al. [Dermatology 2000;201:51-55] as a new epidermal nevus syndrome that was named after the first author of this work. Our case shows identical clinical and histopathological features and represents the second case of this rare syndrome reported in the literature

Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: Neurophysiological and skin biopsy longitudinal analysis

OBJECTIVE - The purpose of this study was to evaluate whether islet transplantation may stabilize polyneuropathy in uremic type 1 diabetic patients (end-stage renal disease [ESRD] and type 1 diabetes), who received a successful islet-after-kidney transplantation (KI-s). RESEARCH DESIGN AND METHODS - Eighteen KI-s patients underwent electroneurographic tests of sural, peroneal, ulnar, and median nerves: the nerve conduction velocity (NCV) index and amplitudes of both sensory action potentials (SAPs) and compound motor action potentials (CMAPs) were analyzed longitudinally at 2, 4, and 6 years after islet transplantation. Skin content of advanced glycation end products (AGEs) and expression of their specific receptors (RAGE) were also studied at the 4-year follow-up. Nine patients with ESRD and type 1 diabetes who received kidney transplantation alone (KD) served as control subjects. RESULTS - The NCV score improved in the KI-s group up to the 4-year time point (P = 0.01 versus baseline) and stabilized 2 years later, whereas the same parameter did not change significantly in the KD group throughout the follow-up period or when a cross-sectional analysis between groups was performed. Either SAP or CMAP amplitudes recovered in the KI-s group, whereas they continued worsening in KD control subjects. AGE and RAGE levels in perineurium and vasa nervorum of skin biopsies were lower in the KI-s than in the KD group (P < 0.01 for RAGE). CONCLUSIONS - Islet transplantation seems to prevent long-term worsening of polyneuropathy in patients with ESRD and type 1 diabetes who receive islets after kidney transplantation. No statistical differences between the two groups were evident on cross-sectional analysis. A reduction in AGE/RAGE expression in the peripheral nervous system was shown in patients receiving islet transplantation. © 2007 by the American Diabetes Association

Etiological research in pediatric multiple sclerosis: A tool to assess environmental exposures (PEDiatric Italian Genetic and enviRonment ExposurE Questionnaire)

Background: The etiology of pediatric-onset multiple sclerosis is unknown although putative genetic and environmental factors appear to be involved. Among children multiple sclerosis onset occurs closer to the susceptibility window thank in adults and the exposure to etiological environmental factors is more informative. An Italian multicentre case-control study (the PEDiatric Italian Genetic and enviRonment ExposurE, PEDIGREE study) was designed to investigate environmental exposures in pediatric-onset multiple sclerosis and their interaction with genetics. Objectives: To collect evidence on exposures to environmental risk factors in pediatric-onset multiple sclerosis, a questionnaire was developed for the Italian population (PEDIGREE Questionnaire) and is presented. Methods: PEDIGREE Questionnaire develops from an existing tool used in case-control studies on pediatric-onset multiple sclerosis in US Americans, and was translated, adapted and tested for the contents perceived relevance, acceptability, feasibility and reliability in a population of Italian pediatric subjects and their parents recruited from clinics and general population. Results: PEDIGREE Questionnaire contents were overall deemed relevant by the study population, acceptable for 100% participants and feasible for at least 98%. PEDIGREE Questionnaire degree of reliability ranged 56% to 72%. Conclusion: PEDIGREE Questionnaire proves to be an efficient tool to assess environmental exposures in the Italian pediatric population. We encourage the dissemination of population-specific questionnaires and shared methodology to optimize efforts in MS etiological research