Familial Mediterranean fever: an ancient hereditary disease

Familial Mediterranean fever (FMF) is an autosomal recessive disorder that mainly affects people living around the Mediterranean sea (i.e. Turks, Armenians, Arabs and Jews), but cases of FMF are now being increasingly diagnosed in every country of the world (including Italy). Described for the first time in 1945, it has recently become more relevant, after the discovery of the responsible gene, the MEFV gene which encodes a 781-aminoacid protein called pyrin that seems to play a role in the regulation of the inflammatory process. As the prototype of an emerging group of disorders fated to become more and more popular--the hereditary auto-inflammatory disorders--FMF is an under-diagnosed cause of fever of unknown origin. Fever is the main but not the only symptom; sterile serosites are the most common associated features. The classical clinical picture is being continuously enriched. Geno-phenotype correlations and interval-free symptoms are the new clinical insights, while fundamentally important studies attempt to enlighten its obscure pathogenesis. In spite of the introduction of alternative treatments, colchicine is still the only suitable drug for the prevention of acute episodes and the development of amyloidosis.     

Influenza: New insights into an old disease

In the United States each year, influenza accounts for an estimated 20,000 to 40,000 deaths, nearly 300,000 hospitalizations, and millions of days lost from work. In the past few years, there has been an explosion of information in the medical literature related to influenza. This paper reviews these latest developments that enhance our understanding of influenza epidemiology and virology and expand our prevention and treatment options. Diminishing the impact of influenza in this country will require continued intense surveillance, increased use of influenza vaccine, and the availability of alternative vaccines and antivirals with the potential for broader protection against shift-and-drift strains of influenza.     

Influenza and risk of later celiac disease: a cohort study of 2.6 million people

Objectives: Influenza has been linked to autoimmune conditions, but its relationship to subsequent celiac disease (CD) is unknown. Our primary aim was to determine the risk of CD after influenza. A secondary analysis examined the risk of CD following pandemic influenza vaccination.

Methods: This nationwide register-based cohort study included 2,637,746 Norwegians (born between 1967–2013) followed during 2006–2014 with information on influenza diagnosed in primary or non-primary care, pandemic vaccination (Pandemrix), and subsequent CD. Cox regression yielded hazard ratios adjusted (HR) for socio-demographic characteristics and earlier healthcare use.

Results: During 13,011,323 person-years of follow-up 7321 individuals were diagnosed with CD (56/100,000 person-years). There were 351,666 individuals diagnosed with influenza, including 82,980 during the 2009–2010 pandemic, and 969,968 individuals were vaccinated. Compared with participants without influenza, who had a CD incidence of 55/100,000 person-years, those diagnosed with seasonal and pandemic influenza had a rate of 68 and 78, per 100,000 person-years, respectively. The HR for CD was 1.29 (95%CI, 1.21–1.38) after seasonal influenza and 1.29 (95%CI, 1.15–1.44) after pandemic influenza; HRs remained significantly increased one year after exposure, when restricted to laboratory-confirmed influenza, and after multivariate adjustments. The reverse association, i.e., risk of influenza after CD, was not significant (HR 1.05; 95%CI, 0.98–1.12). The HR for CD after pandemic vaccination was 1.08 (95%CI, 1.03–1.14).

Conclusion: A positive association with influenza diagnosis is consistent with the hypothesis that infections may play a role in CD development. We could neither confirm a causal association with pandemic vaccination, nor refute entirely a small excess risk.     

Osteoarthritis: new insights. Part 1: the disease and its risk factors

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors (such as genetics, dietary intake, estrogen use, and bone density) and of local biomechanical factors (such as muscle weakness, obesity, and joint laxity). These risk factors are particularly important in weight-bearing joints, and modifying them may present opportunities for prevention of osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 1 of a two-part summary of a National Institutes of Health conference. The conference brought together experts on osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 1 focuses on a new understanding of what osteoarthritis is and on risk factors that predispose to disease occurrence. It concludes with a discussion of the impact of osteoarthritis on disability.     

Paroxysmal nocturnal haemoglobinuria (PNH): novel therapies for an ancient disease

In the UK, early work on paroxysmal nocturnal haemoglobinuria (PNH) was conducted by John Dacie who, at the Hammersmith Hospital, first hypothesised that the PNH abnormality might arise through a somatic mutation; and who outlined with S.M. Lewis the relationship between PNH and aplastic anaemia. When the phosphatidylinositol glycan anchor biosynthesis Class A (PIGA) gene was identified by Taroh Kinoshita’s group, jointly with him the Hammersmith group proved that PNH is caused in most patients by a single somatic mutation in the PIGA gene. At the same time, after Bruno Rotoli had spent a sabbatical at the Hammersmith, the ‘immune escape model’ for the pathogenesis of PNH was developed. Early this century, Peter Hillmen, formerly at the Hammersmith and now in Leeds, spearheaded the use of the complement-blocking (anti-C5) antibody eculizumab. This new medicine radically changed the management and the clinical course of patients with PNH. Recently a derivative of eculizumab with more favourable pharmacokinetics has been introduced. In view of the fact that these agents are associated with C3-dependent extravascular haemolysis, it is important that a number of inhibitors of the proximal complement pathway are now in the offing and may further improve the life of patients with PNH.     

Wilson's disease: an old disease keeps its old secrets

Wilson's disease is a rare condition characterized by a defect in biliary excretion of copper, due to a mutation of both alleles of "Wilson's disease" gene (ATP7b gene). Many different mutations have been identified in affected patients. Since the clinical presentation of the disease is highly heterogeneous, it has been suspected that this variability could be related to different phenotypes. In this paper, Folhoffer et al. report a series of 109 Hungarian patients with Wilson's disease. The authors identified 8 novel, previously unreported, mutations of ATP7b gene in their population. However, 17% of patients with an established diagnosis of Wilson's disease still did not have any identifiable mutation. Since not all exons were analyzed, more studies are needed to identify the corresponding mutations. Overall, the authors failed to document any genotype-phenotype correlation suggesting that non genetical factors are involved in the clinical variability of the disease.     

Proteinuria: an underappreciated risk factor in cardiovascular disease

Changes in renal function produced by hypertension appear to be associated with higher cardiovascular morbidity and mortality. Indices of altered renal function (eg, micro-albuminuria, increased serum creatinine concentrations, decrease in estimated creatinine clearance, or overt proteinuria) are independent predictors of cardiovascular morbidity and mortality. The Framingham Heart Study documented the relevance of proteinuria for cardiovascular prognosis in the community. The International Nifedipine GITS study: Intervention as a goal in Hypertension Treatment (INSIGHT) study assessed the role of proteinuria as a very powerful risk factor. Several studies demonstrated that microalbuminuria is a predictor of cardiovascular disease. It has been shown that the presence of microalbuminuria in primary hypertension carries an elevated cardiovascular risk. Furthermore, recent data indicate that even minor derangements of renal function are associated with an increase in cardiovascular risk factors, and promote progression of atherosclerosis. All these parameters should routinely be evaluated in clinical practice, and in the future must be considered in any stratification of cardiovascular risk in hypertensive patients.