Raffaele Manna

Familial Mediterranean fever is no longer a rare disease in Italy

Familial Mediterranean fever (FMF) is an autosomal recessive disorder, characterised by short, recurrent attacks of fever with abdominal, chest or joint pain and erysipelas-like erythema. It is an ethnically restricted genetic disease, found commonly among Mediterranean populations, as well as Armenians, Turks, Arabs and Jews. Traditionally, Italians have been considered little affected by FMF, despite the geographical position of Italy (northern Mediterranean basin) and the migratory changes in its population. The objective was to characterise the demographic, clinical and genetic features of FMF in Italy. Patients of Italian origin were recruited from those referred to Italian-French medical centres for FUO (Fever of Unknown Origin) or ‘surgical’ emergencies; clinical history, genealogy and physical examination were recorded; all other possible infectious, neoplastic, auto-immune and metabolic diseases were excluded. Mutational analysis of the gene responsible for FMF (MEFV on 16p13.3) was performed, after which geno-phenotypical correlations were established. Italian FMF patients, 40 women and 31 men, aged from 3 to 75 years, have shown all the clinical manifestations indicative of FMF described in the literature, but with a lower incidence of amyloidosis. The genetic tests have been contributive in 42% of cases. The frequency of each different mutation has been similar to that found in a series of ‘endemic’ countries. The geno-phenotypical correlations have suggested the existence of genetic and/or environmental modifier-factors. Among Italians FMF seems to be more frequent than was believed in the past. The data presented are consistent with their geographical location and their history.

Pharmacological and Clinical Basis of Treatment of Familial Mediterranean Fever (FMF) with Colchicine or Analogues: An Update

Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding beta-tubulin and making beta-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg/die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and/or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.

Familial Mediterranean fever: a review for clinical management

Familial Mediterranean Fever (FMF) is a hereditary autosomal recessive, autoinflammatory disorder characterized by recurrent, self-limiting episodes of short duration (mean 24-72 h) of fever and serositis. FMF is the most frequent periodic febrile syndrome among the autoinflammatory syndromes (AS), a heterogeneous group of recently identified diseases clinically characterized by recurrent febrile attacks, in the absence of autoantibodies and antigen-specific T lymphocytes. In FMF, periodic attacks show inter- and intra-individual variability in terms of frequency and severity. Usually, they are triggered by apparently innocuous stimuli and may be preceded by a prodromal period. The Mediterranean FeVer gene (MEFV) responsible gene maps on chromosome 16 (16p13) encoding the pyrin-marenostrin protein. The precise pathologic mechanism is still to be definitively elucidated; however a new macromolecular complex, called inflammasome, seems to play a major role in the control of inflammation and it might be involved in the pathogenesis of FMF. The most severe long-term complication is type AA amyloidosis, principally affecting the kidney and the cause of chronic renal failure. Two types of risk factors, genetic and non-genetic, have been identified for this complication. Currently, the only effective treatment of Familial Mediterranean Fever is the colchicine. New drugs in a few colchicine resistant patients have been tried, but additional studies on larger series are necessary to draw definitive conclusions.

Schizophrenic symptoms and SPECT abnormalities in a coeliac patient : regression after a gluten-free diet

De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G, Taranto C, Manna R, Gasbarrini G (Catholic University, Rome, Italy). Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten‐free diet (Case Report). J Intern Med 1997; 242: 421–23.

Insulin and glucagon concentrations in portal and peripheral veins in patients with hepatic cirrhosis

SummaryThe portal vein was catheterized via the umbilical vein under local anaesthesia in 10 non-diabetic subjects about to undergo exploratory laparotomy and in 8 patients with liver cirrhosis. Immunoreactive insulin (IRI) and glucagon (IRG) were assayed in portal and peripheral blood before and during IV infusion of glucose (0.33 g/kg) or arginine (25 g). Basal peripheral plasma (IRI) levels were raised in cirrhotic patients (19±2 versus 10±1 μU/ml; P<0.001). Basal portal insulin values, however, did not differ in the two groups. After glucose cirrhotic patients had higher peripheral insulin concentrations, compared to controls, significant at 45 and 60 minutes. In contrast portal insulin levels were higher in controls than in cirrhotics by 1 minute (403±43 versus 158±38 μU/ml; P<0.001) and remained so for the 60 minutes of study. Similarly, after arginine cirrhotics had significantly higher peripheral insulin concentrations and lower portal concentrations than controls. Peak portal vein insulin levels were delayed in cirrhotics (168±16 μU/ml at 3 min) compared with controls (413±25 μU/ml at 1 min). In the basal state both portal and peripheral glucagon levels were higher in cirrhotics than control subjects. Unlike in controls, IV glucose did not suppress glucagon secretion in cirrhotic patients. Peripheral plasma glucagon concentrations after arginine were also consistently higher in cirrhotics than controls, but unlike insulin portal venous glucagon levels were also raised (1800±360 pg/ml, cirrhotics; 960±87 pg/ml, controls; P<0.001; 1 min after arginine infusion). We conclude that insulin secretion is decreased in liver cirrhosis and that the peripheral hyperinsulinaemia observed reflects diminished hormone metabolism. The high plasma glucagon levels observed in cirrhotic patients are the result of pancreatic hypersecretion of glucagon.

Human papillomavirus vaccine and systemic lupus erythematosus

To investigate the association between human papillomavirus (HPV) vaccination and autoimmune manifestations compatible with systemic lupus erythematosus (SLE) or SLE-like disease, the medical history of six women who presented with SLE or SLE-like disease following HPV immunization was collected. Data regarding type of vaccine, number of immunization, family and personal, clinical and serological features, as well as response to treatments were analyzed. In the reported cases, several common features were observed, such as personal or familial susceptibility to autoimmunity or adverse response to a prior dose of the vaccine, both of which may be associated with a higher risk of post-vaccination autoimmunity. Favorable response to immunosuppressant was observed in all patients. In the current study, a temporal association between immunization with HPV vaccine and the appearance of a spectrum of SLE-like conditions is reported. Additionally, among the patients described, several common features were observed that may enable better identification of subjects at risk. Further studies are required to assess the safety of immunization with the HPV vaccine in patients with autoimmune-rheumatic diseases or in subject at risk of autoimmunity as well as the potential beneficial effect of preventive immunosuppressants.

Delayed hypersensitivity to aminopenicillins is related to major histocompatibility complex genes.

BACKGROUND Although in some cases delayed hypersensitivity may be observed, beta-lactam antibiotics frequently induce immediate allergic IgE-mediated reactions with the specificity localized in the acyl-side chain structure. Generally, delayed immunologic reactions are related to sensitized T lymphocytes and major histocompatibility complex restricted. OBJECTIVE To investigate the prevalence of HLA class I and II antigens in patients with delayed hypersensitivity to aminopenicillins in order to evaluate a relationship between major histocompatibility complex immune response genes and aminopenicillins hypersensitivity. METHODS We assessed 24 patients with history of delayed hypersensitivity to aminopenicillins using (1) skin test with penicilloyl polylysine, minor determinant mixture, benzylpenicillin, amoxicillin, and ampicillin; (2) patch tests with benzylpenicillin, amoxicillin, and ampicillin; (3) RAST for penicilloyls G and V; and (4) oral challenges with amoxicillin, ampicillin, and penicillin V in 18/24 patients. All patients were typed by microlymphotoxicity standard test for HLA class I and II antigens. Statistical analysis by chi2 test 2 x 2 contingency tables, according to Svejgaard, were used for comparison between patients and random Italian population (522 subjects). RESULTS In the patients group we found higher prevalence of HLA A2 (12/24 = 50%, RR = 6.76 P < .001, EF = 0.425), DRw52 (20/24 = 83.3%, RR = 9.28, P < .001, EF = 0.74), and lower frequency of DR4 (3/24 = 12% ns). CONCLUSIONS These data suggest that the immune mechanisms involved in adverse reactions to aminopenicillins in vivo are related to genetic markers of immune response and confirms that the presentation of penicillin-hapten determinants to lymphocyte is major histocompatibility complex restricted.

Anti-Endothelial Autoantibodies in Patients With Sudden Hearing Loss

Objectives/Hypothesis: Sudden hearing loss (HL) can be caused by autoimmune disorders localized to the inner ear or secondary to systemic immune diseases. Studies in autoimmune animal strains showing HL have reported changes in the cochlear stria vascularis. The authors investigated the presence of antiendothelial cell antibodies (AECA) to see if immunemediated vasculitis may play a role in human sudden HL. Study Design: A prospective study in patients with sudden HL. Methods: Fifteen consecutive patients (mean age, 32 y) affected by sudden HL and 14 normal subjects were included. Patients with familial deafness and metabolic diseases were excluded. Extensive audiovestibular, imaging, microbiological, immunological, and routine examinations were performed. AECA were detected on rat kidney tissue sections on the sera collected at −20°C. Results: AECA were positive in 8 of 15 patients (53%) (2 of 5 men and 6 of 10 women), thus differing significantly from the normal control population, in which only 2 of 14 tested AECA positive (P = .023). Conclusions: In patients with sudden HL, immune‐mediated vascular damage can have a pathogenetic role and AECA might represent a serological marker of vasculitis.

Autoinflammatory gene mutations in Behçet’s disease

Background: Behçet’s disease (BD) shares clinical features with well-recognised autoinflammatory disorders. In addition, mutations in genes for familial Mediterranean fever and tumour necrosis factor receptor-associated periodic syndrome have been reported to have increased in patients with BD. Patients and methods: DNA samples from 97 patients with BD and 51 matched healthy controls were analysed for the mevalonate kinase (MVK), cold-induced autoinflammatory syndrome 1 (CIAS1) and proline/serine/threonine phosphatase-interacting protein 1 (PSTPIP1) genes, responsible for mevalonate kinase deficiency (MKD), cryopyrin associated periodic syndromes (CAPS) and pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, respectively. Over 90% of known mutations were screened using restriction fragment length polymorphism analysis and/or sequencing. Results: Two patients had paired mutations in the MVK gene (genotypes V377I/V377I and V377I/S135L) and displayed typical features of BD and MKD. Another was heterozygotic for the V377I genotype. The V198M mutation in the CIAS1 gene was identified in one patient with typical BD but no symptoms of CAPS. No mutations were identified in the control group. PSTPIP1 analysis revealed a new exon 10 insertion variant (c.741+33_741+34insGT) in 2 of 97 patients and in 1 of 51 controls (p>0.05), indicating that it is a polymorphism rather than a true mutation. Discussion: This study could not demonstrate any significant increases in MVK, CIAS1 or PSTPIP1 mutations in patients with BD as compared with controls.

Giant cell arteritis and polymyalgia rheumatica after influenza vaccination: report of 10 cases and review of the literature

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases common in people over the age of 50 years. Herein, we report 10 cases of previously healthy subjects who developed GCA/PMR within 3 months of influenza vaccination (Inf-V). A Medline search uncovered additional 11 isolated cases of GCA/PMR occurring after Inf-V. We discuss the role of individual susceptibility, the potential function of immune adjuvants as triggers of autoimmunity post-vaccination, and the correlation of our observation with the ‘ASIA’ syndrome, i.e. autoimmune/inflammatory syndrome induced by adjuvants and including post-vaccination phenomena.