Bianca Marasini

X Chromosome Monosomy: A Common Mechanism for Autoimmune Diseases

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y α-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 ± 0.3% and 4.3 ± 0.3%, respectively, vs 2.9 ± 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.

Hereditary Angioedema: An Appraisal of 104 Cases

One hundred and four patients affected by hereditary angioedema belonging to 31 families have been studied. Twenty-two percent had the variant form related to the deficiency of the functional activity of serum C1 esterase inhibitor. The remaining 78% of patients had the predominant form, characterized by low antigenic levels and low functional activity of serum C1 esterase inhibitor. Attacks of swelling affected the subcutaneous tissue in 86% of patients; the upper airways in 76% of patients, and the bowel mucose in 75% of patients. Before treatment was available the mortality rate was 56%. One or more attacks a month were present in 46% of cases. The infusion of C1 inhibitor concentrate promptly reversed 14 severe attacks without any side effect. Twenty-nine patients were given long term prophylactic treatment with androgen derivatives with full success. Tranexamic acid reduced the frequency of swelling of 70% of the patients.

Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema

Treatment with 17 alpha-methyltestosterone and with some synthetic androgens prevents attacks of hereditary angioedema (HAE). However, the potential hepatotoxicity of 17 alpha-alkylated androgens raises the problem of long-term prophylactic use of these agents. Therefore we compared the efficacy in preventing HAE attacks of 17 alpha-alkylated steroids (danazol and stanozolol) with non-17 alpha-alkylated derivatives (quinbolone, nandrolone decanoate and mesterolone). As the latter group proved ineffective, it seems that a drugs efficacy in preventing HAE attacks is connected to its 17 alpha-alkylation. Moreover, our long-term observations with the minimum effective dose of danazol seem to indicate the absence of important collateral effects.

Plasma free and intraplatelet serotonin in patients with Raynaud's phenomenon☆

Plasma free and intraplatelet serotonin concentrations were measured by high-performance liquid chromatography coupled with electrochemical detection, in 30 patients with Raynauds phenomenon of various etiologies. Serotonin was significantly higher in plasma (P less than 0.005) and in platelets (P less than 0.005) from Raynauds patients than from normal controls. Moreover, plasma circulating serotonin could differentiate primary from secondary Raynauds phenomenon, with significantly higher levels (P less than 0.05) for patients with an underlying connective tissue disease. Our data indicate a role for serotonin in Raynauds phenomenon.

X Monosomy in Female Systemic Lupus Erythematosus

Abstract:  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, predominantly occurring in women of childbearing age. SLE, like several other autoimmune diseases, is characterized by a striking female predominance and, although sex hormone influences have been suggested as an explanation for this phenomenon, definitive data are still unavailable. Our group recently reported an increased X monosomy in lymphocytes of women, affected with primary biliary cirrhosis (PBC), systemic sclerosis (SSc), and autoimmune thyroiditis (AITD) in comparison to healthy women, thus suggesting the involvement of this chromosome in female predominance and in the deregulation of the immune system that characterizes autoimmunity. We have now evaluated X monosomy rates in SLE using fluorescence in situ hybridization (FISH) on peripheral mononuclear white blood cells (PBMCs) from female patients compared to healthy age‐matched controls. In addition, because of a previous finding of microchimerism as a pathogenetic cause of a number of autoimmune diseases, we investigated the presence of cells carrying the Y chromosome. We did not identify an increased X monosomy in women with SLE compared to controls (P= 0.3960, SLE vs. HCs, Students t‐test), thus suggesting that a different mechanism of immune deregulation might be predominant in the female population of patients with SLE.

Treatment of hereditary angioedema.

ZusammenfassungIn der vorliegenden Studie wird über die Ergebnisse verschiedener Behandlungsverfahren bei 20 Patienten mit hereditärem angioneurotischem Ödem berichtet. Die Wirksamkeit des Esterase-Inhibitors Trancxam-Säure zur Verhütung des Ödems wurde bei 15 Patienten erprobt. Bei 12 der 15 Patienten war Trancxam-Säure wirksam und ohne wesentliche Nebenwirkungen. 15 schwere Anfälle von angioneurotischem Ödem wurden behandelt mit intravenösen Infusionen entweder von Kallikrein-Inhibitor (8 Fälle) oder einem Konzentrat eines C1-Esterase-Inhibitors (7 Fälle). Nach dem Kallikrein-Inhibitor blieb nur in 1 Fall ein Erfolg aus. Das Konzentrat von C 1-Esterase-Inhibitor zeigte sich äußerst wirksam in der Behandlung akuter Anfälle (1 Mißerfolg infolge zu geringer Dosierung). Nebenwirkungen wurden bei beiden Behandlungsverfahren nicht beobachtet, jedoch konnte die Besserung mit Hilfe des C 1-Esterase-Inhibitors schneller erreicht werden. Die Serumspiegel von C 4- und C 1-Esterase-Inhibitor und die Aktivität von C 1-Esterase-Inhibitor vor und nach Langzeitprophylaxe und nach Therapie akuter Anfälle wurden untersucht.SummaryThe purpose of this study was to report the results of different treatments in 20 patients with hereditary angioedema. Effectiveness of tranexamic acid in preventing swellings was evaluated in 15 patients: in all but 3 subjects tranexamic acid was effective without serious side effects. 15 severe attacks of edema were managed with intravenous infusions of either kallikrein inhibitor (8 cases) or concentrate of C 1 esterase inhibitor (7 cases). In only 1 case was the kallikrein inhibitor unsuccessful. C 1 esterase inhibitor concentrate proved highly effective in the treatment of acute attacks (the result was lacking in one patient because of too low dosage of the drug). No side effects were observed with both treatments, but improvement was more rapidly achieved with infusion of C 1 esterase inhibitor. The serum levels of C 4 and C 1 esterase inhibitor and the activity of C 1 esterase inhibitor before and after long-term prophylaxis and acute attacks treatment were investigated.

Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab-related hepatotoxicity

Inhibitors of Tumor Necrosis Factor (TNF) alpha (infliximab, etanercept, adalimumab) are nowadays widely used for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), not responding to conventional therapies. Anti-TNF alpha drugs have demonstrated great efficacy in slowing the disease, however, to date, concern still remains regarding acute and long-term toxicity related to TNF block. Increase in liver tests may be observed during treatment with anti-TNF agents, more often related to concomitant drugs (i.e. NSAIDS, methotrexate) or to reactivation of chronic HBV or HCV infections. However, liver damage directly induced by the drug has been described in patients treated with infliximab or adalimumab. To our knowledge, no cases of liver injury closely related to etanercept have been reported so far. We report the case of a patient with PsA who presented liver dysfunction during adalimumab, subsequently successfully treated with etanercept.

Cigarette smoking and platelet function

To assess the influence of cigarette smoking on platelet activation, we studied the changes in intraplatelet and platelet-released serotonin (5-HT) and plasma levels and platelet-associated production of thromboxane B2 (TXB2), in 6 non smokers and 6 habitual smokers, before and after acute exposure to smoke. Before smoking, habitual smokers showed slightly higher, albeit not significantly, 5-HT platelet concentrations and TXB2 plasma levels, as well as lower TXB2 platelet production after collagen and even more after ADP stimulation (0.59 +/- 0.27 vs 1.35 +/- 0.46 and 0.99 +/- 0.47 vs 2.08 +/- 0.51 ng/10(8) platelets for habitual smokers vs controls, 4 and 10 min after ADP, p less than 0.02). No significant differences in platelet 5-HT release were observed. Acute smoking did not induce any significant change from baseline in either 5-HT or TXB2 for controls, while significantly reduced TXB2 production from ADP-challenged platelets from habitual smokers (0.30 +/- 0.15 vs 0.59 +/- 0.27 ng/10(8) platelets, immediately after smoking vs baseline, p less than 0.01). Ninety min after the completion of the smoking, the values had returned to baseline. Immediately after smoking, significant differences were found between habitual smokers and controls for TXB2 platelet production (2.76 +/- 1.78 vs 6.42 +/- 1.60, p less than 0.025 and 3.01 +/- 1.90 vs 6.44 +/- 2.26 ng/10(8) platelets, p less than 0.05, for habitual smokers vs controls, 4 and 10 min after the addition of collagen; 0.30 +/- 0.15 vs 1.20 +/- 0.84 and 0.79 +/- 0.50 vs 1.70 +/- 0.74 ng/10(8) platelets, p less than 0.05, after ADP stimulation). Differences were no longer significant 90 min after smoking. Our data indicate that cigarette smoking is associated with platelet dysfunction, which seems due to impairment of metabolic platelet capacity rather than increased platelet activation in vivo.

Immunochemical quantitation of acute phase reactive proteins in myocardial infarction

Abstract This study reports the serial changes of the acute phase reactive proteins ( α 1 -antitrypsin, orosomucoid, haptoglobin, and β 1A -globulin) in the serum of 51 patients with myocardial infarction. All these proteins increased after myocardial infarction. Haptoglobin and orosomucoid showed the most pronounced changes. The normalization of the serum levels of these proteins is more rapid in the cases with favorable evolution. It is suggested that the normalization of these proteins might be an index that the healing of the infarcted area is accomplished.

Hepatic Function and Fibrinolysis in Patients with Hereditary Angioedema Undergoing Long‐Term Treatment with Tranexamic Acid

Prophylactic treatment with antifibrinolytic agents, epsilon‐aminocapriod and tranexamic acid, reduces the incidence and severits of attacks in patients with hereditary angioedema. Long‐term ellectivenessor risk of antifibrinolytic agents has not been established. Sixteen patients needing continuous prophylaxis because of frequency and severity of attacks were treated with tranexamic acid. In four patients this treatment was ineffective and the drug was withdrawn after 2 months. A remission or reduction in the frequency or serverity of attacks was observed in 12 patients treated for a period ranging from 8 to 34 months. Hepatic tests and blood fibrinolytic activity were not influenced by long term oral treatment with tranexamic acid.