Drug-induced agranulocytosis in rheumatology. A retrospective study of 12 cases

OBJECTIVE: the aim of this study is to determine the clinical characteristics of drug-induced agranulocytosis in rheumatology. PATIENTS AND METHOD: it is a retrospective monocentric study, including all cases of rheumatologic drug-induced agranulocytosis followed between January 1985 and December 2005. RESULTS: eight female and 4 men, mean age 62.5 years (range: 17-79), were included in the present study. The causative drugs were: anti-inflammatory agents (n=5, 41.6%), methotrexate (n=3, 25%), sulfasalazine (n=2, 16.6%), noramidopyrine (n=1) and dapsone (n=1). Main clinical features included infectious disorders in 9 cases (75%) with 4 cases of septicemia (33.3%) and 2 cases of septic shock (16.6%). The mean neutrophils count was 0.132 x 10(9)/L (range, 0-0.4). Outcome was favorable in 11 patients (91.6%). One patient died of septic complications. CONCLUSION: in rheumatology, drug-induced agranulocytosis is a rare but life-threatening disorder.     

Heterogeneity in type IIB von Willebrand disease: two unrelated cases with no family history and mild abnormalities of ristocetin-induced interaction between von Willebrand factor and platelets

Two patients from two separate families were diagnosed as having type IIB von Willebrand disease, because they had lifelong bleeding tendencies, prolonged bleeding times, no large von Willebrand factor multimers, and low levels of ristocetin cofactor in plasma with heightened ristocetin-induced platelet aggregation. There was no history of bleeding, and no laboratory abnormalities were found in the parents and sibship of either propositi, in contrast with the autosomal dominant pattern of inheritance usually observed in type IIB von Willebrand disease. Abnormalities of ristocetin-induced von Willebrand factor-platelet interactions were less severe than in a patient from a previously reported family with type IIB von Willebrand disease studied in parallel. The peculiar features of these cases provide additional evidence of the existence of heterogeneity within this variant.     

Increased von Willebrand factor antigen in the plasma of patients with vasculitis

The plasma concentrations of von Willebrand factor antigen (vWF:Ag) were determined in 101 patients who had the following diagnoses: vasculitis 8 patients, systemic lupus erythematosus (SLE) 51, rheumatoid arthritis (RA) 28, asthma 7, hereditary angioedema 7. The greatest mean concentration of vWF:Ag, 469% (normal 100% +/- 50), was observed in patients with vasculitis, often without elevation of the erythrocyte sedimentation rate. The mean concentration of vWF:Ag was also increased in both SLE (277%) and RA (194%). Twenty-four patients (15 with SLE, 6 with vasculitis, 3 with RA) had vWF:Ag concentrations greater than 300%. Four of these patients died within 1 year of the date of the study. Of the 15 SLE patients, 9 had vasculitis and 2 had active glomerulonephritis. The 3 RA patients had severe disease associated with extraarticular manifestations. Elevated vWF:Ag may reflect vascular damage, while markedly elevated levels of vWF:Ag appear to indicate a poor prognosis.     

Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction.

In 20 patients with acute myocardial infarction (AMI) treated with streptokinase (SK, n = 7), recombinant single-chain tissue plasminogen activator (rt-PA, n = 7) or urokinase (UK, n = 6), the behavior of plasma von Willebrand factor (vWF) was studied before and 1.5, 3, 24, 48, and 72 hours after beginning thrombolytic therapy. vWF antigen (vWF:Ag) was high in plasma, especially after SK. The ristocetin cofactor (RiCof) activity of vWF, high before therapy, tended to decrease soon after therapy. This pattern of vWF changes was paralleled by the early loss of higher molecular weight multimers. By immunoblotting of immunopurified and reduced vWF and monoclonal antibody epitope mapping, we found that vWF was degraded after thrombolysis, especially after SK, as indicated by the higher values of two plasmin-generated fragments of 176 and 145 Kd. There were more plasmin-generated fragments in the five patients who had bleeding complications than in the remaining 15 who did not. In conclusion, quantitative and qualitative changes of vWF compatible with proteolytic degradation of the protein occur during thrombolytic therapy. Such degradation, roughly proportional to the degree of the general lytic state induced by each agent, might be a cofactor of the bleeding complications occurring in treated patients.     

Metabolomics signature improves the prediction of cardiovascular events in elderly subjects

Aims

Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors.

Methods and results

Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n = 67, mean age = 85 ± 3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models.At follow-up (median = 3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence = 7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR = 1.77 (95%CI = 1.11–2.81, p = 0.016) and HR = 2.18 (95%CI = 1.17–4.07, p = 0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 7%, p = 0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI = 0.79 (p = 0.005).

Conclusions

Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors.     

“The Linosa Study”: Epidemiological and heritability data of the metabolic syndrome in a Caucasian genetic isolate

Background and aimsGrowing evidence suggests that the metabolic syndrome (MetS) has both a genetic and environmental basis. To evaluate the possibility of a further genetic analysis, we estimated prevalence rates and heritabilities for the MetS and its individual traits in the adult population of Linosa, a small and isolated Italian Island in the southern-central part of the Mediterranean Sea.Methods and resultsThe Linosa Study (LiS) group consisted of 293 Caucasian native subjects from 51 families (123 parents; 170 offsprings). The MetS was defined according to NCEP/ATP III criteria and the following prevalence rates were calculated: hyperglycaemia 20.3%; central obesity 34.9%; hypertension 43.4%; hypertriglyceridaemia 29.9%; “low HDL” 56.6%; MetS 29.9%. Waist circumference was significantly related to all the quantitative parameters included in the NCEP/ATP III MetS definition. The MetS showed a heritability of 27% (p = 0.0012) and among its individual components, treated as continuous and discrete traits, heritability ranged from 10% for blood glucose to 54% for HDL-cholesterol. Among MetS subtypes, the clustering of central obesity, hypertriglyceridaemia and “Iow HDL” had the highest heritability (31%; p < 0.001).ConclusionThese data showed high prevalence rates for the MetS and its related traits in an isolated and small Caucasian population. The appreciable heritability estimates for the MetS and some of its components/clusters in the LiS population might support the observation of genetic factors underlying the pathogenesis of the MetS and encourage further analysis to identify new susceptibility genes.     

Structural requirements of endopolygalacturonase for the interaction with PGIP (polygalacturonase-inhibiting protein)

To invade a plant tissue, phytopathogenic fungi produce several cell wall-degrading enzymes; among them, endopolygalacturonase (PG) catalyzes the fragmentation and solubilization of homogalacturonan. Polygalacturonase-inhibiting proteins (PGIPs), found in the cell wall of many plants, counteract fungal PGs by forming specific complexes with them. We report the crystal structure at 1.73 A resolution of PG from the phytopathogenic fungus Fusarium moniliforme (FmPG). The structure of FmPG was useful to study the mode of interaction of the enzyme with PGIP-2 from Phaseolus vulgaris. Several amino acids of FmPG were mutated, and their contribution to the formation of the complex with PGIP-2 was investigated by surface plasmon resonance. The residues Lys-269 and Arg-267, located inside the active site cleft, and His-188, at the edge of the active site cleft, are critical for the formation of the complex, which is consistent with the observed competitive inhibition of the enzyme played by PGIP-2. The replacement of His-188 with a proline or the insertion of a tryptophan after position 270, variations that both occur in plant PGs, interferes with the formation of the complex. We suggest that these variations are important structural requirements of plant PGs to prevent PGIP binding.