ObjectiveTwo tumor necrosis factor α (TNFα) antagonists were recently licensed in the US. Infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). Etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti‐TNFα agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products.MethodsThe US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept.ResultsTen cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept, and all resided in HC‐endemic regions.ConclusionPostlicensure surveillance suggests that acute life‐threatening histoplasmosis may complicate immunotherapy with TNFα antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC‐endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.
Objective. Tumor necrosis factor ␣ (TNF␣) has been implicated in the pathogenesis of certain inflammatory diseases. Two TNF␣-neutralizing agents are licensed in the US. Infliximab is licensed for the treatment of Crohn's disease (CD) and, when used with methotrexate, for the treatment of rheumatoid arthritis (RA). Etanercept is licensed for the treatment of RA, including juvenile RA, and, more recently, was licensed for the treatment of psoriatic arthritis. Because of the potential for decreased host resistance to infectious agents due to treatment with anti-TNF␣ agents, we sought to evaluate postlicensure cases of opportunistic infection, including Listeria monocytogenes, in patients treated with these products.Methods. The FDA Adverse Event Reporting System, a passive monitoring system, was reviewed to identify all reports of adverse events (through December 2001) associated with L monocytogenes infection in patients treated with infliximab or etanercept.Results. Fifteen cases of L monocytogenes infection associated with infliximab or etanercept treatment were identified. In 14 of these cases, patients had received infliximab. The median age of all patients was 69.5 years (range 17-80 years); 53% were female. Six deaths were reported. Among patients for whom an indication for use was reported, there were 9 patients (64%) with RA and 5 patients (36%) with CD (information was not reported for 1 patient). All patients for whom information was reported were receiving concurrent immunosuppressant drugs. Conclusion.Postlicensure surveillance suggests that L monocytogenes infection may be a serious complication of treatment with TNF␣-neutralizing agents, particularly infliximab.
Two of the four principal cationic proteins of the eosinophil granule, major basic protein (MBP) and eosinophil peroxidase (EPO), were shown to be platelet agonists. Both MBP and EPO evoked a dose-dependent nonlytic secretion of platelet 5-hydroxytryptamine in unstirred platelet suspensions even in the presence of 10 microM indomethacin. MBP also evoked secretion of platelet alpha granule and lysosome components. Secretion by MBP and EPO was inhibited by 1 microM PGE1, but the nature of the inhibition differed from that observed with thrombin. Thus, MBP and EPO can be classified as strong platelet agonists with a distinct mechanism of activation.
Major basic protein (MBP), one of several cationic proteins associated with the eosinophil granule, is cytotoxic to respiratory epithelium and is present in the sputum of asthmatics and on damaged bronchial epithelium from patients dying of asthma. The present experiments were performed in order to determine the effects of MBP on the responsiveness of airway smooth muscle. Rings of guinea pig trachea, in some of which the epithelium had been gently removed by rubbing, were incubated for 5 h in modified Krebs-Ringer bicarbonate solution containing buffer or human MBP (100 micrograms/ml). The tracheal rings were then suspended for isometric tension recording in organ chambers filled with Krebs-Ringer solution containing indomethacin. MBP did not affect the reactivity of rings in which the epithelium had been removed, but significantly augmented that of unrubbed rings to acetylcholine and histamine. The results suggest that MBP, by inhibiting the function of epithelial but not smooth muscle cells, causes hyperreactivity of respiratory smooth muscle, which may contribute to the hyperreactivity observed in chronic respiratory disease.
We investigated the genetic aspects of congenital nevomelanocytic nevi (CNN) by comparing the prevalence rate of CNN in sibs of probands to that of CNN in newborn infants. Probands included all individuals with small (less than 40 mm) CNN registered photographically during 1982 in a children's hospital dermatology service. A CNN was defined on the basis of gross appearance and presence (according to parents) within the first 2 weeks of life. The 39 probands with small CNN had a total of 65 sibs. Eight of the 65 (12.3%) also had one or more small CNN. This prevalence rate in sibs is 11 times the population-based prevalence rate of CNN in newborn infants (1.1%) based on a published report surveying newborn infants in the same city within the past decade. In five of our 39 study families we also detected an affected parent with CNN. We conclude that small CNN may aggregate in families. Autosomal dominant inheritance with incomplete penetrance or multifactorial determination could account for this observation.
The eosinophil granule contains a series of basic proteins, including major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP). Both EDN and ECP are neurotoxins and helminthotoxins. Comparison of the partial N-terminal amino acid sequences of EDN and ECP showed 67% identity; surprisingly, they also showed structural homology to pancreatic ribonuclease (RNase). Therefore, we determined whether EDN and ECP possess RNase enzymatic activity. By spectrophotometric assay of acid soluble nucleotides formed from yeast RNA, purified EDN showed RNase activity similar to bovine pancreatic RNase, whereas ECP was 50 to 100 times less active. The RNase activity associated with ECP was not significantly inhibited after exposure of ECP to polyclonal or monoclonal antibody to EDN. These results indicate that EDN and ECP both possess RNase activity, the RNase activity of EDN and ECP is specific, and EDN and ECP have maintained not only structural but also functional homology to pancreatic RNase.
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