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Antimalarials (AMs) reduce disease activity and improve survival in patients with systemic lupus erythematosus (SLE), but studies have reported low AM prescribing frequencies. Using a real-world electronic health record cohort, we examined if patient or provider characteristics impacted AM prescribing. We identified 977 SLE cases, 94% of whom were ever prescribed an AM. Older patients and patients with SLE nephritis were less likely to be on AMs. Current age (odds ratio = 0.97, < 0.01) and nephritis (odds ratio = 0.16, < 0.01) were both significantly associated with ever AM use after adjustment for sex and race. Of the 244 SLE nephritis cases, only 63% were currently on AMs. SLE nephritis subjects who were currently prescribed AMs were more likely to be followed by a rheumatologist than a nephrologist and less likely to have undergone dialysis or renal transplant (both < 0.001). Non-current versus current SLE nephritis AM users had higher serum creatinine ( < 0.001), higher urine protein ( = 0.05), and lower hemoglobin levels ( < 0.01). As AMs reduce disease damage and improve survival in patients with SLE, our results demonstrate an opportunity to target future efforts to improve prescribing rates among multi-specialty providers.
Neutrophil extracellular traps are associated with a unique form of cell death distinct from apoptosis or necrosis, whereby invading microbes are trapped and killed. Neutrophil extracellular traps can contribute to autoimmunity by exposing autoantigens, inducing IFN-α production, and activating the complement system. The association of neutrophil extracellular traps with autoimmune diseases, particularly systemic lupus erythematosus, will be reviewed. Increased neutrophil extracellular trap formation is seen in psoriasis, antineutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid antibody syndrome rheumatoid arthritis, and systemic lupus erythematosus. Neutrophil extracellular traps may promote thrombus formation in antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid antibody syndrome. In systemic lupus erythematosus, increased neutrophil extracellular trap formation is associated with increased disease activity and renal disease, suggesting that neutrophil extracellular traps could be a disease activity marker. Neutrophil extracellular traps can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus. As neutrophil extracellular traps induce IFN-α production, measuring neutrophil extracellular traps may estimate IFN-α levels and identify which systemic lupus erythematosus patients have elevated levels and may be more likely to respond to emerging anti-IFN-α therapies. In addition to anti-IFN-α therapies, other novel agents, such as N-acetyl-cysteine, DNase I, and peptidylarginine deiminase inhibitor 4, target neutrophil extracellular traps. Neutrophil extracellular traps offer insight into the pathogenesis of autoimmune diseases and provide promise in developing disease markers and novel therapeutic agents in systemic lupus erythematosus. Priority areas for basic research based on clinical research insights will be identified, specifically the potential role of neutrophil extracellular traps as a biomarker and therapeutic target in systemic lupus erythematosus.
© Society for Leukocyte Biology.
Sarcoidois is an inflammatory disease of unknown origin characterized by the abnormal accumulation of noncaseating granulomas at sites of disease activity in multiple organs throughout the body with a predilection for the lungs. Because the exact trigger that leads to disease activity is still under investigation, current treatment options are contingent on the organ or organs affected. Corticosteroids are the therapy of choice, but antimalarials and TNF-α antagonists are also commonly prescribed. Recent findings provide evidence for the use of CD20 B-cell-depleting therapy as an alternative method of choice. However, because sarcoidosis is predominantly a T-helper cell-driven disorder, an overwhelming amount of compelling evidence exists for the use of CD4(+) T-cell targeted therapy.
Several analogues of the natural compound prodigiosin with modified A- and C-rings were synthesised as were some of their tin, cobalt, boron and zinc complexes. The antimalarial activity of these prodigiosenes was evaluated in vitro using the 3D7 Plasmodium falciparum strain. The presence of a nitrogen atom in the A-ring is needed for antimalarial activity but the presence of an alkyl group at the β'-position of the C-ring seems detrimental. Dibutyl tin complexes exhibit IC50 values mostly in the nanomolar range with equal or improved activity compared to the free-base prodigiosene ligand, despite the fact that the general toxicity of such tin complexes is demonstrably lower than that of the free-bases.
Chloroquine and hydroxychloroquine are used to chronically treat certain rheumatologic diseases and are generally considered safe. We describe 2 patients with skeletal myopathy and fatal cardiomyopathy-uncommon and underrecognized adverse effects of these agents. Both patients developed arrhythmias and heart failure, and 1 patient had documented diaphragmatic involvement. Muscle specimens showed typical vacuolar myopathy (indicative of impaired autophagy) with myeloid bodies in both patients and curvilinear bodies in 1 patient. Antimalarial-induced cardiomyopathy should be considered in patients receiving these medications with otherwise unexplained muscle weakness or cardiac symptoms. Whether autophagy enhancers can be used to manage such myopathies merits investigation.
BACKGROUND - Presumptive treatment for malaria is common in resource-limited settings, yet controversial given the imprecision of clinical diagnosis. The researchers compared costs of diagnosis and drugs for two strategies: (1) empirical treatment of malaria via clinical diagnosis; and (2) empirical diagnosis followed by treatment only with Giemsa smear confirmation.
METHODS - Patients with a diagnosis of clinical malaria were recruited from a mission/university teaching hospital in southwestern Nigeria. The patients underwent free Giemsa thick (diagnosis) and thin (differentiation) smears, but paid for all anti-malarial drugs. Clinical diagnosis was made on clinicians' judgments based on symptoms, including fever, diarrhoea, headache, and body aches. The paediatric regimen was artesunate (6-9 tablets of 3 mg/kg on day one and 1.5 mg/kg for the next four days) plus amodiaquine (10 mg/kg day 1-2 and 5 mg/kg on day three in suspension). Adults were given two treatment options: option one (four and one-half 50 mg artesunate tablets on day one and nine tablets for the next four days, plus three 500 mg sulphadoxine/25 mg pyrimethamine tablets) and option two (same artesunate regimen plus nine 200 mg tablets of amodiaquine at 10 mg/kg day 1-2 and 5 mg/kg on day three). The researchers calculated the costs of smears/drugs from standard hospital charges.
RESULTS - Doctors diagnosed 304 patients (170 adults ages >16 years and 134 pediatric) with clinical malaria, prescribing antimalarial drugs to all. Giemsa thick smears were positive in 115/304 (38%). The typical patient cost for a Giemsa smear was 550 Naira (US$3.74 in 2009). For children, the cost of testing all, but treating only Giemsa positives was N888 ($6.04)/child; the cost of empiric treatment of all who were clinically diagnosed was lower, N660 ($4.49)/child. For adults, the cost of testing all, but treating only Giemsa positives was N711 ($4.84)/adult for treatment option one (artesunate and sulphadoxine/pyrimethamine) and N730 ($4.97)/adult for option two (artesunate and amodiaquine). This contrasts to lower costs of empiric treatment for both options one (N610 = $4.14/adult) and two (N680=$4.63/adult).
CONCLUSIONS - Empiric treatment of all suspected cases of malaria was cheaper (at the end of the dry to the beginning of the rainy season) than only treating those who had microscopy-confirmed diagnoses of malaria, even though the majority of patients suspected to have malaria were negative via microscopy. One can acknowledge that giving many malaria-uninfected Nigerians anti-malarial drugs is undesirable for both their personal health and fears of drug resistance with overuse. Therefore, funding of rapid diagnostic tests whose performance exceeds the Giemsa smear is needed to achieve an ideal of diagnostic confirmation before treatment.
The completion of the Plasmodium falciparum clone 3D7 genome provides a basis on which to conduct comparative proteomics studies of this human pathogen. Here, we applied a high-throughput proteomics approach to identify new potential drug and vaccine targets and to better understand the biology of this complex protozoan parasite. We characterized four stages of the parasite life cycle (sporozoites, merozoites, trophozoites and gametocytes) by multidimensional protein identification technology. Functional profiling of over 2,400 proteins agreed with the physiology of each stage. Unexpectedly, the antigenically variant proteins of var and rif genes, defined as molecules on the surface of infected erythrocytes, were also largely expressed in sporozoites. The detection of chromosomal clusters encoding co-expressed proteins suggested a potential mechanism for controlling gene expression.
Natural killer T (NKT) cells are a unique population of lymphocytes that coexpress a semiinvariant T cell and natural killer cell receptors, which are particularly abundant in the liver. To investigate the possible effect of these cells on the development of the liver stages of malaria parasites, a glycolipid, alpha-galactosylceramide (alpha-GalCer), known to selectively activate Valpha14 NKT cells in the context of CD1d molecules, was administered to sporozoite-inoculated mice. The administration of alpha-GalCer resulted in rapid, strong antimalaria activity, inhibiting the development of the intrahepatocytic stages of the rodent malaria parasites Plasmodium yoelii and Plasmodium berghei. The antimalaria activity mediated by alpha-GalCer is stage-specific, since the course of blood-stage-induced infection was not inhibited by administration of this glycolipid. Furthermore, it was determined that IFN-gamma is essential for the antimalaria activity mediated by the glycolipid. Taken together, our results provide the clear evidence that NKT cells can mediate protection against an intracellular microbial infection.
Mass drug administration (MDA) in 1981 reduced the incidence rates of both Plasmodium vivax and P falciparum infection in Nicaragua. Impact on P vivax cases lasted for four months and on P falciparum for seven. Subtherapeutic primaquine doses, the shorter extrinsic cycle of P vivax in the insect vector, and the timing of MDA at a high-transmission period of the year may explain the limited effects of the campaign. Positive results of the anti-malaria campaign included improvements in case-finding and routine surveillance, the apparent prevention of at least 9200 malaria cases, the training of some 70 000 antimalaria volunteers, and the participation of about 70% of the population in anti-malarial activities.
A malaria control effort in Nicaragua involving the mass, short-term distribution of anti-malaria medicines to a target population of all citizens above one year of age is detailed. About 70% of the population received anti-malarials in November, 1981 and 8 million packets of chloroquine and primaquine were distributed by 70,000 health campaign workers and their assistants. Training and mobilization efforts used volunteers from local community organizations. Mass public education was a key focus in the weeks before drug administration. The effects of the campaign were immediately apparent with a rapid decline in incidence after drug administration. Ongoing community environmental control, case finding, and health education activities continued to improve the malaria situation post-campaign. Further, the campaign promoted the decentralization of malaria control activities and integration of the malaria efforts with the nationwide primary health care system.