Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)
Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCAnegative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.
Objective. To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG).Methods. Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting ؍ 1 point) or major (e.g., alveolar hemorrhage ؍ 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG.Results. We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r ؍ 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (withincase) correlation coefficients in the 2 simulation exercises was r ؍ 0.93 for the BVAS/WG and r ؍ 0.88 for the PGA in the first and r ؍ 0.91 for the BVAS/WG and r ؍ 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r ؍ 0.73 (95% confidence interval 0.43-0.83).Conclusion. The BVAS/WG is a valid, diseasespecific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good interand intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.The investigation of new therapies for the treatment of systemic vasculitis and the organization of
SummaryBackground and objectives Approximately 70% of illicit cocaine consumed in the United States is contaminated with levamisole. Most commonly used as a veterinary antihelminthic agent, levamisole is a known immunomodulating agent. Prolonged use in humans has been associated with cutaneous vasculitis and agranulocytosis. We describe the development of a systemic autoimmune disease associated with antineutrophil cytoplasmic antibodies (ANCA) in cocaine users. This complication appears to be linked to combined cocaine and levamisole exposure. Design, setting, participants, & measurements Cases were identified between March 2009and November 2010 at Massachusetts General Hospital's ANCA laboratory. Cocaine exposure was identified from patient history in all cases. Medical records were reviewed for clinical presentation and for laboratory and diagnostic evaluation.Results Thirty cases of ANCA positivity associated with cocaine ingestion were identified. All had antimyeloperoxidase antibodies and 50% also had antiproteinase 3 antibodies. Complete clinical and laboratory data were available for 18 patients. Arthralgia (83%) and skin lesions (61%) were the most frequent complaints at presentation. Seventy-two percent of patients reported constitutional symptoms, including fever, night sweats, weight loss, or malaise. Four patients had biopsy-proven vasculitis. Two cases of acute kidney injury and three cases of pulmonary hemorrhage occurred. From the entire cohort of 30, two cases were identified during the first 3 months of our study period and nine cases presented during the last 3 months. ConclusionsWe describe an association between the ingestion of levamisole-contaminated cocaine and ANCA-associated systemic autoimmune disease. Our data suggest that this is a potentially life-threatening complication of cocaine use.
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