Thomas P. Baker

Randomized Controlled Trial Comparing Aerosolized Swallowed Fluticasone to Esomeprazole for Esophageal Eosinophilia

OBJECTIVES:Patients with clinical symptoms of esophageal dysfunction and dense eosinophilic infiltration of the esophageal mucosa are suspected to have eosinophilic esophagitis (EoE). Topical steroids are often used as first-line therapy for EoE, although some patients respond clinically to proton pump inhibitors (PPIs). The purpose of this study was to compare the histological and clinical response of patients with esophageal eosinophilia treated with aerosolized swallowed fluticasone propionate vs. esomeprazole.METHODS:This prospective single-blinded randomized controlled trial enrolled newly diagnosed patients with suspected EoE, defined as having clinical symptoms related to esophageal dysfunction with at least 15 eosinophils/high power field (hpf). Patients underwent 24-h pH/impedance monitoring to establish gastroesophageal reflux disease (GERD). Patients were stratified by the presence of GERD and randomized to receive fluticasone 440 mcg twice daily or esomeprazole 40 mg once daily for 8 weeks followed by repeat endoscopy with biopsies. The primary outcome was histological response of esophageal eosinophilia, defined as <7 eosinophils/hpf. Secondary outcomes included clinical change in symptoms using the validated Mayo dysphagia questionnaire (MDQ) and interval change in endoscopic findings following treatment.RESULTS:Forty-two patients (90% male, 81% white, mean age 38±10 years) were randomized into fluticasone (n=21) and esomeprazole (n=21) treatment arms. In all, 19% (8/42) of patients had coexisting GERD and were equally stratified into each arm (n=4). Overall, there was no significant difference in resolution of esophageal eosinophilia between fluticasone and esomeprazole (19 vs. 33%, P=0.484). In patients with established GERD, resolution of esophageal eosinophilia was noted in 0% (0/4) of the fluticasone group compared with 100% (4/4) of the esomeprazole group (P=0.029). In GERD-negative patients, there was no significant difference in resolution of esophageal eosinophilia between treatment arms with fluticasone and esomeprazole (24 vs.18%, P=1.00). The MDQ score significantly decreased after treatment with esomeprazole (19±21 vs. 1.4±4.5, P<0.001), but not with fluticasone (17±18 vs. 12±16, P=0.162). Improvement in endoscopic findings and other histological markers were similar between treatment groups.CONCLUSIONS:Fluticasone and esomeprazole provide a similar histological response for esophageal eosinophilia. With regard to clinical response, esomeprazole was superior to fluticasone, particularly in patients with established GERD.

Association of Prescription of Oral Sodium Polystyrene Sulfonate With Sorbitol in an Inpatient Setting With Colonic Necrosis: A Retrospective Cohort Study

BACKGROUND Colonic necrosis has been reported after sodium polystyrene sulfonate (SPS)/sorbitol use, but the incidence and relative risk (RR) are not established. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 123,391 adult inpatients at a tertiary medical center. PREDICTOR Receipt of SPS prescriptions (exposed) or a prescription other than SPS (unexposed internal comparison group) between September 1, 2001, and October 31, 2010. OUTCOMES The main outcome measure was tissue-confirmed diagnosis of colonic necrosis, considered SPS-associated if SPS was prescribed 30 or fewer days before tissue accession date. MEASUREMENTS Demographics, serum chemistry test results, hospital location, and International Classification of Diseases, Ninth Revision diagnostic codes. RESULTS SPS was prescribed to 2,194 inpatients. 82 inpatient colonic necrosis cases were identified. 3 received oral SPS (1 gram per 4 milliliters of 33% sorbitol) 30 or fewer days before the colonic necrosis accession date (3.7% of inpatient colonic necrosis cases). The data were linked with 123,391 individuals who received inpatient prescriptions between the same dates. Colonic necrosis incidence was 0.14% (95% CI, 0.03%-0.40%) in those prescribed SPS versus 0.07% (95% CI, 0.05-0.08%) in those not prescribed SPS (RR, 2.10; 95% CI, 0.68-6.48; P = 0.2). The number needed to harm was 1,395 (95% CI, 298-5,100). Subgroup analysis (age >65 years; estimated glomerular filtration rate, <30 mL/min/1.73 m(2), intensive care unit admission, or surgical ward status) did not show significant associations. Sample-size analysis indicated that 4,974 SPS-treated individuals older than 65 years and a comparison group 10 times larger would be required for rigorous multivariate analysis of SPS-associated colonic necrosis risk. LIMITATIONS Individuals with colonic necrosis admitted to non-Department of Defense hospitals would not have been ascertained. Only individuals who had colonic biopsy or surgical tissue submitted for pathologic review could be ascertained as having colonic necrosis. CONCLUSIONS SPS-associated colonic necrosis is rare, and inpatient SPS/sorbitol prescription was not associated significantly with an increased RR of colonic necrosis in this retrospective cohort analysis. Multivariate analysis would require retrospective clinical cohorts from larger or more than one hospital system(s).

Asymptomatic Autoantibodies Associate with Future Anti-glomerular Basement Membrane Disease

The pathophysiology of anti-glomerular basement membrane (anti-GBM) disease before clinical presentation is unknown. The presence of anti-GBM, anti-proteinase 3 (PR3), and anti-myeloperoxidase (MPO) antibodies associate with the disease at the time of diagnosis, but little is known about the presence of these autoantibodies before diagnosis. We used serum samples from the Department of Defense Serum Repository to conduct a case-control study involving 30 patients diagnosed with anti-GBM disease and 30 healthy controls matched for the age, gender, race, and age of the serum samples. We analyzed a maximum of three samples from each subject: the most recent sample before diagnosis, the penultimate sample before diagnosis, and the oldest sample available; the average time between the most recent sample and diagnosis was 195 days (range, 4 to 1346 days). Elevated anti-GBM levels (≥3 U/ml) were present in four patients, all less than 1 year before diagnosis but in no controls. Detectable anti-GBM antibody levels (≥1 U/ml but <3 U/ml) in a single serum sample before diagnosis were more frequent in cases than controls (70% versus 17%, P < 0.001). Only study patients had detectable anti-GBM levels in multiple samples before diagnosis (50% versus 0%, P < 0.001). Almost all patients had detectable anti-PR3 and/or anti-MPO that preceded the onset of disease. Among patients with a clear antecedent antibody, anti-PR3 or anti-MPO always became detectable before the anti-GBM antibody. In summary, our data describe the subclinical formation of autoantibodies, which improves our understanding of the pathophysiology of anti-GBM disease.

Comparison of eotaxin-3 biomarker in patients with eosinophilic oesophagitis, proton pump inhibitor-responsive oesophageal eosinophilia and gastro-oesophageal reflux disease

Proton pump inhibitor‐responsive oesophageal eosinophilia (PPI‐REE) is a recently described entity which resembles oeosinophilic oesophagitis (EoE), yet responds to acid suppressive treatment.

Increased Serum Free Light Chains Precede the Presentation of Immunoglobulin Light Chain Amyloidosis

PURPOSE Patients with immunoglobulin light chain amyloidosis (AL amyloidosis) generally present with advanced organ dysfunction and have a high risk of early death. We sought to characterize monoclonal immunoglobulin (M-Ig) light chains before clinical presentation of AL amyloidosis. PATIENTS AND METHODS We obtained prediagnostic sera from 20 cases with AL amyloidosis and 20 healthy controls matched for age, sex, race, and age of serum sample from the Department of Defense Serum Repository. Serum protein electrophoresis with immunofixation and serum free light chain (FLC) analysis were performed on all samples. RESULTS An M-Ig was detected in 100% of cases and 0% of controls (P < .001). The M-Ig was present in 100%, 80%, and 42% of cases at less than 4 years, 4 to 11 years, and more than 11 years before diagnosis, respectively. The median FLC differential (FLC-diff) was higher in cases compared with controls at all time periods, less than 4 years (174.8 v 0.3 mg/L; P < .001), 4 to 11 years (65.1 v 2.2 mg/L; P < .001), and more than 11 years (4.5 v 0.4 mg/L; P = .03) before diagnosis. The FLC-diff was greater than 23 mg/L in 85% of cases and 0% of controls (P < .001). The FLC-diff level increased more than 10% per year in 84% of cases compared with 16% of controls (P < .001). CONCLUSION Increase of FLCs, including within the accepted normal range, precedes the development of AL amyloidosis for many years.

Elevated Subclinical Double-Stranded DNA Antibodies and Future Proliferative Lupus Nephritis

BACKGROUND AND OBJECTIVES Elevated anti-double-stranded DNA (dsDNA) antibody and C-reactive protein are associated with proliferative lupus nephritis (PLN). Progression of quantitative anti-dsDNA antibody in patients with PLN has not been compared with that in patients with systemic lupus erythematosus (SLE) without LN before diagnosis. The temporal relationship between anti-dsDNA antibody and C-reactive protein elevation has also not been evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This case-control Department of Defense Serum Repository (established in 1985) study compared longitudinal prediagnostic quantitative anti-dsDNA antibody and C-reactive protein levels in 23 patients with biopsy-proven PLN (Walter Reed Army Medical Center, 1993-2009) with levels in 21 controls with SLE but without LN matched for patient age, sex, race, and age of serum sample. The oldest (median, 2601 days; 25%, 1245 days, 75%, 3075 days), the second to last (368; 212, 635 days), and the last (180; 135, 477 days) serum sample before diagnosis were analyzed. RESULTS More patients with PLN had an elevated anti-dsDNA antibody level than did the matched controls at any point (78% versus 5%; P<0.001), <1 year (82% versus 8%; P<0.001), 1-4 years (53% versus 0%; P<0.001), and >4 years (33% versus 0%; P=0.04) before diagnosis. A rate of increase >1 IU/ml per year (70% versus 0%; P<0.001) was most specific for PLN. The anti-dsDNA antibody levels increased before C-reactive protein did in most patients with an antecedent elevation (92% versus 8%; P<0.001). CONCLUSIONS Elevated anti-dsDNA antibody usually precedes both clinical and subclinical evidence of proliferative LN, which suggests direct pathogenicity. Absolute anti-dsDNA antibody level and rate of increase could better establish risk of future PLN in patients with SLE.

Longitudinal Evaluation of Noninvasive Biomarkers for Eosinophilic Esophagitis.

Background: The diagnosis and management of eosinophilic esophagitis (EoE) often requires multiple endoscopies. Serum biomarkers can be elevated in EoE patients, but their clinical utility in diagnosis and assessing response to treatment is not well established. Goals: To evaluate serum biomarkers in EoE subjects compared with controls and assess longitudinally in response to treatment. Study: We conducted a prospective cohort study of children and adults undergoing esophagogastroduodenoscopy for suspected EoE. After completing an 8-week course of proton-pump inhibitor therapy, esophageal mucosal biopsies were obtained, as well as, serum analysis of absolute eosinophil count (AEC), eotaxin-3, eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP) and interleukin-5. Subjects with normal endoscopic and histologic findings constituted controls. Those meeting criteria for EoE underwent repeat esophagogastroduodenoscopy and biomarker measurements following treatment with topical steroids for 8 weeks. Results: Median levels of AEC (263.50 vs. 102 cu/mm, P<0.001), ECP (26.98 vs. 5.20 ng/mL, P<0.001) and EDN (31.70 vs. 14.18 ng/mL, P=0.004) were significantly elevated in EoE subjects compared with controls and correlated with esophageal eosinophilia. Levels of AEC (odds ratio, 1.79; 95% confidence interval, 1.28-2.64) and ECP (odds ratio, 1.61; 95% confidence interval, 1.23-2.36) were associated with a diagnosis of EoE. Among the 5 biomarkers evaluated, only AEC significantly predicted esophageal eosinophilia following topical steroid therapy in EoE subjects (P=0.006). Conclusions: AEC, ECP, and EDN were higher in EoE subjects compared with controls and correlated with degree of esophageal eosinophilia. Furthermore, AEC predicted post-treatment eosinophilia, suggesting a potential role in monitoring EoE disease activity.

Possible potassium chlorate nephrotoxicity associated with chronic matchstick ingestion

We present a case of a 48-year-old active duty male soldier with a history of chronic exposure to potassium chlorate, later diagnosed with chronic interstitial nephritis. He reported regular matchstick consumption to prevent chigger (Trombicula autumnalis) bites, amounting to ∼5.8 g of potassium chlorate over 3 years. Potassium chlorate can cause anuric renal failure within days of a toxic dose. Its slow excretion and mechanism of action suggest that renal toxicity may result from lower-dose chronic exposure. This case represents possible sequelae of chronic potassium chlorate ingestion.