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Purpose of ReviewComplement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis.Recent FindingsComplement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg/C3 and iC3b/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system.SummaryAbnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.

Advocacy for Lyme disease has become an increasingly important part of an antiscience movement that denies both the viral cause of AIDS and the benefits of vaccines and that supports unproven (sometimes dangerous) alternative medical treatments. Some activists portray Lyme disease, a geographically limited tick-borne infection, as a disease that is insidious, ubiquitous, difficult to diagnose, and almost incurable; they also propose that the disease causes mainly non-specific symptoms that can be treated only with long-term antibiotics and other unorthodox and unvalidated treatments. Similar to other antiscience groups, these advocates have created a pseudoscientific and alternative selection of practitioners, research, and publications and have coordinated public protests, accused opponents of both corruption and conspiracy, and spurred legislative efforts to subvert evidence-based medicine and peer-reviewed science. The relations and actions of some activists, medical practitioners, and commercial bodies involved in Lyme disease advocacy pose a threat to public health.

ObjectiveTo evaluate the clinical utility of the multianalyte assay panel (MAP), commercially known as AVISE Lupus test (Exagen Inc.), in patients suspected of SLE.MethodsA systematic review of medical records of ANA-positive patients with a positive (>0.1) or negative (<−0.1) MAP score was conducted when the MAP was ordered (T0), when the test results were reviewed (T1) and at a later time (T2, ≥8 months after T1). Confidence in the diagnosis of SLE and initiation of hydroxychloroquine (HCQ) were assessed.ResultsA total of 161 patient records from 12 centres were reviewed at T0 and T1. T2 occurred for 90 patients. At T0, low, moderate and high confidence in SLE diagnosis was reported for 58%, 30% and 12% patients, respectively. Confidence in SLE diagnosis increased for the MAP positive, while MAP negative made SLE less likely. Odds of higher confidence in SLE diagnosis increased by 1.74-fold for every unit of increase of the MAP score (p<0.001). Using the MAP-negative/anti-double-stranded DNA-negative patients as reference, the HR of assigning an International Classification of Diseases, Tenth Revision lupus code was 7.02-fold, 11.2-fold and 14.8-fold higher in the low tier-2, high tier-2 and tier-1 positive, respectively (p<0.001). The HR of initiating HCQ therapy after T0 was 2.90-fold, 4.22-fold and 3.98-fold higher, respectively (p<0.001).ConclusionThe MAP helps increase the confidence in ruling-in and ruling-out SLE in patients suspected of the disease and informs on appropriate treatment decisions.

Objective Diagnosis of systemic lupus erythematosus (SLE) made by standard diagnostic laboratory tests (SDLTs) has sensitivity and specificity of 83% and 76%, respectively. A multivariate assay panel (MAP) combining complement C4d activation products on erythrocytes and B cells with SDLTs yields a sensitivity and specificity of 80% and 86%, respectively, presumably enabling earlier SLE diagnosis at lower severity, with associated lower health care costs compared with SDLT diagnoses. We compared the payer budget impact of diagnosing SLE using MAP (incremental cost of$108) versus SDLTs. Methods We modeled a health plan of 1 million enrollees. SLE diagnosis among suspected patients was 9.2%. The MAP arm assumed 80%/20% of patients were tested with MAP/SDLTs, versus 100% tested with SDLTs in the SDLT arm. Prediagnosis direct costs were estimated from claims data, and postdiagnosis costs were obtained from the literature. Based on improved MAP performance, the assumed hazard ratio for diagnosis rate compared with SDLTs was 1.74 (71%, 87%, 90%, and 91% of patients who develop SLE are diagnosed in years 1 to 4 compared with 53%, 75%, 84%, and 88% of patients diagnosed with SDLTs). Results Total 4‐year pre‐ and postdiagnosis direct costs for patients with suspected SLE tested with MAP were $ 59 183 666 compared with$61 174 818 tested by SDLTs, with lower costs in the MAP arm due primarily to prediagnosis savings related to reduced hospital admissions. Conclusion Incorporating MAP into SLE diagnosis results in estimated 4‐year direct cost savings of $ 1 991 152 ($0.04 per member per month). By facilitating earlier diagnosis of SLE, MAP may enhance patient outcomes.

Objective To evaluate the usefulness of biomarkers to predict the evolution of patients suspected of systemic lupus erythematosus (SLE), designated as probable SLE (pSLE), into classifiable SLE according to the American College of Rheumatology (ACR) classification criteria. Methods Patients suspected of SLE were enrolled by lupus experts if they fulfilled three ACR criteria for SLE and were followed for approximately 1‐3 years to evaluate transition into ACR‐classifiable SLE. Individual cell‐bound complement activation products (CB‐CAPs), serum complement proteins (C3 and C4), and autoantibodies were measured by flow cytometry, turbidimetry, and enzyme‐linked immunosorbent assay, respectively. Blood levels of hydroxychloroquine (HCQ) were measured by mass spectrometry. A multianalyte assay panel (MAP), which includes CB‐CAPs, was also evaluated. A MAP of greater than 0.8 reflected the optimal cutoff for transition to SLE. Time to fulfillment of ACR criteria was evaluated by Kaplan‐Meier analysis and Cox proportional hazards model. Results Of the 92 patients with pSLE enrolled, 74 had one or two follow‐up visits 9‐35 months after enrollment for a total of 128 follow‐up visits. Overall, 28 patients with pSLE (30.4%) transitioned to ACR‐classifiable SLE, including 16 (57%) in the first year and 12 (43%) afterwards. A MAP score of greater than 0.8 at enrollment predicted transition to classifiable SLE during the follow‐up period (hazard ratio = 2.72; P = 0.012), whereas individual biomarkers or fulfillment of Systemic Lupus International Collaborating Clinics criteria did not. HCQ therapy was not associated with the prevention of transition to SLE. Conclusion Approximately one‐third of patients with pSLE transitioned within the study period. MAP of greater than 0.8 predicted disease evolution into classifiable SLE.

ObjectiveWe compared the physician-assessed diagnostic likelihood of SLE resulting from standard diagnosis laboratory testing (SDLT) to that resulting from multianalyte assay panel (MAP) with cell-bound complement activation products (MAP/CB-CAPs), which reports a two-tiered index test result having 80% sensitivity and 86% specificity for SLE.MethodsPatients (n=145) with a history of positive antinuclear antibody status were evaluated clinically by rheumatologists and randomised to SDLT arm (tests ordered at the discretion of the rheumatologists) or to MAP/CB-CAPs testing arm. The primary endpoint was based on the change in the physician likelihood of SLE on a five-point Likert scale collected before and after testing. Changes in pharmacological treatment based on laboratory results were assessed in both arms. Statistical analysis consisted of Wilcoxon and Fisher’s exact tests.ResultsAt enrolment, patients randomised to SDLT (n=73, age=48±2 years, 94% females) and MAP/CB-CAPs testing arms (n=72, 50±2 years, 93% females) presented with similar pretest likelihood of SLE (1.42±0.06 vs 1.46±0.06 points, respectively; p=0.68). Post-test likelihood of SLE resulting from randomisation in the MAP/CB-CAPs testing arm was significantly lower than that resulting from randomisation to SDLT arm on review of test results (−0.44±0.10 points vs −0.19±0.07 points) and at the 12-week follow-up visit (−0.61±0.10 points vs −0.31±0.10 points) (p<0.05). Among patients randomised to the MAP/CB-CAPs testing arm, two-tiered positive test results associated significantly with initiation of prednisone (p=0.034).ConclusionOur data suggest that MAP/CB-CAPs testing has clinical utility in facilitating SLE diagnosis and treatment decisions.

Aberrant central neurological functioning is believed to contribute to the abnormal sensations of fibromyalgia (FM). This pilot study sought to determine if alterations in regional brain metabolism from baseline occur in FM after undergoing a multidisciplinary therapeutic regimen. Regional brain metabolic activity was estimated using (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG PET). Nine participants with FM received an 8-week comprehensive treatment program. Serial testing with (18)FDG PET and the Fibromyalgia Impact Questionnaire were performed. Statistical analysis was performed using repeated Wilcoxon signed rank tests. A clinical improvement (FIQ median change 20.68, P = 0.005) was noted with treatment. With treatment, increases in brain metabolism were noted in various components of the limbic system (P = 0.004-0.1). An increase in limbic metabolism was noted with concomitant symptomatic improvement, suggesting that the limbic system attenuates FM symptoms.

Background: Data suggest that differences in patient preferences may account for racial disparities in the use of medical interventions. Racial disparities have also been noted in outcomes and the delivery of healthcare services in chronic disease. Whether treatment preferences in chronic disease differ by race is not known. Methods: We elicited treatment preferences for aggressive therapy in patients with rheumatoid arthritis who identified themselves as being black or white. Results: One hundred fifty consecutive eligible patients were invited to participate. Of these, 136 subjects completed the interview. In unadjusted analysis, 51% of white participants preferred aggressive therapy compared with 16% of blacks (P < 0.0001). Subjects who were married and reported having at least some college education had stronger preferences for aggressive therapy compared with their respective counterparts. After adjusting for covariates, race remained the strongest predictor of aggressive therapy examined in this study [adjusted odds ratio (95% confidence interval) = 11.2(1.9-64.9)]. Conclusions: In this study, fewer black patients preferred aggressive treatment compared with white patients with similar disease severity. These results have important clinical implications because use of aggressive treatment improves both short- and long-term outcomes in rheumatoid arthritis. Efforts to improve patient education and physician communication should be made to ensure that all patients have an accurate understanding of the benefits, as well as risks, associated with the best available treatment options.

ABSTRACT Purpose: To compare the efficacy of two formulations of prednisolone acetate 1% in reducing postoperative inflammation in patients having primary phacoemulsification surgery with IOL implantation. Methods: This multicenter study was conducted in randomized, double-masked fashion with a parallel active control group. Patients undergoing phacoemulsification surgery with IOL implantation were assigned to one of two treatment groups receiving study drug in addition to standard therapy. Study drug was administered four times daily beginning one day before surgery, postoperatively for 14 days, then twice daily until the bottle was empty. Clinical efficacy was compared for differences in corneal surface keratitis, anterior chamber cells and flare, and postoperative pain. Results were compared on day 1, 2 weeks, and 4 weeks postoperatively. Results: No statistical differences in clinical efficacy or safety were seen between the two formulations tested at any time point evaluated. Conclusions: In this study of routine cataract patients, both prednisolone acetate 1% formulations are comparably effective and safe when administered for the reduction of inflammation after phacoemulsification surgery with IOL implantation.