Frank B. Cortazar

Long-Term Maintenance Therapy Using Rituximab-Induced Continuous B-Cell Depletion in Patients with ANCA Vasculitis

BACKGROUND AND OBJECTIVES Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined. RESULTS In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase-ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS] = 0) was achieved in all patients. Major relapse (BVAS ≥ 3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population. CONCLUSION This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted.

Inhibitors of mTOR and risks of allograft failure and mortality in kidney transplantation

Data on long‐term outcomes of users of inhibitors of the mammalian target of rapamycin (mTORI) are lacking in kidney transplantation. In an analysis of 139 370 US kidney transplant recipients between 1999 through 2010, we compared clinical outcomes among users of mTORIs versus calcineurin inhibitors (CNI) in their primary immunosuppresive regimen. During the first 2 years posttransplantation, primary use of mTORIs without CNIs (N = 3237) was associated with greater risks of allograft failure and death compared with a CNI‐based regimen (N = 125 623); the hazard ratio (HR) of the composite outcome ranged from 3.67 (95% confidence interval [CI], 3.12–4.32) after discharge to 1.40 (95% CI 1.26–1.57) by year 2. During years 2–8, primary use of mTORIs without CNIs was independently associated with greater risks of death (HR 1.25; 95% CI, 1.11–1.41) and the composite (HR 1.17; 95%CI, 1.08–1.27) in fully adjusted analyses. The results were qualitatively unchanged in subgroups defined by medical history, immunological risk and clinical course during the index transplant hospitalization. In a propensity‐score matched cohort, use of mTORIs was associated with significantly worse outcomes during the first 2 years and greater risks of death (HR 1.21; 95% CI, 1.05–1.39) and the composite (HR 1.18; 95% CI, 1.08–1.30) in years 2–8. Compared with CNI‐based regimens, use of an mTORI‐based regimen for primary immunosuppression in kidney transplantation was associated with inferior recipient survival.

IgG4-related disease and the kidney

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most frequent manifestations in the kidney—IgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4+ T cells. Glucocorticoids are the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches.

Clinical Outcomes in Kidney Transplant Recipients Receiving Long-Term Therapy with Inhibitors of the Mammalian Target of Rapamycin

Inhibitors of the mammalian target of rapamycin (mTOR), sirolimus and everolimus, reduce the incidence of acute rejection following kidney transplantation, but their impact on clinical outcomes beyond 2 years after transplantation is unknown. We examined risks of mortality and allograft loss in a prospective observational study of 993 prevalent kidney transplant recipients who enrolled a median of 72 months after transplantation. During a median follow‐up of 37 months, 87 patients died and 102 suffered allograft loss. In the overall population, use of mTOR inhibitors at enrollment was not associated with altered risk of allograft loss, and their association with increased mortality was of borderline significance. However, history of malignancy was the strongest predictor of both mortality and therapy with an mTOR inhibitor. Among patients without a history of malignancy, use of mTOR inhibitors was associated with significantly increased risk of mortality in propensity score‐adjusted (hazard ratio [HR] 2.6; 95% CI, 1.2, 5.5; p = 0.01), multivariable‐adjusted (HR 3.2; 95% CI, 1.5, 6.5; p = 0.002) and one‐to‐one propensity score‐matched analyses (HR 5.6; 95% CI 1.2, 25.7; p = 0.03). Additional studies are needed to examine the long‐term safety of mTOR inhibitors in kidney transplantation, especially among recipients without a history of malignancy.

Spectroscopic and Thermodynamic Comparisons of Escherichia coli DNA Photolyase and Vibrio cholerae Cryptochrome 1

Escherichia coli DNA photolyase and cryptochrome 1 isolated from Vibrio cholerae, a member of the CRY-DASH family, are directly compared using a variety of experimental methods including UV-vis and Raman spectroscopy, reduction potential measurements, and isothermal titration calorimetry. The semiquinone form of the cryptochrome has an absorption spectrum that is red-shifted from that of the photolyase, but the Raman spectrum indicates that the FAD binding pocket is similar to that of photolyase. The FADH(-)/FADH* reduction potential of the cryptochrome is significantly higher than that of the photolyase at 164 mV vs NHE, but it also increases upon substrate binding (to 195 mV vs NHE), an increase similar to what is observed in photolyase. The FADH(-)/FADH* reduction potential for both proteins was found to be insensitive to ATP binding. Isothermal titration calorimetry found that photolyase binds tighter to substrate (K(A) approximately 10(5) M(-1) for photolyase and approximately 10(4) M(-1) for cryptochrome 1), and the binding constants for both proteins were slightly sensitive to oxidation state. Based upon this work, it appears that this cryptochrome has significant spectroscopic and electrochemical similarities to CPD photolyase. The thermodynamic cycle of the enzymatic repair in the context of this work is discussed.

Effect of Continuous B Cell Depletion With Rituximab on Pathogenic Autoantibodies and Total IgG Levels in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with continuous B cell depletion.

Effect of the Cyclobutane Cytidine Dimer on the Properties of Escherichia coli DNA Photolyase

Cyclobutane pyrimidine dimer (CPD) photolyases are structure specific DNA-repair enzymes that specialize in the repair of CPDs, the major photoproducts that are formed upon irradiation of DNA with ultraviolet light. The purified enzyme binds a flavin adenine dinucleotide (FAD), which is in the neutral radical semiquinone (FADH(*)) form. The CPDs are repaired by a light-driven, electron transfer from the anionic hydroquinone (FADH(-)) singlet excited state to the CPD, which is followed by reductive cleavage of the cyclobutane ring and subsequent monomerization of the pyrimidine bases. CPDs formed between two adjacent thymidine bases (T< >T) are repaired with greater efficiency than those formed between two adjacent cytidine bases (C< >C). In this paper, we investigate the changes in Escherichia coli photolyase that are induced upon binding to DNA containing C< >C lesions using resonance Raman, UV-vis absorption, and transient absorption spectroscopies, spectroelectrochemistry, and computational chemistry. The binding of photolyase to a C< >C lesion modifies the energy levels of FADH(*), the rate of charge recombination between FADH(-) and Trp(306)(*), and protein-FADH(*) interactions differently than binding to a T< >T lesion. However, the reduction potential of the FADH(-)/FADH(*) couple is modified in the same way with both substrates. Our calculations show that the permanent electric dipole moment of C< >C is stronger (12.1 D) and oriented differently than that of T< >T (8.7 D). The possible role of the electric dipole moment of the CPD in modifying the physicochemical properties of photolyase as well as in affecting CPD repair will be discussed.

The effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in ANCA vasculitis

To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with continuous B cell depletion.

Prevalence of Vaccination Rates in Systolic Heart Failure: A Prospective Study of 549 Patients by Age, Race, Ethnicity, and Sex in a Heart Failure Disease Management Program

Healthy People 2010 aims at immunizing 60% of high-risk adults annually against influenza and once against pneumococcal disease. The aim of this study was to evaluate the use of a standardized approach to improve vaccination rates in patients with heart failure (HF); to determine whether disparities exist based on age, race, ethnicity, or sex at baseline and follow-up; and to evaluate the impact of clinical variables on the odds of being vaccinated. A prospective study of 549 indigent patients enrolled in a systolic HF disease management program (HFDMP) began enrollment from August 2007 to January 2009 at Jackson Memorial Hospital. Patients were interviewed at their initial visit for immunization status; those without vaccinations were offered the vaccines. Prevalence of vaccination (POV) for influenza and pneumococcal disease was obtained at baseline and at follow-up. The odds ratio for being vaccinated was calculated using logistic regression. The study population comprised mostly Hispanic (56%), black (37%), and male (70%) patients, with a mean age of 56 ± 12 years and a mean ejection fraction of 25% ± 10%. The initial POV for both was 22% at baseline. At follow-up, POV improved to 60.5%. Of those not vaccinated at baseline, 17.5% refused vaccination. Odds ratios at baseline for age, race/ethnicity, and sex were 0.99 (P=.99), 0.63 (P=.08), and 0.62 (P=.14), respectively. These did not change significantly at follow-up. Prevalence of vaccination in our cohort was low. Enrollment into the HFDMP improved immunization prevalence without creating age, race, ethnicity, or sex disparities.

Corticosteroid and calcineurin inhibitor sparing regimens in kidney transplantation.

Chronic kidney disease is a major public health problem that is associated with increased risks of kidney disease progression, cardiovascular disease and death. Kidney transplantation remains the renal replacement therapy of choice for patients with end-stage kidney disease. Despite impressive strides in short-term allograft survival, there has been little improvement in long-term kidney graft survival, and rates of death with a functioning allograft remain high. Long-term safety profiles of existing immunosuppressive regimens point to a need for continued search for alternative agents. This overview discusses emerging evidence on a few promising therapeutic approaches, juxtaposes conflicting findings and highlights remaining knowledge gaps.