Long-term maintenance rituximab for ANCA-associated vasculitis: relapse and infection prediction models.

OBJECTIVES: Following a maintenance course of rituximab (RTX) for ANCA-associated vasculitis (AAV), relapses occur on cessation of therapy, and further dosing is considered. This study aimed to develop relapse and infection risk prediction models to help guide decision making regarding extended RTX maintenance therapy. METHODS: Patients with a diagnosis of AAV who received 4-8 grams of RTX as maintenance treatment between 2002 and 2018 were included. Both induction and maintenance doses were included; most patients received standard departmental protocol consisting of 2× 1000 mg 2 weeks apart, followed by 1000 mg every 6 months for 2 years. Patients who continued on repeat RTX dosing long-term were excluded. Separate risk prediction models were derived for the outcomes of relapse and infection. RESULTS: A total of 147 patients were included in this study with a median follow-up of 63 months [interquartile range (IQR): 34-93]. Relapse: At time of last RTX, the model comprised seven predictors, with a corresponding C-index of 0.54. Discrimination between individuals using this model was not possible; however, discrimination could be achieved by grouping patients into low- and high-risk groups. When the model was applied 12 months post last RTX, the ability to discriminate relapse risk between individuals improved (C-index 0.65), and once again, clear discrimination was observed between patients from low- and high-risk groups. Infection: At time of last RTX, five predictors were retained in the model. The C-index was 0.64 allowing discrimination between low and high risk of infection groups. At 12 months post RTX, the C-index for the model was 0.63. Again, clear separation of patients from two risk groups was observed. CONCLUSION: While our models had insufficient power to discriminate risk between individual patients they were able to assign patients into risk groups for both relapse and infection. The ability to identify risk groups may help in decisions regarding the potential benefit of ongoing RTX treatment. However, we caution the use of these prediction models until prospective multi-centre validation studies have been performed.

Increasing incidence and improved survival in ANCA-associated vasculitis-a Danish nationwide study.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) carries a high risk of morbidity and mortality, with outcomes modified by treatment and an incidence that may be increasing. We examined temporal changes in incidence and mortality during 2000-15 using nationwide healthcare registries. METHODS: Patients with incident AAV were identified using International Classification of Diseases Version 10 (ICD10) codes and grouped according to inclusion year (Period 1: 2000-04, Period 2: 2005-09, Period 3: 2010-15). Log link cumulative incidence regression adjusted for age, sex, renal function, cardiovascular disease, diabetes, hypertension and advanced disease severity were used to model survival. RESULTS: We identified 1631 patients (52% male), corresponding to an incidence of 18.5 persons/million/year (Period 1: 15.1, Period 2: 18.5, Period 3: 21.4). The slope of incident serologic ANCA testing was steeper than that of AAV (P = 0.002). Mean [standard deviation (SD)] age was 60.2 (16.7) years and mean (SD) follow-up was 6.8 (4.7) years. A total of 571 (35%) patients died (5-year mortality of 22.1%), with an absolute risk ratio (ARR) for Periods 2 and 3 compared with Period 1 of 0.80 [confidence interval (CI) 0.65-0.98, P = 0.031] and 0.39 (CI 0.31-0.50, P < 0.001). About 274 patients developed end-stage renal disease (ESRD) [16.8% (Period 1: 23.3%, Period 2: 17.6%, Period 3: 12.5%)], with ARR decreasing over time: Period 2 0.61 (CI 0.42-0.87, P = 0.007) and Period 3 0.57 (CI 0.39-0.83, P = 0.003). The overall risk of death associated with ESRD or chronic kidney disease was 1.74 (CI 1.29-2.37, P < 0.001) and 1.58 (CI 1.21-2.07, P < 0.001). CONCLUSIONS: Incidence of ANCA testing and AAV diagnosis increased over the test period. Falls over time in mortality and ESRD risk may relate to earlier diagnosis and changes in treatment practice.

Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis.

INTRODUCTION: The value of antineutrophil cytoplasmic antibody (ANCA) measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) to assess disease activity or predict relapse remains controversial, but recent evidence suggests a possible role for rituximab-treated patients. PATIENTS AND METHODS: All patients with active vasculitis and positive proteinase 3 (PR3)-ANCA who were starting a 2-year treatment course of rituximab for induction of remission at Addenbrooke's Hospital between January 2011 and January 2016 were included in this study. Common department practice consists of 6 g of rituximab given over 2 years, concomitant corticosteroids (0.5-1.0 mg/kg) with rapid taper over 3 months, and cessation of oral maintenance immunosuppressive agents at time of first rituximab dose. Clinical and laboratory data were collected retrospectively using electronic patient records. RESULTS: Fifty-seven patients with current PR3-ANCA positivity were included in the analysis. Median follow-up was 59 months. PR3-ANCA negativity was achieved in 25 patients (44%) with a median time of 14 months. Clinical remission was achieved in 53 patients (93%) with a median time of 3 months. Among the 53 patients who achieved remission during follow-up, 24 (45%) relapsed with a median time to relapse of 36 months from remission. Both PR3-ANCA-negative status and 50% reduction in PR3-ANCA from baseline (as time-varying covariates) were significantly associated with a longer time to relapse (PR3-ANCA-negative status: hazards ratio, 0.08 [95% confidence interval, 0.01-0.63, p = 0.016]; 50% reduction in PR3-ANCA: hazards ratio, 0.25 [95% confidence interval, 0.18-0.99, p = 0.046]). CONCLUSIONS: Achieving and maintaining PR3-ANCA negativity after rituximab was associated with longer-lasting remission.

Autonomic Response Testing Compared With Immunoglobulin E Allergy Panel Test Results: Preliminary Report.

Context • Chronically ill patients who have failed standard medical assessment and therapies are often assessed by integrative medical providers for atypical manifestations of allergies as the possible source or contributing factor(s) to their condition. Skin testing and immunoglobulin E (IgE) allergy panels increase the cost of care in these patients. Objective • The objective of this study was to determine the accuracy of autonomic response testing (ART) as compared with IgE allergy panel blood tests. Design • This study was a retrospective chart review of patients who had ART and blood drawn for an IgE allergy panel at the same office visit. Outcome Measures • Sensitivity, specificity, positive predictive value, negative predictive value, overall accuracy, phi coefficient, and Cohen's kappa were calculated. Results • A total of 14 charts were reviewed. All measures of accuracy were of either useful or excellent strength. The strength of association measures of the phi coefficient and Cohen's kappa were strong. Conclusion • This first and preliminary evaluation of the allergy assessment utility of ART is very promising and reveals the need for more vigorous follow-up studies.

Long-term graft outcomes and patient survival are lower posttransplant in patients with a primary renal diagnosis of glomerulonephritis.

Glomerulonephritis (GN) is the primary diagnosis in 20% to 40% of patients receiving a renal transplant. Here we studied patient survival and graft outcomes in patients with GN transplanted in the UK. UK Renal Registry data were used to analyze patient survival and graft failure in incident transplant patients between 1997 to 2009 who had a diagnosis of primary GN, in comparison to patients transplanted with adult polycystic kidney disease (APKD) or diabetes. Multivariable regression analysis adjusted for age, sex, donor type, ethnicity, donor age, time on dialysis, human leukocyte antigen mismatch, cold ischemic time, and graft failure (for patient survival). Patients were followed up through December 2012. Of 4750 patients analyzed, 2975 had GN and 1775 APKD. Graft failure was significantly higher in membranoproliferative glomerulonephritis (MPGN) type II (hazard ratio: 3.5, confidence interval: 1.9-6.6), focal segmental glomerulosclerosis (2.4, 1.8-3.2), MPGN type I (2.3, 1.6-3.3), membranous nephropathy (2.0, 1.4-2.9), and IgA nephropathy (1.6, 1.3-2.0) compared to APKD. Survival was significantly reduced in patients with MPGN type II (4.7, 2.0-10.8), and those with lupus nephritis (1.8, 1.1-2.9). Overall graft failure for patients with GN was similar to those with diabetes. Thus, in comparison to outcomes in APKD, graft survival is significantly lower in most GNs, with variation in outcomes between different GNs. This information should assist in pretransplant counseling of patients. Further study is required to understand the reduced survival seen in lupus nephritis and MPGN type II, and to improve overall graft outcomes.

Cardiovascular disease in retired NFL players: a systematic review.

OBJECTIVE: Despite robust research endeavors exploring post-play health implications in former NFL players, the impact of former-player status on long-term cardiovascular health has not yet been elucidated. The purpose of this systematic review is to describe the available research on the cardiovascular health in former NFL players. METHODS: Relevant studies were included from the PubMed, Scopus, and Embase databases. Studies were evaluated in accordance with PRISMA guidelines. Two independent reviewers conducted the title/abstract screenings and risk of bias determinations. The results of the studies were extracted for inclusion in the review. RESULTS: Sixteen studies met inclusion criteria. Though evidence was discordant among studies, former NFL players appeared to possess more favorable metabolic profiles and decreased mortality compared to community controls. Of note, 90% of former players were found to be overweight or obese. CONCLUSION: Though cardiovascular disease is the leading cause of death among former NFL players, they possess comparable metabolic and cardiovascular profiles to community controls. Further research is necessary to ascertain the impact of NFL play on cardiovascular health and develop tailored preventative care strategies for former players.

Study protocol for a randomised, phase II, double-blind, experimental medicine study of obinutuzumab versus rituximab in ANCA-associated vasculitis: ObiVas.

INTRODUCTION: Relapses in ANCA-associated vasculitis (AAV) increase the incidence of end-organ damage and their prevention requires prolonged immunosuppressive therapy. Rituximab, a type I anti-CD20 B cell depleting monoclonal antibody, is the current standard of care for induction of disease remission. Rituximab is not always effective and is associated with a high subsequent relapse risk. Obinutuzumab is a type II anti-CD20 humanised monoclonal antibody with the potential to obtain greater tissue B cell depletion than rituximab and reduce relapse risk in AAV. METHODS AND ANALYSIS: ObiVas is a randomised, phase II, double-blind controlled trial that will compare the mechanistic effects of rituximab and obinutuzumab in the induction treatment of patients with AAV positive for proteinase 3 ANCA (PR3-ANCA). 26 patients, either newly diagnosed or relapsing, will be recruited from a single centre and randomised in a 1:1 ratio to receive 1000 mg rituximab or obinutuzumab as induction therapy on days 1 and 15, alongside a tapering glucocorticoid regimen. The primary end point is CD19+ B cell depletion in nasal-associated lymphoid tissue (NALT), assessed as change from baseline to week 26. Secondary outcomes will compare the safety and clinical efficacy of rituximab and obinutuzumab and their impact on immune biomarkers, including tissue and peripheral blood lymphocyte subsets and PR3-ANCA binding levels. Patients are followed through to week 78. The trial opened for recruitment in January 2023 and is forecasted to complete recruitment by the end of 2024. ETHICS AND DISSEMINATION: For all patients, informed written consent will be obtained in keeping with Good Clinical Practice. Trial results will be disseminated to the relevant scientific, clinical and patient communities on trial closure. NALT data analysis will start before trial completion. Other analyses will be reported after trial completion. This trial was given ethical approval by Edgbaston (West Midlands) Research Ethics Committee (approval reference 22/WM/0174). TRIAL REGISTRATION NUMBER: ISRCTN13069630.

Age- and time-dependent increases in incident anti-glomerular basement membrane disease: a nationwide cohort study.

Background: Epidemiologic assessments of anti-glomerular basement membrane (GBM) disease have been challenging due to its rare occurrence. We examined changes in the incidence and outcomes from 1998 to 2018 using nationwide healthcare registries. Methods: All patients with incident anti-GBM disease were identified using the International Classification of Diseases, 10th Revision code DM31.0A. Controls were matched 4:1 on birthyear and sex using exposure density sampling. Log link regression adjusted for time, age and sex was applied to model survival. Results: We identified 97 patients with incident anti-GBM disease, corresponding to an incidence of 0.91 cases/million/year [standard deviation (SD) 0.6]. The incidence increased over time [1998-2004: 0.50 (SD 0.2), 2005-2011: 0.80 (SD 0.4), 2012-2018: 1.4 (SD 0.5); P = .02] and with age [0.76 (SD 0.4), 1.5 (SD 1.04) and 4.9 (SD 2.6) for patients <45, 45-75 and >75 years]. The median age was 56 years (interquartile range 46) and 51.6% were female. Dialysis was required in 58.4%, 61.9% and 62.9% of patients at day 30, 180 and 360, respectively. The 1-year kidney survival probability was 0.38 (SD 0.05) and exhibited time-dependent changes [1998-2004: 0.47 (SD 0.13), 2005-2011: 0.16 (SD 0.07), 2012-2018: 0.46 (SD 0.07); P = .035]. The 5-year mortality was 26.8% and mortality remained stable over time (P = .228). The risk of death was greater than that of the matched background population {absolute risk ratio [ARR] 5.27 [confidence interval (CI) 2.45-11.3], P < .001}, however, it was comparable to that of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) requiring renal dialysis at presentation [ARR 0.82 (CI 0.48-1.41), P = .50]. Conclusion: The incidence of anti-GBM disease increased over time, possibly related to temporal demographic changes. Mortality remained high and was comparable with an age- and sex-matched cohort of dialysis-dependent AAV patients.

Orthopedic consequences of modern gladiators: a systematic review of lower extremity musculoskeletal issues in retired NFL players.

OBJECTIVES: The stressors that National Football League (NFL) athletes face are well-described and documented with regard to multisystem afflictions and injury prevalence. However, the majority of literature discusses the short-term effects rather than long-term outcomes of playing professional football. The purpose of this study was to characterize the long-term musculoskeletal issues in the retired NFL population. METHODS: Publications from CENTRAL, Scopus, Medline, PubMed, Embase, and Google Scholar were searched from database inception to February 2021. A total of 9 cohort studies evaluating lower extremity arthritis in retired NFL athletes were included for review. Two reviewers extracted data from the individual studies, including demographic information (age, body mass index, length of career, position), injury descriptions (location of injury, number of injuries, diagnoses), and procedure (total knee and or hip arthroplasty) frequency. RESULTS: Arthritis in retired NFL players was more than twice as prevalent than the general United States male population (95% CI: 2.1-2.3). Ankle osteoarthritis was directly correlated with the number of foot and ankle injuries. Players <50 years of age had a 16.1 and 13.8 times higher risk of undergoing TKA and THA, respectively, when compared to the general population. In older age groups, this trend held with retired NFL players being at least 4.3 and 4.6 times more likely than members of the general population to undergo TKA and THA, respectively. CONCLUSION: This review demonstrates that the effects of NFL-related lower extremity injuries extend beyond the players' careers and present a higher risk for early-onset osteoarthritis and overall frequency of undergoing total knee and hip arthroplasty.

A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol.

BACKGROUND: Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. METHODS: Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. PARTICIPANTS: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. INTERVENTIONS: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. OUTCOMES: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. DISCUSSION: This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. TRIAL REGISTRATION: ClinicalTrials.gov NCT03967925. Registered on May 30, 2019.

Alemtuzumab for refractory primary systemic vasculitis-a randomised controlled dose ranging clinical trial of efficacy and safety (ALEVIATE).

BACKGROUND: Primary systemic vasculitis (PSV) is a heterogeneous group of autoimmune conditions. There is an unmet need for alternative therapies that lead to sustained remission in patients with refractory disease. Alemtuzumab, an anti-CD52 antibody, depletes lymphocytes for prolonged periods and, in retrospective studies, has induced sustained, treatment-free remissions in patients with refractory/relapsing vasculitis but has raised safety concerns of infection and secondary autoimmunity. This phase IIb clinical trial aimed to assess the efficacy and safety of alemtuzumab, at two different doses, in inducing remission in refractory vasculitis patients. METHODS: The ALEVIATE trial was a randomised, prospective, open-label, dose ranging clinical trial. Patients with refractory ANCA-associated vasculitis (AAV) or Behçet's disease (BD) were randomised to receive either 60 mg or 30 mg alemtuzumab. Treatments were administered at baseline and 6 months or earlier where clinically appropriate. A maximum of three treatments were allowed within the 12-month study period. RESULTS: Twenty-three patients received at least one dose of alemtuzumab. Twelve had AAV, and 11 a diagnosis of BD. The median age was 40 years (range 28-44), with a prior disease duration of 61 months (42-103). Sixteen (70%) achieved either complete (6/23, 26%) or partial (10/23, 44%) response at 6 months. Eight (35%) maintained remission to the end of the trial without relapse. Ten severe adverse events were observed in 7 (30%) patients; 4 were related to alemtuzumab. There were no differences in clinical endpoints between the 60 and 30 mg alemtuzumab treatment groups. CONCLUSION: In a selected group of refractory vasculitis patients, alemtuzumab led to remission in two thirds of patients at 6 months. Remission was maintained to 12 months in a third of the patients, and the safety profile was acceptable. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01405807, EudraCT Number: 2009-017087-17. Registered on April 07, 2011.

A Case of Thrombotic Microangiopathy and Acute Sarcoidosis.

Although sarcoidosis is an established cause of multiorgan dysfunction, acute presentation with thrombotic microangiopathy resulting in severe renal and hematological sequelae has not been reported. We describe the case of a patient presenting with hypercalcemia, pancreatitis, and acute renal failure, followed by microangiopathic hemolytic anemia. Although there were no significant respiratory symptoms, thoracic radiology and mediastinal lymph node biopsy results were in keeping with sarcoidosis as the underlying cause of this multisystem presentation. Corticosteroids were commenced with clinical and biochemical improvement. This novel case highlights the need to consider sarcoidosis as part of the differential diagnosis for unusual multiorgan presentations and for early multidisciplinary involvement in such cases to permit optimal treatment.

The Sound of Interconnectivity; The European Vasculitis Society 2022 Report.

The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

Rituximab Associated Hypogammaglobulinemia in Autoimmune Disease.

Objective: To evaluate the characteristics of patients with autoimmune disease with hypogammaglobulinemia following rituximab (RTX) and describe their long-term outcomes, including those who commenced immunoglobulin replacement therapy. Methods: Patients received RTX for autoimmune disease between 2003 and 2012 with immunoglobulin G (IgG) <7g/L were included in this retrospective series. Hypogammaglobulinemia was classified by nadir IgG subgroups of 5 to <7g/L (mild), 3 to <5g/L (moderate) and <3g/L (severe). Characteristics of patients were compared across subgroups and examined for factors associated with greater likelihood of long term hypogammaglobulinemia or immunoglobulin replacement. Results: 142 patients were included; 101 (71%) had anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV), 18 (13%) systemic lupus erythematosus (SLE) and 23 (16%) other conditions. Mean follow-up was 97.2 months from first RTX. Hypogammaglobulinemia continued to be identified during long-term follow-up. Median time to IgG <5g/L was 22.5 months. Greater likelihood of moderate hypogammaglobulinemia (IgG <5g/L) and/or use of immunoglobulin replacement therapy at 60 months was observed in patients with prior cyclophosphamide exposure (odds ratio (OR) 3.60 [95% confidence interval (CI) 1.03 - 12.53], glucocorticoid use at 12 months [OR 7.48 (95% CI 1.28 - 43.55], lower nadir IgG within 12 months of RTX commencement [OR 0.68 (95% CI 0.51 - 0.90)] and female sex [OR 8.57 (95% CI 2.07 - 35.43)]. Immunoglobulin replacement was commenced in 29/142 (20%) and associated with reduction in infection rates, but not severe infection rates. Conclusion: Hypogammaglobulinemia continues to occur in long-term follow-up post-RTX. In patients with recurrent infections, immunoglobulin replacement reduced rates of non-severe infections.

B cell therapy in ANCA-associated vasculitis: current and emerging treatment options.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an organ-threatening and life-threatening multi-system autoimmune disease in which B cell-derived ANCAs cause neutrophil activation and endothelial damage, strongly implicating these autoantibodies in the pathogenesis of AAV. B cell depletion with rituximab combined with glucocorticoids is associated with a reduction in ANCA concentrations and with clinical remission in the majority of patients with AAV. However, the safety profile of rituximab is no better than that of conventional therapy with cyclophosphamide, and long-term glucocorticoid treatment is needed to achieve and maintain disease-free remission. A need for new therapies exists to reduce the time to remission, to spare the use of glucocorticoids and to promote long-lasting remission without the risk of relapse. Over the past 20 years, there has been great interest in therapeutically targeting B cell cytokines, such as B cell-activating factor (BAFF), in many autoimmune disease settings. Dual B cell-targeted immunotherapy that combines B cell depletion and BAFF blockade could potentially be more efficacious than targeting either mechanism alone. In this Review, the theoretical background for use of this combination approach in AAV is presented and discussed.

Publisher Correction: B cell therapy in ANCA-associated vasculitis: current and emerging treatment options.

In the section 'Combining B cell-targeted therapies' in the originally published version of this article, the 24-week interim analysis for the CALIBRATE study was incorrectly given as the 2- to 4-week interim analysis. This error has now been corrected in the HTML and PDF versions of the manuscript.

Elderly patients with chronic kidney disease: do they really need referral to the nephrology clinic?

INTRODUCTION: Chronic kidney disease (CKD) is becoming increasingly common, especially in the elderly. In the UK, there has been a marked increase in the awareness and detection of CKD over the last decade. This is largely attributable to the introduction of automated estimated glomerular filtration rate (eGFR) reporting and renal indicators in the primary care Quality and Outcomes Framework (QOF) initiative, both of which were introduced in 2006. These two initiatives have had a significant impact on referral patterns to renal services. Across the UK there has been a sustained increase in patients referred to nephrology clinics. The increased referrals have led to an older patient cohort, for whom specialist nephrology input is of questionable clinical benefit. This study aims to assess the outcomes of such patients referred to nephrology clinics in Dorset. METHODS: Retrospective data were collected on all new referrals to the nephrology outpatient clinic at Dorset County Hospital between April 2006 and March 2007. We specifically examined all patients >80 years of age who had CKD Stage 4 or 5. Outcomes of interest included the rate of decline in eGFR, renal-specific management implemented by the clinic, need for renal replacement therapy and death. These outcomes were used to compare the difference between those patients kept under regular follow-up in the nephrology clinic and those discharged back to primary care. Patients were followed up until March 2014. RESULTS: In all, 124 patients who were ≥80 years of age had CKD Stage 4 (115 patients) or 5 (9 patients). The mean age was 84.4 (range 80-95) years. In all, 66 patients were kept under regular follow-up in the clinic and 58 patients were discharged back to primary care. Patients kept under follow-up tended to have a lower median eGFR at referral (22 mL/min/1.73 m2 versus 26 mL/min/1.73 m2; P = 0.051) and had a significantly more rapid decline in mean eGFR over the next 7 years (1.58 mL/min/1.73 m2/yr versus 0.357 ml/min/1.73 m2/yr; P = 0.023) compared with those discharged back to primary care. More patients were commenced on erythropoietin (12 versus 3; P = 0.03) and more patients were commenced on dialysis (5 versus 0; P = 0.03) in the follow-up group compared with those discharged back to primary care. No patients from either group underwent a kidney biopsy. In those patients followed up, 55 (83%) died, with a median time to death of 2.66 years [interquartile range (IQR) 1.14-4.97]. Of the patients discharged, 45 (78%) died, with a median time to death of 3.57 years (IQR 2.31-5.68). CONCLUSIONS: This study highlights the uncertain clinical benefit gained from referral to the nephrology clinic for the majority of elderly patients and suggests that for many cases their care could be safely and appropriately managed in the primary care setting. With the increasing prevalence of CKD in the elderly and increasing pressure on new patient clinic slots, referral of a select group in which a specific intervention is being considered may be more appropriate.

Integrative Medicine Approach to Pediatric Obsessive-Compulsive Disorder and Anxiety: A Case Report.

Pediatric obsessive-compulsive disorder (OCD) is prevalent in 1% to 2% of the population. Emerging studies have correlated non-celiac gluten sensitivity with psychiatric conditions such as schizophrenia, depression, mania, and anxiety. This case study is the first reported case of OCD associated with non-celiac gluten sensitivity. The objectives of this case report are to (1) identify gluten sensitivity as a possible contributing factor to OCD in some patients; and (2) point out the possible benefit of an integrative medicine approach to the management of OCD in a patient with suboptimal benefit from a standard treatment regime. A 7-year-old male treated at a multi-physician integrative medicine practice in the United States had marked reduction of OCD symptoms and anxiety along with marked improvement of social behavior and school work after treatment consisting of gluten avoidance and other integrative medicine modalities. The patient's rapid response without side effects behooves the medical research community to further investigate the association of non-celiac gluten sensitivity and pediatric OCD.

El trastorno obsesivo compulsivo (TOC) en niños es prevalente en entre un 1 % y un 2 % de la población. Los estudios emergentes han relacionado la sensibilidad al gluten no celíaca con trastornos psiquiátricos como la esquizofrenia, la depresión, la manía y la ansiedad. Este estudio de un caso es el primer caso comunicado de TOC asociado a la sensibilidad al gluten no celíaca. Los objetivos de este informe de caso son (1) identificar la sensibilidad al gluten como un posible factor que contribuye al TOC en algunos pacientes; y (2) apuntar el posible beneficio de una aproximación de la medicina integral al tratamiento del TOC en un paciente con un beneficio subóptimo a partir de una pauta posológica del tratamiento de referencia. Un niño de 7 años al que se trató en una policlínica de medicina integral de los Estados Unidos tuvo una reducción marcada de los síntomas del TOC y de la ansiedad junto con una mejora del comportamiento social y del trabajo escolar tras el tratamiento que consistía en evitar el gluten y otras modalidades de medicina integral. La rápida respuesta del paciente sin efectos secundarios conmina a la comunidad de investigación médica a indagar exhaustivamente en la asociación de la sensibilidad al gluten no celíaca y el TOC en niños.

Benefits of jasmonate-dependent defenses against vertebrate herbivores in nature.

Endogenous jasmonates are important regulators of plant defenses. If and how they enable plants to maintain their reproductive output when facing community-level herbivory under natural conditions, however, remains unknown. We demonstrate that jasmonate-deficient Nicotiana attenuata plants suffer more damage by arthropod and vertebrate herbivores than jasmonate-producing plants in nature. However, only damage by vertebrate herbivores translates into a significant reduction in flower production. Vertebrate stem peeling has the strongest negative impact on plant flower production. Stems are defended by jasmonate-dependent nicotine, and the native cottontail rabbit Sylvilagus nuttallii avoids jasmonate-producing N. attenuata shoots because of their high levels of nicotine. Thus, endogenous jasmonates enable plants to resist different types of herbivores in nature, and jasmonate-dependent defenses are important for plants to maintain their reproductive potential when facing vertebrate herbivory. Ecological and evolutionary models on plant defense signaling should aim at integrating arthropod and vertebrate herbivory at the community level.