Aspects of Lupus Nephritis

This thesis explores the clinical outcomes of patients with systemic lupus erythematosus (SLE), focussing on Lupus nephritis (LN), specifically on the impact and results of renal replacement therapies on patients and their disease with reference to adherence to treatment. It comprises three separate but related studies. It also reviews the risk factors for renal disease in SLE and their clinical implications as well as the safety of pharmacological treatment options for lupus nephritis. This thesis reviews a combined cohort of adult SLE patients receiving renal transplants (rTp) over a 40-year period (1975-2015) in two tertiary United Kingdom centres, the Royal Free Hospital (RFH) and University College London Hospital (UCLH), and investigates factors influencing mortality, transplant outcome and disease relapses. My research examines the impact of pre-transplant time on dialysis on survival in patients with LN, and investigates the role of non-adherence in graft survival. It also explores further adherence patterns in the LN population of the combined cohort in UCLH and RFH and compares it with one other autoimmune condition, notably vasculitis. Study 1 investigated the time spent on dialysis before rTp and survival following rTp in a cohort of SLE patients. This was a retrospective analysis of 40 adult SLE patients receiving rTp over a 40-year period (1975-2015) and identified that time on dialysis before rTp was the only modifiable survival risk predictor (with a hazard ratio of 1.01 for each additional month spent on dialysis) and suggested that more than 24 months on dialysis adversely affected mortality. No other modifiable predictors associated with mortality, supporting that longer time on dialysis pre-transplantation is an independent modifiable risk factor of mortality in LN. Study 2 examined whether non-adherence is associated with increased rTp graft rejection and/ or failure in patients with LN in the same cohort as Study 1. The role of non-adherence and other potential predictors of graft rejection/ failure were investigated using logistic regression. During a median follow-up of 8.7 years, 17/40 (42.5%) of the patients had evidence of non-adherence. Non-adherent patients had a trend towards increased graft rejection, odds ratio 4.38, (95% confidence interval= 0.73-26.12, p = 0.11.) Interestingly, patients who spent more time on dialysis before rTp were more likely to be subsequently adherent to medication, p=0.01. Study 3 determined self-reported adherence to medication utilising an anonymised questionnaire-based survey and explored influencing factors in LN and renal vasculitis clinics at UCLH and RFH. I compared 114 patients with LN and 80 patients with renal vasculitis to identify emerging patterns, behaviours and differences that could potentially introduce barriers to adherence. Lupus patients were more likely to be female, younger and with longer disease duration (p<0.001). Their adherence decreased with time compared to vasculitis patients (p<0.001). Conversely, the patients with vasculitis had higher attendance at clinic appointments (p=0.02), and were more confident they could manage to take their tablets correctly. "Forgetfulness" regarding medication, and keeping track of hospital appointments were the most common reasons given for non-adherence rather than deliberate non-adherence. Increasing age and taking prednisolone associated with better adherence. In contrast, missing even one outpatient clinic appointment associated with worse adherence. Utilising responses from the survey, a prediction model was proposed to further risk-stratify patients regarding their potential adherence patterns that can identify the "at-risk" patient and alert clinicians to the possibility of poor adherence

Renal transplantation for lupus nephritis: non-adherence and graft survival

Objectives: Poor adherence to immunosuppressive treatment is common in patients with systemic lupus erythematosus and may identify those with lupus nephritis (LN) who have a poorer prognosis. Non-adherence has also been reported to be a potential adverse outcome predictor in renal transplantation (rTp). We investigated whether non-adherence is associated with increased rTp graft rejection and/or failure in patients with LN. Methods: Patients with LN undergoing rTp in two major London hospitals were retrospectively included. Medical and electronic records were reviewed for documented concerns of non-adherence as well as laboratory biochemical drug levels. The role of non-adherence and other potential predictors of graft rejection/failure including demographics, comorbidities, age at systemic lupus erythematosus and LN diagnosis, type of LN, time on dialysis prior to rTp and medication use were investigated using logistic regression. Results: Out of 361 patients with LN, 40 had rTp. During a median follow-up of 8.7 years, 17/40 (42.5%) of these patients had evidence of non-adherence. A total of 12 (30.0%) patients experienced graft rejection or failure or both. In the adherent group 2/23 (8.7%) had graft rejection, whilst in the non-adherent this rose to 5/17 (29.4%, p = 0.11). Graft failure was seen in 5/23 (21.7%) patients from the adherent group and 4/17 (23.5%) in the non-adherent group (p = 0.89). Non-adherent patients had a trend towards increased graft rejection, hazard ratio 4.38, 95% confidence interval = 0.73–26.12, p = 0.11. Patients who spent more time on dialysis prior to rTp were more likely to be adherent to medication, p = 0.01. Conclusion: Poor adherence to immunosuppressive therapy is common and has been shown to associate with a trend towards increased graft failure in patients with LN requiring rTp. This is the first paper to report that shorter periods on dialysis prior to transplantation might lead to increased non-adherence in lupus patients

The incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK Clinical Practice Research Datalink

Objectives: To estimate the incidence, prevalence and mortality of Granulomatosis with polyangiitis (GPA) in the United Kingdom. Methods: We conducted a historical cohort study using data from the Clinical Practice Research Datalink and Hospital Episode Statistics (CPRD-HES). We calculated incidence rate ratios, adjusted for age, gender and ethnicity, using Poisson regression. Results: We identified 462 cases diagnosed between 1997 and 2013. Our overall estimate of incidence was 11.8 (95% CI 10.7-12.9)/million person-years. Incidence in children (aged <16 years) was 0.88 (95% CI 0.40-1.96), and adults 14.0 (95% CI 12.8-15.4). The incidence was lower in females (adjusted IRR 0.68; 95% CI 0.56-0.81) and highest in the 55-69 year age-group (adjusted IRR 9.5, 95% CI 6.9-13.0; reference group 0-39 years). Incidence was not significantly different in the Black / Minority Ethnic population compared to the white population (adjusted odds ratio 0.78, 95% CI 0.53-1.13, p=0.13). The prevalence in 2013 was 134.9 (121.3-149.6) /million. Mortality was 13.6% at 1-year, and higher in HES than CPRD-identified cases (Hazard ratio 3.16, 95% CI 2.19-4.56, p<0.001). Conclusions: By combining primary and secondary care datasets we have found the incidence and mortality of granulomatosis with polyangiitis to be higher than previously reported. We predict that at present each year in the UK there will be approximately 700 new cases of whom 95 will die within 12 months

Impact of pre-transplant time on dialysis on survival in patients with lupus nephritis

Lupus nephritis (LN) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE) often leading to end-stage renal failure (ESRF) and necessitating renal transplantation (rTp). Optimal timing of rTp in SLE patients with ESRF is uncertain and could potentially affect survival. We investigated the time spent on dialysis before rTp and survival following rTp in a cohort of SLE patients. Retrospective analysis of all adult SLE patients receiving rTp over a 40-year period (1975–2015) in two tertiary UK centres. Cox proportional hazard regression and receiver operator curves (ROC) were used to determine the risk associated with time on dialysis before rTp and other potential predictors. Forty patients (age 35 ± 11 years, 34 female, 15 Caucasian, 15 Afro–Caribbean and 10 South Asian) underwent rTp. During a median follow-up of 104 months (IQR 80,145), eight (20%) patients died and the 5-year survival was 95%. Univariate analysis identified time on dialysis prior to rTp as the only potentially modifiable risk predictor of survival with a hazard ratio of 1.013 for each additional month spent on dialysis (95% CI = 1.001–1.026, p = 0.03). ROC curves demonstrated that > 24 months on dialysis had an adverse effect with sensitivity of 0.875 and specificity 0.500 for death. No other modifiable predictors were significantly associated with mortality, indicating that time on dialysis had an independent effect. Increased time on dialysis pre-transplantation is an independent modifiable risk factor of mortality in this cohort of patients with lupus nephritis

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005)

Risk factors associated with post-COVID-19 condition: A systematic review and meta-analysis

IMPORTANCE: Post-COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support. OBJECTIVE To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC. DATA SOURCES: Medline and Embase databases were systematically searched from inception to December 5, 2022. STUDY SELECTION: The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients. DATA EXTRACTION AND SYNTHESIS: Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023. MAIN OUTCOMES AND MEASURES: The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19. RESULTS: The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination

ANCA-associated vasculitis – Should we change the standard of care?

Collaborative clinical trials over the last 25 years have revolutionised the care of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This has led to production of management recommendations and standards of care. This paper reviews the existing standards and the recent evidence that has fed further evolution of standards of care. Pattern recognition remains vital to early diagnosis and therefore initiation treatment. While cyclophosphamide remains the treatment of choice, the advent of rituximab has been shown to be beneficial to patients with relapsing disease. It may be safer in young females and those with a risk of urothelial cancers. Methotrexate and mycophenolate mofetil may not be as good as previously thought for inducing remission. Azathioprine and rituximab are the standards for remission maintenance. There have been recent changes to the nomenclature of vasculitides. It is possible that these will continue to evolve over time to make them more meaningful and inform treatment and prognosis. In the absence of gold-standard biomarkers, we discuss the role of ANCA and histopathology, especially in the Indian setting. Follow-up and monitoring of these patients should include structured evaluation using validated clinical tools, assessing cardiovascular risk, vigilance for infections and other co-morbidities due to exposure to glucocorticoids and immunosuppression

The correct prednisone starting dose in polymyalgia rheumatica is related to body weight but not to disease severity

<p>Abstract</p> <p>Background</p> <p>the mainstay of treatment of polymyalgia rheumatica (PMR) is oral glucocorticoids, but randomized controlled trials of treatment are lacking. As a result, there is no evidence from controlled studies on the efficacy of different initial doses or glucocorticoid tapering. The aim of this study is to test if 12.5 mg prednisone/day is an adequate starting dose in PMR and to evaluate clinical predictors of drug response.</p> <p>Methods</p> <p>60 consecutive PMR patients were treated with a starting dose of 12,5 mg/day prednisone. Clinical, laboratory, and, in a subset of 25 patients, ultrasonographic features were recorded as possible predictors of response to prednisone. Remission was defined as disappearance of at least 75% of the signs and symptoms of PMR and normalization of ESR and CRP within the first month, a scenario allowing steroid tapering.</p> <p>Results</p> <p>47/60 (78.3%) patients responded to 12.5 mg of prednisone after a mean interval of 6.6 ± 5.2 days. In univariate analysis, body weight and gender discriminated the two groups. In multivariate analysis, the only factor predicting a good response was low weight (p = 0.004); the higher response rate observed in women was explained by their lower weight. The mean prednisone dose per kg in the responders was 0.19 ± 0.03 mg in comparison with 0.16 ± 0.03 mg for non responders (p = 0.007).</p> <p>Conclusions</p> <p>12.5 mg prednisone is a sufficient starting dose in ¾ of PMR patients. The main factor driving response to prednisone in PMR was weight, a finding that could help in the clinical care of PMR patients and in designing prospective studies of treatment.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01169597">NCT01169597</a></p