The role of IL-17 in the pathogenesis of glomerulonephritis and ANCA-associated vasculitis

Immune-mediated glomerulonephritis and vasculitis accounts for over 10% of end-stage renal failure in the UK. The anti-neutrophil cytoplasm antibody(ANCA)-associated vasculitides (AAV) are a specific subset, characterised by the production of ANCA, and are idiopathic multi-system vasculitides affecting mainly small-calibre vessels and renal glomeruli. Extensive human and animal work by our group and others has attempted to dissect the mechanisms which underlie the pathogenesis of these conditions. Recently, an important development in our understanding of cellular immunity has been the identification of a subset of T-cells characterised by production of the pro-inflammatory cytokine interleukin-17 (IL-17). T-helper-17 (Th17) cells are implicated as critical mediators of autoimmune disease. I have attempted to characterise whether there is a role for Th17 cells in the pathogenesis of experimental glomerulonephritis and AAV. I have shown that IL-17-deficient mice are protected from nephrotoxic nephritis and have used cell transfer experiments to see whether disease susceptibility or protection can be conferred. Using bone marrow transplant experiments, I have also demonstrated (1) that haematopoietic cells are critical mediators of disease and (2) that local production of IL-17 has an unexpected protective role. In human work, using samples from patients with AAV, I have shown that IL-17 is over-expressed in serum from both acute and convalescent patients and is closely associated with levels of related cytokines such as IL-23. Patients with AAV have memory Th17 cells that respond to stimulation with ANCA autoantigens. IL-23 levels correlate with AAV disease activity. This work demonstrates a role for IL-17 and Th17 cells in experimental glomerulonephritis and AAV. IL-17 blockade is being trialled as a therapy for a number of autoimmune diseases. Improved understanding of the mechanisms of pathogenesis and protection by IL-17 in AAV and glomerulonephritis will enable better prediction of the effects of IL-17 blockade and bring benefits to patients

Management of ANCA-associated vasculitis: Current trends and future prospects

The antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are a spectrum of heterogeneous autoimmune diseases characterized by necrotizing small vessel vasculitis and the presence of ANCA. These chronic multisystem disorders may be life-threatening if there is major organ involvement, such as acute renal failure or pulmonary hemorrhage, and require significant initial immunosuppression and long-term maintenance treatment. Long-established protocols using cyclophosphamide and prednisolone have resulted in dramatically improved outcomes for patients since the 1970s. Subsequently, international collaboration has contributed to a growing evidence base and consensus in the management of these rare disorders. Modifications to traditional treatment protocols by the use of azathioprine or methotrexate rather than cyclophosphamide, and the introduction of newer agents, such as rituximab, has maintained outcomes whilst decreasing toxicity. However, the treatment limitations of incomplete efficacy, infection, and cumulative toxicity persist. These issues have continued to drive the search for safer and more effective modulation of the immune system using targeted immunotherapy. This review will explore the current evidence base for management of ANCA-associated vasculitis and future treatment prospects

Cocaine-induced granulomatosis with polyangiitis—an under-recognized condition

Objectives: Cocaine and cocaine mixed with levamisole are increasingly used in the UK and result in significant direct nasal damage in addition to promoting vasculitis. Our aims were as follows: (1) to identify the main symptoms and presentation of cocaine-induced vasculitis; (2) to provide evidence regarding the best practice for the investigation and diagnosis of cocaine-induced vasculitis; and (3) to analyse the clinical outcomes of patients in order to understand the optimal management for the condition./ Methods: We performed a retrospective case series analysis of patients presenting with cocaine-induced midline destructive lesions or vasculitis compatible with granulomatosis with polyangiitis (GPA) from two large tertiary vasculitis clinics between 2016 and 2021./ Results: Forty-two patients (29 Birmingham, 13 London) with cocaine-induced midline lesions or systemic disease were identified. The median age was 41 years (range 23–66 years). Current cocaine use was common, and 20 of 23 samples provided were positive when routine urine toxicology was performed; 9 patients who denied ever using cocaine were identified as using cocaine based on urine toxicology analysis, and 11 who stated they were ex-users still tested positive. There was a high incidence of septal perforation (75%) and oronasal fistula (15%). Systemic manifestations were less common (27%), and only one patient had acute kidney injury. Fifty-six per cent of our patients were PR3-ANCA positive, with none testing positive for MPO-ANCA. Symptom remission required cocaine discontinuation even when immunosuppression was administered./ Conclusion: Patients with destructive nasal lesions, especially young patients, should have urine toxicology performed for cocaine before diagnosing GPA and considering immunosuppressive therapy. The ANCA pattern is not specific for cocaine-induced midline destructive lesions. Treatment should be focused on cocaine cessation and conservative management in the first instance in the absence of organ-threatening disease

Leukocyte and serum S100A8/S100A9 expression reflects disease activity in ANCA-associated vasculitis and glomerulonephritis.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) commonly results in glomerulonephritis, in which neutrophils and monocytes have important roles. The heterodimer calprotectin (S100A8/S100A9, mrp8/14) is a Toll-like receptor-4 ligand found in neutrophils and monocytes and is elevated in inflammatory conditions. By immunohistochemistry of renal biopsies, patients with focal or crescentic glomerular lesions were found to have the highest expression of calprotectin and those with sclerotic the least. Serum levels of calprotectin as measured by ELISA were elevated in patients with active AAV and the levels decreased but did not normalize during remission, suggesting subclinical inflammation. Calprotectin levels in patients with limited systemic disease increased following treatment withdrawal and were significantly elevated in patients who relapsed compared with those who did not. As assessed by flow cytometry, patients with AAV had higher monocyte and neutrophil cell surface calprotectin expression than healthy controls, but this was not associated with augmented mRNA expression in CD14(+) monocytes or CD16(+) neutrophils. Thus, serum calprotectin is a potential disease biomarker in patients with AAV, and may have a role in disease pathogenesis

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine

Local IL-17 Production Exerts a Protective Role in Murine Experimental Glomerulonephritis

IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1β p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases

Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis

BACKGROUND: Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. METHODS: An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. RESULTS: A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. CONCLUSION: AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required

Patient perceptions of MRSA.

Drug-resistant nosocomial infections are an increasing problem. This issue has received considerable media coverage. To our knowledge there have been no studies investigating patient awareness and perceptions of nosocomial infections. A total of 113 surgical out-patients completed a questionnaire stating whether they had heard of either superbugs or MRSA. A series of questions were asked about the source of any information; methods of transmission and prevention; the consequences of infection and their emotional response if they were to acquire MRSA. Fifty patients (44%) had heard of superbugs or MRSA mainly via the media (58%) or from hospital staff (44%). The majority would feel either angry or afraid if they acquired MRSA in hospital, but there was good awareness of both methods of infection control and the consequences of infection. From our study, we conclude that the media is at least as important as health professionals in providing information. Concerns regarding nosocomial infection may need to be addressed prior to admission