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action at the entheses, thus rapidly induces the central pathogenic features of spondyloarthropathy. These findings suggest that neutralisation of interleukin 23 is a promising therapeutic strategy for treatment of these conditions. Furthermore, since the various systemic features of spondyloarthropathy are fundamentally linked by dysregulation of interleukin 23, the entire disease process can hopefully be treated in a coordinated manner by interleukin-23 inhibition. Since this cytokine has a very direct role in pathology, such treatments will not simply address various downstream features of the disease, but are anticipated to correct the fundamental and primary causes of disease. Disease modification is hoped to be obtainable with amelioration of bone pathology. In spondyloarthropathy, this bone pathology includes not only bone erosion, but also new bone formation and osteopenia, which ultimately results in ossification of entheses and ligaments. Since interleukin 23 alone can induce all these features, interleukin-23 blockade is hoped to inhibit progression of this complex bone pathology in these very challenging conditions. The interleukin-23 pathway is therefore of much interest in these diseases, and several pharmacological approaches could potentially be used to target this pathway. However, future research using targeted monoclonal antibodies to block interleukin 23 specifically—rather than alternative interleukin-23 pathway targets shared with different cytokines, such as the p40 subunit—would enable validation of the hypothesis that interleukin 23 is the pivotal pathogenic driver.

of Oxford, Oxford, UK; and Merck Research Laboratories, Palo Alto, CA, USA (DJC) [email protected]

*Jonathan P Sherlock, Peter C Taylor, Christopher D Buckley, Daniel J Cua

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Rheumatology Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK (JPS, CDB); Kennedy Institute of Rheumatology (PCT) and Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (JPS, PCT), University

JPS was an employee of Merck Research Laboratories during 2009–12, where the work on spondyloarthropathy15,16 was done, and has received personal fees from Janssen. PCT has received personal fees from UCB, Merck, Lilly, Medimmune, and Janssen, and grants from UCB and Janssen. DJC is employed by Merck MSD. CDB declares no competing interests. 1

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Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715–25. Cua DJ, Sherlock JP, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421: 744–48. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004; 199: 125–30. Chan JR, Blumenschein W, Murphy E, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 2006; 203: 2577–87. Ahern PP, Schiering C, Buonocore S, et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 2010; 33: 279–88. Buonocore S, Ahern PP, Uhlig HH, et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 2010; 464: 1371–75. Mielants H, Veys EM, Cuvelier C, et al. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J Rheumatol 1995; 22: 2273–78. Ciccia F, Bombardieri M, Principato A, et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum 2009; 60: 955–65. Burton PR, Clayton DG, Cardon LR, et al, for the Wellcome Trust Case Control Consortium and Australo-Anglo-American Spondylitis Consortium (TASC). Association scan of 14 500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007; 39: 1329–37. Duerr R, Taylor K, Brant S, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–63. Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007; 80: 273–90. Colbert RA, DeLay ML, Klenk EI, Layh-Schmitt G. From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol Rev 2010; 233: 181–202. Bowness P, Ridley A, Shaw J, et al. Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol 2011; 186: 2672–80. McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998; 352: 1137–40. Cua DJ, Sherlock JP. Autoimmunity’s collateral damage: gut microbiota strikes “back”. Nat Med 2011; 17: 1055–60. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4–CD8– entheseal resident T cells. Nat Med 2012; 18: 1069–76.

Dual RAAS blockade for kidney failure: hope for the future See Articles page 2047

2018

Patients with diabetes and chronic kidney disease are at high risk of progression to end-stage kidney failure, requiring maintenance dialysis or transplantation.1 Presence of overt albuminuria (≥300 mg/day) further enhances the risk of kidney function decline, and is an

independent risk marker for cardiovascular disease and all-cause mortality.2 Blood pressure lowering, maintenance of blood glucose control, and use of blockers of the renin-angiotensinaldosterone system (RAAS)—eg, angiotensin-converting www.thelancet.com Vol 385 May 23, 2015

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www.thelancet.com Vol 385 May 23, 2015

which has a key role in the pathogenesis and progression of kidney disease.7 Combination ACE inhibitor and ARB treatment targets different points along the RAAS cascade, thereby inhibiting the conversion of angiotensin I to angiotensin II, and these agents block the angiotensin II type 1 receptor directly.7 Palmer and colleagues6 suggest that, in absolute terms, the incremental value of treating 1000 patients with diabetes and chronic kidney disease with dual ACE inhibitor and ARB treatment versus monotherapy for 1 year would prevent three additional cases of end-stage kidney failure and regress albuminuria in 90 people. The combination would also lead to 38 more patients having acute kidney injury and 65 more cases of hyperkalaemia. However, the implications of the compromise between benefits and safety of dual RAAS blockade are not straightforward. The definition of acute kidney injury varied widely across the individual trials and it is not clear how many participants in Palmer and colleagues’ network metaanalysis6 needed acute dialysis or admission to hospital for this adverse event. Likewise, an emergency department visit or admission was not a stated requirement for hyperkalaemia.8 Acute kidney injury might be associated with prolonged admission and incomplete recovery of kidney function, particularly in older patients with comorbidities.9 In the USA, the cost of treating an episode of acute kidney injury in hospital varies according to the extent of the rise in serum creatinine, ranging from US$4886 to $7982.10 The annual cost per patient of maintenance dialysis for end-stage kidney failure has reached $100 000.11 Thus, a distinction about severity and course of acute kidney injury is important to assess comprehensively the benefits and drawbacks of dual ACE inhibitor and ARB treatment, and to permit clinically meaningful decision making. This equation would also take into account whether reduction in albuminuria translates into a reduction in end-stage kidney failure— still an unanswered question.12 Although statistical homogeneity was present in the network meta-analysis,6 about 80% of studies included patients with type 2 diabetes and chronic kidney disease, with or without albuminuria. Evaluation of the effect of dual ACE inhibitor and ARB treatment could be informative in this population. The findings of the network meta-analysis will be useful for data safety and monitoring committees, although the comprehensiveness of safety outcomes is limited by short follow-up (≤12 months) in

Saturn Stills/Science Photo Library

enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)—are among the few established agents known to slow the decline in kidney function in individuals with diabetes.3 However, combination treatment with an ACE inhibitor and ARB, which was once favoured for the additional effect of decreased albuminuria, is no longer recommended. Large randomised controlled trials of this combination were terminated prematurely because of concerns about an increased risk of hyperkalaemia or acute kidney injury.4,5 Moreover, evidence of a benefit of dual RAAS blockade in the progression of chronic kidney disease was scant.4,5 In The Lancet, Suetonia Palmer and colleagues6 report a network meta-analysis of the comparative effectiveness of antihypertensive regimens in 43 256 participants with diabetes and chronic kidney disease from 157 randomised controlled trials. With respect to end-stage kidney failure, dual ACE inhibitor and ARB treatment ranked first in terms of benefit (odds ratio 0·62, 95% CI 0·43–0·90), followed by ARB monotherapy (0·77, 0·65–0·92). This benefit was independent of a blood pressure-lowering effect and was recorded mainly in patients with type 2 diabetes and overt albuminuria. Although the combination of a calciumchannel blocker and an ACE inhibitor ranked highly for prolonged survival, no antihypertensive regimen was superior to placebo for reduction of mortality. The adverse events of hyperkalaemia and acute kidney injury were most frequent among individuals treated with the combination of an ACE inhibitor and ARB, although the risks were slight (odds ratio 2·69, 95% CI 0·97–7·47 and 2·69, 0·98–7·38, respectively). These findings reignite the debate about the potential usefulness of dual RAAS blockade, and caution is needed in patients with diabetes and chronic kidney disease. Pooling data from several trials increases the power and precision of estimates of treatment effects and safety data. This approach is especially relevant when trials are terminated prematurely for safety and, therefore, are likely to underestimate the true treatment effect on the primary outcome (eg, end-stage kidney failure) and overestimate risk for adverse events. Pooling data also increases the sample size of clinically important high-risk subgroups that are generally under-represented in trials. The noted benefit of dual RAAS blockade on progression to end-stage kidney failure is biologically plausible. Angiotensin II mediates glomerular hypertension via an increase in efferent arteriolar constriction,

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many trials. Palmer and colleagues’ findings will be helpful for designing future trials, including appropriate selection of patients, choice of antihypertensive regimen, and meaningful definitions of adverse outcomes. The Kidney Disease Improving Global Outcomes (KDIGO) classification and staging of acute kidney injury could serve as a guide for defining this adverse event in future research.13 Emerging treatments for hyperkalaemia are likely to improve the safety profile of RAAS blockers.14 About 350 million people in the world have diabetes.15 A substantial proportion of these individuals will develop end-stage kidney failure, which underscores the need for preventive treatments.3 Screening for albuminuria and prompt initiation of lifestyle and pharmacological interventions is likely to prevent progression of chronic kidney disease and cardiovascular disease.3 Addition of dual ACE inhibitor and ARB treatment to this multifactorial management approach—if confirmed to be efficacious and cost effective—might further improve patients’ outcomes in regions of the world where careful selection of patients and close monitoring are possible.

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*Tazeen Hasan Jafar, Pryseley Nkouibert Assam Health Services and Systems Research (THJ) and Centre for Quantitative Medicine (PNA), Duke-NUS Graduate Medical School, Singapore 169857 [email protected]

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Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. JAMA 1997; 278: 2069–74. Fox CS, Matsushita K, Woodward M, et al, for the Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380: 1662–73. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382: 339–52. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369: 1892–903. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59. Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015; 385: 2047–56. Gurley SB, Coffman TM. The renin-angiotensin system and diabetic nephropathy. Semin Nephrol 2007; 27: 144–52. Raebel MA, Ross C, Xu S, et al. Diabetes and drug-associated hyperkalemia: effect of potassium monitoring. J Gen Intern Med 2010; 25: 326–33. Anderson S, Eldadah B, Halter JB, et al. Acute kidney injury in older adults. J Am Soc Nephrol 2011; 22: 28–38. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–70. Foley RN, Collins AJ. The USRDS: what you need to know about what it can and can’t tell us about ESRD. Clin J Am Soc Nephrol 2013; 8: 845–51. Inker LA, Levey AS, Pandya K, Stoycheff N, Okparavero A, Greene T. Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis. Am J Kidney Dis 2014; 64: 74–85. Thomas ME, Blaine C, Dawnay A, et al. The definition of acute kidney injury and its use in practice. Kidney Int 2015; 87: 62–73. Ingelfinger JR. A new era for the treatment of hyperkalemia? N Engl J Med 2015; 372: 275–77. Danaei G, Finucane MM, Lu Y, et al, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet 2011; 378: 31–40.

We declare no competing interests.

An alternative combination therapy for type 2 diabetes? See Articles page 2057

2020

In The Lancet, Lawrence Blonde and colleagues1 present data from a randomised controlled trial of the latest glucagon-like peptide-1 (GLP-1) receptor agonist. Dulaglutide has few known discriminating features compared with the other long-acting GLP-1 receptor agonists on the market with full diurnal GLP-1 activity.2,3 Yet, in the present trial, Blonde and colleagues have turned things upside down and tested this drug as an antihyperglycaemic backbone to pre-prandial shortacting insulin and metformin treatment in patients with type 2 diabetes. This combination of a GLP-1 receptor agonist and insulin has, until now, not been formally tested against the last resort of treatment intensification in patients with type 2 diabetes—namely, long-acting (basal) insulin and mealtime insulin.

The results are particularly interesting because the improvements in several safety and efficacy outcomes reported with dulaglutide (0·75 mg or 1·5 mg once weekly) plus mealtime insulin lispro (three times daily) were significantly greater than those with titrated insulin glargine (once daily) plus mealtime insulin lispro (three times daily). Recruited patients were already receiving insulin (up to two times a day) suggesting that most had deficits in insulin secretory capacity. Irrespective of these deficits, dulaglutide was effective. In our opinion, the glucagonostatic effect4,5 might be an important contributor to the retained efficacy of GLP-1 receptor agonists also in the later stages of type 2 diabetes. Unfortunately, an absence of glucagon data in Blonde and colleagues’ study1 www.thelancet.com Vol 385 May 23, 2015

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