Subclinical Cytomegalovirus Reactivation in Acute ANCA-associated Vasculitis : Subclinical Cytomegalovirus Reactivation in Patients With Newly Diagnosed or Relapsed ANCA-associated Vasculitis and Adverse Clinical Outcomes

INTRODUCTION/BACKGROUND:This is an observational study to determine the frequency and magnitude of CMV reactivation in patients with AAV in the acute phase of the disease (within 12 months of diagnosis or relapse and commencement of induction of remission therapy).AAVs are systemic autoimmune inflammatory conditions characterized by necrotising inflammation affecting small to medium blood vessels leading to end-organ damage. Without treatment AAV is life-threatening; treatment involves powerful immunosuppression to induce remission, followed by maintenance treatment to prevent disease relapse. Treatment induction for both new-onset AAV and major life-threatening relapses is usually in the form of corticosteroids in combination with either cyclophosphamide or rituximab. Whilst prognosis has significantly improved with current treatment options for AAV, there remains significant morbidity and mortality associated with these conditions, especially during the first 12 months following diagnosis and commencement of induction of remission therapy. Infection is the leading cause of death within the first 12 months, accounting for approximately 50% of mortality as well as considerable morbidity and hospitalisation.Cytomegalovirus (CMV) is a widely prevalent herpesvirus that is not cleared after primary infection and establishes a state of persistent infection. CMV is present in over half the population by middle age and is thought to undergo a state of latency with intermittent periods of viral reactivation. This can be a significant clinical problem amongst patients that receive immunosuppression for bone marrow or solid organ transplants. Although, patients with AAV are heavily immunosuppressed, symptomatic CMV disease is uncommon in this patient group (2%). However, asymptomatic reactivation is not uncommon. In a proof-of-concept study, the investigators have shown that asymptomatic subclinical reactivation of CMV is a frequent event amongst patients with stable AAV in remission, occurring in approximately 1 in 4 CMV seropositive AAV patients in remission over a 12-month period. The investigators and others have shown that asymptomatic CMV infection is associated with key adverse clinical outcomes amongst patients with AAV, such as reduced kidney function, increased risk of infection and mortality, increased risk of venous thromboembolism, and increased arterial stiffness, a marker of cardiovascular mortality.The investigators have previously demonstrated that subclinical reactivation of CMV is associated with the expansion of a cytotoxic T-cell subset known as CD4+CD28null T-cells. Importantly, significant expansion of CD4+CD28null T-cells is exclusively seen in CMV seropositive patients. The investigators recently demonstrated that CD4+CD28null T-cells expansion is linked to a reduced functional capacity of the CD4 compartment and subsequent reduced response to the pneumonia vaccine, amongst patients with AAV in remission. Importantly, the investigators found that participants with evidence of subclinical CMV reactivation during the 6 months preceding the vaccination did not mount a response to the vaccine, but treatment with antiviral Valacyclovir suppressed CD4+CD28null T-cells expansion and suppression of CD4+CD28null T-cells was in itself associated with a better response to pneumococcal vaccination.The investigators anticipate that CMV reactivation will be significantly higher during the acute phase of the disease process, both with de-novo disease and major relapses, at a time where patients are exposed to intensive immunosuppressive therapy and heightened inflammation. However, the degree to which subclinical reactivation of CMV occurs during the acute phase of AAV is not currently known.The mechanism of CMV-induced kidney damage is not yet known. The investigators have developed preliminary unpublished data that has led them to hypothesise that subclinical CMV reactivation may amplify renal injury in AAV via the expansion of CCR2 expressing pro-inflammatory monocytes. These preliminary findings suggest that in these patients, the more CCR2 expressing monocytes in the blood, the worse the kidney function. There is also an increasing amount of evidence now that blocking CCR2 monocytes in mice reduces kidney damage across a wide variety of kidney conditions. This suggests that this monocyte-induced kidney damage pathway is not just limited to patients with vasculitis and this research could be relevant to other inflammatory renal conditions.RATIONALE:If this current proposed study confirms that subclinical CMV reactivation occurs frequently during the acute phase of AAV and is linked to worse patient outcomes, the investigators would propose that suppression of CMV during the acute phase of the disease would be a potentially valuable therapeutic target to improve patient outcomes and will seek funding for a multi-centre interventional study to test this hypothesis.Another important aim of this study is to investigate the contribution of monocyte induced renal damage in AAV via the CCR2 / CCL2 axis and to determine whether repeated rounds of CMV reactivation drive expansions of CCR2 monocytes that amplify renal injury. The investigators anticipate that this will be highly relevant to other conditions where there is intra-renal inflammation. The findings of this present study may facilitate patient selection for clinical trials to maximise the benefit of CCR2 blockade treatment approaches as well as open new exciting therapeutic opportunities in AAV and other renal conditions, including diabetic kidney disease.DESIGN:Up to 50 CMV seropositive and 20 CMV seronegative participants will be recruited within 14 days of disease presentation or major disease relapse and commencement of induction of remission therapy, over a period of 18 months. For the purposes of this study, a major relapse will be defined as a disease relapse that requires re-induction of remission therapy with high dose corticosteroids AND either rituximab or cyclophosphamide.Study participants will be followed up for a total of 12 months during their usual clinical visits at the NIHR / Wellcome Trust Clinical Research Facility (WTCRF) at University Hospitals Birmingham NHS Foundation Trust (UHBFT). Some study visits may be conducted at a remote offsite location in order to minimize patient hospital visits in light of the current COVID-19 pandemic. It is estimated that the study will take 36 months to complete.OBJECTIVES:Aim 1:To determine the frequency and clinical importance of CMV reactivation during the acute phase (first 12 months) following diagnosis or relapse of AAV and commencement of induction of remission therapyBlood and urine samples will be drawn at all time points to measure CMV viral DNA copies by quantitative PCR.This will be performed at UHBFT virology laboratory using a validated commercial assay, which is routinely utilized for clinical samples. As this test does not form part of standard of care for these patients, the CMV PCR results will be held back by the Virology Laboratory and released to the research team at the end of the study. The investigators will therefore be blind to the frequency of subclinical CMV reactivation over the 12-month study period whilst the clinical outcome data is collected.In cases where there is clinical suspicion of symptomatic CMV reactivation or CMV end-organ disease, separate relevant samples will be sent as per clinical need. Should symptomatic CMV reactivation or CMV end-organ disease be diagnosed or strongly suspected, the management will be as per standard clinical practice.Subclinical asymptomatic CMV reactivation will be defined as a detectable viral titre of > 20 copies / ml in at least one sample of blood or urine in the absence of symptoms or signs in keeping with CMV disease, and in the absence of symptoms or signs of what would be consistent with CMV syndrome (CMV syndrome as defined in the transplant population). Patients with symptomatic CMV reactivation and / or CMV end-organ disease would be excluded from these comparisons. However, based on clinical experience, the investigators anticipate that such symptomatic disease will be very uncommon in this population.Associations between subclinical asymptomatic CMV and the following outcomes will be assessed:Clinical vasculitis outcomes: Birmingham Vasculitis Activity score (BVAS), time to achieve disease remission, proteinuria (urine albumin creatinine ratio), kidney function, time to renal recovery, C-reactive protein (CRP) concentration and concentration of urinary markers of inflammation (MCP-1, CD163)Disease damage: Vasculitis Damage Index (VDI) at 12 monthsPatient well-being: Patient-reported outcome using AAV-PRO at 12 monthsFrailty measures: frailty index, Short physical performance battery (SPPB) and hand grip strength at 12 monthsThe incidence of non-CMV infections over the 12-month study periodThe immune response to clinically indicated vacci....

Medienart:	Klinische Studie

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	ClinicalTrials.gov - (2023) vom: 18. Jan. Zur Gesamtaufnahme - year:2023

Sprache:	Englisch

Links:	Volltext [kostenfrei]

Themen:	610 Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Recruitment Status: Recruiting Study Type: Observational Vasculitis

Anmerkungen:	Source: Link to the current ClinicalTrials.gov record., First posted: June 7, 2021, Last downloaded: ClinicalTrials.gov processed this data on January 25, 2023, Last updated: January 25, 2023

Study ID:

NCT04916704 294850

Veröffentlichungen zur Studie:

Morgan MD, Pachnio A, Begum J, Roberts D, Rasmussen N, Neil DA, Bajema I, Savage CO, Moss PA, Harper L. CD4+CD28- T cell expansion in granulomatosis with polyangiitis (Wegener's) is driven by latent cytomegalovirus infection and is associated with an increased risk of infection and mortality. Arthritis Rheum. 2011 Jul;63(7):2127-37. doi: 10.1002/art.30366. Chanouzas D, Sagmeister M, Dyall L, Sharp P, Powley L, Johal S, Bowen J, Nightingale P, Ferro CJ, Morgan MD, Moss P, Harper L. The host cellular immune response to cytomegalovirus targets the endothelium and is associated with increased arterial stiffness in ANCA-associated vasculitis. Arthritis Res Ther. 2018 Aug 29;20(1):194. doi: 10.1186/s13075-018-1695-8. Chanouzas D, Sagmeister M, Faustini S, Nightingale P, Richter A, Ferro CJ, Morgan MD, Moss P, Harper L. Subclinical Reactivation of Cytomegalovirus Drives CD4+CD28null T-Cell Expansion and Impaired Immune Response to Pneumococcal Vaccination in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. J Infect Dis. 2019 Jan 7;219(2):234-244. doi: 10.1093/infdis/jiy493.

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PPN (Katalog-ID):	CTG007684754