Subclinical Cytomegalovirus Reactivation in Acute ANCA-associated Vasculitis

NCT04916704 | Active Not Recruiting

• 1 other identifier: 294850
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

This is a prospective observational study to determine the frequency and magnitude of Cytomegalovirus (CMV) reactivation in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) in the acute phase of the disease (within 12 months of diagnosis or relapse and commencement of induction of remission therapy) and its association with clinical outcomes. The investigators will also explore whether CMV reactivation causes an increase in CCR2 expressing monocytes, and whether these monocytes cause persistent kidney damage in AAV. The investigators hypothesise that reactivation of CMV during the initial 12 months following diagnosis or relapse of AAV occurs frequently but is generally asymptomatic. Based on the investigators' preliminary data the investigators further hypothesise that subclinical reactivation of CMV during this period will be associated with adverse clinical outcomes, including the severity of vasculitis, the response to treatment and the damage caused by vasculitis. Finally, they hypothesise that subclinical CMV reactivation leads to amplification of renal damage in AAV through a monocyte CCR2/CCL2 driven pathway. The investigators' research has recently shown that asymptomatic reactivation of CMV is a frequent event in AAV patients, occurring in roughly 25% of AAV patients in remission. However, the frequency of asymptomatic reactivation of CMV during the acute phase of the disease is not known. The investigators have previously shown that CMV infection and surrogate markers of CMV reactivation in patients with AAV are associated with worse outcomes such as reduced kidney function, increased risk of infection and death, increased risk of blood clots and increased stiffness of the blood vessels, which is a risk factor for heart disease and stroke. The investigators also have preliminary findings suggesting that in patients with AAV and CMV reactivation, the more CCR2 expressing monocytes in the blood, the worse the kidney function. If CMV reactivation during the acute phase of the disease is common and linked with worse outcomes, this study may then lead on to future research involving treatment to prevent CMV reactivation aiming to improve patient outcomes. The investigators will be looking to recruit patients under the care of the Queen Elizabeth Hospital with newly diagnosed or recently relapsed AAV in the last 2 weeks who are positive for previous CMV infection.The investigators will follow these patients up with 10 visits over 12 months; where possible these will coincide with participants' usual vasculitis clinic appointments. At each visit the participants will be required to give blood and urine samples and answer questions related to their vasculitis. Kidney biopsy tissue taken at diagnosis will be used to assess mechanisms of injury during CMV reactivation.

Conditions

ANCA Associated Vasculitis

Keywords

CMV reactivation; ANCA associated vasculitis; CD4+CD28null T-cells; Infection; Immunosuppression

Outcome Measures

Primary Outcomes (1)

• To determine the frequency of CMV reactivation during the acute phase (first 12 months) following diagnosis or relapse of AAV and commencement of induction of remission therapy

  As assessed by measurable viral load (titre \>20 viral copies/ml) on quantitative PCR assessment of any blood or urine sample during the 12 month study period

  This will be assessed at month 12 (end of study)

Secondary Outcomes (15)

• The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and Birmingham Vasculitis Activity Score (BVAS)

  This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12.

• The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and time to achieve disease remission

  This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12 to identify disease remission

• The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and urine albumin creatinine ratio (ACR) at 12 months

  This will be assessed at month 12.

• The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and renal function at 12 months

  This will be assessed at month 12.

• The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and the time to renal recovery

  This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12 to identify renal recovery

Other Outcomes (1)

• The correlation between subclinical CMV reactivation during the acute phase of AAV and the proportion and phenotype of pro-inflammatory peripheral blood T-cell and monocyte subsets

  This will be assessed at baseline, month 3, 6, 10 and 12

Study Arms (2)

CMV seropositive

New diagnosis of AAV as evidenced by relevant biopsy and / or clinical diagnosis in the context of a positive ANCA antibody OR major relapse of previously diagnosed AAV that requires re-induction of remission treatment with intravenous rituximab or cyclophosphamide together with high dose oral corticosteroids. CMV IgG positive.

CMV seronegative

New diagnosis of AAV as evidenced by relevant biopsy and / or clinical diagnosis in the context of a positive ANCA antibody OR major relapse of previously diagnosed AAV that requires re-induction of remission treatment with intravenous rituximab or cyclophosphamide together with high dose oral corticosteroids. CMV IgG positive. CMV IgG negative.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with new or relapsing AAV will be identified through the vasculitis multi-disciplinary weekly meeting, clinician colleagues and the vasculitis specialist nurse. Up to 70 participants (50 CMV seropositive and 50 CMV seronegative) 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.

You may qualify if:

• New diagnosis of AAV as evidenced by relevant biopsy and / or clinical diagnosis in the context of a positive ANCA antibody OR major relapse of previously diagnosed AAV that requires re-induction of remission treatment with intravenous rituximab or cyclophosphamide together with high dose oral corticosteroids
• Age \>18 years
• Willingness to participate in the study and attend clinic and study visits
• Able to provide written informed consent

You may not qualify if:

• Strong suspicion of alternative diagnosis other than AAV
• Subjects who do not have capacity to consent to study participation as defined by the Mental Capacity Act 2005
• Inability or unwillingness to attend study visits

Sponsors & Collaborators

• University Hospital Birmingham NHS Foundation Trust: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University Hospitals Birmingham

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 21437878 BACKGROUND

• 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.

  PMID: 30157919 BACKGROUND

• 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.

  PMID: 30102389 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

The investigators will collect blood and urine samples. Blood will be processed to derive peripheral blood mononuclear cells (PBMC), PBMC pellets to allow DNA isolation and plasma.

MeSH Terms

Conditions

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Infections

Condition Hierarchy (Ancestors)

Systemic Vasculitis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Dimitrios Chanouzas, MBChB, PhD

  University Hospital Birmingham NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant Nephrologist

Study Record Dates

• First Submitted: May 18, 2021
• First Posted: June 7, 2021
• Study Start: April 19, 2022
• Primary Completion: December 22, 2024
• Study Completion: December 22, 2025
• Last Updated: July 11, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)