Molecular Determinants of Systemic Immune Reactivation in Patients with ANCA-Associated Vasculitis

Profiling deep immune changes before AAV relapse to identify predictive biomarkers and therapeutic targets for this difficult-to-manage autoimmune vasculitis.
Completed Systemic Diseases Vasculitis Autoantibodies Bioinformatics Biological & Mechanistic Biomarker Discovery Data-Driven & Quantitative Disease Subtyping Early Disease Detection Experimental Platforms & Models Human Cohorts Immune Profiling Precision Medicine Translational & Clinical

Funding Year: 2023

Project Overview

ANCA-associated vasculitis is a multiorgan autoimmune vasculitis characterized by frequent, unpredictable relapses that lead to over- and under-treatment, complications, and reduced quality of life. This project leverages a longitudinal cohort of 77 AAV patients — exceeding enrollment goals with 153 visits — performing deep immune profiling at the molecular level before symptoms of relapse appear. Preliminary results from 101 samples demonstrate that deep immune profiling can distinguish AAV patients from healthy controls with 100% accuracy, and principal component analysis reveals substantial immune cell heterogeneity among AAV patients compared to relatively similar healthy controls. Forthcoming analyses will integrate machine learning subgroup identification, temporal immune change modeling, and upper airway molecular data from 16S rRNA sequencing to predict relapse and treatment response.

Impact & Innovation

Catching AAV relapse in the immune system before it reaches the clinic.

 

Deep immune profiling already distinguishes AAV patients from healthy controls with 100% accuracy — and longitudinal sampling before relapse symptoms appear positions this project to deliver the first predictive biomarker panel for AAV reactivation.

  • Demonstrates that deep immune profiling captures substantial heterogeneity among AAV patients, providing a foundation for identifying relapse-predictive biomarkers and disease subgroups through machine learning
  • Generates potential for novel neutrophil-focused biomarker panels and therapeutic targets by integrating nasal and blood molecular profiling, with a $2.5M NIH R01 awarded to expand this work
  • Advances the Consortium’s Integrated Data and Discovery Platforms pillar by building a longitudinal, multi-modal immune profiling dataset that links deep immune phenotyping with clinical outcomes and upper airway molecular data in AAV
Research Approach

A framework designed for discovery

This project combines longitudinal deep immune profiling, clinical monitoring, and multi-modal molecular data integration to identify the immune changes that precede relapse in ANCA-associated vasculitis. The work moves from cohort assembly and preliminary profiling through machine learning subgroup analysis and predictive biomarker development.

Longitudinal deep immune profiling of blood samples from 77 AAV patients across 153 visits; comparison with healthy controls using principal component analysis and logistic regression classifiers; supervised and unsupervised machine learning to identify clinical subgroups and disease subtypes; temporal immune change analysis linking profiling data to relapse and treatment response; and integration with upper airway molecular data from RNA sequencing and 16S rRNA sequencing of nasal mucosa.

Deep immune profiling datasets from 101 analyzed samples across 77 AAV patients and healthy controls; clinical outcome data including relapse events, disease subtype, and treatment response; preliminary logistic regression classifier datasets with cross-validation; and upper airway molecular profiling data from 52 recently processed samples integrating RNA and 16S rRNA sequencing.

Identification of predictive immune biomarkers and molecular determinants of relapse in AAV, with translational goals including development of novel biomarker panels, disease subgroup stratification, and therapeutic target discovery. Findings will support at least two manuscripts and are directly integrated into a $2.5M NIH R01-NIAMS award (R01-AR084646, start date 07/2024) expanding upper airway and deep immune profiling studies.

Investigators & Institutions

Powering the science

Principal Investigator

Rennie Rhee, MD, MSCE, Colton Consortium Member

Assistant Professor, Department of Medicine (Rheumatology), Perelman School of Medicine, University of Pennsylvania

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine

Research Outputs

From insight to impact

Publications

A randomized, double-blind, placebo-controlled trial of abatacept for the treatment of relapsing, non-severe granulomatosis with polyangiitis

Arthritis & Rheumatology
Langford, CA; Khalidi, N; Springer, J; Friedman, M; Hellmich, B; Pagnoux, C; Dehghan, N; Gewurz-Singer, O; Koening, CL; Lin, YC; Monach, PA; Moreland, LW; Fifi-Mah, A; Flossmann, O; Forbess, LJ; Lanyon, P; Molloy, E; Specks, U; Spiera, R; Yacyshyn, E; McAlear, CA; Burroughs, C; Jones, RB; Rhee, RL; Hajj-Ali, R; Warrington, KJ; Cuthbertson, D; Krischer, JP; Jayne, D; Merkel, PA; Vasculitis Clinical Research Consortium and the European Vasculitis Society June 2025
Biological & MechanisticClinical TrialsCross-institutional CollaborationExperimental Platforms & ModelsHuman CohortsPrecision MedicineT Cell BiologyTherapeutic DevelopmentTranslational & ClinicalSystemic DiseasesVasculitisUniversity of Pennsylvania

Assessment of damage in Takayasu’s arteritis

Rheumatology
Kermani, TA; Sreih, AG; Cuthbertson, D; Khalidi, NA; Koening, CL; Langford, CA; McAlear, CA; Monach, PA; Moreland, L; Pagnoux, C; Rhee, RL; Seo, P; Warrington, KJ; Merkel, PA February 2025
Biomarker DiscoveryDisease SubtypingExperimental Platforms & ModelsHuman CohortsPatient-reported OutcomesPopulation & Patient-CenteredReal-world EvidenceTranslational & ClinicalCross-Cutting & Special PopulationsRare Autoimmune DiseasesSystemic DiseasesVasculitisUniversity of Pennsylvania

Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study

The Journal of Clinical Investigation
Wang, WX; Spiegelman, D; Rao, PK; Rhee, RL; Ford, AL; Miner, JJ; Apte, RS December 2024
Biological & MechanisticClinical TrialsDrug RepurposingExperimental Platforms & ModelsHuman CohortsHuman GeneticsInnate ImmunityPrecision MedicineTherapeutic DevelopmentTranslational & ClinicalCross-Cutting & Special PopulationsOtherRare Autoimmune DiseasesUniversity of Pennsylvania

Plasma proteome profiling in giant cell arteritis

Annals of the Rheumatic Diseases
Cunningham, KY; Hur, B; Gupta, VK; Koster, MJ; Weyand, CM; Cuthbertson, D; Khalidi, NA; Koening, CL; Langford, CA; McAlear, CA; Monach, PA; Moreland, LW; Pagnoux, C; Rhee, RL; Seo, P; Merkel, PA; Warrington, KJ; Sung, J December 2024
BioinformaticsBiomarker DiscoveryData-Driven & QuantitativeDisease SubtypingExperimental Platforms & ModelsHuman CohortsImmune ProfilingMulti-omics IntegrationTranslational & ClinicalSystemic DiseasesVasculitisUniversity of Pennsylvania

Vessel wall MRI in giant cell arteritis: standardized protocol and scoring approach developed by an international working group

Rheumatology
Rhee, RL; Bathla, G; Rebello, R; Kurtz, RM; Junek, M; Warrington, KJ; Khalidi, N; Merkel, PA; Guggenberger, KV; Tamhankar, MA; Bley, TA; Vasculitis Clinical Research Consortium May 2025
Biomarker DiscoveryCollaboration & InnovationCross-institutional CollaborationDisease SubtypingEarly Disease DetectionExperimental Platforms & ModelsHuman CohortsReal-world EvidenceRegulatory ScienceTranslational & ClinicalSystemic DiseasesVasculitisUniversity of Pennsylvania

Additional Outputs

NIH-NIAMS R01-AR084646 — $2.5M (start date 07/2024): To support upper airway molecular and clinical profiling studies integrated with deep immune profiling data generated from this project.

Two manuscripts anticipated upon completion of full data analysis: 

  • Relationship of deep immune profiling with clinical subgroups, outcomes, and treatment

  • Relationship of deep immune profiling with molecular profiling of nasal mucosa