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Infection is a leading cause of death in antineutrophil cytoplasmic antibody–associated vasculitis. Here we show that suppression of subclinical reactivation of cytomegalovirus limits CD4+CD28null T-cell expansion and that this is associated with improved immune response to a T-cell–dependent pneumococcal vaccine challenge. Abstract Background Infection is the leading cause of death in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Expansion of CD4+CD28null T cells is associated with increased risk of infection and mortality, but is only present in cytomegalovirus (CMV)–seropositive individuals. We hypothesized that subclinical CMV reactivation drives CD4+CD28null T-cell expansion, that this is associated with impaired immune response to heterologous antigens, and that antiviral therapy may ameliorate this. Methods In a proof-of-concept open-label clinical trial, 38 CMV-seropositive AAV patients were randomized to receive valacyclovir for 6 months or no intervention. CMV reactivation was measured monthly in plasma and urine. CD4+CD28null T cells were enumerated at baseline and at 6 months. At 6 months, 36 patients were vaccinated with a 13-valent pneumococcal vaccine. Serotype-specific immunoglobulin G was assayed before and 4 weeks postvaccination to calculate the antibody response ratio. Results Valacyclovir treatment suppressed subclinical CMV reactivation and reduced CD4+CD28null T-cell proportion. CD4+CD28null T-cell reduction correlated with improved vaccine response, whereas CMV reactivation associated with reduced response to vaccination. Furthermore, expansion of CD4+CD28null T cells was associated with a reduction in the functional capacity of the CD4 compartment. Conclusions Suppression of CMV may improve the immune response to a T-cell–dependent pneumococcal vaccination in patients with AAV, thus offering potential clinical benefit. Clinical Trials Registration NCT01633476.

Introduction The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study. Methods Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised. Results Median duration of follow-up was 4.3 years (IQR, 2.95–5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs. Discussion Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

ObjectiveTo develop and validate classification criteria for microscopic polyangiitis (MPA).MethodsPatients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators.ResultsThe development set for MPA consisted of 149 cases of MPA and 408 comparators. The validation set consisted of an additional 142 cases of MPA and 414 comparators. From 91 candidate items, regression analysis identified 10 items for MPA, 6 of which were retained. The final criteria and their weights were as follows: perinuclear antineutrophil cytoplasmic antibody (ANCA) or anti-myeloperoxidase-ANCA positivity (+6), pauci-immune glomerulonephritis (+3), lung fibrosis or interstitial lung disease (+3), sino-nasal symptoms or signs (−3), cytoplasmic ANCA or anti-proteinase 3 ANCA positivity (−1) and eosinophil count ≥1×109/L (−4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having MPA with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 91% (95% CI 85% to 95%) and the specificity was 94% (95% CI 92% to 96%).ConclusionThe 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for MPA are now validated for use in clinical research.

ObjectiveTo develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA).MethodsPatients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators.ResultsThe development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (−1); and eosinophil count ≥1×109 /L (−4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% CI 87% to 96%) and the specificity was 94% (95% CI 89% to 97%).ConclusionThe 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophil-mediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis. NETs from ANCA-stimulated neutrophils caused endothelial cell (EC) damage in vitro. This effect was prevented by (i) pharmacologic inhibition of RIPK1 or (ii) enzymatic NET degradation. The alternative complement pathway (AP) was recently implicated in AAV, and C5a inhibition is currently being tested in clinical studies. We observed that NETs provided a scaffold for AP activation that in turn contributed to EC damage. We further established the in vivo relevance of NETs and the requirement of RIPK1/3/MLKL-dependent necroptosis, specifically in the bone marrow-derived compartment, for disease induction using murine AAV models and in human kidney biopsies. In summary, we identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, the AP, and endothelial damage. RIPK1 inhibitors are currently being evaluated in clinical trials and exhibit a novel therapeutic strategy in AAV.

Determinants of outcome in ANCA-associated glomerulonephritis: A prospective clinico-histopathological analysis of 96 patients. The predictive value of clinical and renal histological features for renal outcome in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis was investigated in a prospective analysis of 96 patients with ANCA-associated vasculitis, and moderate renal involvement (creatinine <500 μmol/L). The extent of 39 histological features in 96 biopsies (performed at entry in a clinical trial) was scored by two independent observers, according to a standardized protocol. Age, gender, diagnosis, glomerular filtration rate at entry (GFR0), ANCA-specificity, proteinuria, and treatment of these 96 patients were also taken into account. Treatment was standardized and started after the biopsy was performed. End-points included renal function at 18 months (GFR18), GFR18 corrected for GFR0 (CORGFR18), and the occurrence of relapse or death. Parameters that most strongly correlated with GFR18 were GFR0 (r = 0.67), interstitial fibrosis (r = -0.45), glomerulosclerosis (r = -0.37), and tubular atrophy (r = -0.36). Parameters that most strongly correlated with CORGFR18 were segmental (r = 0.45) and cellular (r = 0.30) crescents, and fibrinoid necrosis (r = 0.46). None of the clinical and histological features predicted the occurrence of relapse or death. By applying a stepwise linear multiple regression analysis, we designed a formula for the estimation of renal function at 18 months: GFR18 (mL/min) = 17 + 0.71 × GFR0 (mL/min) + 0.34 × fibrinoid necrosis (%) + 0.33 × segmental crescents (%), (r2 = 0.60; standard deviation = 19 mL/min). Our results were independent of diagnosis, ANCA-specificity, and treatment limb. These data suggest that in ANCA-associated glomerulonephritis, GFR0 and predominantly chronic renal lesions are potent predictors of GFR18. Active lesions are associated with renal function recovery and may be reversible. The formula for the estimation of GFR18 shows that a combination of GFR0 and renal histology is a better predictor for GFR18 than GFR0 only.

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4 + and CD8 + T cells as a pathogenic signature. We then utilize these transcriptomic profiles for digital pharmacology and identify ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the strongest therapeutic drug to use. Moreover, four patients with relapsing ANCA-GN are treated with ustekinumab in combination with low-dose cyclophosphamide and steroids, with ustekinumab given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients are followed up for 26 weeks to find this treatment well-tolerated and inducing clinical responses, including improved kidney function and Birmingham Vasculitis Activity Score, in all ANCA-GN patients. Our findings thus suggest that targeting of pathogenic T cells in ANCA-GN patients with ustekinumab might represent a potential approach and warrants further investigation in clinical trials. Antineutrophil cytoplasmic antibody (ANCA) is currently treated with broad-spectrum immune suppressive drugs. Here the authors decipher inflammatory niches in the kidney of patients with ANCA-GN by combining spatial and single-cell transcriptomics to identify ustekinumab as a promising treatment option and successfully treat four ANCA-GN patients.

Drug-induced autoimmune diseases are increasingly recognized, although mechanistic insight into disease causation is lacking. Hydralazine exposure has been linked to autoimmune diseases, including antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Our hypothesis posits that hydralazine covalently binds to myeloperoxidase (MPO), triggering the autoimmune response in ANCA vasculitis. In vitro, we observed formation of carbonyl derivatives on amine groups in the presence of acrolein. This facilitated the subsequent binding of hydralazine to heme-containing proteins, including MPO, via a Michael addition. Our studies demonstrated that carbonyl derivatives and hydrazone adducts induced conformational changes in the MPO heavy chain, potentially changing its immunogenicity. We identified hydrazone adducts on circulating MPO in patients with hydralazine-associated ANCA vasculitis. These patients exhibited elevated anti-MPO IgM levels, while anti-MPO IgG levels were comparable between hydralazine-associated and nonhydralazine-associated vasculitis patients. IgM isolated from patients with hydralazine-associated MPO ANCA demonstrated a heightened affinity to hydralazine-modified MPO and activated neutrophil-like HL-60 cells. Hydralazine-modified MPO was pathogenic, as demonstrated by splenocyte transfer in a mouse model of ANCA vasculitis. Our findings unveil a mechanism of drug-induced autoimmunity wherein stepwise chemical modifications of MPO lead to conformational changes and hydrazone adduct formation, producing a neoantigen that generates pathogenic autoantibodies.