MELBOURNE, Australia — The underlying histopathologic class of antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis may influence the response to immunosuppressive treatment, according to a presentation at the 22nd International Vasculitis Workshop (IVW) 2026.

Study presenter Martina Uzzo, MD, of University Medical Center Groningen in Netherlands and Humanitas University, Milan, Italy, told the conference that histopathology is known to be a predictor of kidney prognosis in glomerulonephritis, with the lowest rates of renal failure seen in the focal class and the highest rates in the sclerotic class.

However, “prospective and retrospective studies so far did not show significant differences in kidney outcomes between the main induction regimens, so we don’t know whether histopathological lesions may influence the efficacy of different immunosuppressive regimens,” she said.

Uzzo presented data from a retrospective, multicenter study involving 304 patients with biopsy-proven ANCA-associated glomerulonephritis. The aim of the study was to determine if the histopathology of the disease could or should influence the choice of immunosuppressant for the induction regimen.

Participants were recruited from 11 European referral centers between 1997 and 2019. Around one third of the cohort had a mix of histopathologic lesions, 31.6% had crescentic lesions, 23.3% had focal lesions, and 11.8% had sclerotic lesions. One-quarter had been treated with a combination of cyclophosphamide and rituximab, 17.1% with rituximab alone, and 58.6% with cyclophosphamide alone.

In general, patients with focal class lesions had the most favorable outcomes, although changes in estimated glomerular filtration rate (eGFR) were comparable across treatments in all the histopathologic classes. However, the analysis did suggest that rituximab was less effective in patients with crescentic lesions, whose odds of achieving eGFR recovery at 6 months were 77% lower than among those treated with cyclophosphamide (P = .047).

Researchers also noted that patients with crescentic lesions who were induced with rituximab had significantly lower kidney-failure-free survival than those treated with cyclophosphamide. No other treatment differences were seen in any of the other histopathologic classes.

“This finding suggests that rituximab monotherapy may be less effective than cyclophosphamide to lower quickly the glomerular inflammation that characterizes crescentic lesions, so this may result in suboptimal functional recovery,” Uzzo said. 

Speaking to Medscape Medical News, Uzzo stressed that because ANCA-associated vasculitis is a relatively rare disease and researchers categorized and then subcategorized study participants according to histopathology and treatment, the study was underpowered and the findings needed to be confirmed with larger numbers.

Uzzo said there was a biologic rationale to the finding, given that rituximab’s targeting of CD20 B lymphocytes provides more focused immunosuppression than cyclophosphamide, which provides broad immunosuppression affecting both B cells and T cells. She commented that the findings raise the question of whether rituximab monotherapy is less effective than cyclophosphamide at dampening down the intense glomerular inflammation linked to crescentic lesions.

Commenting on the study, Benoit Brilland, MD, PhD, of Angers University Hospital Center, Angers, France, and McGill University in Montreal, Canada, agreed that caution was needed in interpreting the data, given the small numbers of patients in each subgroup.

Can Predictors of Relapse Risk Be Found?

Besides predicting which histopathologic phenotypes of ANCA-associated glomerulonephritis respond best to immunosuppressive treatments, Brilland noted that another “major unmet need in this field is to personalize relapse risk stratification in order to better balance treatment toxicity versus disease and relapse burden, so we need dynamic- and phenotypic-specific models.”

In a separate study presented at IVW 2026, Brilland and colleagues reported being unable to find any clear indicators of relapse risk in patients with ANCA-associated glomerulonephritis.

The retrospective study involved 460 adults with suspected or confirmed ANCA-associated vasculitis with glomerulonephritis from seven hospitals across France. Over a mean of 62 months of follow-up, 23% of the cohort experienced at least one relapse, defined as any new disease manifestation occurring more than 3 months after diagnosis.

Among those who relapsed, 80% experienced only one relapse over the course of the study, 14% experienced two relapses, 4.7% experienced three relapses, and one patient had four relapses.

The analysis revealed that the majority of relapses occurred after 36 months, with a median time to relapse of 43 months. The timing of relapse in patients with a granulomatosis with polyangiitis (GPA) phenotype peaked at 3-5 years after diagnosis, but in those with microscopic polyangiitis (MPA), the incidence of relapse was fairly stable over time.

The most commonly affected organ at relapse was the kidney in both GPA and MPA phenotypes. Among patients with the MPA phenotype, the second most commonly affected site of relapse was the lung, followed by joints, but in those with the GPA phenotype, the joints were the second most common site of relapse, followed by the ear, nose, and throat.

Patients who relapsed had lower kidney survival than those who didn’t relapse, “but we were not able yet to find a clear cumulative effect, meaning that the weight of the relapse was mostly worn by the first relapse,” Brilland said.

The analysis didn’t reveal any significant baseline predictors of relapse risk, including proteinuria or hematuria. “Baseline clinical variables are not good biomarkers to predict upcoming events,” Brilland told Medscape Medical News. “So far, the ones that appear to be the most interesting in the field appear to be urinary soluble CD163, and we know that it’s not much about the level of this biomarker but the evolution over time.”

No funding or conflicts of interest were declared.