Study Finds 3 Gene Variants Linked with Poor Outcomes in AAV Patients

Patients with ANCA-associated vasculitis (AAV) carrying specific variants of the glucocorticoid receptor (GR) gene NR3C1 have a greater risk of death and of developing end-stage renal disease, according to a large study.

Also, patients with a variant of the gene coding for an enzyme that regulates glucocorticoids — HSD11B1 — have an increased risk of disease relapse.

The research, “Clinical outcome in anti-neutrophil cytoplasmic antibody-associated vasculitis and gene variants of 11β-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor,” appeared in the journal Rheumatology.

AAV patients are typically treated with high initial doses of the glucocorticoid prednisolone. However, this approach is associated with diverse adverse events and variable treatment efficacy.

Personalized medicine, targeting specific AAV processes and identifying distinct disease subsets, has been increasingly applied in AAV. These approaches have included finding genetic polymorphisms — or gene variants — related to treatment efficacy and/or toxicity.

HSD11B1 converts cortisone into cortisol, which may induce adverse cardiometabolic effects. HSD11B1 deficiency may worsen inflammatory diseases or complicate their treatment. Also, a frequent genetic polymorphism — or variant — of HSD11B1, rs11119328, may lead to reduced production of the enzyme. However, the impact of rs11119328 on inflammation has not been addressed.

Both cortisol and prednisolone bind to the GR, altering gene expression. Several variants have been described for the GR gene, differentially affecting the response to glucocorticoids and being associated with distinct clinical manifestations, such as the inflammatory diseases multiple sclerosis and rheumatoid arthritis.

A team from the Netherlands assessed the impact of five GR gene variants and one variant of HSD11B1 (rs11119328) on the efficacy and toxicity of high-dose prednisolone in patients with AAV.

The scientists hypothesized that the GR gene variants N363S and BclI — previously linked with increased sensitivity to glucocorticoids — would be associated with greater risk of cardiometabolic adverse events and that variants ER22/23EK and 9β (of GR) and rs11119328 (of HSD11B1) would correlate with more severe disease activity and a higher risk of relapse.

A total of 241 AAV patients (56% males, median age at diagnosis 56 years) were included. They were diagnosed between 1990 and 2015 and received treatment with glucocorticoids combined with another immunosuppressive medication as initial treatment. The patients were treated with a median initial prednisolone dose of 60 mg/day, lowered to 7.5 mg/day after six months.

Cyclophosphamide was the most frequently used medication for induction therapy (68%) and azathioprine for maintenance therapy (47%), in addition to prednisolone. One year after diagnosis, 60% of patients stopped treatment with prednisolone.

The participants underwent genetic analysis of the GR and HSD11B1 genes. GR gene haplotypes — a set of variants that tend to be inherited together — were predicted based on results. Results showed similar frequencies for the different polymorphisms compared to the general population.

The team then compared relapse-free survival, mortality, renal survival, metabolic adverse events, and infections between carriers and non-carriers of GR gene haplotypes and the HSD11B1 genotype.

Overall, 53% of patients experienced a relapse, 24% died, and 11% developed end-stage renal disease (ESRD) within 10 years of diagnosis. Relapse-free survival was 92% after one year, 53% after five years, and 38% after 10 years. In turn, survival was 97% after one year, 88% after five years, and 72% after 10 years.

A total of 103 patients had an infection requiring antimicrobial treatment during the first year. After 10 years, 67% of patients had hypertension, 31% had diabetes and 29% had dyslipidemia, which refers to an abnormal amount of lipids (fat) in the blood.

Patients carrying a combination of minor variants of the ER22/23EK, 9β and TthIII1 polymorphisms (haplotype 4) had a significantly higher five-year mortality risk and a higher risk of developing ESRD.

This combination has been previously linked with more aggressive multiple sclerosis, the team noted. The TthIII1 polymorphism was previously thought to have no influence on glucocorticoid sensitivity.

Carriers of a minor variant of HSD11B1 more frequently experienced AAV relapse unless they also carried the minor variant of the BclI polymorphism of GR (haplotype 1).

Also, patients carrying haplotype 1 in both GR gene copies had a higher risk of developing dyslipidemia. The incidence of infections did not differ among the groups.

Overall, the scientists considered that the results “might prove useful in guiding treatment for individual patients.” If the results are confirmed in future studies, potential applications include “more intensive induction therapy for carriers of haplotype 4 with renal disease activity” and “longer duration of maintenance therapy for carriers of an HSD11B1 variant without haplotype 1,” they said.