HLA-DR4 and DRB4: Potential risk alleles for COVID-19 vaccination-related ANCA-associated vasculitis.

Dear Editor,

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes the sweeping pandemic known as the coronavirus‐induced disease (COVID‐19). Vaccination effectively reduces SARS‐CoV‐2 transmission and lowers COVID‐19‐related critical illness. The side effect profiles of available vaccines are expanding, and recent reports raise the concern of immune‐mediated organ injuries. Cases of post‐COVID‐19 vaccination anti‐nuclear cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) have been reported [1]. Rare studies investigated the role of human leukocyte antigen (HLA) genes in post‐COVID vaccination AAV susceptibility. We reported two such cases with complete HLA typing results.

Case 1 was a 75‐year‐old female with a history of heart failure presented with days of dizziness and general weakness. She received her first dose of mRNA‐1273 (Moderna) 11 weeks before presentation, did not have evidence of COVID‐19 infection, and developed acute kidney injury (AKI) (serum creatinine (sCr) 6.34 mg/dl and potassium 7.0 mmol/L). Dipstick urine protein was 2+, and spot urine protein‐to‐creatinine ratio was 2744 mg/g. Her anti‐myeloperoxidase antibody titer was >134 IU/ml (negative <3.5 IU/ml), and microscopic polyangiitis (MPA)‐related AAV was diagnosed. Hemodialysis was arranged, and renal biopsy showed crescentic glomerulonephritis without immunoglobulin deposition (Figure 1A). Pulse steroid and rituximab were given, and she recovered renal function with dialysis independence. Case 2 was a 59‐year‐old male without asthma or eosinophilia receiving his first dose of ChAdOx1 nCoV‐19 (AstraZeneca), developing AKI with sCr 2.01 mg/dl weeks later. He also had negative SARS‐CoV‐2 results. Dipstick urine protein was 3+. His anti‐myeloperoxidase antibody was 57 IU/ml. Renal biopsy showed crescentic glomerulonephritis as well (Figure 1B), and he received plasma exchange, followed by steroid pulse therapy and rituximab, with renal function improvement. During HLA typing, Cases 1 and 2 did not have common HLA‐DQ allele but both carried HLA‐DR4 and HLA‐DRB4 (Figure 1C).

FIGURE 1

Glomerular crescent in cases 1 (A) and 2 (B). Human leukocyte antigen (HLA) typing results of Cases 1 and 2 (C)

SARS‐CoV‐2 vaccination appears to induce an increase in vasculitis incidence, including IgA vasculitis, AAV, leukocytoclastic, urticarial, and lymphocytic vasculitis. The risk exists regardless of vaccine type (mRNA or adenovirus vector‐based ones). Although the course is mostly mild to moderate, there are cases of irreversible AAV‐induced crescentic glomerulonephritis culminating in end‐stage kidney disease reported, necessitating our attention. The pathogenesis of AAV remains inadequately understood, particularly genetic susceptibility traits modulating the risk of drug‐related AAV. In 2012, large genome‐wide association studies of AAV cases and controls revealed associations between patients with MPO‐ANCA and HLA‐DQ mainly [2]. However, for drug‐induced AAV with crescentic glomerulonephritis, HLA‐DR4 has been reported to confer an increased risk [3]. In addition, HLA‐DRB4 was reportedly enriched in patients with MPO‐ANCA, and strong binding between HLA‐DRB4 and MPO epitopes was shown to facilitate autoreactive T‐cell production [4]. Our preliminary findings hint at the possibility of performing HLA typing prior to COVID‐19 vaccination to potentially lower the risk of renal complications afterward. However, it should be noted that our observation was based on case series only, and result applicability remains to be tested in other populations.

CONFLICT OF INTEREST

The authors declare no conflict of interest.