Background/Purpose: Systemic juvenile idiopathic arthritis (sJIA) is characterized by unique clinical features and it is considered as a polygenic autoinflammatory disease. Macrophage activation syndrome (MAS) and lung disease (LD) are two life threatening complications of sJIA. An association of HLA-DRB1*15 alleles with sJIA complicated by LD has been recently reported.

Methods: DNA was extracted by automatic system Qiagen EZ1 Advanced XL from blood samples collected from sJIA patients followed in a single Pediatric Rheumatology tertiary center. The AllType NGS 11-Loci Amplification Kit (Thermo Fisher, One Lambda, Canoga Park, CA) was used to amplify target DNA regions. The PCR cycling conditions were followed as suggested by the manufacturer. The kit uses one multiplexed PCR amplifying the full HLA-A/B/C/DQA1/DPA1 genes and exon 2 to 3UTR for HLA-DRB1/3/4/5/DQB/ DPB1 genes. Reads were analyzed with the HLA TypeStream VisualTM Software (Thermo Fisher, One Lambda, Canoga Park, CA), version 2.0.0. The IPD-IMGT/HLA Database release used was the 3.41. The strength of association between HLA alleles was estimated by 99% confidence intervals.

Results: Samples were collected from 98 sJIA patients, 52 females, all White Caucasian, except of 2 of African origin (1 from North-Africa and 1 from Sub-Saharan Africa) and 1 of mixed origin (Caribbean and Caucasian), with median age at disease onset of 6.9 years. The HLA-DRB1*15 allele was found in 20 (20%) out of 98 sJIA patients with a median age at disease onset of 5.4 years. These results were compared with a reference group of 1017 healthy Italian individuals, previously typed in our laboratory and representative of HLA allele frequency distribution in Italy. Eighteen, out of the 196 different HLA haplotypes observed in the patients studied, were positive for HLA-DRB1*15:01 (9.1%) compared to 94, out of 2034 (4.6%) in the healthy group with a p value of 0.006. However, using the Bonferronis correction for multiple tests, the significant association was lost (p=0.14), probably due to the small sample size.

Of those 20 HLA-DRB1*15 positive patients, 7 (35%) had refractory sJIA, as defined by Erkens (1), compared to 14 (17%) of the HLA-DRB1*15 negative patients. Five out of 20 (25%) HLA-DRB1*15 positive patients had LD compared to 2 (3%) of negative patients. Furthermore, 12 out 20 (60%) HLA-DRB1*15 positive patients had one or more MAS episode compared to 41 (52%) negative patients. Only 3 patients of the entire cohort experienced a drug adverse reaction to tocilizumab; all 3 had LD and carried the HLA-DRB1*15 allele. Notably, the lung involvement in these 3 patients developed before the drug reaction.

Conclusion: The HLA-DRB1*15 allele seems to be more frequently carried by sJIA patients compared to healthy Italian population and therefore might be identified as a potential marker of susceptibility to the disease. This allele appears to be more frequent in a subgroup of sJIA patients with early disease onset, refractory course and with lung involvement. These data are of course limited to a small population and need to be confirmed in a larger international and multiracial cohort.

Reference.

1. Erkens R. et al, Rheum Dis Clin North Am. 2021

This project has been funded by the systemic JIA Foundation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-drb115-alleles-in-systemic-juvenile-idiopathic-arthritis-with-lung-disease-and-macrophage-activation-syndrome-in-italy/