Screening of Patients with Adult-Onset Idiopathic Polyarteritis Nodosa for Deficiency of Adenosine Deaminase 2

Oskar Schnappauf¹, Monique Stoffels², Ivona Aksentijevich², Daniel L. Kastner², Peter C. Grayson³, David Cuthbertson⁴, Simon Carette⁵, Sharon A. Chung⁶, Lindsy J. Forbess⁷, Nader A. Khalidi⁸, Curry L. Koening⁹, Carol Langford¹⁰, Carol A. McAlear¹¹, Paul A. Monach¹², Larry W. Moreland¹³, Christian Pagnoux¹⁴, Philip Seo¹⁵, Jason Springer¹⁶, Antoine G. Sreih¹⁷, Kenneth J. Warrington¹⁸, Steven R. Ytterberg¹⁸ and Peter A. Merkel¹⁹, ¹NHGRI, National Institutes of Health, Bethesda, MD, ²Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, ³National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, ⁴Biostatistics and Informatics, Department of Pediatrics, Department of Biostatistics and Informatics, Department of Pediatrics, University of South Florida, Tampa, FL, ⁵Division of Rheumatology, Mount Sinai Hospital, Toronto, ON, Canada, ⁶Russell/Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, CA, ⁷Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ⁸Rheumatology, McMaster University, Hamilton, ON, Canada, ⁹Rheumatology, Division of Rheumatology, University of Utah, Salt Lake City, UT, ¹⁰Rheumatic and Immunologic Diseases, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, ¹¹Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, ¹²Section of Rheumatology, Boston University School of Medicine, Boston, MA, ¹³Division of Rheumatology and Clinical Immunology, Division of Rheumatology, University of Pittsburgh, Pittsburgh, PA, ¹⁴Division of Rheumatology, Division of Rheumatology, Mount Sinai Hospital, Toronto, ON, Canada, ¹⁵Medicine, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, ¹⁶Department of Internal Medicine, The University of Kansas Medical Center, Division of Allergy, Clinical Immunology & Rheumatology, Kansas City, KS, ¹⁷Rheumatology, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, ¹⁸Rheumatology, Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, ¹⁹Division of Rheumatology and the Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: anti-TNF therapy, Genetic disorders, polyarteritis nodosa and vasculitis

Session Information

Date: Tuesday, October 23, 2018

Title: 5T046 ACR Abstract: Plenary Session III (2785–2790)

Session Type: ACR Plenary Session

Session Time: 11:00AM-12:30PM

Background/Purpose:

Deficiency of adenosine deaminase 2 (DADA2) is the first described type of monogenic vasculitis. Patients usually present in childhood, but age of onset, disease severity, and organ involvement of DADA2-associated vasculitis is highly variable and clinical features overlap with the typical features of polyarteritis nodosa (PAN). This study aimed to test the prevalence of DADA2 in patients with presumed idiopathic PAN.

Methods:

Patients (n=117) with idiopathic PAN, all of whom tested negative for hepatitis B virus infection, were screened for mutations in ADA2 (formerly known as CECR1). DNA was extracted from whole blood by standard methods. Standard PCR amplification and Sanger sequencing was performed for the 9 coding exons of the ADA2 gene. To further assess the pathogenicity of identified variants on a functional level, ADA2 activity was determined using the adenosine deaminase assay kit from Diazyme.

Results:

Eight of 117 patients (6.8%) were identified as having rare missense variants in ADA2 with a minor allele frequency of < 0.005. Four patients (3.4%) were homozygous or compound heterozygous for variants in ADA2. Of the 7 distinct variants present in these 4 patients, G47A, G47W, R169Q, E328K, F355L, and G383S had previously been reported as causative for DADA2. The remaining variant, P106S, is a rare variant predicted to be damaging to protein function by the PROVEAN algorithm. Four additional patients were carriers for the monoallelic variants R34W, T65M, M309I, and V349I. R34W was reported in DADA2 before, while the 3 remaining variants are of unknown clinical significance.

Serum samples were available on patients with the G383S/G383S and E328K/F355L genotypes and measurements showed markedly reduced ADA2 enzyme activity, comparable to levels seen in patients with DADA2. ADA2 activity in the serum of 2 of the monoallelic carriers was not reduced, confirming the non-pathogenicity of T65M and V349I. The median age at diagnosis for the 4 patients with biallelic ADA2 mutations was considerably younger (median 23.0 years, range 17.4-24.4) than for the 4 patients with heterozygous ADA2 variants (median 42.0 years, range 16.5-59.0) or the other 109 patients in the cohort (median 47.0 years, range 33.3-56.7) (p=0.04). There were no marked differences in the types of clinical manifestations between patients with or without ADA2 mutations, including neurologic disease.

Conclusion:

This is the first study to report biallelic pathogenic variants in ADA2 in patients with adult-onset, HBV-negative PAN, and demonstrates that DADA2 accounts for a subset of patients with idiopathic PAN. Given the potential efficacy of TNF-inhibitors in DADA2, that anti-TNF treatment is not the conventional therapy in PAN, and the consequences for other family members, these findings suggest that ADA2 testing should be considered in patients with HBV-negative idiopathic PAN, especially in patients with an early onset of this potentially life-threatening disease.

Disclosure: O. Schnappauf, None; M. Stoffels, None; I. Aksentijevich, None; D. L. Kastner, None; P. C. Grayson, None; D. Cuthbertson, None; S. Carette, None; S. A. Chung, None; L. J. Forbess, None; N. A. Khalidi, None; C. L. Koening, None; C. Langford, None; C. A. McAlear, None; P. A. Monach, None; L. W. Moreland, None; C. Pagnoux, None; P. Seo, None; J. Springer, None; A. G. Sreih, None; K. J. Warrington, GlaxoSmithKline, 2,Eli Lilly and Co., 2,Sanofi, 5; S. R. Ytterberg, None; P. A. Merkel, None.

To cite this abstract in AMA style:

Schnappauf O, Stoffels M, Aksentijevich I, Kastner DL, Grayson PC, Cuthbertson D, Carette S, Chung SA, Forbess LJ, Khalidi NA, Koening CL, Langford C, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Seo P, Springer J, Sreih AG, Warrington KJ, Ytterberg SR, Merkel PA. Screening of Patients with Adult-Onset Idiopathic Polyarteritis Nodosa for Deficiency of Adenosine Deaminase 2 [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/screening-of-patients-with-adult-onset-idiopathic-polyarteritis-nodosa-for-deficiency-of-adenosine-deaminase-2/. Accessed .

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