Israel Medical Association Journal

Background: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disorder caused by loss-of-function mutations in the ADA2 gene, with a broad phenotype spanning systemic vasculitis, hematologic, immune deficiency, and autoinflammatory manifestations.

Objectives: To describe a decade of DADA2 management within a uniquely diverse population.

Methods: We conducted a single-center retrospective cohort study of genetically confirmed DADA2 patients (2014–2024). Demographics, clinical manifestations, laboratory findings, treatments, and long-term outcomes were reviewed.

Results: Seventeen pediatric patients were included from two ethnic groups: Arab Muslim (12/17, 70%) and Georgian Jewish (5/17, 29%). The median age at symptom onset was 3.5 months and at diagnosis 4 years. Phenotypes were purely vasculitic/inflammatory (5/17), purely hematologic (3/17), mixed hematologic-inflammatory (6/17), or mixed hematologic-immunodeficiency (3/17). None had isolated immune deficiency. The purely vasculitic/inflammatory phenotype was confined to Georgian Jewish patients, all homozygous for p.Gly47Arg, presenting with cutaneous and ischemic manifestations. Twelve patients received TNF-α inhibitors: 9 achieved complete response, 1 partial, and 2 none, with no subsequent strokes. Arab patients more often presented with fever, red cell aplasia, cytopenias, and immunodeficiency at younger ages. Three patients underwent hematopoietic stem cell transplantation (HSCT). Two responded favorably, one died of infection-related complications after engraftment.

Conclusions: We observed a distinct, ethnicity-driven genotype–phenotype correlation: Georgian Jewish patients with homozygous p.Gly47Arg had a pure vasculitic/inflammatory phenotype responsive to TNF-α inhibitors, whereas Arab patients harbored heterogeneous variants with hematologic/ immune deficiency phenotype potentially benefiting from HSCT. Early, genetically informed diagnosis and phenotype-driven, multidisciplinary management are essential to improve outcomes.

Lung involvement is a well-recognized extra-articular manifestation of ankylosing spondylitis (AS). Anecdotal reports suggest that the use of anti-TNF drugs may be related to lung disease and pulmonary fibrosis. To examine the association between anti-TNF drugs and the development of lung disease in patients with AS or  psoriatic arthritis (PsA) we conducted a systematic review. Of the 670 papers identified by means of key word and hand search, only one full-text paper was considered potentially relevant but had to be discarded as it did not meet the eligibility criteria. Although no conclusion was reached, this is the first systematic review to examine this problem which is becoming increasingly important as these drugs are widely prescribed in patients with spondyloarthritis.

Long-term extension studies and observational drug registers have revealed an increased risk of serious infections in patients treated with anti-tumor necrosis factor agents, particularly infliximab, etanercept and adalimumab. The same may be true for the newer biological drugs rituximab, tocilizumab and abatacept, although this has yet to be confirmed by long-term observational studies. We review the risk of tuberculosis, herpes zoster and other opportunistic infections, and the recommendations for screening for tuberculosis and hepatitis B and C infections in patients affected by rheumatoid arthritis, with the aim of informing patients and encouraging greater awareness among physicians.