Leukocyte adhesion deficiency type 1 (LAD1) is caused by pathogenic variants in the ITGB2 gene, which encodes the CD18 subunit of b2 integrins. Defective neutrophil adhesion and migration results in predisposition to infection, periodontitis, and excessive inflammation. Inflamed tissues exhibit an IL-23 and IL-17 signature, and blockade of this pathway with ustekinumab has twice been reported as an effective adjunct therapy in LAD1 patients with severe skin and periodontal lesions
We describe clinical and biochemical response of 3 patients from two families with LAD1 treated with ustekinumab. Family 1 included three affected children, two females and one male, aged 4, 2, and 3 months old, respectively. The eldest child presented with recurrent infections, periodontitis, and neutrophilia. CD11b and CD18 expression on neutrophils was absent, and genetics confirmed a homozygous missense mutation in the ITBG2 gene for all three children. Both girls had significant periodontitis with marked gingival recession prior to commencing ustekinumab. Family 2 included a single female diagnosed with LAD1 at 6 years old, following a suspected subcapsular splenic infection complicated by systemic hyperinflammation. This was against a background of long-standing poor wound healing and severe periodontitis. CD18 expression was absent, and genetics revealed compound heterozygous pathogenic variants in ITGB2. She was treated with corticosteroid therapy for her hyperinflammation and subsequently transitioned to ustekinumab and is currently planned for HSCT.
All three patients received ustekinumab subcutaneously with a dosing regimen of 0.75 mg/kg at weeks 0 and 4, then every 12 weeks thereafter. There was a significant improvement in the severity of periodontal disease and a reduction in inflammatory markers.
We demonstrate effective use of ustekinumab to treat inflammatory and dental complications in LAD1 patients. Questions remain regarding the long-term safety, including vaccination recommendations and infectious complications, particularly the risk of invasive fungal infections, given IL-23 has an important role upstream of Th17 lymphocyte activation.
