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Science in the News

A Recent Case Report Describes Off-Label Use of a Biologic Agent to Modulate the Inflammatory Response in a Rare Primary Immunodeficiency that Manifests with Severe Periodontal Disease

May 05, 2017 Leukocyte adhesion deficiency type 1 (LAD1) is a rare (i.e., affecting 1 in 1 million individuals) autosomal recessive primary immunodeficiency characterized by life-threatening, recurrent bacterial infections of the skin, mouth, and respiratory tract.1 LAD1 is caused by mutations in the ITGB2 gene (21q22.3), encoding the beta-2-integrin, CD18, which is essential for firm adhesion of leukocytes to the endothelium; disease severity correlates with the degree of CD18 deficiency. Prognosis depends on the severity of the disease. Without hematopoietic stem-cell transplantation, patients with the severe form of the disease will generally die of infection within the first 2 years of life; whereas, patients with a more moderate form of the disease have a better chance of surviving into adulthood with effective infection management, including antibiotics.  However, in people with less severe forms of the disease, severe periodontitis is often present later in life and leads to early tooth loss.1  The mucocutaneous lesions in LAD1 had been assumed to be due to infections that were a result of the relative tissue neutropenia caused by the inability of LAD1 neutrophils to enter tissues and control microbes.2 However, research has shown that LAD1-associated oral disease is actually a hyperinflammatory tissue response to oral microbes.2  LAD1 periodontal lesions have a strong interleukin-23–interleukin-17 signature, which stimulates local immunopathologic processes and bone resorption. A recent case report2 by Moutsopoulos et al. published in the New England Journal of Medicine describes a patient with LAD1, severe periodontitis, and a deep, nonhealing sacral wound, and who was treated with an FDA-approved novel biologic interleukin subunit antibody used in an off-label fashion.

A 19-year-old man with LAD1 and a history of prior systemic infections (e.g., urinary tract, skin, pneumonia) presented for evaluation of severe periodontal disease.2  His recurrent oral ulcers had been treated with systemic glucocorticoids and acyclovir. Severe periodontitis began in his early teens, and he had been advised to have his teeth extracted. He also had a chronic sacral wound that had progressed despite treatment.  After 4 months of standard-of-care treatments, including deep dental cleanings and wound management, he still had oral ulcers and persistent, severe oral inflammation (approximately 90% of gingival areas bled on probing); the sacral wound was unchanged. Gingival tissue biopsy revealed dense lymphocytic infiltrates with intense interleukin-17 staining.  Ustekinumab (Stelara®, Janssen) is a monoclonal antibody approved for use by the U.S. Food and Drug Administration for treatment of psoriasis, psoriatic arthritis, and moderate-to-severe Crohn’s disease.  The biologic inhibits interleukin-12 and interleukin-23 signaling and, thereby, the downstream interleukin-17 proinflammatory response.  Researchers administered ustekinumab off-label using the dosing regimen approved for psoriasis.  After 1 year of therapy, the patient had resolution of his inflammatory oral and sacral lesions without serious infections or adverse reactions.

In a related editorial,3 Dr. Klaus Ley states, “…Moutsopoulos et al. report an important discovery and medical advance that has the potential to meaningfully improve the management of LAD1 and perhaps other forms of leukocyte adhesion deficiency,” and “This remarkable case report suggests that blocking the interleukin-12–interleukin-23–interleukin-17 axis may benefit patients with LAD1.”

References

  1. Orphanet (version 5.03.1). Leukocyte adhesion deficiency type I. Accessed May 3, 2017.
  2. Moutsopoulos NM, Zerbe CS, Wild T, et al. Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1. N Engl J Med 2017;376(12):1141-46.
  3. Ley K. Breaking a Vicious Cycle. N Engl J Med 2017;376(12):1172-74.

Prepared by: Center for Scientific Information, ADA Science Institute

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