Orofacial Granulomatosis Treated With Combination of Intralesional Steroids and Hydroxychloroquine

Orofacial granulomatosis (OFG) is an uncommon granulomatous inflammatory condition characterized by recurrent or persistent swelling of the orofacial soft tissues, oral ulcerations, gingivitis, and/or cheilitis.^1,2 Treatment of OFG can be challenging due to limited evidence regarding therapeutic benefit of many documented treatments.¹ As discussed in this case report, combination therapy may be necessary for effective management of this disorder.

A 39-year-old female patient complained of painless, spontaneous, upper lip swelling that occurred over the course of 2 years. She reported the lip swelling initially occurred monthly and would subside after about 12 hours. The swelling had become persistent during the past year. The patient had been evaluated by an allergist and an otolaryngologist and completed a 3-month course of cetirizine 10 mg daily and ranitidine 600 mg daily without benefit. Medical history was significant for postural orthostatic tachycardia syndrome and allergic rhinitis. Medication included 1.5 mg to 30 mg of Loestrin^® daily. Review of systems revealed diaphoresis, shortness of breath when exercising, occasional heart palpitations, intermittent dry cough, sporadic left-side pleuritic-type chest pain, and two pre-syncopal episodes. Clinical examination revealed significant swelling of the upper lip with scattered erythematous papules and crusted epithelium (Figure 1) and a localized, slightly raised lesion on the maxillary anterior gingiva (Figure 2).

Allergy patch testing, including dental materials was negative. Antineutrophil cytoplasmic antibody level, angiotensin-converting enzyme, and C1 esterase inhibitor were within normal limits. Chest x-ray was unremarkable. An incisional biopsy of maxillary gingival tissue revealed numerous granulomas composed of epithelioid histiocytes admixed with multinucleated giant cells and a diffuse infiltrate of lymphocytes and plasma cells (Figure 3). Periodic acid Schiff, Gomori methanamine silver stain, and acid fast bacilli stain did not reveal any fungal or mycobacterial organisms.

On the basis of the histological findings, OFG, sarcoidosis, and Crohn's disease were primarily considered in the differential diagnosis. Esophagogastroduodenoscopy, colonoscopy, and capsule endoscopy did not reveal evidence of inflammatory bowel disease. Ophthalmalogic examination did not reveal signs of ocular involvement of sarcoidosis. Myocardial positron emission tomography (PET) and computed tomography (CT) scans were performed due to cardiac symptoms and did not reveal evidence of myocardial inflammation suggestive of cardiac involvement of sarcoidosis. The patient was prescribed 200 mg of doxycycline daily for 6 weeks without benefit. Intralesional injections of 0.3 mL of sterile aqueous suspension providing 3 mg of triamcinolone (10 mg/mL) to the upper lip were performed every 8 weeks for 6 months. In addition, 400 mg of hydroxychloroquine daily was prescribed. The patient experienced significant improvement with this treatment combination (Figure 4).

OFG is an uncommon granulomatous inflammatory condition characterized by recurrent or persistent swelling of the orofacial soft tissues, oral ulcerations, gingivitis, and/or cheilitis.^1,2 The precise etiology of OFG is unknown, with genetic, immunologic, environmental, and infectious etiologies suggested.^1-3 Allergic reaction to dietary additives, oral hygiene products, and dental materials has also been discussed as a possible cause of OFG.¹ Histologically, OFG is typically characterized by formation of noncaseating granulomas and infiltration of inflammatory cells. Since granulomatous inflammation is not constantly observed, the absence of noncaseating granulomas in microscopic analysis does not exclude the diagnosis.^1,4

Systemic granulomatous disorders, including sarcoidosis and Crohn's disease, may resemble OFG. Additional diagnostic studies may be needed to exclude granulomatous conditions with similar features.^3,4 These studies include a skin patch test to rule out an allergy, chest radiography to evaluate for findings seen in sarcoidosis and tuberculosis such as hilar adenopathy, special immunohistochemistry stains of tissue to rule out microbial organisms, and endoscopy if granulomatous inflammatory bowel disease is suspected.¹

Non-granulomatous causes of lip swelling may include angioedema. Angioedema refers to localized edema of the soft tissues commonly involving the orofacial region.⁵ Most cases result from allergic etiologies, but non-allergic angioedema can result from a range of mechanisms.⁵ Allergic angioedema is thought to be mast cell-mediated or immunoglobulin E (IgE)−mediated, whereas non-allergic angioedema is believed to be bradykinin-mediated.^5-6 Foods and medications, among other agents, can trigger angioedema through histamine production in persons with IgE-mediated hypersensitivity.⁶ Non-allergic angioedema includes acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitors, idiopathic non-histaminergic acquired angioedema (InH-AAE), acquired C1 inhibitor deficiency (C1INH-AAE), and hereditary angioedema.⁶ Angioedema associated with ACE inhibitors usually affects females around the age of 65 years and occurs shortly after starting ACE-inhibitor medications.⁶ Idiopathic non-histaminergic angioedema typically affects young adults. The symptoms last for less than 48 hours but frequently reoccur.⁶ Angioedema related to acquired C1-INH deficiency is commonly associated with hematological conditions, such as lymphoma and multiple myeloma, and the level of C1-INH is usually low in laboratory studies.⁶

Treatment of OFG can be challenging due to limited evidence regarding therapeutic benefit of many documented treatments.¹ Topical treatments using corticosteroids and tacrolimus may be used for mild cases.^1,7 Intralesional triamcinolone acetonide in a dose of 10 mg/mL is considered an effective and safe therapy, manifesting fewer side effects than systemic corticosteroids.^1,7 Antimicrobial therapy, including doxycycline, minocycline, and azithromycin, has been used to treat OFG with variable results.^1-7 Immunosuppressive treatments have been used with inconsistent results; these include hydroxychloroquine, mycophenolate mofetil, dapsone, and azathioprine, as well as tumor necrosis factor-alpha inhibitors such as infliximab and adalimumab.^1-7 Combination therapy may be necessary for effective management of OFG.

The diagnosis of OFG can be challenging to oral healthcare providers due to the overlap of its clinical and histological features with several systemic diseases. Systemic granulomatous diseases and allergic reactions should be ruled out when OFG is suspected. Additionally, a gingival biopsy can be beneficial in the diagnosis of OFG. The use of more than one therapy is sometimes needed to achieve the desired result in the medical management of OFG.

Mohammed A. Bindakhil, DDS, MS
Assistant Professor, Department of Oral Biology and Diagnostic Sciences, Division of Oral Medicine, Dental College of Georgia, Augusta University, Augusta, Georgia

Eric T. Stoopler, DMD
Professor of Oral Medicine, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania

Faizan Alawi, DDS
Associate Dean for Academic Affairs, Division of Oral and Maxillofacial Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania

Thomas P. Sollecito, DMD
Professor and Chairman, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania