Gingival hyperplasia as first sign of recurrence of granulomatosis with polyangiitis (Wegener’s granulomatosis): case report and review of the literature

GPA, formerly referred to as Wegener’s granulomatosis, is a rare, systemic disease of unknown etiology characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis and vasculitis [1]. Moreover, nasal deformations with saddle nose manifestation, sinusitis and ulceration of the palate or nasal mucosa are not extraordinary in GPA. General GPA can affect all areas of the body, including the oral cavity [2, 3]. In European Union countries, any disease affecting less than one person in 2.000 is considered “rare” [4]. GPA has a prevalence of 1–9/100.000 and therefore is listed as a rare disease [5]. About 5.000 rare diseases are of genetic origin and approximately 15 % of these present manifestations at the orofacial region [6]. Oral symptoms in GPA have been reported in 10–62 % [7]. The typical oral manifestations occur as nonspecific erosive/ulcerative lesions of oral cavity or appear with hyperplastic gingivitis, a so-called “strawberry gingivitis”. GPA can affect patients at any age, whereas diagnosis is mostly done when patients range between 40 and 55 years of age. The disease is more common in Caucasians and no gender-specific differences were identified [8]. The pathogenetic cause of GPA is mediated by a T-cell reaction leading to the production and release of pro-inflammatory cytokines like TNF-α and IFN-γ which induce the expression of surface antigens on activated neutrophil granulocytes. One of these antigens is proteinase 3 which is the target of antineutrophil cytoplasmatic antibodies (c-ANCA). This interaction leads to degranulation of neutrophil granulocytes which release proteases and effector molecules being responsible for the tissue damage [9]. Generally, the clinical manifestation of the disease varies from patient to patient. Rapid progression in combination with multiorgan failure will lead to death if untreated [10]. Two types of GPA are known: diffuse forms, manifesting primarily by renal and pulmonary contribution and localized forms, limited to the upper respiratory tract. Localized forms are in contrast to diffuse forms more recurrent while diffuse forms are initially more fatal but less recurrent [11, 12]. A transition from limited to localized GPA and the other way around is possible [12]. Since the disease develops over an extended period of time, it usually takes 4.7–15 months from the beginning of the symptoms to the diagnosis [8]. The American College of Rheumatology proposes that for the diagnosis of “GPA” two or more of the following criteria have to be fulfilled: (1) ulcerative lesions in the oral mucosa or nasal bleeding or swelling, (2) nodules, infiltrates or cavities on chest radiograph, (3) abnormal urinary sediment, or (4) granulomatous inflammation on biopsy [13]. Here, we report about an extremely rare case with gingival hyperplasia as the first sign of recurrence of GPA in the absence of oral manifestations in the primary disease.

A 72 year-old female was transferred to our Department of Cranio-Maxillofacial Surgery at the University Hospital of Münster with a hyperplastic gingivitis and intraoral pain in October 2015.

Cases of GPA with oral symptoms were described in several reports [2, 3, 7, 14‐18]. However, a systematic search in PubMed generated by “granulomatosis with polyangiitis, Wegener’s granulomatosis, gingivitis, recurrent, recurrence” indicated only one report describing the recurrence of GPA without any oral symptoms in the initial presentation of the disease reported by Staines et al. [14]. Comparable to our case, gingival hyperplasia was evident only on recurrence in this single reported case. The standard therapy of initial GPA consisted of glucocorticoids or cyclophosphamide, or a combination of both [19]. Although standard therapy does improve the survival rate of the patients, there are also therapy-related malignancies like squamous cell carcinoma, Kaposi sarcoma or basal cell carcinoma which was also applicable to our patient [20]. In contrast to the standard therapy of initial GPA, there are reports of successful treatment of refractory head and neck GPA with rituximab [14]. Rituximab is a chimeric, monoclonal antibody targeting the CD20-antigen expressed by B-cells. Successful treatment with rituximab leading to full remission is reported in 62 % of all treated patients by Martinez et al. [21]. About 15 % of all rare diseases show orofacial manifestations [6, 22]. Typical oral manifestations in GPA are unspecific erosive lesions in the oral mucosa or hyperplastic gingivitis as reported here. Differential diagnosis for the gingival enlargement could be caused by medications [2] (such as phenytoin, cyclosporine and some oral contraceptives), other granulomatous diseases like sarcoidosis and Crohn’s disease or blood dyscrasia like leukemia [7]. Since oral lesions can be localized a long time before multiorgan involvement actually occurs [15], the often overlooked oral manifestation may be interpreted as the first sign of GPA and could be pathognostic for the disease. Histopathological pattern of GPA include granulomatous inflammation, vasculitis, necrosis and multinucleated giant cells. Often, however, histopathological findings are less specific and cannot be considered as clinical diagnostics [16]. Furthermore, it is known that rare diseases with oral components benefit more from an early diagnosis than rare diseases without oral components [23]. Misdiagnosed oral manifestations which are often overlooked by physicans and by dentists may be interpreted as the first evidence of resurgent GPA in general and therefore could be pathognostic for the disease. A dental specialist has a high chance of identifying GPA based on the characteristics of the oral findings. Moreover, the dentist might be the first one being consulted by the patient with oral manifestations such as gingival hyperplasia. Gingival hyperplasia that is not associated with remission after periodontal therapy or with drug delivery should be investigated then with regard to internal diseases like GPA or leukemia. This example affirms why health professionals should be acquainted with orofacial manifestations of rare diseases such as GPA. As a consequence faster referrals to other medical specialists like rheumatologist, nephrologist, or pulmonologist will be possible and enable them to start with the treatment early on, on the one hand [17]. On the other hand, dentists may receive referrals from physicans for evaluating oral symptoms.

Overall, this case demonstrates an important role for the dentist in the early diagnosis of GPA. Instead of gingivectomy with conceivably fatal consequences, treatment of the underlying disease based on oral symptoms was performed. In conclusion, dentists should be acquainted with orofacial manifestations of rare diseases such as GPA, because they could be the first in detecting early symptoms of a rare disease. Thus, the dentist will be able to assist in the early diagnosis of this fatal rare disease more easily which is the most important factor in the management and prognosis for patients suffering from GPA or other rare diseases [18].

c-ANCA, antineutrophil cytoplasmatic antibodies; GPA, granulomatosis with polyangiitis