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Chronic Ulcerative Disorder (ex-CUS) with SES-ANA

Lorenzo Azzi1*
  • 1 University of Insubria, Department of Medicine and Surgery, Italy

A middle-aged female patient visited our dental clinic complaining of a chronic painful sensation in her mouth, which she described as burning. Oral examination revealed the presence of widespread erosive and ulcerative lesions surrounded by white hyperkeratotic striae resembling those of erosive OLP. The blood test results were negative, and histopathological analysis revealed the presence of lichenoid stomatitis. The patient was initially administered 0.05% topical clobetasol ointment for one month, but the lesions did not show any clinical signs of improvement. Due to the failure of topical corticosteroid therapy, systemic betamethasone followed by systemic prednisone in association with topical triamcinolone were prescribed, followed by systemic azathioprine and methotrexate, but the immunosuppressive therapy was not successful (Figure 1). It was interesting that the patient suffered of a lichen planus (LP) lesion on her left foot 13 years earlier; the surgical treatment of which resulted in loss of the nail on her hallux. The incisional biopsy in the oral cavity was repeated, and multiple biopsy specimens were collected. This time, fresh samples were also analysed by direct immunofluorescence (DIF). Haematoxylin and eosin staining confirmed the presence of lichenoid stomatitis, with an admixed sub-epithelial inflammatory infiltrate composed of lymphocytes and plasma cells (Figure 2A). The skin biopsy of the foot performed several years earlier was reviewed and showed lichenoid band-like inflammation with lymphocytes and plasma cells, closely resembling the inflammatory infiltrate detected in the oral cavity. Interestingly, DIF of the oral lesions revealed the presence of IgG antibodies against the nuclei of epithelial cells in the lower third of the epithelium (Figure 2B). Together, the clinical appearance of the disease, the low response to corticosteroid and immunosuppressive therapy, and the finding of specific antibodies in the lower third of the epithelium by DIF analysis led to the final diagnosis of Chronic Ulcerative Stomatitis (CUS). CUS is a painful chronic ulcerative process that occurs in the mouth but can occasionally be associated with skin lesions. CUS is defined as an immune-mediated disorder characterized by oral erosions and ulcers that are usually refractory to conventional treatments. This condition was originally described by Jaremko and Parodi as being similar to erosive oral lichen planus but associated with an antinuclear autoantibody mostly recognized as a specific immunological marker, i.e., stratified epithelium-specific antinuclear antibody (SES-ANA). CUS mainly affects middle-aged or older women, and it should be highlighted that the mean age at disease onset is usually different from the age at diagnosis, underlying a very common diagnostic delay in this disease. On local examination, such patients exhibit painful oral erosions and/or ulcers, which may sometimes appear non-specific. Other times, these ulcers may be indistinguishable from the typical lesions of erosive oral LP and be surrounded by white striae. The most common intraoral sites are the buccal mucosa, the gingiva and the tongue, even though the labial mucosa and hard palate may also be involved. Gingival lesions usually appear clinically in the form of desquamative gingivitis. Despite the name of CUS, extra-oral involvement is not uncommon, especially in the skin, even though some case reports described ocular manifestations. The histopathological findings of CUS are non-specific and could be misinterpreted as oral LP. Although non-specific chronic mucositis is reported in some cases, lichenoid stomatitis is described in the majority of oral cases. In contrast, all papers dealing with CUS have revealed the presence of a specific speckled deposition of IgG antibodies within the lower third of the epithelium (SES-ANA) in biopsy specimens, either mucosal or cutaneous. Another feature reported for several CUS samples is the deposition of fibrinogen, described as having a pattern similar to that of LP, i.e., fluorescence outlining the basement membrane zone (BMZ) with irregular extensions into the superficial lamina propria, yielding a shaggy appearance. Patient serum samples can be analysed also by indirect immunofluorescence analysis, the distinguishing feature of which is the presence of serum IgG antibodies specifically binding to epithelial nuclei within the basal layer in a speckled pattern. In this case, the use of epithelial substrates, such as monkey oesophagus and guinea pig oesophagus are recommended, while the classic HEp-2 substrate does not provide positive results. The CUSP antigen is an approximately 70 kDa protein with a cDNA sequence identical to that of ∆Np63α, a p63 isoform predominantly expressed in the nuclei of basal cells in the progenitor cell compartment of the stratified epithelium. There, it plays a critical role in the maintenance of epithelium integrity and homeostasis. The disrupted ∆Np63α activity may end in epithelial breakdown with poor healing manifesting clinically as non-healing ulcers and erosions, as suggested by a three-dimensional in vitro study of CUS reporting reduced expression levels of α6β4 integrins and hemidesmosome components after disruption of the basement membrane interface. However, the most troublesome feature of the disease is that CUS does not respond to corticosteroid therapy, both topical and systemic. Nevertheless, a very interesting feature is that it seems to respond to antimalarials: in fact, many authors have reported successful outcomes after treatment with hydroxychloroquine or related drugs. Jaremko was the first to describe remission in a patient who was erroneously diagnosed with lupus erythematosus. Another patient reported by Beutner showed unexpected improvement after taking antimalarials to prevent infectious disease during a journey in Africa. In our patient, systemic corticosteroid treatment was interrupted after diagnosis, and hydroxychloroquine was prescribed at a dosage of 400 mg/day. After one month, the ulcers were completely cleared from the oral mucosa and only thin, asymptomatic hyperkeratotic striae remained (Figure 3). After 1 year of treatment with hydroxychloroquine, the patient experienced only scattered, mild relapses during seasonal changes, but these relapses quickly resolved after the topical application of 0.05% clobetasol ointment. It can be affirmed that the therapeutic protocol of CUS consists of a combination of low doses of both antimalarial and corticosteroid drugs for a prolonged time. Based on the considerations described in this review, the term CUS appears inadequate for describing the disease and should be changed. For example, the term Chronic ulcerative disorder with SES-ANA (CUD) could be more adequate. In this context, it may be defined as oral CUD and/or cutaneous CUD, similarly to the well-established distinction between oral LP and LP. A detailed review of the topic, accompanied by the proposal of updated diagnostic criteria, has been accepted for publication on Oral Diseases on October 11th, 2018.

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References

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Keywords: Chronic Ulcerative Disorder, Chronic ulcerative stomatitis, SES-ANA, Direct immunofluorescence (DIF), Hydroxychloroquine

Conference: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.

Presentation Type: oral presentation

Topic: Oral Diseases

Citation: Azzi L (2019). Chronic Ulcerative Disorder (ex-CUS) with SES-ANA. Front. Physiol. Conference Abstract: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine.. doi: 10.3389/conf.fphys.2019.27.00076

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Received: 28 Nov 2018; Published Online: 09 Dec 2019.

* Correspondence: Dr. Lorenzo Azzi, University of Insubria, Department of Medicine and Surgery, Varese, Lombardia, 21100, Italy, marcomascitti86@hotmail.it