Is inhaled glucocorticoids the only culprit in angina bullosa hemorrhagica?

Angina bullosa hemorrhagica (ABH) is an infrequent dermatosis characterized by acute onset of hemorrhagic bulla in the oral cavity. Clinical presentation of ABH may be quite worrisome, and clinicians often feel skeptical regarding their clinical diagnosis and lack confidence in managing this distinct entity. Indeed, ABH is a completely benign and self-limited disorder. The exact etiopathogenesis of ABH is still unknown. There have been reports in the literature addressing a central role for mechanical instability of the epithelial-connective tissue connection in the pathogenesis of ABH. Moreover, it has been claimed that long-term usage of inhaled glucocorticoids (GCs) is involved in the development of ABH, since most of the reported cases are asthmatic patients, who were treated with inhaled GCs, and GCs are well known for their degradative activities on collagen formation. Here, we describe a case with ABH, who had a drug history of inhaled GCs and nonsteroidal anti-inflammatory drugs (NSAIDs). We assume that our case not only supports the association of inhaled GCs with ABH but also suggests a possible role for NSAIDs in the pathogenesis of ABH.

Introduction

Angina bullosa hemorrhagica (ABH), which is also known as localized oral purpura stomatopompholyx haemorrhagica and recurrent oral hemophlyctenosis, is a self-limited, benign oral mucosal disorder.[12345678910] It goes back to 1960s when Badram first described clinical features of this condition and coined the term “angina bullosa hemorrhagica.”[11] ABH is a rare dermatosis with limited available data in the literature.[1234567891011] Here, we report a case with ABH, who presents typical clinical characteristics of this entity. We not only highlight distinctive clinical features but also discuss the possible roles of inhaled glucocorticoids (GCs) and nonsteroidal anti-inflammatory drugs (NSAIDs) in the pathogenesis of ABH.

Case Report

A 57-year-old female came to our outpatient department with a sudden onset blood-filled blister on her tongue. She had a medical history of gastritis and asthma, for which she was receiving inhaled GCs and proton-pump inhibitors. However, a detailed query revealed that she used to take NSAIDs for headache prevention and she had taken naproxen 550 mg twice daily on the previous day of admission. She told that identical lesions had developed almost exactly on the same localization three or four times before, all of which spontaneously ruptured after a short period of time and completely disappeared around a week. However, she did not recall whether she had taken NSAIDs before the eruption of these similar lesions. Oral mucosal examination of the patient revealed a hemorrhagic bulla on the right lateral border of the tongue [Figure 1]. Laboratory investigations including complete blood count and differential, prothrombin time, and activated partial thromboplastin time were within normal limits. Based on typical history, clinical and laboratory findings, we made a diagnosis of ABH. Due to benign nature of the disease, we did not consider to perform a lesional biopsy; in addition, the patient did not want any invasive procedure. The patient reassured about the nature of the disorder and taken under follow-up. At the 2-week appointment, it was discovered that the lesion was completely recovered.

Figure 1

A hemorrhagic bull about 1.5 cm × 1 cm in diameter on the right lateral border of the tongue

Discussion

ABH is characterized by acute onset hemorrhagic bulla in the oral cavity. The bulla is almost always solitary and the main localization is the junction of the hard and soft palate. On the other hand, the buccal mucosa, the lateral and ventral border of the tongue may be also affected. Typically blood-filled bulla bursts spontaneously in 24–48 h leaving superficial erosions that heal without scarring within 1 or 2 weeks. Initially, the intact bulla can be painful; however, after the rupture, the pain wanes. ABH has been reported to be seen more commonly in women with a peak incidence over the fifth decade. A unique feature of ABH is that the history of each occurrence is special and specific and identical for each patient.[12345678910]

The precise etiopathogenesis of ABH still needs to be elucidated. There have been factors implicated in the development of ABH. Among them, local factors (trauma, dental procedures, and endoscopy) and long-term usage of inhaled GCs for asthma are mostly appreciated ones. It has been suggested that a mechanical instability of the epithelial-connective tissue connection, which may induce a susceptibleness of the nonkeratinized mucosa to damage, is the primary pathogenetic mechanism in this disorder.[12345678910] We also agree on these presumed etiological factors and suggest that an explanation lies in understanding the morphology and cellular dynamics of the human skin.

It is well known that cutaneous atrophy is one of the utmost primary adverse effects of topical GC therapy. On the skin, long-term usage of topical GCs is associated with atrophic changes, characterized by an extensive increase in transparency of skin, rupturing, and bruising.[12] The physiopathology of skin atrophy induced by topical GCs involves the synthesis of lipocortin protein that suppresses the activity of phospholipase A2 (PLA2). As a result of the inhibition of PLA2, because of reduced release of arachidonic acid (AA), the inflammatory process is inhibited, but also mitotic activity and protein synthesis are impaired.[13] AA is also involved in the coagulation cascade. Free AA is a precursor for thromboxane A2, which is a dominant vasoconstrictor and inducer of platelet aggregation. Therefore, reduced release of AA leads to inactivation of the coagulation cascade.[14] Considering all these data, we suggest that long-term inhaled GC therapy is the main triggering factor in our patient. However, we appreciate the possible additive etiologic potential of NSAIDs, since NSAIDS are inhibitors of cyclooxygenase, the enzyme which mediates the bioconversion of AA to prostaglandins and thromboxanes. It is well known that NSAIDs have antiplatelet properties.[1516]

The most essential differential diagnosis of ABH comprises vesiculobullous diseases including pemphigus vulgaris, bullous pemphigoid, oral bullous lichen planus, and acquired epidermolysis bullosa, also blood dyscrasias.[17] The laboratory investigations of our patient were completely normal, and we did not detect any clinical signs of hematological diseases; thus, we ruled out blood dyscrasias. The characteristic solitary oral lesion without any other cutaneous finding apparently pointed to the diagnosis of ABH. Our patient did not have any other dermatological manifestation that suggests diseases included in the differential diagnosis.

The diagnosis of a ABH is essentially clinical. Symptomatic treatment is sufficient in these patients, and indeed no further evaluation and treatment are necessary. The most important responsibility is the reassurance of the patient. Awareness of this entity is very important to avoid misdiagnosis and unnecessary diagnostic procedures.[12345678910] In our opinion, ABH is one of the most peculiar diseases of dermatology practice. This case report highlights the underlying pathophysiology and clinical presentation of ABH. We assume that ABH is a multifactorial phenomenon and concomitant usage of inhaled GCs, and NSAIDs are the causative factor in our patient. On the other hand, causality assessment based on Naranjo Algorithm probability scale [18] showed that the drug-induced effect of NSAIDs in ABH is possible (score 2). We suggest that the reason for the low score is that the patient could not recall any association of NSAIDs intake with previous occurrences of ABH. As far as we know, there is not any other report in the literature describing a causal relationship of NSAIDs with ABH. Further case reports are needed to demonstrate typical clinical features of this uncommon disorder and to elucidate possible roles of inhaled GCs and NSAIDs in the pathogenesis of ABH.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.