A Nascent Nasal Phenomenon

A 33-year-old woman presented to dermatology with a rash limited to her distal nose for approximately 6 years. Her medical history included childhood atopic dermatitis (AD), recurrent herpes labialis and Crohn disease (CD). Her CD was newly controlled with ustekinumab, commenced in the last year. Previous treatments for CD included 6-mercaptopurine, azathioprine and adalimumab. Adalimumab was commenced in 2012 and was continued until 2021, excluding a break for fertility treatment from 2016 to 2018. The onset of nasal rash occurred between 2018 and 2019. It flared monthly, often coinciding with a herpes labialis flare. She denied any recreational drug use or facial injectable treatments including fillers. On examination she had patchy scaly erythema and crusting affecting her nasal tip, nasal septum, alar sidewalls and columella (Figures 1-3). There was loss of the normal nostril contour with a cicatricial indentation present at the apex of the nasal soft triangle bilaterally. Clinically, she had herpes labialis on the left upper lip. Full skin examination was otherwise unremarkable. Blood testing showed normal inflammatory markers including CRP and ESR, and raised eosinophils (1 × 109/L; reference range 0.04–0.4 × 109/L). Herpes simplex virus type 1 (HSV-1) PCR from a nasal swab was negative, despite clinical signs of infection. Nasal bacterial swabs showed commensal species only. A 4 mm punch biopsy taken from the left nasal tip showed acanthosis, spongiosis and surface crust with a dermal mixed inflammatory infiltrate including lymphocytes, histiocytes and numerous neutrophils (Figure 4). There was focal ulceration and intraepithelial small abscesses. No features of granulomatous inflammation, cutaneous CD or lupus pernio were seen. Additionally, there was no evidence of HSV-1 infection, likely due to a delay in biopsy sampling and the initiation of antiviral therapy before tissue collection. This is a case of triangular nasal notch sign. This sign was first described in 2019 by Mesnard et al., [1] and to our knowledge, this is the only prior publication on this novel clinical sign. The group reported eight patients with CD exposed to TNF inhibitors presenting with a cicatricial triangular notch in the nasal soft triangle, preceded by nasal dermatitis. It was hypothesised that TNF inhibition specifically was implicated in the development of nasal dermatitis with scarring, and withdrawal of the anti-TNF led to symptom improvement. Similarly to these cases, our patient had CD, was exposed to the TNF inhibitor adalimumab, and presented with nasal dermatitis and cicatricial notching. A novel feature of our case, is the persistence of the patient's nasal dermatitis throughout a biologic-free period, and the association with herpes labialis. Biologics that neutralise TNF are amongst the most successful drugs for the treatment of a variety of inflammatory and autoimmune conditions and are widely prescribed. Paradoxically, these drugs however can induce or exacerbate inflammatory disorders, which can persist in up to one-third of patients even after withdrawal of the causative drug [2] The pathophysiology of TNF inhibitor-induced nasal dermatitis and the subsequent development of triangular nasal notch sign is not fully understood. It has been hypothesised that it is within the scope of paradoxical reactions, such as paradoxical psoriasis, eczema and lupus erythematosus, all of which are reported with this drug class [2] In this case, the patient's rash both clinically and histologically was eczematous. This suggests an altered local immunological signature precipitated by adalimumab. The rash had persisted on ustekinumab, an IL12/23 blocking agent, which limits downstream signalling of Th1 and Th17. This may favour a persistently dominant Th2 cutaneous signal which presents as an eczematous rash. We hypothesise that this alteration in cutaneous immune signatures may have secondary effects on the cutaneous microbiota. A Th2 dominant cutaneous immune profile facilitates a permissive environment for Staphylococcus aureus and HSV-1, which in turn act as secondary drivers of chronic inflammation, resulting in focal tissue damage at a susceptible site. This may partially explain why the eczematous rash observed is limited to the nose, as this site may act as a reservoir for these micro-organisms. Given the temporal association of nasal flares with herpes labialis, it is possible that episodes of HSV-1 involving the nasal tip contribute to at least some of the patient's flares. Clinical flares of eczema secondary to both bacterial and viral infections are well described [3] however an association with HSV-1 has not been previously reported in the context of triangular nasal notch sign. Prophylactic valaciclovir (500 mg once daily) was initiated to minimise further flares of HSV-1. Topical intranasal mupirocin and pulsed azithromycin (500 mg three times weekly) were introduced to reduce the burden of pro-inflammatory commensal bacteria, and the latter for its anti-inflammatory immunomodulatory properties [4, 5]. She was also treated with topical corticosteroids. Clinical improvement in the focal area of nasal inflammation was achieved with this regimen. This supports a role for modification of the local microbiome in this condition for its beneficial immunomodulatory effects. We encourage greater reporting of this phenomenon, to increase awareness amongst clinicians and to help identify the exact pathomechanism and optimal treatment. A.L. conceptualisation, writing (original draft); C.Q., L.M., N.L. and J.C. writing (review & editing). All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication. The authors declare no conflicts of interest. The authors have nothing to report.