Peripheral ulcerative keratitis associated with tralokinumab therapy: a case report and review of IL-13 inhibitor-associated ocular surface disease

Atopic dermatitis (AD) is a common skin condition reported to impact up to one-fifth of individuals during their lifetime, with variable prevalence and severity depending on climate and environment [10]. In developed countries, AD is diagnosed in up to 20% of children and 1–3% of adults [11]. While corticosteroids are the mainstays of AD management, they are only effective in around 20% of patients with moderate-to-severe disease, with treatment options limited by adverse effect such as skin atrophy, pigmentation changes, and hypothalamus-pituitary-adrenal axis suppression [12]. Immunomodulatory therapies have recently emerged as effective options in the treatment of moderate-to-severe AD, with conjunctivitis and other ocular surface disease being identified as the most common adverse events related to such treatment.

Peripheral ulcerative keratitis (PUK) is an inflammatory condition of the cornea that typically presents with perilimbal, crescentic inflammation of the corneal stroma. This inflammation can lead to breakdown of the overlying epithelium and progressive, collagenolytic thinning of the corneal stroma [13]. The peripheral cornea, unlike the avascular central cornea, has a robust vascular supply, allowing for deposition of cellular and molecular inflammatory mediators. Although the exact mechanism of PUK is not fully understood and involves a complex interplay of many factors, both cell-mediated and antibody-mediated immune activation have been implicated in pathogenesis, with inflammatory cells from limbal vasculature triggering complement activation and matrix-metalloproteinase-driven destruction of the corneal stroma [14‐16]. PUK may have local triggers including infectious, postsurgical, and traumatic etiologies or be an ocular manifestation of systemic autoimmune disorders, including rheumatoid arthritis, ANCA vasculitides, collagen vascular disease, and inflammatory bowel disease. While autoimmune diseases are associated with more than half of PUK cases, with rheumatoid arthritis being the most common [13], there are increasing reports of ulcerative keratitis occurring in association with immune-modulatory biologics that alter cytokine levels and inflammatory pathways [17]. Our patient’s history of longstanding atopic dermatitis is itself a risk factor for PUK [18], as are other dermatologic conditions such as rosacea, mucous membrane pemphigoid, Stevens-Johnson syndrome, and psoriasis [16, 19]. However, this 61-year-old patient had suffered from atopic dermatitis all his life, with no prior history of any ocular manifestations of atopic disease before starting tralokinumab therapy. Given prior reports of ulcerative keratitis occurring in association with the IL-4 and IL-13 inhibitor dupilumab [2, 9], we hypothesize that the conjunctivitis and ocular surface inflammation known to be triggered by the IL-13 inhibitor tralokinumab may have been a contributing factor in this episode of PUK.

Dupilumab, an interleukin (IL)-4 and IL-13 binding monoclonal antibody (Ab), and tralokinumab-ldrm, an IL-13 binding monoclonal Ab, are human monoclonal IgG4 biologics that have demonstrated efficacy in the treatment of moderate-to-severe atopic dermatitis [1]. Although keratitis and conjunctivitis are more common in patients with atopic disease in general, treatment of atopic dermatitis with these monoclonal antibodies has been noted to worsen these ocular conditions or to trigger them in patients with no prior ophthalmic manifestations of atopic disease [20, 21].

A phase 2b study (NCT02347176) demonstrated development of conjunctivitis in 5.9% of patients treated with tralokinumab [22]. ECZTRA 1 and ECZTRA 2 were randomized, double-masked, placebo-controlled clinical trials where conjunctivitis was found to be the most common adverse ocular event seen with tralokinumab treatment. This was more common in the treatment group versus the placebo group, and only subjects receiving tralokinumab were diagnosed with keratoconjunctivitis affecting the corneal epithelium over the course of the trials [23]. In the double-masked, placebo-controlled phase 3 trial (ECZTRA 3), conjunctivitis was noted more in the tralokinumab treatment group (13.1%) than the placebo group (5.6%), though no patients required cessation of the medication [24].

Across numerous industry-sponsored clinical trials, conjunctivitis rates associated with dupilumab and tralokinumab range from 3 to 31% and 2–13% respectively.¹ Case series publications since the clinical launch of these medications have shown a higher proportion of conjunctivitis with dupilumab use, ranging from 43–69%,[4‐6,29] with these higher rates of ocular surface disease not being mirrored in the literature regarding tralokinumab. More severe ocular surface disease associated with dupilumab has also been reported, including conjunctival cicatrization, periocular skin changes, punctal stenosis, madarosis, peripheral ulcerative keratitis, and even corneal perforation.[2,4], 8‐9, 25−30] Per a review of PubMed, Google Scholar, and Cochrane Database performed on December 18, 2023, severe ocular surface disease beyond conjunctivitis has not been reported in association with tralokinumab therapy.

Although the pathogenic mechanisms of dupilumab and tralokinumab-associated ocular surface disease is not fully elucidated, it had been shown that inhibition of IL-13 prevents conjunctival goblet cells from being activated, inducing goblet cell hypoplasia and reduced mucin secretion [31, 32]. This, in turn, decreases tear film stability and may lead to conjunctivitis via increased surface friction and disruption of the mucosal-epithelial barrier. Barnett et al. [31] has demonstrated mucin deficiency in patients using dupilumab, while Bakker et al. [32] has documented a paucity of conjunctival goblet cells along with increased T-cell and eosinophilic infiltrates in conjunctival biopsies of AD patients diagnosed with dupilumab-associated conjunctivitis. This combination of mucosal-epithelial breakdown and T-cell infiltration provides an environment primed to cascade into keratitis and potentially corneal stromal ulceration.

While there are no current standards for the management of dupilumab and tralokinumab-associated ocular surface disease, many such cases of conjunctivitis are easily managed with topical medications, and cessation of monoclonal antibody therapy is rarely necessary [1]. Counseling and anticipation of potential ocular side effects is important, as is close communication between prescribing dermatologists or allergists and ophthalmic providers. Mild conjunctivitis can be managed using aggressive lubrication and topical antihistamine/mast cell stabilizer drops. In moderate-to-severe conjunctivitis, adding anti-inflammatory therapies such as corticosteroids (prednisolone 1%, fluoromethalone 0.1%), calcineurin inhibitors (cyclosporine 0.05-2%, tacrolimus 0.03–0.1%), or lifitigrast can be highly effective to achieve and maintain inflammatory control [33‐36]. More severe forms of ocular surface disease, or those that cannot be controlled with safe dosing of topical anti-inflammatories, may require reduced dosing or cessation of monoclonal antibody therapy [26, 37].

Both dupilumab and tralokinumab are effective and increasingly popular in the management of moderate-to-severe AD. While the literature shows high rates of conjunctivitis and reports of more severe ocular surface disease occurring in association with dupilumab, this has not previously been described with tralokinumab. However, while the underlying pathogenesis for such adverse ocular events is not clear and likely involves both drug-specific effects as well as a predisposition related to AD and/or pre-existing ocular disorders, the most likely underlying mechanisms for drug-induced ocular inflammation are secondary to IL-13 inhibition, which is common to both medications. This case documents the first known report of ulcerative keratitis in association with tralokinumab in a patient with no rheumatologic history and no previously-known ocular surface disease. It highlights the need for both ophthalmologists and prescribing dermatologists/allergists to counsel patients carefully with respect to these medications, to treat early IL-13 inhibitor-associated ocular surface inflammation aggressively, and to be wary of potential progressive keratitis in patients receiving these therapies.