INTRODUCTION

Ulcerative colitis is a long-term inflammatory condition that affects the colon. Current therapies are often limited by heightened risks of infection, cancer, and diminishing clinical effectiveness [1].

Ustekinumab is a fully human monoclonal antibody designed to inhibit the activity of interleukin-12 and interleukin-23 by targeting their shared p40 subunit. It has been widely approved for managing several immune-mediated conditions, including ulcerative colitis, Crohn’s disease, psoriasis, and psoriatic arthritis [2].

Although ustekinumab shows to be promising as a therapeutic option for other conditions, additional clinical data is necessary to fully evaluate its safety and efficacy.

In this report, we describe a unique case of a localized ichthyosiform drug eruption occurring in a patient receiving ustekinumab therapy.

CASE REPORT

A male in his sixties, diagnosed with severe ulcerative colitis seven years ago, was referred to our department for evaluation. Over the previous years, he had undergone treatment with a range of conventional anti-inflammatory medications, including non-steroidal anti-inflammatory drugs (NSAIDs), mesalazine, and immunomodulators such as corticosteroids and azathioprine. Despite these treatments, his condition remained poorly controlled, leading to corticosteroid dependency. As a result, TNF-a inhibitor therapy (infliximab) was administered for over three years yet proved unsuccessful. Consequently, ustekinumab therapy was initiated.

Approximately three months after starting ustekinumab, the patient developed acquired ichthyosis affecting his legs (Fig. 1a). A dermatological examination revealed thickened, shiny, plate-like patches with extensive scaling on both lower extremities (Fig. 1b). Additionally, the patient experienced severe generalized xerosis and reported intense pruritus, which worsened following ustekinumab injections.

Figure 1: a) Acquired ichthyosis developed in both lower limbs of the patient three months after initiating treatment with ustekinumab. b) Higher magnification showing thickened and scaly patches.

The physical examination was otherwise unremarkable, with no signs of organomegaly or superficial lymphadenopathy. Based on the clinical findings, the differential diagnosis included ichthyosiform mycosis fungoides and drug-induced acquired ichthyosis secondary to ustekinumab.

A skin biopsy of the affected areas showed histological features consistent with lamellar ichthyosis, including compact ortho-hyperkeratosis with focal parakeratosis, a reduced granular cell layer, and a band-like lymphohistiocytic infiltrate. The pharmacovigilance assessment strongly implicated ustekinumab as the likely cause of the adverse reaction.

Topical urea and topical retinoids were poorly tolerated due to secondary xerosis, skin cracking, and fissuring. However, moderate improvement was achieved with petrolatum/lanolin ointment, allowing the patient to continue ustekinumab therapy without further complications.

DISCUSSION

Ichthyosis encompasses a group of cutaneous disorders, either inherited or acquired, characterized by abnormal keratinization. Acquired ichthyosis may occur before or alongside various systemic diseases or as an adverse drug reaction [3].

This condition typically manifests as pruritus and xerosis, accompanied by fine, flaky scales affecting the extensor surfaces of the legs and back without a familial history of ichthyosis or atopic disease. The spectrum of associated diseases is broad and diverse, including cancers, hematological malignancies, infections, hormonal imbalances, autoimmune diseases, granulomatous diseases, severe malnutrition, vitamin A deficiency, and chronic kidney disease [3]. The most common malignancy associated with acquired ichthyosis is Hodgkin’s lymphoma [4].

Drug-induced acquired ichthyosis is a rare phenomenon that may be caused by various medications, such as statins, isoniazid, acitretin, butyrophenones, dixyrazine, maprotiline, cimetidine, allopurinol, hydroxyurea, and clofazimine [4,5].

In the literature, about 8% of acquired ichthyosis cases have been attributed to drug-induced reactions, which generally develop within weeks to months after starting the medication and tend to resolve once the drug is discontinued or its dosage is reduced [4].

Clinically, acquired ichthyosis often resembles ichthyosis vulgaris, presenting with pruritus and xerosis accompanied by fine, white-to-brown flaky scales, typically affecting the extensor surfaces of the lower legs and the back. Histologically, acquired ichthyosis shares features with ichthyosis vulgaris [5].

Instances of drug-induced acquired ichthyosis are sporadically reported in the literature and have been documented across various medical specialties beyond dermatology, leading to potential misdiagnosis of this condition.

In the safety assessment conducted during the induction trial of ustekinumab involving 961 cases of moderate-to-severe ulcerative colitis, various side effects have been reported: nasopharyngitis, headache, anemia, influenza, opportunistic infections, cancers, and cardiovascular events [1]. To the best of our knowledge, no cases of ichthyosis linked to ustekinumab therapy have been reported to date.

The treatment approach of acquired ichthyosis focuses on symptomatic relief through emollients, keratolytics, retinoids or corticosteroids, and in rare instances, oral retinoids.

CONCLUSION

Drug-induced ichthyosis presents considerable diagnostic and therapeutic challenges due to its visible and symptomatic presentation, potentially requiring dosage adjustments or the discontinuation of the causative treatment.

To our knowledge, this case represented the first reported instance of acquired ichthyosis attributed to ustekinumab therapy.

REFERENCES

1.Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381:1201-14.

2.Stelara (ustekinumab) for intravenous and subcutaneous use. Horsham, PA:Janssen Biotech;2017 Oct. (package insert). Available from:https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761044lbl.pdf

3.Kouismi H, Bourkadi JE, Iraqi G. Cutaneous ichthyosis secondary to isoniazid. Egypt J Chest Dis Tuberc. 2013;62:353-5.

4.Haber R, Feghali J, Nadir U, Yi MD, Cahn BA. Acquired ichthyosis:A clinical review. Arch Dermatol Res. 2023;315:2529-43.

5.Souissi A, Smoller B, Bagherani N. Disorders of keratinization. In:Smoller B, Bagherani N, editors. Atlas of Dermatology, Dermatopathology and Venereology. Cham:Springer;2021.