Hypopigmented mycosis fungoides-like eruption following ixekizumab treatment

Introduction

With increasing understanding of the immunopathogenesis of psoriasis, biologics targeting cytokines such as tumor necrosis factor, interleukin (IL)-17, and IL-23 have dramatically improved treatment of moderate-to-severe psoriasis. However, biologics are not without risk, including increased risk of serious infection. Whether biologics may affect the fine balance among different T-cell subsets and their clinical significance is not well understood. Cutaneous T-cell lymphoma (CTCL) following biologic therapy is rare, and the risk of developing CTCL in patients using biologics for psoriasis has not been well-characterized.1, 2, 3 CTCL development has previously been described in the setting of tumor necrosis factor inhibitors, IL-17 inhibitors, and IL-12/23 inhibitors, but not in the setting of IL-23 inhibitors.² Herein, we present a unique case of a 31-year-old woman with psoriasis who developed hypopigmented mycosis fungoides (HMF)-like eruption after treatment with an IL-17 monoclonal antibody, ixekizumab.

Case report

A 31-year-old woman with Fitzpatrick skin type II presented for treatment of psoriasis diagnosed in 2008. Previous treatments included the following: methotrexate (discontinued due to lack of efficacy), apremilast (discontinued due to history of depression), and ixekizumab started in May 2023. After 20 weeks of treatment with ixekizumab, her psoriasis was mostly clear. However, she developed expanding, asymptomatic hypopigmented patches on her forearms, distinct from the typical distribution of prior psoriatic lesions on the trunk, scalp, and ears. Examination revealed a 2.5-cm hypopigmented patch on the left forearm and a 1-cm hypopigmented patch on the right forearm (Fig 1). Wood’s lamp examination was equivocal.

Fig 1.

Cutaneous examination of the left dorsal forearm (left) and right dorsal forearm (right) showing hypopigmented patches 20 weeks into treatment of psoriasis with ixekizumab.

Punch biopsy of the left forearm revealed hyperchromatic lymphocytes present at the dermo-epidermal junction and found extending into the epidermis (Fig 2). Lymphocytes in the epidermis demonstrated a predominance of CD8+ cells, with a CD4:CD8 ratio of 1:8 (Fig 3). High-throughput sequencing for evaluation of T-cell receptor clonality revealed one dominant T-cell receptor-gamma sequence. Clinicopathologic correlation based on epidermotropism of atypical lymphocytes on histology with an abnormal CD4:CD8 ratio and the presence of a monoclonal T-cell population suggested a possible diagnosis of hypopigmented CTCL, but a lymphomatoid drug reaction cannot be excluded.

Fig 2.

Histologic examination shows epidermotropism of hyperchromatic lymphocytes.

Fig 3.

Immunohistochemical staining for CD4 (A) and CD8 (B) demonstrating an abnormal CD4:CD8 ratio of 1:8.

Ixekizumab was discontinued. The hypopigmented patches were treated with topical corticosteroids and gradually reduced in size and appearance. No new lesions were identified on follow-up. After discontinuation of ixekizumab, psoriasis eventually recurred, prompting treatment initiation with risankizumab.

Discussion

We describe the case of an HMF-like eruption in a 31-year-old woman with psoriasis. HMF is an uncommon variant of mycosis fungoides (MF) consisting of hypopigmented patches mainly distributed on the trunk, limbs, and buttocks.⁴ HMF most commonly affects children with darkly pigmented skin (Fitzpatrick skin type IV-VI).⁴ Timely diagnosis relies on early recognition with a high level of suspicion and biopsy for histology, immunohistochemistry staining of T-cell subpopulation, and T-cell receptor clonality analysis, if necessary. Diagnosis should involve clinicopathologic correlation, with skin biopsy often revealing epidermotropism of atypical CD8+ lymphocytes.⁴ The interval from disease onset to diagnosis can range from months to several years; latency in diagnosis presents one of the greatest challenges, as this increases the risk of progression to more advanced stages.⁴ Additionally, HMF is frequently misdiagnosed as vitiligo, tinea versicolor, pityriasis alba, or other pigmented disorders.⁴ Despite this, HMF has a favorable prognosis with current treatment options, including psoralen with ultraviolet A, narrowband ultraviolet B, topical nitrogen mustard, topical carmustine, and total electron beam therapy.⁴ The etiology and pathogenesis of HMF are unclear and might be related to atypical lymphocytes causing damage at the dermo-epidermal junction leading to pigment incontinence.⁴ HTLV-1 virus has been suggested as a possible triggering factor.⁴

While no medications have been specifically reported to be associated with the development of HMF, there are reports of MF or MF-like reactions associated with biologics.^2,3,5

A systematic review identified 23 cases of CTCL associated with dupilumab.³ Prior case series have described dupilumab-associated lymphomatoid reactions (LRs) in patients with atopic dermatitis.¹ LRs may be mistaken for flaring or may mimic early-stage CTCL in both clinical symptoms and histopathologic findings.¹ LRs can be distinguished from flares as they appear as different morphologic skin lesions associated with burning or pain. LRs are further distinguished from CTCL by no loss of pan-T-cell markers (CD2, CD3, and CD5) and the presence of small cerebriform lymphocytes in the upper epidermal section, whereas lymphocytes in early-stage MF are lined up in the basal layer of the epidermis.¹ Another systematic review identified 38 cases of CTCL in the setting of psoriasis biologic treatment.² The majority of the CTCL cases reported (34/38) were associated with TNF inhibitors.² There have been 2 cases of classical and erythrodermic MF after starting the IL-17 monoclonal antibody secukinumab.⁵ It is challenging to establish the true risk of CTCL related to biologics. Many patients have undergone multiple systemic therapies longitudinally, and there is no clear understanding whether psoriasis is associated with an increased risk of CTCL. Additionally, there is no consensus on whether these biologic-related MF cases represent true MF cases or MF-like LRs since both share similar clinical and pathologic presentations.

Determining causation in our case is challenging, particularly given the absence of prior lesions in the areas affected by HMF-like lesions, rendering histologic evaluation impossible initially. The patient's extensive medical history, confirmed by biopsy and positive responses to systemic psoriasis-targeted biologic therapy, strongly suggests the diagnosis of psoriasis. The localization of HMF-like lesions to sites not previously affected by psoriasis suggests a novel development rather than a misdiagnosis or extension of existing psoriasis. Furthermore, upon discontinuation of ixekizumab, the patient’s HMF-like lesions slowly resolved, but she experienced a typical psoriasis flare, prompting treatment initiation with alternative biologic therapy. The timing of the development and improvement of the hypopigmented lesions after initiation and discontinuation of ixekizumab, strongly suggests a possible association.

In conclusion, we report a case of a psoriasis patient who developed an HMF-like eruption after treatment with ixekizumab. This is the first reported case of an HMF-like eruption in the setting of psoriasis with ixekizumab. There should be more awareness regarding the potential risk of developing atypical MF in psoriasis patients under biologic treatment. Further research is necessary to understand the pathogenesis and long-term risk of CTCL in psoriasis patients on biologic therapy.

Conflicts of interest

None disclosed.