Novel Combination of UVA‐1 Phototherapy With Topical Tofacitinib for Treating Eosinophilic Fasciitis With Morphea: Case Report

ABSTRACT

Eosinophilic fasciitis (EF) and morphea are rare sclerosing connective tissue disorders, and there remains debate about whether these entities are pathologically distinct or related. This case report describes the successful treatment of an adolescent patient who developed progressive morphea plaques while being treated with systemic corticosteroids, intravenous immunoglobulin, and methotrexate for EF. A novel combination of topical tofacitinib, a Janus kinase (JAK) inhibitor, and UVA‐1 phototherapy induced clinical remission and was well tolerated, warranting further investigation into such combination therapy.

1. Introduction

Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by acute or subacute onset of symmetric edema and erythema over the extremities, followed by progressive sclerosis of deep structures, from dermis to fascia. EF is distinguished from systemic sclerosis by the absence of Raynaud's phenomenon, nail fold capillary changes, and sclerodactyly. Visceral involvement is extremely rare [1, 2]. A hallmark of EF is that it responds to corticosteroids [2]. A recent review found that initial treatment with systemic corticosteroids combined with methotrexate may be more effective in inducing complete remission versus corticosteroids alone [2].

EF and morphea are clinically distinguishable. However, in approximately 300 reported cases of EF, about 19%–65% of patients are also diagnosed with forms of morphea before, at the time of, or after a diagnosis of EF [2, 3, 4, 5, 6, 7, 8]. Morphea is a localized form of scleroderma and can be further classified into linear, circumscribed, generalized, pansclerotic or mixed subtypes [9]. Morphea is characterized by inflammatory skin lesions that progress to sclerotic plaques. Fascia and muscle can be involved. In children, early intervention is prudent to limit joint contractures and associated lifelong morbidity [1]. Topical treatment options for superficial lesions of morphea include vitamin D analogues, corticosteroids, tacrolimus, or adjunctive ultraviolet A‐1 (UVA‐1) phototherapy [1, 2, 10, 11]. Systemic corticosteroids combined with intravenous immunoglobulin (IVIg), methotrexate, or mycophenolate mofetil are used to treat generalized morphea lesions, as well as EF [2, 11, 12].

To date, there are limited reports on the use of topical small molecules targeted at the inflammatory pathways implicated in eosinophilic fasciitis and morphea. This case report describes the successful treatment of an adolescent patient who developed morphea while being treated for EF. Novel combination of topical tofacitinib, a Janus kinase (JAK) inhibitor, and UVA‐1 therapy, in addition to systemic corticosteroids and methotrexate, induced clinical remission.

2. Case Report

A 13‐year‐old Caucasian female competitive swimmer and skier presented with a 4‐month history of pain and swelling of the left ankle, followed by subcutaneous swelling of all extremities, skin stiffness, joint stiffness, and reduced range of motion of bilateral fingers, wrists, hips, knees, and ankles. Her medical history was significant for eczema, perioral dermatitis, and rosacea. She has a first‐degree relative with psoriasis.

Physical examination revealed muscle weakness in the left hip flexors and extensors (4/5). There was reduced range of motion in the wrists, metacarpal joints (unable to tuck and flex all digits), interphalangeal joints, and subcutaneous swelling of the dorsum of both hands and thenar eminences. In the lower extremities, she had decreased range of motion in the left hip, knees, and ankles (left more than right). There was a small effusion of the left knee.

Detailed skin examination revealed edema over the hands and wrists and deep induration involving bilateral forearms. The skin over the right distal digits was mildly tight. From bilateral mid‐thigh to feet, her skin was indurated and bound down (Figure 1). Her modified Rodnan skin score was 18/51, the worst area being the left leg.

FIGURE 1.

Upper extremities on presentation with edema, erythema, and bound‐down skin, characteristic of EF. There was restricted range of motion.

She had an elevated eosinophil count of 1.9 × 10⁹/L (reference range 0.04–0.53 × 10⁹/L). Serology showed the presence of antinuclear antibody (1:80), anti‐Smith, anti‐RNP, and tissue transglutaminase IgA. Celiac disease was later confirmed by endoscopy. Magnetic resonance imaging showed diffuse T2 hyperintense enhancement and edema of the subcutaneous tissues, fascia, muscles, and tendons of the left lower limb. Pulmonary function test and echocardiogram were normal.

She underwent a biopsy of the skin, fascia and muscle of the left thigh, which showed acute and chronic inflammatory infiltrates involving the dermis, adipose tissue, fascia, and muscle. The inflammatory infiltrate contained lymphocytes, plasma cells, histiocytes, and scattered eosinophils, with associated fibrinoid necrosis. The epidermis was normal. Given these findings, she was diagnosed with eosinophilic fasciitis. Due to the extent of involvement and decreased joint mobility, she was treated with a combined regimen of prednisone 60 mg daily for 1 week, followed by a slow taper over 7 weeks; weekly oral methotrexate (15 mg/m² weekly); physiotherapy; and occupational therapy.

One month after starting treatment, she developed new well‐circumscribed ovoid plaques that were hypopigmented, waxy centrally, bound down, and had a violaceous border over the right hip and left lateral ankle to midfoot (Figure 2). Furthermore, from the left mid‐thigh to the ankle, she developed a slightly depressed linear plaque with superficial skin atrophy and hyperpigmentation (Figure 2). These findings were consistent with plaque‐type and linear morphea. The diagnosis was revised to EF with morphea overlap. Although EF responded, her treatment was intensified to a six‐month course of methylprednisolone (MP) 1000 mg IV monthly with intravenous immune globulin (IVIg) 2 g/kg monthly while continuing methotrexate (15 mg/m² weekly). EF significantly improved: subcutaneous edema resolved, the modified Rodnan skin score improved to 9/51, and range of motion in all extremities (except the left lower limb) returned to normal limits. There were no significant cutaneous sequelae of EF, specifically, peau d'orange or subcutaneous atrophy.

FIGURE 2.

Plaque morphea lesions over the right hip (A) and left ankle to foot (B), and linear morphea over the left leg (B) that developed 1 month after starting methylprednisolone, methotrexate, and IVIg infusions for treatment of EF.

Concurrent with systemic therapy, the morphea plaques were treated with calcipotriol/betamethasone dipropionate 50 mcg–0.5 mg ointment and tacrolimus 0.1% ointment for 3 months. Most of the morphea plaques responded, but the linear morphea lesion over the left leg and the plaque morphea lesion over the left ankle progressed and continued to restrict motion.

Six months after completing MP and IVIg infusions, the patient remained on weekly methotrexate. Topical therapy for morphea was switched to tofacitinib 2% ointment, applied over the linear morphea plaque, and purposely applied only to the anterior half of the ankle lesion to evaluate response. The patient received 18 treatments of UVA‐1 phototherapy to the left lower extremity (over 4 weeks). One month after completing phototherapy, a positive response was noted: the anterior half of the plaque over the left foot, where tofacitinib was applied, was less thickened and softer than the posterior unexposed half (Figure 3). The linear morphea plaque, which was treated with UVA‐1 and topical tofacitinib, was no longer well‐demarcated and the skin texture improved.

FIGURE 3.

Three months after starting topical tofacitinib and 1 month after UVA‐1 treatment, the skin over the anterior (encircled) portion of the circumscribed morphea plaque over the left foot (treated with tofacitinib) was less thickened and softer than the posterior portion of the lesion (not treated with tofacitinib).

After 1 year of treatment with methotrexate and topical tofacitinib over the entire surface of the plaques, morphea was deemed clinically inactive. There remain patches of ill‐defined hyperpigmented skin where the linear morphea lesion used to be, with normal skin texture. There remains an indurated heterogeneous light brown plaque over the left lateral ankle and right hip, but the overlying skin demonstrates normal creasing (Figure 4). She has full range of motion in all extremities. Methotrexate was discontinued after a total 3‐year course, and 1 year later there are no signs of clinically active EF or morphea.

FIGURE 4.

Right hip (A) and left lower extremity (B) demonstrating residual hyperpigmentation with normal texture and creasing after a subsequent 1 year of treatment with tofacitinib ointment and oral methotrexate.

3. Discussion

Consistent with the literature, EF in this patient responded to high‐dose methylprednisolone and a long‐term course of methotrexate. Emergence of morphea lesions while on treatment for EF has been reported [2, 3, 4, 5, 6, 7, 8, 9]. Although EF responded, methylprednisolone and IVIg infusions were added to methotrexate to treat emerging morphea, but the latter progressed. The novel combination of UVA‐1 phototherapy with topical tofacitinib, in addition to methotrexate, was followed by subjective improvement of the linear morphea plaque and the treated half of the morphea plaque over the left foot—these areas softened compared to the remaining half of the ankle and foot lesion that was unexposed to tofacitinib.

Proposed classification systems position EF and morphea on a spectrum of localized scleroderma, but this remains controversial in the literature [1, 2, 3, 4, 5, 8, 9, 13]. Clinically, EF and morphea are distinctive. However, the pathogenesis and etiology of EF, morphea, and their overlap are complex and require further elucidation. Increased markers of vascular injury (vascular cell adhesion molecule‐1, intercellular adhesion molecule‐1), aberrant proliferation and activation of inflammatory cells (especially CD4+ lymphocytes), and inappropriate activation of fibrotic pathways (mediated by interleukin‐4, transforming growth factor‐, and more) are shared themes in the pathogenesis of systemic scleroderma, EF, and morphea [1, 14]. Perhaps more distinct to EF, results of small immunophenotyping studies suggest an imbalance between tissue inhibitors of metalloproteinase‐1 and matrix metalloproteinases in the extracellular matrix, leading to abnormal fibrosis [1, 2, 7]. A number of authors have proposed that Janus kinase inhibitors (such as tofacitinib) or anti‐interferon monoclonal antibodies are appropriate treatment targets because these cell signals are upstream to inflammatory and fibrotic processes implicated in EF and morphea [14, 15]. Endo et al. suggested that morphea in EF represents a superficial progression of inflammation [16]. Perhaps combining UVA‐1 phototherapy with topical tofacitinib had a synergistic effect on superficial tissues. Notably, successful treatment of vitiligo with UVA‐1 phototherapy and topical corticosteroids or topical calcineurin inhibitors has similarly been reported [17].

This is the first reported application of combined methotrexate, UVA‐1 phototherapy, and topical tofacitinib to treat EF with morphea overlap. Monotherapies were not evaluated. Further studies into proposed mechanisms of EF, morphea, overlap syndromes, and the effects of combined therapies are needed to more precisely guide treatment.

Ethics Statement

Per the Conjoint Health Research Ethics Board (CHREB) at the University of Calgary and the second edition of the Tri‐Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2), clinical case reports are “anecdotal accounts of individual cases” and “do not fall within the definition of research.” Thus, CHREB approval was not required. This study conforms to the TCPS 2.

Consent

Written consent was obtained from the patient and their caregivers to participate in this publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.