Baricitinib Successfully Treated a Teenager with Refractory Livedoid Vasculopathy: A Case Report and Literature Review

Background

Livedoid vasculopathy (LV) is a rare, chronic, and recurrent cutaneous vascular obstructive disease, with clinical manifestations broadly classified into three stages. The first stage presents as purplish-red maculae and papules, often symmetrically distributed in the lower limbs, ankles, and back of the foot. The second stage progress into painful ulcers. The third stage involves ulcer healing resulting in a porcelain white atrophic scar, which may be accompanied by telangiectasia and pigment-like changes.¹ Notably, peripheral neuropathy may occur in some patients.² LV primarily affects middle-aged women and tends to worsen in summer while being less severe in winter.³

The pathogenesis of LV remains insufficiently understood and may involve vascular embolism and a potential inflammatory response due to hypercoagulability.⁴ Although drugs such as anticoagulants, antiplatelet agents, vasodilators, and steroid exhibit favorable results in certain cases, some patients still respond poorly to conventional treatment. The present case provides new evidence regarding the efficacy of JAK inhibitors in the treatment of refractory LV.

Case Presentation

In June 2023, a 14-year-old girl presented to our hospital with a history of painful recurrent ulcers on the lateral ankles and back of both feet for over 1 year. Physical examination revealed multiple necrotic ulcers on the feet and ankles surrounded by erythema, porcelain white atrophic scars, and pigmentation (Figure 1). The composite clinical score was 7, with 2, 2, and 3 points for moderate pain, skin ulcer, and severe erythema, respectively. The patient previously received oral rivaroxaban combined with external use of heparin sodium cream for 3 months. However, she failed to achieve sustained remission following drug discontinuation. Notably, no recurrent oral ulcers, genital ulcer, fever, Raynaud phenomenon, frostbite rash, butterfly erythema, purpura rash, finger numbness, arthralgia, alopecia, celialgia, polydipsia, polyuria, dyspnea, fatigue, hypertension, lymphadenopathy, or weight loss were complained. Laboratory and imaging examinations revealed normal or negative results for complete blood cell count, hemoglobin, platelet count, urinalysis, renal function, antineutrophil cytoplasmic antibodies, cold agglutinin test, protein electrophoresis, erythrocyte sedimentation rate, antinuclear antibody, anti-ribosome antibody, anti-Smith antibody, anti-SSA/Ro52 antibody, anti-SSA/Ro60 antibody, anti-SSB antibody, anti-double-stranded DNA antibody, anti-nucleosome antibody, anti-histone antibody, anti-ribosomal antibody, anti-cardiolipin antibody, rheumatoid factor, complement, prothrombin time, bleeding time, blood glucose, tuberculosis interferon-gamma release assay, serology for Epstein-Barr virus and cytomegalovirus, lower extremity vascular ultrasound, chest CT, and cardiac ultrasound. The patient denied any significant travel history, medical history, or family history of deep vein thrombosis, autoimmune diseases, or other diseases affecting the coagulation status. A skin biopsy revealed focal epidermal ulceration, superficial dermal edema, vascular proliferation and dilation, partial vascular endothelial cell proliferation, partial vascular wall destruction, partial vascular wall thickening and occlusion, and partial deposition of cellulose in the vascular wall. Furthermore, erythrocyte exosmosis and the infiltration of interstitial inflammatory cells were also observed. All these pathological manifestations were consistent with a diagnosis of LV (Figure 2).

Figure 1 Initial skin appearance Painful recurrent ulcers on the lateral ankles and back of both feet when LV before baricitinib used.

Figure 2 The histological features Histopathological examination showed focal epidermal ulceration, superficial dermal edema, vascular proliferation and dilation, partial vascular endothelial cell proliferation, partial vascular wall destruction, partial vascular wall thickening and occlusion, and partial deposition of cellulose in the vascular wall. Furthermore, erythrocyte exosmosis and the infiltration of interstitial inflammatory cells were observed. (hematoxylin–eosin, ×200).

As the patient was a school-aged girl with growth and development needs and the convenience of oral preparations, a treatment regimen of baricitinib (4 mg daily) in combination with amlodipine (5m g daily) were developed. Following 2 weeks of treatment, the erythema became notably lighter in color and significantly smaller, with a part of the scab falling off and replaced with new skin (Figure 3A). The ulcers healed completely following treatment for 3 months, without any new lesions (Figure 3B). The composite clinical score was 1, including 0, 0, and 1 point for pain, intact skin, and mild erythema, respectively. At the most recent follow-up in March 2024, the patient only had pigmentation on feet and ankles (Figure 3C). Amlodipine was continued until its withdrawal in February 2024. Baricitinib was reduced to 3, 2, and 1mg daily in September 2023, November 2023, and January 2024, respectively, and finally discontinued in March 2024. During the course of treatment, the patient did not experience any drug-related adverse reactions, including infection, liver function injury, or gastrointestinal symptoms.

Figure 3 Clinical Response of Livedoid Vasculopathy to Baricitinib Therapy. (A) After 2 weeks of treatment, the rash was obviously lighter in color and significantly smaller in scope, and part of the scab fell off and was covered by new skin. (B) After 3 months of treatment, the ulcers healed completely, and there was no new lesion presented. (C) the patient had only pigmentation on feet and ankle in March 2024.

Discussion and Conclusions

The pathogenesis of LV is complex, with no consensus regarding its treatment plan. Furthermore, evaluation of its clinical efficacy is challenging because of its rare and recurrent occurrence. Specifically, the current mature treatment of LV is mainly limited to anticoagulants, platelet inhibitors, fibrinolytic solvents, and vasodilators, as the mechanism underlying LV may mainly involve vascular embolism and the potential inflammatory response due to hypercoagulability. Immunosuppressants, including glucocorticoids, cyclophosphamide, and azathioprine, are also candidate drugs for its treatment as immune mechanisms may also play a role in its development. Moreover, anti-inflammatory drugs such as colchicine, which inhibit neutrophils, can also be used for treating the acute stage of LV. Additionally, some physical therapies, including hyperbaric oxygen therapy and 8-methoxypsoralen combined with A-band ultraviolet therapy, may be effective.^5–7 However, not all patients benefit from these treatments.

In patients with refractory LV, JAK inhibitors, particularly baricitinib, have demonstrated some efficacy, which was confirmed in 14 patients, including children, adolescents, and adults, in 5 studies (Table 1).^8–12 Baricitinib can be administered alone or in combination with other drugs at a starting dose of 2 mg/ day or 4 mg/ day. Skin improvement can be observed after 2–12 weeks and it is safe without side effects.^8–12 In the present case, the initial dose of baricitinib was 4 mg/ day, corresponding to the 60.4 kg body weight of the patient. The drug was discontinued at approximately 9 months. The skin symptoms, including pain, ulceration, and erythema, were relieved at approximately 2 weeks, the ulcer healed completely at approximately 3 months, and no recurrence or drug-related adverse reactions during baricitinib reduction were observed.

Table 1 Patient Characteristics and Response to Baricitinib Therapy

Nevertheless, the mechanism of JAK action remains unclear from the perspective of thrombosis. Meanwhile, JAK is increasingly used in rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, MDA5+ dermatomyositis, and other immune-mediated inflammatory diseases. The occurrence of thromboembolic events, as a drug-related adverse reaction should be considered when using JAK inhibitors.¹³ In contrast, a study also reported that JAK inhibitors can reduce the upregulation of critical prothrombotic pathways and prevent increased leukocyte-endothelial adhesion.¹⁴ From an inflammatory perspective, a pathological study involving 137 patients with LV reported that the occlusion of small vessels may represent a phenomenon secondary to lymphocytic vasculitis, explaining the effectiveness of anti-inflammatory agents, including intravenous immunoglobulin, tumor necrosis factor-α inhibitors, and JAK inhibitors, in LV.¹⁵

In addition to baricitinib, other biologics, including rituximab, adalimumab, and etanercept, can also be used to treat LV, although the underlying therapeutic mechanism remains unclear and limited to case reports.^16–19 Vieira et al reported a case of a 58-year-old female patient with sensory disorders in the back of the foot and recurrent episodes for many years, exhibiting poor response to conventional drugs. Rituximab was administered to the patient as a 1.0 g infusion, followed by another 1.0 g infusion 14 days later. The ulcer healed completely, and sensory disorders in the back of the foot improved after 1 year.¹⁹ In another study on the efficacy of etanercept for LV, five patients with LV were administered subcutaneous injections of etanercept 25–50 mg once a week for 12 consecutive weeks. Notably, pain, erythema, and ulcer improved at average times of 2, 8.8, and 10.6 weeks, respectively, and the LV severity score, numerical rating scale, and dermatology life quality index decreased by 26.1%, 32.0%, and 34.3%, respectively, after 12 weeks of treatment without any adverse reactions.¹⁸

In conclusion, biologics for LV treatment are still being explored. The successful treatment of our patient with baricitinib provides additional evidence for the potential therapeutic effect of JAK1/JAK2 inhibitors in the LV, providing a reference for the dosage tapering regime of baricitinib in LV.