Successful Treatment of Refractory Livedoid Vasculopathy with Upadacitinib: A Case Report

Introduction

Livedoid vasculopathy (LV) is a chronic, painful thrombo-occlusive condition of the microvasculature. Its clinical presentation includes reticulated erythema, purpuric lesions, and refractory ulcers on the lower extremities, often exhibiting symptomatic exacerbation during the summer. Histopathology reveals fibrinoid vascular occlusion, thrombosis, and endothelial proliferation, implicating hypercoagulability and inflammation.¹ The estimated annual incidence of LV is approximately 1 per 100,000 individuals, with a female-to-male ratio of roughly 3:1.² The management of LV remains challenging, which is attributed to the variability in treatment response among existing therapeutic options and the substantial proportion of refractory cases. Current therapeutic strategies encompass conventional approaches including antiplatelet agents, anticoagulants, and immunosuppressants, as well as the option of Janus kinase (JAK) inhibitors.² Although JAK inhibitors (tofacitinib/baricitinib/abrocitinib) show efficacy in LV,^3–6 Baricitinib, which selectively inhibits JAK1 and JAK2, is frequently used in the treatment of LV by blocking cytokine signaling pathways and antagonizing the effects of inflammatory cytokines.⁴ The median time to remission following baricitinib initiation was 7.75 weeks.⁴ Upadacitinib, a highly selective JAK1 inhibitor, has demonstrated robust efficacy in the treatment of various immune-mediated disorders, including atopic dermatitis and rheumatoid arthritis. However, the role of upadacitinib in the management of LV remains largely unexplored and warrants further investigation. We present a refractory LV case to investigate its potential.

Case Presentation

A 54-year-old woman presented with a 3-month history of refractory purpuric lesions and painful ulcers on the lower legs and dorsal feet, showing no improvement after compound glycyrrhizinate and betamethasone injections. Clinical examination of the lower extremities revealed bilateral, tender, focal, purpuric ulcerative lesions accompanied by atrophic scarring, telangiectasias, hemosiderin deposition, and hyperpigmentation (Figure 1a). Additionally, multiple tender ulcers surrounded by violaceous erythema were observed on the right pretibial area (Figure 1b), medial malleolus (Figure 1c), and lateral malleolus (Figure 1d), with scattered purpuric changes noted on the dorsal right foot (Figure 1e). The clinical scoring scale consisted of three evaluation dimensions to assess the clinical severity of the condition before and after treatment with upadacitinib. The total score ranged from 0 to 8, with the following items being rated: pain (0 = none; 1 = mild; 2 = moderate; 3 = severe), ulceration (0 = intact skin; 1 = erosion; 2 = ulceration), and erythema (0 = none; 1 = mild; 2 = moderate; 3 = severe). The composite clinical score was 7 (severe pain: 3; ulceration: 2; moderate erythema: 2). Laboratory investigations—including complete blood count, renal function, coagulation profile, erythrocyte sedimentation rate, autoantibodies (Anti-Neutrophil Cytoplasmic Antibodies, Extractable Nuclear Antigens, anticardiolipin, rheumatoid factor), complement levels, viral serologies (hepatitis, Epstein–Barr virus, Cytomegalovirus), and T-cell Spot Test for Tuberculosis—were within normal limits. Histopathological examination at three different magnifications revealed the following features: parakeratosis with capillary proliferation in the superficial dermis and densely arranged collagen bundles in the mid to deep dermis (Figure 2a); occluded small vessels with intravascular hyaline thrombi and mild perivascular lymphocytic infiltration in the superficial dermis (Figure 2b); and fibrinoid deposition in the walls of superficial dermal vessels accompanied by extensive extravasation of erythrocytes (Figure 2c). Initiation of upadacitinib (15 mg/day) resulted in rapid pain reduction (score 7→3 on day 1), erythema fading with crust formation by day 4 (Figure 3Aa–Ae), partial eschar detachment on day 9 (Figure 3Ba–Be), and clinical remission (score 2) by day 24 (Figure 3Ca–Ce). At day 52, near-complete healing was observed with only a pea-sized eschar persisting at the right malleolar ulcer (Figure 3Da–De). The sole adverse event was self-resolved herpes labialis on day 3 (Figure 4), with no laboratory abnormalities detected.

Figure 1 Clinical Images of the lower limb before the upadacitinib treatment. (a) Bilateral tender purpuric ulcers with atrophic scarring, telangiectasias, hemosiderin deposition, and hyperpigmentation on the lower extremities; (b) Multiple tender ulcers with violaceous erythematous borders on right pretibial skin; (c) Ulcer with violaceous erythematous border on right medial malleolus; (d) Deep ulcer with erythematous border superior to right lateral malleolus; (e) Multiple purpuric eruptions and ulcers on right dorsal foot.

Figure 2 Histopathological image of the skin lesion on the right dorsal foot. (a) Parakeratosis; capillary proliferation in superficial dermis; densely arranged collagen bundles in mid and deep dermis (HE×40); (b) Occluded small vessels with hyaline thrombi in superficial dermis; mild perivascular lymphocytic infiltration (HE×100); (c) Fibrinoid deposition in superficial dermal vessel walls with extensive extravasated erythrocytes (HE×400).

Figure 3 Clinical Images of the lower limb during the upadacitinib treatment (From left to right: overall view, right anterior tibial region, right medial malleolus, right lateral calf, and right dorsum of the foot) (Aa–Ae) 4 days of upadacitinib treatment. (Ba–Be) 9 days of upadacitinib treatment. (Ca–Ce) 24 days of upadacitinib treatment. (Da–De) 52 days of upadacitinib treatment.

Figure 4 Clinical photograph of herpes labialis.

Discussion

Livedoid vasculopathy (LV) presents a complex pathogenic landscape where consensus remains elusive. The currently reported pathophysiological mechanisms of this disease encompass plasmatic hypercoagulability, impaired fibrinolysis, platelet hyperaggregability, T-cell activation, and endothelial dysfunction.⁷ Therapeutic strategies—including anticoagulants, platelet inhibitors, vasodilators, and immunosuppressants—yield inconsistent outcomes. Rivaroxaban was the most frequently administered anticoagulant, followed by low-molecular-weight heparin, unfractionated heparin, and warfarin.⁷ While rivaroxaban demonstrates efficacy in select cohorts,⁸ agents targeting inflammatory pathways (eg, TNF-α inhibitors [adalimumab/etanercept],⁹ rituximab,¹⁰ IVIg,¹¹ anabolic steroids,¹² ozone therapy¹³) underscore the role of immune activation. Notably, rituximab may uniquely mitigate associated neuropathic symptoms.¹⁰

Mechanistically, upadacitinib competitively inhibits ATP binding to JAKs, suppressing kinase activity and STAT phosphorylation.¹⁴ Its pronounced selectivity for JAK1 (>40-fold vs JAK2)¹⁵ enables targeted modulation of cytokine signaling (eg, IL-6/IL-7).¹⁶ Common trial-associated AEs include acne, upper respiratory infections, and CPK elevation.¹⁵ Our patient experienced only self-limiting herpes labialis, with no hepatic, renal, hematologic, or metabolic disturbances.

Two key innovations are presented in this study. Therapeutic Alternative: JAK inhibitors rescue ~41.5% of LV cases refractory to conventional therapy.^6,16 Baricitinib (2–4 mg/day) dominates current reports,^16,17 but upadacitinib introduces a new option. Accelerated Response: Our patient achieved remission in 24 days—approaching the lowest reported value for baricitinib while remaining below its mean (Mean remission time: 7.75 ± 3.45 weeks; range, 3–13).⁴ This contrasts with rivaroxaban’s 7.8-week median for 50%. In a separate case series, baricitinib treatment resulted in complete lesion healing within 1, 2, and 6 months in three patients with LV.¹⁸ Additional cases are necessary to further substantiate these findings.

Conclusion

In conclusion, while livedoid vasculopathy poses persistent therapeutic challenges, this first documented case establishes upadacitinib as a viable JAK inhibitor alternative for refractory disease. The observed rapid clinical remission (24 days) and healing of deep ulcers highlight its potential efficacy. Prospective multi-center studies with larger cohorts are warranted to validate these preliminary findings and define optimal dosing regimens.