Long-term efficacy and safety of JAKi in refractory livedoid vasculopathy

Dear Editor,

Livedoid vasculopathy (LV) is a rare, chronic ulcerative disorder primarily affecting females. Numerous treatment modalities have been tried with varying efficacy for LV, include anticoagulants and glucocorticoids.^1,2 Recent case reports and series have suggested the potential of Janus kinase inhibitors (JAKi), particularly baricitinib, in managing LV.^3-5 However, the long-term efficacy and safety profile of JAKi remain unclear and require further investigation. This is especially true considering the thrombotic risks associated with JAKi highlighted by FDA warnings. We report long-term follow-up of two cases of LV treated with JAKi.

Two female patients aged 16 and 26 years presented with painful erythematous and irregular necrotic ulcerated lesions present on the ankles, dorsa of both feet, calves and thigh for the duration of 3 and 2 years respectively [Figure 1], suggestive of Livedoid vasculopathy (LV). The clinical diagnosis of LV was confirmed on histology [Figure 2], arteriovenous ultrasounds, and coagulation parameters. Both patients did not respond to the conventional treatments, including steroids and anticoagulants. Treatment with Janus kinase inhibitors (JAKi) and regular monitoring of haematologic profiles, coagulation parameters, and hepatic and renal functions were initiated with informed consent. Clinical details, including site, previous treatments, and laboratory results, have been summarised in Table 1.

Close

Figure 1:

Patient 2. Lesion at baseline showing erythema and ulcers covered with crusts.

Export to PPT

Close

Figure 2:

Patient 2: Thrombo-occlusive changes in dermal vessels with perivascular lymphocytes. (Haematoxylin & eosin, 100x).

Export to PPT

Patient 1 was started on 2 mg of baricitinib daily, leading to significant improvement by the 8^th week. The clinical assessment score dropped from 9 (erythema 3/ulceration 3/pain 3) to 3 (erythema 0/ulceration 2/pain 1). Follow-up was disrupted after week 10 due to COVID-19, leading to a 12-week pause in treatment and the recurrence of painful lesions on the dorsa of both feet. She was then started on rivaroxaban which had to be discontinued due to severe bone pains. Subsequently, she was initiated on tofacitinib (5mg twice daily) for 33 weeks, stabilising her condition with mild adverse effects of nausea and dizziness. Later, she was re-administered baricitinib 2 mg daily and maintained a response for over 32 weeks with no significant side effects [Figure 3].

Close

Figure 3:

At week 42, post treatment complete resolution of the lesions.

Export to PPT

Patient 2 also experienced rapid relief on baricitinib (4 mg daily) for 12 weeks and her clinical assessment score reduced from 8 (erythema 2, ulceration 2, pain 3) to 1 (erythema 0, ulceration 0, pain 1). She was maintained in remission even after reducing the dose to 2 mg daily and later every alternate day over 42 weeks. In December 2022, she experienced a flare-up post-COVID-19 infection. The severe recurrence was managed by increasing the baricitinib dosage back to 2 mg daily.

LV is categorised as an obstructive vasculopathy with ischaemic-thrombotic alteration as its primary pathogenesis. This understanding supports the effectiveness of anticoagulants such as rivaroxaban.^1,2 There is however, also a role of inflammation in the pathogenetic pathways for LV which supports the rationale of using JAK inhibitors in LV. In 2020, Jia and colleagues reported rapid symptomatic relief in LV with tofacitinib.³ Similar outcomes were observed with baricitinib, with a mean remission time of 7.75 ± 3.45 weeks among eight patients.⁴ Our findings are consistent with these reports, showing remission in two patients within 8 and 12 weeks. Additionally, the selective JAK1 inhibitor, abrocitinib demonstrated significant improvements in another isolated case.⁵

Managing this chronic disease raises concerns about the long-term efficacy, as previous cases had a relatively short follow-up period ranging from 10 to 28 weeks.^4,5 Both patients received JAKi with a cumulative duration of over 62 and 75 weeks. Regarding the recurrences, in a previous case report on tofacitinib, no flare-ups of pain or ulcers were noted within a 52-week follow-up.³ However, in our study, both patients reported recurrences; first after discontinuing baricitinib but responded well to subsequent treatment with tofacitinib and baricitinib, maintaining remission thereafter. In the second patient, exacerbation could be attributed to COVID-19 infection, a scenario which has been reported previously.^6,7

For safety concerns, off-label use of JAKi in LV warrants caution due to associated thrombotic risks, as highlighted by FDA warnings. Previously, no side effects were reported among LV patients treated with JAKi.^3,5 In our cases, mild nausea and dizziness were reported with tofacitinib, with no adverse events noted during extended treatment with baricitinib.

In summary, our cases demonstrate that both tofacitinib and baricitinib could be relatively safe and effective options for treating and maintaining remission in LV. However, more cases with long-term follow-ups are necessary in the future to fully elucidate the efficacy and safety profiles of JAKi.