A Refractory Livedoid Vasculopathy Accompanied by Methylene Tetrahydrofolate Reductase Gene Polymorphism Successfully Treated with Hyperbaric Oxygen Therapy

Abstract

Livedoid vasculopathy (LV) is a chronic coagulation disorder characterized by recurrent, painful ulcers on the lower extremities. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphism is associated with coagulopathy. Therapeutic options usually include anti-inflammatory or immunosuppressive agents. However, the condition is still highly challenging to manage and no consensus over the first-line treatment for LV exists. Furthermore, when LV is accompanied with MTHFR gene polymorphism, clinical presentations could be more severe and resistant to treatment. We report a case of refractory LV accompanied by MTHFR gene polymorphism, which was successfully treated with hyperbaric oxygen therapy (HBOT). A 63-year-old female patient presented with multiple painful ulcers, atrophie blanches, and retiform purpura on both lower legs and feet. Histopathologic findings were compatible with LV. LV was diagnosed based on these clinicopathological findings. Following the diagnosis, we treated the patient with pentoxifylline, aspirin, systemic corticosteroid, antihistamine, and antibiotics. In spite of six-month treatment, the skin lesions did not improve; hence, HBOT was performed. It was performed at 2.0 absolute atmosphere for 120 minutes each time, three times a week. After 4 sessions, the ulcers began to heal and after 13 sessions, the skin lesions almost healed. During the eight-month follow-up period, the skin ulcers did not recur and the symptoms remained stable. Additionally, it was confirmed that she had MTHFR gene polymorphism after a genetic test. In conclusion, we wish to provide evidence regarding the effectiveness of HBOT and suggest that HBOT might be a considerable treatment option in refractory LV.

INTRODUCTION

Livedoid vasculopathy (LV) is a chronic, recurrent, hyalinizing vascular disease characterized by thrombosis and painful ulcers on the lower legs¹,². Pentoxifylline, dipyridamole, and low-dose aspirin can be used as treatments, but achieving satisfactory effects is difficult. The cause of this disease is not exactly known, but it is thought to be caused by a problem with the underlying blood coagulation system³. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphism is one of the causes of hypercoagulation regarding this disease⁴. We earlier had a case of LV with hyperhomocysteinemia due to MTHFR gene polymorphism, which was improved by folic acid supplementation⁵.

Hyperbaric oxygen therapy (HBOT) is a treatment modality involving 100% oxygen breathing at a pressure higher than 1 atmospheres absolute (ATA). HBOT has been reported as an adjuvant therapy for LV, promoting symptomatic relief⁶. However, there have been no reports on the effect of HBOT on LV with MTHFR gene polymorphism.

Herein, we report a case of refractory LV accompanied by MTHFR gene polymorphism, which improved dramatically after HBOT.

CASE REPORT

A 63-year-old Korean woman visited the dermatology department with a 3-month history of multiple erythematous to brownish pruritic macules on both lower legs and atrophie blanches with painful ulceration on both dorsa of her feet. She had a history of hypertension, but no coagulopathy, spontaneous abortion or familial history. Blood test results, including the complete blood count, blood chemistry tests, urinalysis, prothrombin time, partial thromboplastin time and antinuclear antibody analyses, were all normal, and there was no abnormality on Doppler ultrasound imaging, which was performed to evaluate circulation in the lower legs. Histopathologic findings from the dorsa of the feet revealed hyalinized vascular wall, luminal occlusion of the vessels, and fibrinoid necrosis (Fig. 1).

Fig. 1. Histopathological findings were compatible with livedoid vasculopathy, showing epidermal ulceration, hyalinization of vascular wall, perivascular fibrinoid necrosis, and luminal occlusion.

Treatment with methylprednisolone (8 mg/day) and pentoxifylline (800 mg/day) was started, but after 6 weeks, skin lesions worsened; thus, we added doxycycline and aspirin to the treatment. After three weeks, skin lesions slightly improved, and the methylprednisolone dose was reduced to 2 mg/day for five weeks and discontinued thereafter. After five weeks of doxycycline and aspirin treatment, skin lesions worsened again. To consider HBOT as an additional adjunct therapy, we referred the patient to our HBOT center. HBOT was performed in a multiplace chamber, with initial compression to 2.0 ATA and 100% O₂ applied for 120 minutes. After 120 minutes at 2.0 ATA, decompression was performed to atmospheric pressure and the treatment session was completed. During HBOT, we continued conservative treatment with doxycycline and aspirin. In total, 13 sessions were conducted over 7 weeks. Skin lesions drastically improved (Fig. 2A) and pain was alleviated during HBOT. The erythema improved significantly, and the ulcers also healed (Fig. 2B).

Fig. 2. Clinical features of lesions before and after hyperbaric oxygen therapy (HBOT). (A) Skin lesions were gradually improved as HBOT sessions progressed (before HBOT, session number 4, session number 13, after 7 weeks of HBOT). (B) Comparison of representative lesions before and after HBOT. Ulcerative lesions were completely healed after 7 weeks of HBOT.

After HBOT, skin lesions remained stable as postinflammatory hyperpigmentation with aspirin for approximately 1 year. At the next outpatient visit, new purpuric lesions were observed on both forearms, genetic testing for MTHFR gene polymorphism confirmed MTHFR 677T/T homozygous polymorphism. Serum homocysteine levels were 16.6 µmol/L (normal range: 6.72~15.2 µmol/L). Protein S activity was normal. We added pentoxifylline to the treatment again, and then skin lesions remained well.

DISCUSSION

LV, also known as livedoid vasculitis or livedo vasculitis, appears as painful, recurrent ulcers on the lower extremities and is associated with impaired quality of life⁷. Treatment can be tried with anticoagulants, antiplatelets, anabolic steroids, thrombolytics, etc, but obtaining satisfactory effects is difficult. A systematic review of LV treatments showed varying degrees of success with various treatments⁸. Relatively recently, it has been reported that the addition of rivaroxaban, a direct factor Xa inhibitor, to previous treatment is effective and reduces the severity of recurrence⁹. Our patient visited the hospital before this evidence was presented; therefore, we empirically treated the patient with systemic steroids and antiplatelets. If LV recurs afterward, additional administration of rivaroxaban should be considered. Conditions such as systemic lupus erythematosus, antithrombin III deficiency, protein C deficiency, antiphospholipid syndrome, and hyperhomocysteinemia have been reported to possibly cause hypercoagulation in LV, but there have been many cases in which the cause could not be identified³. Methyltetrahydrofolate (MTHF), which is produced by the expression of the MTHFR gene, acts on the remethylation process of homocysteine. If polymorphisms in the MTHFR gene occur, serum homocysteine concentration may increase¹⁰.

Since 1873, HBOT has been a primary therapy for decompression sickness. In addition, HBOT is well known as an effective adjuvant treatment modality for chronic refractory skin wounds such as diabetic foot ulcers and Fournier’s gangrene¹¹. HBOT works by delivering 100% oxygen in a hyperbaric condition (increasing the pressure up to 2.0~3.0 ATA). Under hyperbaric conditions, a high oxygen gradient is formed across necrotic wounds, improving the thrombosis of microcirculation. HBOT is relatively safe in the general patient population, except for a few absolute contraindications including untreated pneumothorax, restrictive airway diseases, and concomitant chemotherapy¹². HBOT as an alternative treatment for LV was first reported by Yang et al.⁶ It has been reported that HBOT stimulates the fibrinolytic pathway and promotes angiogenesis and wound healing. In a clinical study, 8 out of 12 patients with LV ulcers obtained complete healing following HBOT therapy¹³. Also, Bhutani et al.¹⁴ have described two LV patients responding to HBOT by ulcer closure. In 2015, Ray et al.¹⁵ reported on a patient with increased homocysteine levels and LV ulcers treated successfully with HBOT. As opposed to our case, however, a combination of hyperhomocysteinemia and MTHFR gene polymorphism has not previously been reported in LV patients treated with HBOT.

Our patient had suffered from refractory LV that did not improve with conventional medications. Skin lesions that did not improve even after variable medicinal treatment for about six months, showed dramatic improvement with HBOT for seven weeks. Due to the natural course of the LV, which includes waxing and waning over time, the improvement observed in this patient may be spontaneous remission. However, the effectiveness of HBOT cannot be overlooked as HBOT resulted in a marked improvement in a short period of time. Considering the patient’s disease burden, the rapid treatment effect of HBOT has significant implications for refractory LV. Our case also revealed an MTHFR 677T/T homozygous polymorphism and a slight increase in serum homocysteine level at the follow-up visit. Irani-Hakime et al.¹⁶ reported that supplementation of folic acid and vitamin B12 was effective for an LV patient with MTHFR gene polymorphism. In 2013, we also reported a case of LV with MTHFR gene polymorphism, which was improved with the administration of 1 mg of folic acid daily⁵. According to a recent report, approximately one-third of 28 Korean LV patients who visited a single center had the MTHFR C677T TT homozygous polymorphism as seen in our case¹⁷. Although there were no significant differences in the severity and homocysteine level of LV according to the presence or absence of MTHFR C677T polymorphism in their study, we would like to report cases involving MTHFR C677T TT homozygous polymorphism in refractory LV patients. Thus far, there has been no recurrence of the skin lesion after HBOT, but if LV recurs, rivaroxaban, folic acid, and vitamin B12 should be added as additional medications.

In conclusion, we presented the effect of HBOT on refractory LV accompanied by MTHFR gene polymorphism.