Volume 27 Number 2

Key messages

• LV ulcers occur mainly in middle-aged women
• Comorbidities are frequent, venous insufficiency, hypertension and prothrombotic conditions being the most frequent
• The main treatment consists of compression and antithrombotic/anticoagulant therapy

Introduction

Livedoid vasculopathy (LV) is a chronic, recurrent thrombo-occlusive cutaneous disease of the dermal vessels.^1,2 The hallmarks of LV are a combination of active and healed lesions, especially around the ankles. Active lesions consist of erythematous or purpuric plaques and papules that are painful, punched-out ulcers, and healed lesions consist of residual atrophic stellate white scars called atrophie blanche (AB) (Figure 1).^2,3 Clinical diagnosis is confirmed by the presence of fibrin occlusion and thrombus formation involving the upper and mid-dermal capillaries on the biopsies.³ According to Alavi et al, the main differential diagnosis of LV is cutaneous polyarteritis nodosa, but it must be distinguished also from other conditions that produce similar cutaneous lesions on legs.⁴

 

Figure 1. Atrophie blanche.

 

LV can be primary (idiopathic) or associated with abnormalities in coagulation or fibrinolysis, or with autoimmune or other diseases. It is estimated that 50% of the patients with LV have no identifiable association with a hypercoagulable condition.⁵

Its estimated prevalence is 1 in 100,000 people in North America.⁶ Women are particularly affected; in a Chinese study the female to male ratio was 3:1.⁷ Livedoid vasculopathy commonly occurs between the ages of 15 and 50 years.¹ In a recent Korean study of 40 patients, the youngest LV patient was 12 and the oldest was 65.⁸ There is currently no data regarding LV in European Nordic countries.

We reviewed retrospectively the epidemiological and clinical features, as well as comorbidities, treatment, and outcomes in LV patients that attended a tertiary care hospital, Department of Dermatology, Helsinki University Hospital (HUH)) between the beginning of the year 2014 and the end of 2019. Patients were referred to our department from primary care from the Uusimaa region when there was suspicion of an atypical wound or a wound that did not show signs of healing within two months.

Methods

Patients were identified from our database from 1 January 2014 to 31 December 2019 with the ICD 10 code for Livedoid Vasculopathy, L95.0. Diagnosis of LV was confirmed based on clinical and histopathological findings. Inclusion criteria were clinical features,¹ including punched-out ulcers or AB on the feet, ankle or leg; and histopathological features⁶ demonstrating fibrinoid deposits at blood vessel walls or intraluminal thrombosis. Patients with another cause for leg ulcers were excluded.

We collected for each patient the following: gender, age at diagnosis, place of birth, ethnicity, family history of LV, smoking, localisation of the lesions, comorbidities including coagulopathies and autoimmune diseases, treatment and outcomes. As there are no specific guidelines for the treatment of livedoid vasculopathy, patients were treated with a personalised approach depending on the severity of the disease. Outcomes were classified as “complete improvement”, “partial improvement” and “no improvement”. Complete improvement was defined as complete ulcer healing. Partial improvement was defined as improvement in ulcerative lesions after treatment without reaching complete healing. Patients with no improvement were patients that had new lesions or active lesions despite treatment.

The study protocol was approved by the Inflammatory Center Research Committee of Helsinki University Hospital.

Results

Twenty-four patients were included, of which 62.5% were women, female to male ratio being 1,7:1.  Demographic data, prothrombotic and inflammatory conditions, and comorbidities of the LV patients are given in Table 1.

 

Table 1 Demographic data, prothrombotic and inflammatory conditions and comorbidities of 24 patients with livedoid vasculopathy (LV).

 

Twenty-one of our 24 LV patients were screened, and we found prothrombotic and inflammatory markers in 12 (57%) of them. Five (42%) of those 12 patients were men. The mean age of those 12 at the time of symptom onset was almost the same; 48.5 years, compared to 46.4 years of the total group. Current mean age of those 12 was 63 years, compared to 55 years of the total group. Mean age at the time of diagnosis was 61 years, which is six years later than the total group (55 years). Mean time of symptom duration was 12.3 years, a little longer than 9.7 years of the population. 58% of the 12 had a history of deep vein insufficiency detected by duplex ultrasound, and 33.3% had deep vein thrombosis; these figures are almost equal in both groups. 17% had peripheral arterial disease, and 17% had rheumatoid arthritis. One of these patients was the most difficult LV case treated at our clinic, but the other 11 had a similar clinical presentation of LV than all others. The only difference in comorbidities between the groups was that 17% of the 12 had rheumatoid arthritis, compared to 12% of the whole group.

Nineteen of our LV patients had one or more comorbidity. The most frequent comorbidities in our patients were venous insufficiency 58%, hypertension 38%, deep vein thrombosis 33%, and hyperlipidemia 29%.

Table 2 shows dermatological manifestations in LV patients and the locations of punched-out ulcers. Most of the patients (96%) present the classical features of LV (punched out ulcers, purpura, pigmentation and atrophie blanche) (Figure 2). Half of the patients had ulcers on the 1/3 inferior part of the leg. Livedo racemosa (16.7%) was rare. Four patients had livedo racemosa in lower legs and three had it on foot. Two had livedo racemosa in upper leg and lower arm, and one had livedo racemosa on upper arm and trunk. Interestingly, there was only one seasonal exacerbation, and it was in summer.

 

Table 2 Clinical characteristics of LV lesions in our cohort.

 

Treatments and treatment efficacy for medications are shown in Tables 3, 4, and 5. Most of our patients had already had some medication before being referred to our clinic. Compression therapy is the standard care for every LV patient, if no contraindication.⁹ It usually starts with bandages, and once the wounds were healed, it is continued with compression stockings. 11/24 of our LV patients used bandages at some point, and 16/24 were able to use compression stockings in the end.

 

Table 3. First treatment and treatment efficacy, 24 LV patients.

 

Table 4. Second treatment and treatment efficacy, 19 LV patients needed second treatments.

 

Table 5 Third treatment, 8 patients needed third treatments.

 

Table 3 shows the medication we continued or the medication we started at the first appointment in our clinic. The most common first-line treatments were aspirin in 10/24 patients, and prednisolone in 10/24 respectively. 17 (79%) patients were completely healed, but due to the recurrent nature of LV, second-line treatments were needed in 12 of the 17 (70.5%). Three of the patients did not heal with first-line treatment, two of them were female and the age at LV diagnosis varied between 23 and 56. One had Factor V Leiden mutation. All of them were first treated with aspirin, and two of them had also prednisolone.

The most common second-line medications were enoxaparin in 6/19 patients, and prednisolone 6/19. With the second treatment, 15 patients recovered completely and two received partial improvement. Two patients did not heal with second-line treatment. They were both females, and their ages at the time of diagnosis were 52 and 54. The duration of their symptoms was seven and 38 years, respectively. Both had prothrombotic conditions, the other activated protein C resistance and Factor V Leiden Mutation, and the other had elevated Factor VIII activity. Second-line treatments for them were warfarin for the other, and aspirin combined with pentoxifylline for the other. Third-line treatment was needed in 8/24 cases.

Table 6 shows total healing time in months and the treatment at the end date of the study for all the 24 patients. 18/24 patients had totally healed wounds. Four patients had recurrent wounds, the wounds were healed, but then opened again. The wounds opened again within 2–9 months. The same previously mentioned two patients had open wounds that were not totally healed at any time during this study. Their treatment at the end date of the study was rivaroxaban and enoxaparin. The most common treatment at the end was enoxaparin (10 patients), either alone or combined with other treatments. The next most common treatments were rivaroxaban in four patients and aspirin combined with pentoxifylline in three patients. The duration of the treatment is shown in the last column of Table 6. The median duration of treatment was 11 months.

 

Table 6. Total wound healing, months and treatment at the end date of the study or when wounds healed, 24 LV patients

 

Discussion

To the best of our knowledge, we report here the very first series of LV patients in the Nordic countries.

We found a female predominance in our cohort (62.5%). The median age of the study population at the time of diagnosis was 53.5 years. Both facts are similar to data published by Weishaupt et al³, while others^10,11 have described higher percentages of females. In the study conducted by Criado et al¹⁰ and Gardette et al¹², 78.66% and 70%, respectively, were women. A study by Renner et al¹³ found a women to men ratio 2.1:1. Other studies have also reported a younger population; the median age was 39.97 years in Criado et al study¹⁰ and 45 years in Hairston et al study.¹⁴

The mean time between symptom onset and definitive diagnosis was 8.3 years. This is a considerably longer interval than found in Gardette et al study,¹² which had a median interval of 3.4 years. In Criado et al study⁹ the time between symptom onset and LV diagnosis ranged from 1 to 20 years, the median was 6.65 years. In general, the diagnosis is often delayed because many LV ulcers are treated as “merely” venous insufficiency ulcers, not considering the possibility of LV. The delay in diagnosis indicates that the disease is still rather poorly known and difficult to diagnose. Of course, the delay can be attributed also to differences in health care organisation.

One of our patients had a positive family history of LV, but the family history was documented in patient files only in 11/24 patients. Documentation was also lacking often on smoking. This underlines the importance of checklists when assessing a patient with a wound, which has been recommended in earlier publications.¹⁵

With regards to prothrombotic and proinflammatory conditions, 21 patients were screened, and we found positive parameters in 12 of them (57 %). One patient could have more than one prothrombotic/inflammatory condition. This is in line with other literature, as it has been estimated that 50% of the patients with LV have an identifiable association with a hypercoagulable condition.⁵ The Weishaupt et al study found prothrombotic parameters in 11/25 (44%) of LV patients.³

The full-blown form of LV is characterised by the triad of ulcerations on the distal aspects of legs, atrophie blanche and livedo racemosa. These typical features do not necessarily have to be present simultaneously.² The occurrence of ulcers in our study was 95.8% in LV patients, and the distribution was typical: all of the patients had ulcers in the ankle region, 59.1% of them had ulcers also in foot, and 50% also in lower legs. Previous studies have shown that livedo racemosa is often, but not always, associated with LV, and that lesions occur in a manner that is generally symmetrical.¹ In our study, only 4 patients (16.7%) had livedo racemosa. 14 patients (58.3%) had bilateral disease. Surprisingly seasonal (summer) exacerbation was detected only in 1/24 patients. In the Criado et al study,¹⁰ LV flares related to seasonality were reported by 38.66%, and in other studies, the number has been as high as 87.5%.⁷ One possible explanation for this difference is that in Finland outside temperature fluctuates a lot, but inside temperatures are almost always the same, and summers are quite mild, so there is less venous stasis and oedema in lower legs during summertime.

Nineteen of our 24 LV patients had one or more comorbidities. The most frequent comorbidity was venous insufficiency detected by dupplex ultrasound (58.3%). The frequency of deep vein thrombosis was 33.3%. This figure is much higher than found in the Weishaupt et al study, where the frequency was 11%.³ Five of our eight deep vein thrombosis patients had also prothrombotic conditions; three had activated protein C resistance, one had elevated factor VIII activity and one had factor V Leiden mutation. Also, peripheral arterial disease (16.7%) was common. Diseases that have earlier been reported to be associated with LV are, among others, cutaneous vasculitis, rheumatoid arthritis (RA),¹⁶ and mixed connective tissue disorders (MCTD).¹⁷ 12.5% of our patients had RA, and one had MCTD.

There is currently no consensus on treatment of LV, as no randomised or controlled studies have been performed.¹⁸ Finding an effective therapy is a challenge because response to treatments remains variable from one patient to another, durations of flares can vary, and patients might heal spontaneously.¹² Also, the incidence of the disease is low. In a recent study an algorithmic therapeutic approach of livedoid vasculopathy was proposed.¹⁹ In a review the most prescribed treatment was anticoagulation in 98% of cases and among anticoagulant therapies, rivaroxaban was the most common (54%).⁶ In our study, prednisolone and aspirin were most often used as a first-line therapy. Patients with livedoid vasculopathy do not receive reimbursement from the Finnish Social Insurance Institution for anticoagulant drugs, and thus in Finland, the treatment is often started with cheaper alternatives. However, considering the tendency for slow healing and painful ulcers, it is obvious, that anticoagulant medication is a proper option already from the beginning, especially for recurrent or very painful ulcers. If those don’t help, pentoxifylline is often added or treatment is switched to enoxaparin or rivaroxaban.

Limitations and recommendations

The limitations of our study include the retrospective collection of data, which led to some discrepancies in data collection (e.g. smoking). One limitation is also the relatively small number of patients, as the prevalence of LV is low. Further studies should explore prospective data with a structured demographic collection and clear outcomes.

Conclusion and implications for clinical practice

LV belongs to the category of atypical wounds. Its prevalence is low, and it has a female predominace. The full-blown form of LV is characterised by the triad of ulcerations on the distal aspects of legs, atrophie blanche and livedo racemosa. These typical features do not necessarily have to be present simultaneously. Comorbidities are frequent, as well as prothrombotic conditions. The main treatment consists of compression therapy, aspirin and prednisolone, but second-line treatments include anticoagulants, such as enoxaparin and rivaroxaban.

Author contributions

Hanna Köykkä collected, analyzed and reported the data. Nicolas Kluger and Kirsi Isoherranen contributed to the study protocol, reporting and writing the final version of the manuscript.

Conflict of interest

The authors declare no conflicts of interest.

Funding

The authors received no funding for this study.

Author(s)

Hanna Köykkä¹, Nicolas Kluger¹ and Kirsi Isoherranen*¹ ORCID 0000-0002-0253-2567
¹Department of Dermatology, Inflammatory Center, Helsinki University Hospital and Helsinki University, Finland

*Corresponding author email Kirsi.isoherranen@hus.fi

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