Prevalence of Livedoid Vasculopathy Among Patients with Connective Tissue Diseases and Its Association with Thrombophilic Factors: A Hospital-Based Retrospective Cohort (2014–2021)

Introduction

Livedoid vasculopathy (LV) is an uncommon, persistent inflammatory skin disorder characterised by painful, ulcerative lesions that usually affect the veins supplying the lower limbs.¹ LV has also been referred to as livedo vasculitis, livedoid vasculitis, and livedo reticularis with summer ulceration.² The term LV was first used by Bard and Winkelman in 1967.³ LV is identified as a recurring thrombo-occlusive vascular disorder with an unknown precise etiology. It is believed to be complex and potentially related to autoimmune and microvascular dysfunction. Increased thrombotic activity, decreased fibrinolytic activity, and endothelial injury are thought to contribute to thrombus development in the capillary vasculature, leading to the disease.⁴

Although inflammation is secondary in LV, hypercoagulability is the primary pathology. Consequently, LV differs from inflammatory vasculitis and is categorized as a vasculopathy, a coagulation disorder that occurs when a thrombus forms in the arterial lumen, impairing blood flow. LV often affects both legs and has a chronic history with sporadic and recurrent exacerbations.⁵ Definitive diagnosis of LV is based on histopathological results and clinical symptoms. LV significantly impacts patients’ quality of life due to its painful, scarring, and recurring clinical course. The main complaint from LV patients is acute pain, which significantly affects social activities, daily routines, study, work, walking, and overall quality of life.⁶ Early disease prognosis and treatment approaches may reduce discomfort and minimize scarring, deformity, and other complications.² Prompt recognition of LV especially in patients with systemic autoimmune disease should trigger evaluation for thrombophilia and microvascular dysfunction. Management is often antithrombotic (± immunomodulation) rather than immunosuppression alone, with early, multidisciplinary care improving pain, healing, and scarring.⁷

A group of autoimmune diseases known as connective tissue diseases (CTDs) damage and inflame the body’s connective tissues, causing inflammation and harm to various organs. A higher risk of vascular problems has been linked to several CTDs, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s syndrome (SS), and dermatomyositis/polymyositis (DM/PM).⁸ CTDs often involve microvascular injury—eg, Raynaud phenomenon and digital ischemia in SSc (endothelial dysfunction, luminal narrowing), immune-complex vasculitis in SLE (complement-mediated endothelial damage), and aPL-related hypercoagulability—mechanisms that align with LV’s thrombo-occlusive pathophysiology. Prior evidence is largely small case reports/series linking LV with SLE, SSc, SS, RA, and aPL positivity, typically without biopsy confirmation, clear denominators, or comparator groups. This study addresses that gap by quantifying LV within a defined, hospital-screened cohort and testing CTD-linked clinical and serologic associations.

Although LV appears rare in the general population based mainly on small clinic-based series, patients with CTDs who are predisposed to microvascular injury and thrombosis may carry a higher burden. However, the association between LV and CTDs remains incompletely defined, and prevalence data in CTD cohorts are limited. Therefore, this study investigates the hospital-based prevalence of LV among patients with CTDs and explores relevant clinical associations. Clarifying this relationship may illuminate shared pathogenic mechanisms and inform more targeted diagnostic and treatment strategies for LV in CTD populations.

Materials and Methods

This epidemiological study used a retrospective cohort design to estimate the prevalence of livedoid vasculopathy (LV) among patients with connective tissue diseases (CTDs) within Mass General Brigham (MGB), an integrated continuum-of-care system serving ~6 million patients. We queried the MGB Research Patient Data Registry (RPDR; ~6 million patients) for encounters between January 1, 2014, and June 1, 2021, identifying adults with CTDs—including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), and dermatomyositis/polymyositis (DM/PM)—and ascertaining LV using diagnosis codes and targeted keyword searches (with chart review as needed). All eligible CTD patients in RPDR during the study window were included.

Electronic medical records (EMRs) of eligible patients were reviewed to collect relevant demographic and clinical data, including age, gender, type of CTD, duration of CTD diagnosis, presence of LV, and all pertinent laboratory findings such as antiphospholipid antibodies, cryoglobulins, and antinuclear antibodies. Diagnosis of LV was established based on clinical manifestations consistent with the condition, including painful ulcers with atrophic, porcelain-white centers, surrounded by purpuric borders, on the lower extremities. Histopathological confirmation was not mandatory for inclusion.

This study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Mass General Brigham. Patient confidentiality was strictly maintained throughout the study, and informed consent was waived due to its retrospective nature.

Statistical analysis was performed using SPSS version 26. Chi-square test or Fisher’s exact test was used to compare categorical variables. A p-value < 0.05 was considered statistically significant.

Results

A total of 1730 charts were reviewed, resulting in 108 patients diagnosed with LV. Among the reviewed group, LV represented 6.2% (108/1730). Relative to the 6,000,000 patients in the MGB RPDR, this reflects a hospital-system registered prevalence of 0.0018% (108/6,000,000), or 1.8 per 100,000. Most of the patients were women (80/108, 74.1%), while men made up 28/108 (25.9%). The average age was 44.9 ± 8.2 years. Age distribution was: 41–50 years: 32/108 (29.6%); 51–60 years: 23/108 (21.3%). Race/ethnicity data show: White 91/108 (84.3%), Asian 7/108 (6.5%), Hispanic 5/108 (4.6%). Table 1

Table 1 Demographic Characteristics of the Patients with LV (n=108)

The results regarding the prevalence of autoimmune disorders in conjunction with LV are summarized in Table 2. A total of 17 patients had autoimmune diseases, with a higher number of females, 14 (82.35%), compared to males, 3 (17.64%). The largest group was those aged 31–40 years, with 5 patients (29.41%). Concerning racial demographics, most individuals were White 11 (64.70%), while a smaller proportion identified as Black 2 (11.76%), Hispanic 2 (11.76%), Asian 1 (5.88%), and Other 1 (5.88%) (Table 2).

Table 2 Frequency of Autoimmune Disease with LV (n=17)

In this study, encompassing 17 (15.74%) patients diagnosed with autoimmune diseases, systemic lupus erythematosus (SLE) emerged as the predominant condition, affecting 10 (58.82%) individuals. The majority of SLE cases comprised female patients (70%), with 5 (50%) falling within the age group of 41–50 years. Dermatomyositis was identified in 2 (11.76%) patients, all of whom were female and primarily within the 41–50 age group. Systemic sclerosis was manifested in 2 (11.76%) patients, all female, concentrated within the 50-year age group. Additionally, Sjogren’s syndrome was identified in 3(17.64%) patients, all female and in the age group >50 years. Figure 1

Figure 1 Patients with Autoimmune disease.

In examining serological markers for LV, positive results were observed in 62 (57.40%) for phospholipid antibodies, while 46 (42.59%) tested negative, yielding a p-value of 0.065. For anticardiolipin antibodies, 47 (43.51%) tested positive, while 61 (56.48%) were negative, resulting in a p-value of 0.095. Hyperhomocysteinemia was detected in 56 (51.85%) and absent in 52 (48.14%), showing a non-significant p-value of 0.952. Activated C resistance was found in 13 (12.03%), while 95 (87.96%) showed no evidence, with a p-value of 0.088. Table 3.

Table 3 Comparison of Serological Marker Prevalence Among Patients with Livedoid Vasculopathy (n=108)

Discussion

Livedoid vasculopathy (LV) is an uncommon disorder, with an approximated prevalence rate of 1 in 100,000.⁸ It significantly infects females as compared to males, with a ratio of 3:1, and affects primarily young to middle-aged individuals.^9,10 Consistent with these studies, our findings indicate a prevalence rate of 1.8% in individuals with connective tissue disease. Similarly, a significant female predominance was observed, with 80% of patients being female.¹¹ This increased risk for LV in women was related to sex-specific physiological conditions, such as pregnancy¹² or a higher incidence of LV-associated conditions, such as connective tissue diseases, hypercoagulable states, and venous stasis, in women.

The high prevalence rate was observed among the 41–50-year age group screened for connective tissue diseases (CTDs). This indicates that LV primarily affects middle-aged adults, which aligns with previous reports showing the age range from 32 to 53 years in other study populations.^13–15 This finding offers valuable data on the prevalence of LV within this specific patient population. The racial distribution of the sample showed that the majority of patients infected with LV were white,^16–19 followed by Asian,^20–23 and the Hispanic population.²⁴ While the study offers a snapshot of the racial composition within our specific patient population, the racial distribution (majority white) may not accurately represent the broader population. Further research involving more diverse populations is necessary to ascertain whether racial disparities exist in LV prevalence among CTD patients.

LV disorders are most common in individuals with connective tissue issues compared to the general population. A retrospective study on 45 patients with LV, Hairston et al found that six individuals had associated connective tissue diseases.²⁵ However, these abrasions were initially linked to vasculitis, but now it has been investigated that inflammation injury of vessels has been associated with fewer than 20% of lesions in CTD populations.²⁶ A significant association was observed between LV and the presence of autoimmune disorders. Our study showed that up to 15.74% of the LV-infected individuals were positive for CTD, including systemic lupus erythematosus (SLE), which emerged as the predominant condition co-occurring with LV, with the majority of SLE cases comprising female patients. Subsequently, Sjogren’s syndrome was identified as a moderate condition in LV patients, all of whom were females. Remarkably, all individuals with Sjogren’s syndrome identified were females over 50 years old, suggesting a potential age-related link. In contrast, previous studies show that LV is uncommon in systemic lupus erythematosus (SLE); however, when it persists, it is mostly associated with antiphospholipid antibodies. Sopeña et al reported that individuals with a previous history of LV and a background of SLE reveal negative antiphospholipid antibodies,²⁷ Indicating that alternative pathways, such as the presence of circulating immune complexes, may play a crucial role in the progression of lupus vasculitis (LV) within the systemic lupus erythematosus (SLE) population. However, other studies have reported that rheumatoid arthritis (RA) is the most common connective tissue disease (CTD) associated with LV. Additionally, undifferentiated CTDs, mixed CTDs, and scleroderma were also observed within the CTD population in similar proportions.^25,28 A subsequent study conducted by Cardoso et al examined LV within a population afflicted by Sjögren’s syndrome, indicating that the condition has been associated with mutations in the enzyme methylenetetrahydrofolate reductase, which contribute to a hypercoagulable state. This finding implies a potential correlation between LV and Sjögren’s disease.¹⁹ However, Further exploration with larger sample sizes is required to validate these associations and investigate underlying pathways.

Regarding serological markers, our findings indicate the presence of phospholipid antibodies with moderate positivity following anticardiolipin antibodies. Hyperhomocysteinemia and Activated C resistance did not demonstrate significant evidence respectively. Individuals with antiphospholipid antibodies are particularly exposed to LV. In a retrospective study conducted by Hairston et al,²⁵ shows that anticoagulant was detected in 17.9% of individuals exhibiting LV, whilst anticardiolipin antibodies were identified in 28.6% of the subjects. Additionally, a separate study suggested that LV might represent a manifestation of antiphospholipid syndrome, which is associated with elevated levels of anticardiolipin antibodies.²⁹ However, the serological marker in our study shows no significant importance. Therefore, larger studies with accurate control groups are essential to definitively determine the association of these markers with LV in CTD individuals. Finally, this investigation provides valuable insights into the characteristics of LV patients within the CTD population. The observed co-occurrence of LV with autoimmune disorders, particularly SLE, suggests a potential link. However, limitations such as selection bias and non-significant serological marker analysis require further investigation. Replicating the study with a more diverse population, including control groups without LV to strengthen comparisons, investigating the biological mechanisms connecting LV and specific autoimmune disorders, and exploring the potential influence of CTD medications on LV development are necessary. Conducting additional research could lead to a more comprehensive understanding of LV in CTD patients, ultimately improving diagnostic tools and treatments approaches.

Conclusion

This study reveals a notable prevalence of livedoid vasculopathy (LV) among patients with connective tissue diseases (CTDs), with a significant female predominance and a higher occurrence in middle-aged adults. The link between LV and autoimmune conditions, particularly systemic lupus erythematosus (SLE), underscores the need for increased clinical vigilance. Although serological markers such as phospholipid antibodies, anticardiolipin antibodies, hyperhomocysteinemia, and activated C resistance showed trends toward association with LV, they were not statistically significant.