What's new?

This study highlights the significance of cutaneous vasculitis (CV) as a marker of severe systemic lupus erythematosus (SLE). Our analysis of 1021 Polish patients with SLE (the largest cohort to date) showed that CV was associated with a longer disease duration, severe manifestations (such as heart failure and central nervous system involvement), and a specific autoantibody profile. Additionally, CV patients required more intensive immunosuppressive treatments, including azathioprine, belimumab, and cyclophosphamide. These findings underscore the need for early detection and aggressive management of CV in SLE to mitigate long‑term complications, especially damage to life‑critical organs, such as the heart and central nervous system.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems. It is characterized by production of autoantibodies against nuclear antigens, deposition of immune complexes, and persistent inflammation targeting the skin, joints, and kidneys.¹ The pathophysiology of SLE involves a complex interplay of genetic, environmental, and immune dysregulation factors, including defective clearance of immune complexes, impaired apoptotic cell removal, and abnormal activation of the type 1 interferon pathway, all of which contribute to the breakdown of immune tolerance and tissue damage.² Among the key pathological processes in SLE, vasculitis, defined as inflammatory infiltration and necrosis of blood vessel walls, is particularly significant.^3,4 This includes both systemic and cutaneous vasculitis (CV), with the latter referring specifically to inflammation involving vasculature of the skin.³ Not only does it serve as a hallmark of disease progression, but it is also one of the leading causes of mortality in individuals with established SLE.^3,4 The clinical presentation varies according to the vessel size and location, ranging from mild to severe complications.³ In general, skin lesions and rashes are among the most frequent dermatologic symptoms observed in patients with SLE, stemming from inflammation affecting small and medium‑sized blood vessels in the skin. CV often serves as a warning sign of potentially more severe and life‑threatening inflammatory processes occurring in vital organs of the body.⁵

Given its clinical significance, understanding the role of vasculitis in SLE is crucial for optimal clinical management. This vascular inflammatory process is highlighted in disease activity metrics, such as the SLE Disease Activity Inde × 2000 (SLEDAI‑2K), underscoring its importance in monitoring and managing SLE.⁴ Proper identification and management of vasculitis are crucial, as this condition often requires more aggressive treatment strategies to mitigate potentially fatal outcomes.⁶ The prevalence of SLE‑associated vasculitis has been reported to range from 11% to 36%, with small vessel vasculitis of the skin being the most commonly observed type, accounting for 82%–89% of cases.⁷ Ramos‑Casals et al⁸ identified CV in 68 of 670 patients with SLE, corresponding to a prevalence of 10.1%. However, these prevalence rates may be overestimated, and confirmation via skin biopsy could improve diagnostic precision and reduce overestimation.⁷ CV, often linked to systemic vasculitis or underlying connective tissue diseases such as SLE, requires prompt recognition and systematic evaluation to guide effective management and improve outcomes.⁹ Interestingly, in pediatric SLE patients, CV is notably prevalent, affecting 36% of cases, and is associated with unique features, such as male predominance, younger age at diagnosis, family history of SLE, conjunctivitis, low C3 levels, and presence of cytoplasmic antineutrophil cytoplasmic antibodies.¹⁰

In recent years, increasing attention has been paid to the pathophysiology of vasculitis in the course of SLE. For instance, Wu et al¹¹ observed elevated serum levels of growth arrest–specific protein 6 in SLE patients with CV, highlighting the role of this protein in inflammatory processes and its potential as a biomarker of disease activity. Next, endothelial cell activation, reflected by increased plasma levels of tissue plasminogen activator antigen, von Willebrand factor antigen, and tissue factor, was shown to play a central role in the pathophysiology of CV in SLE, contributing to a shift from an anticoagulant to a prothrombotic state, and driving local fibrin deposition and inflammatory vascular damage.¹² Furthermore, based on a study by D’Cruz et al,¹³ a high prevalence of antiendothelial cell antibodies in SLE patients with urticarial vasculitis highlights the potential role of these antibodies in endothelial damage and the pathogenesis of CV in this context. According to a study by Sahin et al,¹⁴ serum pentraxin‑3 levels are elevated in childhood‑onset SLE, and may serve as a significant mediator of active CV, correlating with disease activity, particularly in patients with mucocutaneous manifestations and Raynaud phenomenon.

Importantly, the diverse skin manifestations of lupus not only aid in making a diagnosis (through characteristic clinicopathological correlations) but also provide crucial prognostic and therapeutic guidance, highlighting the need for tailored treatment strategies based on specific lesion types and associated systemic risks.¹⁵ In fact, accurate diagnosis of cutaneous lupus erythematosus requires careful analysis of clinical, histological, serological, and immunofluorescence findings, particularly when dealing with lesser‑known variants and newly described features.¹⁶ Episodes of vasculitis in SLE frequently coincide with disease flares and are often accompanied by constitutional symptoms, such as fever, fatigue, and weight loss.³ Additionally, patients with vasculitis may exhibit higher rates of livedo reticularis, anemia, elevated erythrocyte sedimentation rate, and anti–Sjögren syndrome (SS) type B autoantibody positivity.³ Furthermore, overlapping conditions linked to SLE, such as SS and cryoglobulinemia, can also manifest as CV, complicating the classification and diagnostic framework of SLE‑associated vasculitis.⁷ Patients with CV may also report purpura, petechiae, or ulcers, particularly on the lower extremities, which consitute important diagnostic clues.⁷

To our knowledge, no studies to date have examined CV in a large cohort of SLE patients from Central or Eastern Europe, including Poland. Given the potential regional variations in clinical presentation and health care practices, such data may provide valuable insights into disease heterogeneity. To address this gap, we analyzed the clinical characteristics, laboratory features, and treatment outcomes of CV in a large Polish cohort of patients with SLE.

Patients and methods

Results

Discussion

This study presented clinical and laboratory characteristics of a large cohort of SLE patients treated at a single center, with a focus on individuals with CV. Our findings show that the presence of skin vasculitis impacts the clinical course of the disease. The variations in the occurrence of CV in SLE not only underscore the heterogeneous nature of the disease but also highlight critical pathways that may inform more personalized and targeted clinical interventions, which are highly recommended nowadays.²² To our best knowledge, this study describes one of the largest Polish cohorts of SLE patients in the literature, comparing various aspects of the disease based on the presence of skin vasculitis.

CV changes are not prevalent in SLE.²¹ In our study, only 6.27% of the patients presented with such manifestations. Our findings are in line with those reported in a multicenter cohort analyzed by Breillat et al.⁷ The authors concluded that CV in SLE was relatively rare, with a significant proportion of patients exhibiting no signs of active SLE at the time of diagnosis, emphasizing the need to rule out other potential causes of vasculitis. Importantly, Breillat et al⁷ investigated vasculitis in 39 SLE patients, with diagnoses confirmed by histologic examination in all of them—an aspect that significantly strengthens the validity of their findings in contrast to our study. However, in a study by Kallas et al,¹⁹ CV was found to be relatively frequent in SLE patients, with almost one‑fifth (17.4%) of the analyzed cohort presenting with skin vasculitis. These discrepancies might be related to different definitions of CV in SLE, and the findings should be interpreted with caution.

Our demographic analysis showed that the CV and non‑CV groups were comparable in terms of sex distribution and age at the time of the study. However, the patients with CV were younger at the onset of SLE, which aligns with previous reports suggesting that early‑onset lupus may be associated with more severe disease manifestations and complications.^23,24 The mortality rate was similar in both groups. It has been shown that skin manifestation in SLE may differ according to the age at the onset of the disease. Based on a study by Chottawornsak et al,²⁵ in juvenile‑onset SLE, acute cutaneous lupus erythematosus and nonscarring alopecia were associated with an increased risk of arthralgia, whereas in adult‑onset SLE, CV correlated with myositis, highlighting the distinct systemic involvements based on the age of onset.

CV in SLE is a significant manifestation, increasing the risk of complications and mortality.²⁶ The pathogenesis involves immune complex deposition in blood vessel walls, triggering inflammation and complement activation, leading to vascular damage.²⁶ Additionally, the presence of APLAs in SLE elevates the risk of thrombosis, worsening vascular complications and organ damage, especially involving the kidneys and cardiovascular system.²⁶ Chronic vascular inflammation might cause irreversible organ damage and increase susceptibility to infections due to immunosuppressive treatments used in managing SLE.²⁷ Our results emphasize that the primary cause of death in the CV group was linked to SLE exacerbation. Therefore, alongside CV, other vasculitic changes, such as those occurring in the CNS, should be considered as potential risk factors for death.

The clinical manifestations of SLE were markedly more severe in the CV group, with higher incidence of constitutional symptoms, mucocutaneous manifestations, and joint issues. Specifically, constitutional symptoms, such as fever, myalgia, weight loss, and lymphadenopathy, were more common in the CV group, as were mucocutaneous manifestations, including urticaria and oral / nasal ulcers. Interestingly, clinical presentations such as myositis and hematological manifestations have been suggested as predictors of CV development.¹⁹ In our analysis, no differences were found regarding the prevalence of kidney involvement. Thus, our results are in line with those reported by Shinjo et al,²⁸ who showed that among the SLE patients with CV, the frequency of renal and CNS involvement was similar to that observed in the non‑CV individuals. In contrast, Kallas et al¹⁹ highlighted that juvenile SLE patients presenting with CV alone may exhibit more granular casts in the urine sediment. Similarly, adult patients with CV may be more likely to develop renal symptoms in the course of SLE.¹⁹ However, in general, increased frequency of kidney involvement, including urinary casts, erythrocyturia, and leucocyturia, is a critical complication in SLE, and translates to worse long‑term prognosis.²⁹ Interestingly, we found no significant differences between the CV and non‑CV groups in terms of lung involvement, serositis, or lupoid hepatitis. Hence, reports of gastrointestinal and pulmonary vasculitis in patients with SLE are uncommon in the literature.²²

Of note, the CV group showed a higher prevalence of HF, a serious comorbidity that could contribute to their mortality rate. It seems that monitoring cardiovascular health in patients with SLE and CV is crucial, as HF may represent a significant complication that warrants early intervention and more aggressive management.³⁰ Furthermore, a recent study by Saleh et al³¹ pointed out the importance of monitoring systemic features, such as Raynaud phenomenon and cardiovascular involvement (both of which are predictive of CV) to facilitate timely intervention. In our study, Raynaud phenomenon was relatively frequent and occurred at a similar rate in both CV and non‑CV groups. Skin microvascular dysfunction in SLE patients, even without evident cardiovascular disease, may indicate early vascular damage, warranting further investigation.³² On the other hand, no significant differences between the CV and non‑CV patients were observed with respect to the frequency of arterial thromboembolic events or VTE occurrence, which might reflect similar thromboembolic risk profiles in both groups. Indeed, CV in SLE is important; as recently indicated by Saleh et al,³¹ patients with CV are more likely to develop at least 1 item of organ damage.

In our study, the prevalence of APS diagnosis was similar in the CV and non‑CV groups. A lack of differences in anticoagulant treatment further supports these findings. Classic APLAs (LA, aCL, and aβ2GPI of the IgG or IgM isotypes) are not always detectable in patients with clinical manifestations of APS.^33,34 In such cases, particularly when unexplained thromboembolic events or obstetric complications suggestive of APS are present, the possibility of noncriteria antibody presence should be considered.³³ These include IgA isotypes of aCL and aβ2GPI, antiphosphatidylserine‑prothrombin antibodies, and antibodies against domain I of β2GPI.³³ Testing for these noncriteria APLAs may be especially valuable in the cases of suspected seronegative APS, or when standard laboratory criteria yield inconclusive results despite clear clinical symptoms.³³

Early recognition of CV is essential, as it can serve as a key indicator of systemic involvement, particularly in autoimmune diseases such as SLE, and prompt appropriate diagnostic workup and treatment.³⁵ Indeed, presence of CV in SLE is associated with an increased risk of organ damage.¹⁹ Importantly, in a study by Lun et al,³⁶ vasculitis was identified as a significant risk factor for the development of pulmonary arterial hypertension in patients with SLE, with a higher risk observed in those with combined vasculitis (OR, 1.50; 95% CI, 1.08–2.07; P <⁠0.05).

SLE is a complex immune‑mediated disease associated with production of a wide variety of autoantibodies. In our study, the antibody profile of SLE patients with CV showed distinct differences in comparison with that of the non‑CV individuals, with anti‑SSA and anti‑RNP antibodies being more common in the CV group. These findings are consistent with previous studies reporting a strong association between certain autoantibodies, such as anti‑SSA and anti‑RNP, and more severe forms of SLE. While we observed no significant differences in other autoimmune markers, such as anti‑dsDNA or APLAs, the higher prevalence of anti‑SSA and anti‑RNP antibodies in the CV group could be indicative of a specific immunological subtype of SLE that is more prone to developing CV. Saleh et al³¹ observed a strong association of CV with anti‑Smith antibodies, anti‑dsDNA, and hypocomplementemia, which might highlight the role of autoantibodies and complement activation in its pathogenesis, reinforcing the need for serological monitoring in high‑risk SLE patients. Moreover, anti‑Ro antibody might serve as an independent serological marker for the development of CV in patients with SLE.³⁷ Recent research has focused on finding new antibodies that are potentially related to SLE manifestations and might explain its complex pathogenesis. For example, the findings from a study by Shi et al³⁸ underscore the importance of exploring nonroutinely measured autoantibodies, such as antiacidic ribosomal protein P0 and anti–galectin 3, which may play a key role in skin lesion development. These antibodies were found to correlate with lupus‑specific CV and other clinical manifestations, such as leukopenia and C3 deficiency, suggesting that they could serve as potential biomarkers of disease activity and provide new insights into the immune mechanisms underlying SLE‑related organ damage. In a study by Shinjo et al,²⁸ patients with SLE and CV were characterized by a higher prevalence of Raynaud phenomenon and anti–ribosomal P antibodies.

It has been postulated that CV might be related to disease activity in SLE.¹⁹ We did not collect data on disease activity (such as the SLEDAI score or complement levels) in our cohort. Nevertheless, Gamal et al³⁹ showed that higher SLEDAI scores at the disease onset were linked to the development of vasculitis, suggesting that high disease activity may drive vascular complications. In a study by Gheita et al,²⁶ hypocomplementemia, specifically low C3 and C4 levels, was found to be closely associated with CV in SLE, highlighting the role of complement activation in its pathogenesis. Additionally, the authors observed significant links between CV and lupus nephritis, cardiovascular manifestations, and SS, suggesting that CV may indicate more severe systemic involvement in SLE.

Cutaneous manifestations in general, such as subacute cutaneous lupus erythematosus and malar rash, are not only common in SLE patients but also closely correlate with higher disease activity and systemic involvement.⁴⁰ Clinicians should be particularly vigilant when observing these lesions, as they may signal more severe disease progression and an increased risk of complications, such as vasculitis, nephritis, and skin infections, warranting more frequent monitoring and aggressive management. Importantly, in a study by Olbrich et al,⁴¹ cutaneous lupus erythematosus, particularly its chronic discoid subtype, was found to be associated with an increased risk of various cardiac and vascular diseases, including thromboembolic events, such as pulmonary embolism, cerebral infarction, and acute myocardial infarction. Heil et al⁴² reported that lupus erythematosus skin disease was found to be common among SLE patients, and was associated with photosensitivity and presence of specific autoantibodies, but it did not significantly impact the severity of SLE sequelae, disease flares, or overall survival.

Regarding treatment, SLE patients with CV were more frequently prescribed aggressive immunosuppressive therapies, including azathioprine, cyclophosphamide, and belimumab. This reflects the more severe nature of their disease, as these treatments are typically used for patients with active or refractory disease. The fact that the CV group received a more intensive immunosuppressive regimen emphasizes the need for tailored treatment strategies for patients with this complication. However, it is also worth noting that both groups were similarly often treated with glucocorticoids, which remain a cornerstone of SLE therapy. Overall, our study highlights the more severe clinical course and worse prognosis of SLE patients with CV. These patients exhibit more frequent and severe systemic manifestations, higher comorbidity rates, and distinct antibody profiles, as compared with those without CV. Timely and targeted treatment of vascular changes in SLE is crucial, with antimalarials being the first‑line option for CV. More severe cases with visceral organ involvement may require aggressive immunosuppressive therapy, including corticosteroids, cyclophosphamide, and emerging biologics, such as like rituximab and belimumab for refractory cases.³ In fact, the marked decline in CV incidence over the 20‑year follow‑up, as reported by Saleh et al,³¹ suggests improvements in SLE management, particularly through the widespread use of antimalarials and immunosuppressants.