Capillaroscopic insights: exploring the connection between microvascular changes and pulmonary manifestations in systemic sclerosis

This cross-sectional study included 63 patients diagnosed as SSc, according to the ACR/EULAR criteria for SSc [15]. The SSc patients who presented to the clinic of Rheumatology of the Emergency County Hospital of Craiova, were consecutively included in the study between January 2015 and January 2019. The exclusion criteria for the study were being younger than 18 years of age, having hand disorders related to diabetes mellitus, neurological disorders, erosive osteoarthritis, hand surgery or trauma.

For all patients detailed medical history and clinical examination were performed. The presence of digital ulcer (DU) were evaluated separately, and the severity was assessed based on the Visual Analogue Scales (VAS). The dermal skin thickness was measured by the modified Rodnan skin score (mRSS). Modified Rodnan skin score (mRSS) has been classified as: normal = 0, mild between 1 and 14, moderate between 15 and 29, severe between 30 and 39, endstage >40 [18]. Pain, fatigue, and patient global assessment (PGA) were also evaluated on VAS. The Health Assessment Questionnaire (HAQ) was used to evaluate physical disability. All of the patients included in the database gave their informed consent, and the study was approved by the institutional Ethics Committee.

Internal organ involvement was evaluated based on patient presentation using high-resolution chest CT (HRCT) without contrast. All patients underwent pulmonary function tests (PFTs) with diffusing capacity for carbon monoxide (DLCO) adjusted for hemoglobin levels. Restrictive lung disease was diagnosed in patients with a DLCO of less than 70%. Additionally, a Doppler echocardiogram was performed to assess left ventricular ejection fraction and estimate pulmonary artery systolic pressure (sPAP); an estimated sPAP of ≥25 mmHg was considered abnormal [19].

Nailfold videocapillaroscopy (NVC) was performed on all patients by the same operator, blinded to clinical details, using an optical probe videocapillaroscopy (Smart G-Scope, Genie Tech, Seoul, Republic of Korea) equipped with ×250 contact lenses. Fingers affected by local recent trauma were excluded from analysis as well as those with recent manicure during the previous 4 weeks. The hand was placed at the heart level, without pressure over the table with standard temperature to avoid any influence on the circulation. A drop of cedar oil was placed over the nailfold to improve skin transparency. About a millimeter of the nailfold area was visualized in order to provide the opportunity for assessment of both capillary distribution and density as well as details in the morphology of single-capillary loops. After acclimatizing the patients for 15–20 minuted at room temperature (around 25°C), capillaroscopic examination was performed at 8 fingers (II–V bilaterally).

Capillaries were classified as dilated if the arterial limb diameter exceeded 15 µm or the venous limb diameter exceeded 20 µm. Microvessels with diameters over 50 µm were labeled as giant capillary loops or megacapillaries. Mean capillary density, defined as the number of capillary loops per 1 mm in the distal row, typically ranged from 7 to 16 capillaries per mm. Avascular areas were gaps greater than 500 µm between adjacent capillary loops in the distal rows. Neoangiogenesis was identified by the presence of more than 1–3 capillary loops originating from the same vessel in a single dermal papilla, with a ramified and bushy appearance.

The following parameters were evaluated based on previous classifications: the presence of dilated and giant capillaries, hemorrhages, capillary loss (avascularity), and ramified or bushy capillaries.

Statistical analyses were conducted using GraphPad Prism version 8. Initially, the normality of the data was assessed using both the Shapiro-Wilk test and the Kolmogorov-Smirnov test. Data that passed the normality checks were analyzed for statistical significance using the one-way ANOVA test. For data that did not meet the normality criteria, the Kruskal-Wallis test was employed to determine statistical significance. To evaluate the relationships and correlations between different groups, Pearson correlation analysis (Pearson r) was performed. Statistical significance was defined as a p-value of less than 0.05. All results were reported with their respective 95% confidence intervals and R squared values where applicable.

Understanding and managing SSc requires early detection of microvascular abnormalities, which precede other pathological events. NVC has emerged as a valuable non-invasive tool for visualizing these microvascular changes, making it an essential technique in the clinical assessment of SSc. At the nailfold, capillaries run parallel to the skin surface rather than perpendicular, allowing their structure to be easily visualized [21].

SSc microangiopathy is an initial and evolving phenomenon that can transition through various stages of microvascular damage as the disease progresses. Over a five-year follow-up period, 47% of SSc patients transitioned from an ‘early’ to an ‘active’ or ‘late’ pattern of microangiopathy [22]. The relationship between NVC patterns and clinical manifestations of SSc likely stems from shared pathogenic mechanisms affecting the microvasculature at multiple levels, reinforcing the idea that microvessel injury is a central component of the disease’s complex pathogenesis.

The prognosis of SSc is largely influenced by the degree and severity of internal organ involvement, especially cardiopulmonary complications, which are the primary causes of mortality in this population. The often subtle onset of heart and lung disease that gradually advances to more severe stages necessitates the early detection of specific SSc subgroups at higher risk for cardiopulmonary complications. This remains a significant unmet need in everyday clinical practice [23,24].

Pulmonary complications in SSc encompass interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). Screening all SSc patients for ILD and PAH at the time of diagnosis and regularly thereafter is essential. These conditions are the leading causes of mortality in SSc, contributing to 33% and 28% of deaths, respectively [23]. Although ILD is more frequently observed in diffuse cutaneous SSc (dcSSc) and PAH in limited cutaneous SSc (lcSSc), both conditions can occur in any SSc subset.

Recent guidelines recommend the use of high-resolution computed tomography (HRCT) for diagnosing ILD in SSc patients during the initial visit and after confirming an ILD diagnosis. To assess the extent and severity of ILD, a combination of HRCT and pulmonary function tests is advised. Screening for PAH involves transthoracic echocardiography, which has a sensitivity of 90%, although a definitive diagnosis should be confirmed through right heart catheterization [25,26].

Nailfold videocapillaroscopy (NVC) is a validated method for assessing peripheral vascular damage. Numerous studies indicate that NVC provides an accurate evaluation of microvascular damage in SSc and can predict internal organ involvement, such as lung impairment [27].

Our study investigated the demographic, clinical, and microvascular characteristics of 63 SSc patients, utilizing NVC to classify the patterns of microangiopathy and correlate these with various clinical manifestations. The predominantly female cohort (95%) had an average age of 49 years and a disease duration of approximately 42 months, indicating a population in the middle stages of disease progression. The study’s findings underscore the significant burden of systemic manifestations and complications in this population, particularly ILD and PAH.

The analysis of NVC patterns revealed a clear progression of microvascular damage from early to late stages of SSc. In the early pattern group, patients predominantly exhibited lcSSc with minimal skin involvement, as evidenced by a low mean modified Rodnan skin score (mRSS) of 2.36 and the absence of digital ulcers (DU). These patients also had lower rates of ILD (38.10%) and PAH (4.76%), reflecting less severe systemic involvement. This early stage is characterized by better overall functional status, as indicated by lower Health Assessment Questionnaire (HAQ) scores (mean 0.30), moderate fatigue (mean Visual Analogue Scale (VAS) score of 3.29), and moderate disease impact (mean Patient Global Assessment (PGA) score of 4.71). Pain levels were notably higher in this group (mean VAS score of 5.00), possibly due to the initial inflammatory processes associated with the disease onset.

As the disease progresses to the active pattern, there is a notable shift towards more severe involvement. The proportion of patients with dcSSc increases to 34.38%, accompanied by a higher mean mRSS of 10.40, indicating more significant skin thickening. The emergence of DU in 15.63% of patients signifies worsening vascular involvement. This stage also shows an increased prevalence of ILD (65.63%) and PAH (37.5%), suggesting that as SSc progresses, there is a marked escalation in systemic complications. Functional impairment becomes more pronounced in the active pattern, with higher fatigue levels (mean VAS score of 5.81), increased disease burden (mean PGA score of 5.52), and greater disability (mean HAQ score of 0.48). Pain levels decrease in this stage (mean VAS score of 2.78), which might be attributed to the transition from inflammatory to fibrotic processes.

The late pattern group represents the most advanced stage of SSc, with severe microvascular and systemic involvement. This group has the highest mean mRSS of 18.00, reflecting extensive skin thickening. DU are prevalent in 80% of these patients, underscoring the severe vascular complications. The majority of patients in this stage have dcSSc (70%), which is associated with the highest rates of ILD (90%) and PAH (70%). The functional status of patients in the late pattern is significantly impaired, with the highest levels of fatigue (mean VAS score of 6.30) and functional disability (mean HAQ score of 0.62), despite the lowest pain levels (mean VAS score of 2.50). This pattern illustrates the cumulative impact of long-term disease progression and the substantial burden on patients’ quality of life.

The study’s correlation analyses provide further insights into the relationships between microvascular damage and systemic complications. The strong positive correlation between ILD and capillary loss (Pearson r = 0.7255) indicates that as capillary loss increases, the severity or presence of ILD also tends to increase. The 95% confidence interval (0.5824 to 0.8250) and the R squared value of 0.5263 suggest that capillary loss explains a substantial portion of the variance in ILD, highlighting its critical role in the disease process. The highly significant p value (<0.0001) reinforces the reliability of this finding and underscores the importance of monitoring capillary changes as a potential indicator of lung involvement in SSc. These results suggest that early detection of capillary loss through NVC could facilitate timely interventions to mitigate the progression of ILD.

Similarly, the correlation between PAH and capillary loss (Pearson r = 0.6369) reveals a substantial relationship, with capillary loss explaining approximately 40.57% of the variance in PAH. The 95% confidence interval (0.4621 to 0.7641) and the significant p value (<0.0001) confirm the robustness of this association. This finding suggests that capillary loss is a significant factor in the development or severity of PAH in SSc patients. Additionally, the moderate positive correlation between PAH and neoangiogenesis (Pearson r = 0.5592) indicates that increased neoangiogenesis is associated with higher instances or severity of PAH, though to a lesser extent than capillary loss. The R squared value of 0.3127 and the significant p value (<0.0001) support the validity of this relationship, highlighting the complex interplay between vascular remodeling processes and pulmonary hypertension in SSc.

Moreover, the study’s findings have important clinical implications. Early detection of microvascular abnormalities through NVC can help identify patients at higher risk for severe complications such as ILD and PAH. This early identification is crucial for timely and targeted therapeutic interventions aimed at preserving vascular integrity and managing systemic involvement. The progression from limited to diffuse cutaneous involvement, increasing functional disability, and worsening internal organ complications emphasize the need for comprehensive management strategies in SSc. Interventions that can slow or reverse microvascular damage may improve outcomes and quality of life for patients [28].

The significant correlations between NVC patterns and clinical manifestations of SSc underscore the relevance of NVC as a diagnostic and prognostic tool. NVC abnormalities correlate with disease activity and severity and may be predictive of disease progression. Successful treatments have been shown to reduce NVC abnormalities in SSc cases, supporting the importance of NVC in monitoring SSc patients and suggesting its potential role as an outcome measure for microangiopathy in clinical trials [29].

Furthermore, this study highlights the dynamic progression of microvascular damage in SSc and its correlation with functional impairment and internal organ involvement. The findings reinforce the need for integrated care approaches that address both the vascular and systemic aspects of SSc, aiming to improve patient outcomes through early detection and targeted treatment strategies. Monitoring and managing microvascular health is crucial in mitigating the development and progression of severe complications such as ILD and PAH in SSc patients.

Our study’s findings align closely with those from the reviews and meta-analyses by Erdem Gürsoy et al. (2022) and Umashankar et al. (2021), highlighting the critical role of NVC in the assessment and management of SSc.

Also, the study by Erdem Gürsoy et al. investigated the relationship between NVC patterns and clinical features, functional status, pain, and fatigue in SSc patients. Their findings underscore the importance of NVC in identifying severe disease manifestations, echoing our results.

Both studies observed that capillary loss is a significant marker of disease severity. In our study, capillary loss was strongly correlated with increased severity of ILD and PAH. Similarly, Erdem Gürsoy et al. found that capillary loss was associated with digital ulcers, pulmonary hypertension, and gastrointestinal involvement. This consistency across studies reinforces the role of capillary loss as a critical indicator of systemic complications in SSc.

The comparison of functional status and disease severity revealed similar trends. While Erdem Gürsoy et al. did not find significant differences in HAQ scores between different NVC patterns, likely due to their smaller sample size, our study demonstrated a clear increase in HAQ scores from early to late NVC patterns. This indicates worsening functional status as the disease progresses. Furthermore, both studies noted variations in fatigue and pain levels. Erdem Gürsoy et al. reported similar levels across NVC patterns, whereas our study found higher pain levels in the early pattern group and increased fatigue in the late pattern group. This suggests that pain may be more prominent during the initial inflammatory stages, while fatigue increases with progressive fibrosis and systemic involvement.

The meta-analysis by Umashankar et al. focused on the role of NVC in classifying and diagnosing ILD in connective tissue diseases, including SSc. Their findings support our observations about the diagnostic utility of NVC. Umashankar et al. reported that the prevalence of NVC abnormalities is highest in connective tissue disease-related ILD (CTD-ILD), with a prevalence ratio of 80.4%. This aligns with our findings that NVC is a crucial diagnostic tool for identifying ILD in SSc patients, as capillary abnormalities are strongly associated with the presence and severity of ILD. Within the CTD-ILD cohort, the late scleroderma pattern was most prevalent, consistent with our observation that advanced NVC patterns correlate with more severe disease manifestations, including ILD.

The meta-analysis also highlighted the importance of a multidisciplinary approach in utilizing NVC for diagnosing ILD, which aligns with our recommendation to integrate NVC findings with other clinical assessments such as HRCT and pulmonary function tests. This comprehensive approach ensures a thorough evaluation of SSc patients, improving diagnostic accuracy and patient management.

Moreover, Umashankar et al. emphasized the potential prognostic value of NVC in predicting disease progression and severity. Our correlation analyses between capillary loss and systemic complications, such as ILD and PAH, reinforce the utility of NVC as a prognostic tool in SSc. Early detection of capillary loss through NVC enables timely interventions, potentially mitigating the progression of severe complications.

Both our study and the reviewed literature underscore the critical role of early detection of microvascular abnormalities through NVC. Identifying these changes early allows for prompt therapeutic interventions aimed at preserving vascular integrity and managing systemic involvement, ultimately improving patient outcomes. Successful treatments have been shown to reduce NVC abnormalities, further supporting the importance of NVC in monitoring SSc patients and suggesting its potential role as an outcome measure for microangiopathy in clinical trials.

The significant correlations between NVC patterns and clinical manifestations of SSc underscore the relevance of NVC as both a diagnostic and prognostic tool. Monitoring and managing microvascular health is crucial in mitigating the development and progression of severe complications such as ILD and PAH in SSc patients. The integrated care approach, which addresses both the vascular and systemic aspects of SSc, is essential for improving patient outcomes through early detection and targeted treatment strategies.

Our study introduces several novel insights into the management of SSc using NVC. We provide robust statistical correlations between NVC patterns and the severity of ILD and PAH, demonstrating that capillary loss is a significant predictor of these complications. Additionally, we offer a dynamic view of disease progression by categorizing patients into early, active, and late NVC patterns, enhancing our understanding of SSc pathogenesis. Our emphasis on early detection through NVC highlights its role in identifying systemic involvement early, allowing for timely interventions, which is more pronounced in our study compared to previous literature.

We also correlate NVC patterns with measures of functional status and quality of life, such as HAQ and VAS scores, illustrating how these factors deteriorate as NVC patterns progress. Advocating for a multidisciplinary approach, we recommend integrating NVC findings with other clinical assessments for enhanced diagnostic accuracy and patient management. Our findings support the inclusion of NVC in clinical guidelines for SSc management, emphasizing its potential for monitoring treatment efficacy and guiding therapeutic strategies. These contributions advance the understanding and management of SSc, highlighting NVC’s critical role in improving patient outcomes.

A limitation of our study is the absence of post-hoc tests when comparing three or more subgroups. This omission may impact the robustness of our subgroup comparisons and the accuracy of our conclusions regarding subgroup differences. Additionally, the relatively small sample size may limit the generalizability of our findings and reduce statistical power, making it more challenging to detect subtle effects or differences among groups. The lack of a multivariate analysis is another limitation, as it restricts our ability to control for potential confounding variables and evaluate the independent effects of each factor on the outcomes studied.