Nailfold capillaroscopy in the rheumatological current clinical practice in Italy: results of a national survey.

This cross-sectional online study was designed by the study group on Capillaroscopy and Microcirculation in Rheumatic Diseases (CAP) of the Italian Society of Rheumatology (SIR) to provide an overview of the management of nailfold capillaroscopy in Italian rheumatology centers. Therefore, SIR distributed the survey to its members in July 2021, and each center's physician with the most expertise in capillaroscopy completed the questionnaire. The survey was completed by 102 centers, with at least one representative from each Italian region. Ninety-three centers perform capillaroscopy, and 52 (56) conduct more than 200 investigations annually. Seventy-eight (84%) of respondents have more than five years of experience with the technique, and 75 centers (80.6%) have received certification from specific national or international training courses. In 85 centers, a videocapillaroscope with 200x magnification is employed (91.4%). The average waiting period for the examination is 2.4 months, and less than 3 months in 64 of the locations (68.8%). The study demonstrates that capillaroscopy is an integral part of both the diagnostic phase of Raynaud's phenomenon and the monitoring of autoimmune connective tissue diseases (CTDs). However, the reporting methods and timing of patient followup are heterogeneous.

Body composition and bone status in relation to microvascular damage in systemic sclerosis patients.

AIM: To evaluate, in Systemic sclerosis (SSc) patients, the body composition and the bone status according to the peripheral microcirculatory condition, assessed and scored by nailfold videocapillaroscopy (NVC, "Early", "Active", "Late" patterns). METHODS: Body composition and bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and dedicated software (GE Lunar USA) in 37 female SSc patients classified according to the 2013 EULAR/ACR criteria and 40 sex-matched healthy subjects. Clinical, laboratory, body composition and bone parameters were analyzed according to the different NVC patterns. Means were compared by the Student's t test or one-way analysis of variance; medians were compared by the Kruskal-Wallis test; and frequencies by the chi-square test. RESULTS: Higher prevalence of vertebral (21% vs 7%) and femoral (35% vs 7%) osteoporosis (OP) was found in SSc. Particularly SSc patients with "Late" NVC pattern showed a significantly higher prevalence of vertebral (p = 0.018) and femoral OP (p = 0.016). Regional assessment of bone mass (BM) in seven different body areas showed a significantly lower BMD only at the total spine (p = 0.008) and femoral neck (p = 0.027) in advanced microvascular damage. Patients with "Late" NVC pattern showed a lower whole-body lean mass (LM) compared to "Early" and "Active" NVC patterns, particularly at upper limbs. To note, in all body sites, BMD correlates with LM and BMC according to NVC pattern severity. CONCLUSIONS: SSc patients with most severe microvascular damage show a significantly altered body composition and bone status suggesting a strong link between microvascular failure and associated muscle/bone sufferance.

Progression of nailfold capillaroscopic patterns and correlation with organ involvement in systemic sclerosis: a 12 year study.

OBJECTIVE: The aim of this observational study was to investigate the evolution of scleroderma microangiopathy throughout different nailfold videocapillaroscopy (NVC) patterns ('early', 'active', 'late') as well as the prevalence of organ involvement in SSc patients during a 12-year follow-up. METHODS: Thirty-four SSc patients showing at baseline (first capillaroscopic analysis) the 'early' NVC pattern of microangiopathy were enrolled and followed for 12 years (s.d. 2). Complete NVC analysis and clinical and serological findings were collected. Patients were in a standard therapeutic care setting. Statistical analysis was carried out by non-parametric tests. RESULTS: After a 12-year follow-up, the 'early' NVC pattern changed from baseline in 76% of the patients. The NVC pattern was found to be 'active' in 9 patients (26%), 'late' in 13 (38%) and characterized by non-specific capillary abnormalities in 4 (12%). In the subgroup whose microangiopathy progressed from the 'early' to the 'late' NVC pattern, the median time of progression from the 'early' to the 'active' pattern was significantly shorter (11 months) when compared with patients who progressed from the 'early' to the 'active' NVC pattern (55 months) (P = 0.002). The median time of progression between NVC patterns was significantly shorter in SSc patients showing either a nucleolar ANA pattern or Scl70 autoantibodies (P = 0.048). Organ involvement was progressively greater in SSc patients with 'early', 'active' and 'late' NVC patterns, respectively. CONCLUSIONS: This longitudinal study confirms over a 12-year follow-up the evolution of specific NVC patterns associated with the progressive severity of organ involvement in SSc patients in a standard clinical care setting.

Correlations between nailfold microvascular damage and skin involvement in systemic sclerosis patients.

OBJECTIVE: The aim of this study was to identify any correlations between microvascular damage, assessed by nailfold videocapillaroscopy and skin impairment, evaluated by three different methods, the modified Rodnan skin score (mRSS), skin high-frequency ultrasound (US) and the plicometer skin test (PST) in systemic sclerosis (SSc) patients. METHODS: Sixty-three SSc patients and 63 healthy subjects were enrolled. Nailfold videocapillaroscopy (NVC) was used to assess the nailfold capillaroscopy pattern ("Early", "Active" or "Late"), according to the Cutolo classification. All subjects were assessed by mRSS, US and PST to evaluate their dermal thickness (DT) in the seventeen skin areas of the body usually evaluated by mRSS (zygoma, fingers, hands, dorsum of hands, forearms, arms, chest, abdomen, thighs, legs, feet). Statistical evaluation was performed by nonparametric tests. RESULTS: All the three methods demonstrated progressively higher values of skin impairment in patients with "Early", "Active" or "Late" pattern of nailfold microangiopathy (for mRSS p < 0.01, US p < 0.02 and PST p < 0.02). A positive correlation was also observed in SSc patients between the three methods used to evaluate skin involvement (mRSS vs US, mRSS vs PST, PST vs US, p < 0.0001 respectively). CONCLUSIONS: This study demonstrates that there is a correlation between two of the most important aspects to classify and monitor the SSc patients, i.e. microvascular damage progression (evaluated by NVC) and skin damage (assessed by mRss, US and PST).

Long-term follow-up of nailfold videocapillaroscopic changes in dermatomyositis versus systemic sclerosis patients.

To identify nailfold videocapillaroscopy (NVC) changes in patients with dermatomyositis (DM) during a 3-year follow-up and to compare the NVC findings between DM and systemic sclerosis (SSc) patients at their first visit. Retrospective study of 24 DM and 24 SSc patients, matched for age and disease duration at first NVC. Capillaroscopic patterns/scores and clinical parameters had been yearly assessed. Nineteen out of 24 DM patients (79%) showed a NVC "scleroderma-like pattern." No statistically significant variation of all the capillaroscopic scores was observed during the 3-year follow-up. By comparing DM patients with or without anti-Jo-1 positivity, no statistically significant difference of the scores of the main capillary parameters was observed at baseline between the groups. Comparing at baseline DM with SSc patients, the giant capillary and microhemorrhage scores were significantly higher in SSc than those in DM patients (p = 0.04 and p = 0.05, respectively), while capillary density, ramification (abnormally shaped capillaries, expression of angiogenesis), and disorganization scores were higher in DM patients (p = 0.05, p = 0.002, p = 0.004, respectively). The absolute number of ramified capillaries was significantly higher in DM patients (p = 0.002), while the absolute capillary number was significantly higher in SSc patients (p = 0.05) at baseline. This pilot study demonstrates, for the first time, over long-term, that the capillaroscopic manifestations of DM persist in contrast to the progressive changes described in SSc patients, and the anti-Jo-1 positivity does not seem to modify the NVC pattern.

Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients.

OBJECTIVE: To identify possible correlations between skin blood perfusion (BP) and dermal thickness (DT) in different skin areas of systemic sclerosis (SSc) patients. METHODS: Sixty-two SSc patients, according to 2013 EULAR/ACR criteria, and 62 healthy subjects (CNT) were enrolled. Skin BP was analysed by laser speckle contrast analysis (LASCA) at the level of dorsum of the middle phalanx of the third fingers, dorsal aspect of the hands and zygoma. DT was assessed by both skin high frequency ultrasound (US) and modified Rodnan skin score (mRSS) in the same above reported areas. All patients were studied also by nailfold videocapillaroscopy (NVC) to assess the proper pattern of microvascular damage ("Early", "Active", or "Late"). RESULTS: At the level of finger dorsum a statistically significant negative correlation was observed in SSc patients between skin BP and both ultrasound-DT (p=0.0005 r=0.43) and mRSS (p=0.0007 r=0.42), but not at the level of hand dorsum and zygoma. No statistically significant correlation was present between skin BP and ultrasound-DT at any level in CNT. In detail, SSc patients, compared to CNT, showed a statistically significant lower BP only at level of fingers (median PU 72.6 vs 136.1 respectively, p<0.0001) and a statistically significant higher ultrasound-DT at the level of dorsum of 3th finger bilaterally (median mm 0.9 vs 0.7, p<0.0001), dorsum of hands (median mm 0.9 vs 0.7, p<0.0001) and zygoma (median mm 0.8 vs 0.7, p<0.0001). A significant positive correlation between ultrasound-DT and mRSS was observed in SSc patients at level of the three areas (dorsum of fingers p<0.0001 r=0.51; dorsum of hands p=0.03 r=0.27; zygoma p=0.0001 r=0.45). A progressive decrease of skin BP and increase of ultrasound-DT was found correlated with the progression of the severity of NVC patterns. CONCLUSIONS: This study demonstrates for the first time in SSc patients a significant inverse relationship between skin BP, measured by LASCA, and DT, evaluated by both US and mRSS, at the level of dorsum of the middle phalanx of the third fingers.

Assessment of treatment effects on digital ulcer and blood perfusion by laser speckle contrast analysis in a patient affected by systemic sclerosis.

Laser speckle contrast analysis (LASCA) is a good tool to evaluate the variation in peripheral blood perfusion during long-term follow-up and is able to safely monitor digital ulcer evolution in scleroderma patients. It evaluates blood perfusion in different areas within the skin lesions and surrounding them during standard treatment.

Subclinical dermal involvement is detectable by high frequency ultrasound even in patients with limited cutaneous systemic sclerosis.

BACKGROUND: The aim of the study was to detect by skin high-frequency ultrasound (US) possible subclinical skin involvement in patients affected by limited cutaneous systemic sclerosis (lcSSc), in those skin areas apparently not affected by the disease on the basis of a normal modified Rodnan skin score (mRSS). Differences in dermal thickness (DT) in comparison with healthy subjects were investigated. METHODS: Fifty patients with lcSSc (age 62 ± 13 years (mean ± SD), disease duration 5 ± 5 years) and 50 sex-matched and age-matched healthy subjects (age 62 ± 11 years) were enrolled. DT was evaluated by both mRSS and US at the usual 17 skin areas (zygoma, fingers, dorsum of the hands, forearms, upper arms, chest, abdomen, thighs, lower legs and feet). Non-parametric tests were used for the statistical analysis. RESULTS: Subclinical dermal involvement was detected by US even in the skin areas in patients with lcSSc, who had a normal local mRSS. In addition, statistically significantly higher mean DT was found in almost all skin areas, when compared to healthy subjects (p < 0.0001 for all areas). In particular, DT was significantly greater in patients with lcSSc than in healthy subjects in four out of six skin areas with a normal mRSS (score = 0) (upper arm, chest and abdomen), despite the clinical classification of lcSSc. CONCLUSIONS: This study strongly suggests that subclinical dermal involvement may be detectable by US even in skin areas with a normal mRSS in patients classified as having lcSSc. This should be taken into account during SSc subset classification in clinical studies/trials.

Microvascular damage evaluation in systemic sclerosis: the role of nailfold videocapillaroscopy and laser techniques.

Microvascular damage and a decrease in peripheral blood perfusion are typical features of systemic sclerosis (SSc) with serious clinical implications, not only for a very early diagnosis, but also for disease progression. Nailfold videocapillaroscopy is a validated and safe imaging technique able to detect peripheral capillary morphology, as well as to classify and to score any nailfold abnormalities into different microangiopathy patterns. Capillaroscopic analysis is now included in the ACR/EULAR classification criteria for SSc. The decrease in peripheral blood perfusion is usually associated with microvascular damage in SSc, which may be studied by different methods. Several of these make use of safe laser technologies. This paper focuses on these new clinical aspects to assess SSc microvascular impairment.

Plantar pain is not always fasciitis.

The case is described of a patient with chronic plantar pain, diagnosed as fasciitis, which was not improved by conventional treatment. Magnetic resonance imaging revealed flexor hallucis longus tenosynovitis, which improved after local glucocorticoid injection.

Capillaroscopy 2016: new perspectives in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder of unknown aetiology characterized by early impairment of the microvascular system. Nailfold microangiopathy and decreased peripheral blood perfusion are typical clinical aspects of SSc. The best method to evaluate vascular injury is nailfold videocapillaroscopy, which detects peripheral capillary morphology, and classifies and scores the abnormalities into different patterns of microangiopathy. Microangiopathy appears to be the best evaluable predictor of the disease development and has been observed to precede the other symptoms by many years. Peripheral blood perfusion is also impaired in SSc, and there are different methods to assess it: laser Doppler and laser speckle techniques, thermography and other emerging techniques.

Systemic sclerosis: markers and targeted treatments.

Systemic sclerosis (SSc) is characterized by autoantibody production, progressive microvasculopathy, and aberrant extracellular matrix protein (ECM) synthesis in tissues. The disease presents two major clinical hallmarks: Raynaud's phenomenon (RP) and skin involvement, followed by varying prevalences of internal organ involvement. Despite significant advances in the management of certain organ-specific involvements and symptoms, the research for efficient markers and targets, to be used for an optimized treatment, is still ongoing. Therapies targeting the vasculature (i.e. ET-1 receptor antagonists, phosphodiesterase-5 (PDE-5) inhi bitor, agiotensin-converting enzyme inhibition, prostacyclins), the immune system and/or the fibrotic process (i.e. traditional disease modifying anti-rheu - matic drugs DMARDs such as methotrexate, cyclospo - rine or mycophenolate mofetil, biologicals like rituxi - mab, tocilizumab or abatacept) have been or are being eva luated in SSc. Advanced approaches, reserved to unres ponsive SSc patients, include autologous haema - topoietic stem cell transplantation (HSTC) and intravenous immunoglobulins (IVIG). Interestingly, it is expected that new and future possible diagnostic and therapeutical approaches in SSc will come from epigenetic studies (MicroRNAs). Ideally, combination therapy in SSc seems the best approach, together with the early intervention on the major hallmarks of the disease in "at risk" patients, that consists of the microvascular damage/altered function and the autoimmune reaction, followed by the progressive and systemic fibrotic process.

Correlations between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients.

OBJECTIVES: To correlate blood perfusion (BP) values assessed by laser speckle contrast analysis (LASCA) in selected skin areas of hands and face with nailfold capillary damage scores in systemic sclerosis (SSc) patients. METHODS: Seventy SSc patients (mean SSc duration 6 ± 5 years) and 70 volunteer healthy subjects were enrolled after informed consent. LASCA was performed at different areas of the face (forehead, tip of nose, zygomas and perioral region) and at dorsal and volar regions of hands. Microvascular damage was assessed and scored by nailfold videocapillaroscopy (NVC) and the microangiopathy evolution score (MES) was calculated. RESULTS: SSc patients showed a significantly lower BP than healthy subjects at fingertips, periungual areas and palm of hands (p<0.0001), but not at the level of face and dorsum of hands. A gradual decrease of BP at fingertips, periungual and palm areas, was found in SSc patients with progressive severity of NVC patterns of microangiopathy ("early", "active", or "late") (p<0.01). A negative correlation was observed between MES and BP values, as well as between loss of capillaries and BP, at the same areas (p<0.001 and p<0.01, respectively). Patients with diffuse cutaneous SSc (dcSSc) showed lower BP than those with limited cutaneous SSc (p<0.04). CONCLUSIONS: LASCA detects a significant reduction of BP only in those areas usually affected by Raynaud's phenomenon (fingertips, periungual and palm areas), especially in dcSSc patients, and BP values significantly correlate with the nailfold capillaroscopy scores of microangiopathy.

Phenotype modifications of T-cells and their shift toward a Th2 response in patients with systemic lupus erythematosus supplemented with different monthly regimens of vitamin D.

BACKGROUND: Vitamin D receptor is constitutively expressed on the lymphocyte surface. Recent studies highlight that vitamin D may exert actions on T-cells, inhibiting Th1 and Th17 response and enhancing Th2 and T-regulatory (T-reg) function. METHODS: Thirty-four patients with systemic lupus erythematosus (SLE) were randomly enrolled in a two-year prospective study. In the first year, 16 patients were supplemented with an intensive regimen of cholecalciferol (IR) (300.000 UI of cholecalciferol at baseline and 50.000 UI/monthly as maintenance, 850.000 UI annually), whereas 18 with a standard regimen (SR) (25.000 UI of cholecalciferol monthly, 300.000 UI annually). During the second year, patients were switched to the other arm of treatment. Phenotypic analysis of peripheral T lymphocyte and the quantification of cytokine production from peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry. RESULTS: At baseline, no significant difference between the two groups emerged among main T-cell subtypes. Over two years of treatment, we saw an increase in the number of T-reg cells, in the total amount of CD4+CD45RA+CCR7- T-cells, whereas a significant reduction of CD8+CD28- T-cells was observed. In addition, the analysis of PBMCs from eight patients following the IR showed the reduction of the IFN-γ/IL-4 ratio (p = 0.01) among CD8+ T-cells after 12 months. CONCLUSIONS: After a long-term of monthly treatment with vitamin D in SLE patients, an enhancement of T-reg cells and the production of Th2 cytokines should be expected.

Correlations between nailfold microangiopathy severity, finger dermal thickness and fingertip blood perfusion in systemic sclerosis patients.

OBJECTIVE: The aim of this study was to identify possible correlations between nailfold microangiopathy severity, finger dermal thickness (DT) and fingertip blood perfusion (FBP) in systemic sclerosis (SSc) patients. METHODS: Fifty-seven SSc patients and 37 healthy subjects were enrolled. All patients were evaluated by nailfold videocapillaroscopy (NVC) to classify and score the severity of microangiopathy. Both modified Rodnan skin score (mRss) and skin high-frequency ultrasound were used to detect finger DT. Laser Doppler flowmetry (LDF) was employed to detect FBP. RESULTS: A positive correlation was found between nailfold microvascular damage severity and both ultrasound-DT (p=0.028) and mRss values (p<0.0001). In particular, both ultrasound-DT and mRss were found progressively higher in patients with 'Early', 'Active' or 'Late' NVC pattern of microangiopathy. A negative correlation was observed between nailfold microvascular damage severity and FBP (p<0.0001), showing the lowest FBP of the patients with more advanced NVC patterns. A negative correlation was observed between FBP, and both ultrasound-DT (p=0.007) and mRss values (p=0.0002). SSc patients showed a higher ultrasound-DT at the level of the fingers, as well as a lower FBP than healthy subjects (p<0.0001). CONCLUSIONS: This study demonstrates a relationship between nailfold microangiopathy severity, DT and FBP in SSc patients.

Prospective capillaroscopy-based study on transition from primary to secondary Raynaud's phenomenon: preliminary results.

The objective of this prospective study was to investigate the transition from primary (PRP) to secondary (SRP) Raynaud's phenomenon (RP), in a large cohort of patients affected by isolated RP. A total of 2065 patients with RP were investigated by clinical interview, laboratory examinations, and nailfold videocapillaroscopy (NVC). Patients with negative NVC at first visit were yearly followed to monitor either the appearance of specific morphological alterations at NVC, or clinical manifestations of an underlying disease. Capillary abnormalities at NVC were scored, as well as the qualitative patterns of microangiopathy (Early, Active and Late). NVC was found negative at first visit in 1500 subjects; among them, 412 patients were evaluable and they were followed for a mean time of 5±4 years (range 2-13 years). Sixty-eight patients (16%) achieved a diagnosis of SRP during follow-up, showing normal or not specific capillary alterations at NVC 4% of patients (the diagnosis was undifferentiated connective tissue diseases), Early scleroderma-pattern 57%, Active scleroderma-pattern 7%, Late scleroderma-pattern 12%, and scleroderma-like pattern 18% of patients. The time of transition from normal/not specific capillary alterations to Early scleroderma-pattern was 4.4±3.8 years. Enlarged capillaries (diameter between 20 and 50 microns) and mild reduction of capillary density were found the more frequent markers at first NVC visit in patients who progressed to a scleroderma pattern (P=0.01). This study demonstrates in a large cohort, that almost 16% of patients initially diagnosed as affected by RP with negative NVC may transit to SRP during a mean follow-up of 4.4 years. PRP patients showing major notspecific alterations of nailfold capillaries at first NVC should be strictly monitored at least once a year since at higher risk of transition to SRP.

[The role of nailfold videocapillaroscopy in Raynaud's phenomenon monitoring and early diagnosis of systemic sclerosis]. / La videocapillaroscopia ungueale nel monitoraggio del fenomeno di Raynaud e nella diagnosi precoce della sclerosi sistemica.

Several connective tissue diseases, in particular systemic sclerosis (SSc), have Raynaud's phenomenon (RP) as their first clinical manifestation. Primary RP represents a benign condition often observed in otherwise healthy subjects, especially women: it is due to an exaggerated response to the physiological cold-induced vasospasm, whereas the secondary form of RP is typically associated with connective tissue diseases, especially SSc. Nailfold videocapillaroscopy (NVC), particulary after the recent technological advances, is a safe and reliable method to observe the microvascular structure and its early changes, especially during the transition from primary to secondary RP. In case of SSc, by considering validated patterns and scoring systems, NVC is the main tool that rheumatologists can rely on, besides the presence of specific auto-antibodies, to perform a very early diagnosis of the disease. This implies the possibility of early treatment of SSc, with an eye of predicting and preventing its major clinical complications.

[Nailfold capillaroscopy and blood flow laser-doppler analysis of the microvascular damage in systemic sclerosis: preliminary results]. / Studio della microangiopatia sclerodermia mediante valutazione dinamica con laser-Doppler e morfologica con videocapillaroscopia periungueale: risultati preliminari.

OBJECTIVES: Systemic sclerosis (SSc) is characterized by altered microvascular structure and function. Nailfold videocapillaroscopy (NVC) is the tool to evaluate capillary morphological structure and laser-Doppler Blood flowmetry (LDF) can be used to estimate cutaneous blood flow of microvessels. The aim of this study was to investigate possible relationships between capillary morphology and blood flow in SSc. METHODS: Twenty-seven SSc patients and 12 healthy subjects were enrolled. SSc microvascular involvement, as evaluated by NVC, was classified in three different patterns ("Early", "Active", "Late"). LDF analysis was performed at the II, III, IV, V hand fingers in both hands and both at cutaneous temperature and at 36 degrees C. Statistical evaluation was carried out by non-parametric procedures. RESULTS: Blood flow was found significantly lower in SSc patients when compared with healthy subjects (p<0.05). The heating of the probe to 36 degrees C induced a significant increase in peripheral blood flow in all subjects compared to baseline (p <0.05), however, the amount of variation was significantly lower in patients with SSc, compared with healthy controls (p <0.05). The SSc patients with NVC "Late" pattern, showed lower values of peripheral blood flow than patients with NVC "Active" or "Early" patterns (p<0.05). Moreover, a negative correlation between the tissue perfusion score and the progression of the SSc microangiopathy was observed, as well as between the tissue perfusion and the duration of the Raynaud's phenomenon (p <0.03). CONCLUSIONS: LDF can be employed to evaluate blood perfusion in the microvascular circulation in SSc patients. The blood flow changes observed with the LDF seem to correlate with the severity of microvascular damage in SSc as detected by NVC.