Microparticles: potential new contributors to the pathogenesis of systemic sclerosis?

BACKGROUND: Microparticles (MPs) are membrane-derived vesicles released from cells undergoing activation or apoptosis with diverse proinflammatory and prothrombotic activities, that have been implicated in the pathogenesis of systemic sclerosis (SSc). We aimed to evaluate the plasma levels of platelet-derived microparticles (PMPs), endothelial cell-derived microparticles (EMPs), and monocyte-derived microparticles (MMPs) in SSc patients, and the association between MPs and the clinical features of SSc. METHODS: In this cross-sectional study, 70 patients with SSc and 35 age- and sex-matched healthy controls were evaluated. Clinical and nailfold capillaroscopy (NFC) data were obtained from all patients. Plasma levels of PMPs (CD42+/31+), EMPs (CD105+), and MMPs (CD14+) were quantified by flow cytometry. RESULTS: Patients were mainly females (90%), with a mean age of 48.9 years old. PMP, EMP, and MMP levels were significantly increased in SSc patients compared to controls (79.2% ± 17.3% vs. 71.0% ± 19.8%, p = 0.033; 43.5% ± 8.7% vs. 37.8% ± 10.4%, p = 0.004; and 3.5% ± 1.3% vs. 1.1% ± 0.5%, p < 0.0001, respectively). PMP levels were significantly higher in patients with positive anti-topoisomerase-I antibodies (p = 0.030) and in patients with a disease duration > 3 years (p = 0.038). EMP levels were lower in patients with a higher modified Rodnan skin score (p = 0.015), and in those with an avascular score > 1.5 in NFC (p = 0.042). CONCLUSION: The increased levels of PMPs, EMPs and MMPs in scleroderma patients might indicate a possible role for these agents in the pathogenesis of this challenging disease.

Treatment of Inflammatory Arthritis in Systemic Sclerosis.

Joint involvement, including arthralgia, inflammatory arthritis, joint contractures and overlapping with rheumatoid arthritis, is a common manifestation and is associated with impared quality of life in systemic sclerosis (SSc). Few studies have evaluated the treatment of arthritis in SSc. Pharmacological approach includes low-dose corticosteroids, methotrexate, and hydroxychloroquine. Non-tumor necrosis factor biologics, especially rituximab and tocilizumab, may be a promising option for refractory cases.

Vascular parameters and endothelin-1 measurements in glaucoma patients with low- and high-tension optic disc hemorrhages.

This prospective study aimed to compare vascular parameters (endothelin-1 [ET-1] blood levels, laser Doppler imaging [LDI] of distal phalanxes, and nailfold capillaroscopy) between open-angle glaucoma patients with low- and high-tension optic disc hemorrhages (LTDH and HTDH, respectively). The 33 enrolled patients (mean age, 62.3 ± 13 years) were classified as LTDH or HTDH if they presented at the time of DH detection an intraocular pressure (IOP) < 16 mmHg or ≥ 16 mmHg, respectively. Demographic and ophthalmological data, ET-1 concentrations, LDI (before and 1, 10, and 20 min after cold stimulation), and nailfold capillaroscopy findings were evaluated. The ET-1 blood level was 65% higher in the LTDH (2.27 ± 1.46 pg/ml) than in the HTDH (1.37 ± 0.57 pg/ml; p = 0.03) group. Moreover, there was a statistically significant negative correlation between ET-1 blood concentration and IOP at the time of DH detection (r = -0.45, p = 0.02). Blood flow measurements 10 and 20 min after cold stimulation were lower in the LTDH group than in the HTDH group (p < 0.01). Patients developing DH with lower IOPs have higher ET-1 blood levels and more peripheral vascular dysfunction as estimated by LDI than those with higher IOPs. These findings suggest that distinct underlying mechanisms may be involved in patients developing DH within different IOP ranges.

Peripheral Microvascular Abnormalities Associated with Open-Angle Glaucoma.

PURPOSE: To investigate peripheral microvascular abnormalities associated with patients with open-angle glaucoma (OAG). DESIGN: This was a cross-sectional study. PARTICIPANTS: Patients with OAG and controls. METHODS: All subjects underwent detailed ophthalmic evaluation, including Humphrey visual field (HVF) tests and swept source OCT. To evaluate peripheral microvascular abnormalities, nailfold capillaroscopy (NFC) and laser Doppler imaging (LDI) were performed. The presence of microhemorrhages, tortuous capillaries, dilated capillaries, avascular areas, and the capillary density, among other characteristics, were recorded using NFC; fingertip blood flow (FBF) was measured using LDI at different time points, before and 1, 10, and 20 minutes after exposure to a cold stimulus. In addition, venous blood samples were collected to measure serum endothelin-1 (ET-1) concentrations as well as serum autoantibodies. MAIN OUTCOME MEASURES: Presence of microhemorrhages, tortuous capillaries, and dilated capillaries; FBF; ET-1; and autoantibodies. RESULTS: Sixty-eight subjects (43 patients with OAG and 25 controls) were enrolled in the study. Microhemorrhages were found in the nail bed of 65.1% of the patients with OAG compared with 25.0% of the controls (P = 0.003). There was a significant difference in the mean FBF at the baseline in patients with OAG versus controls (293.6 ± 100.2 vs 388.8 ± 52.0 perfusion units, respectively, P < 0.001), together with a significant decrease in the mean FBF 10 and 20 minutes after cold stimulus in patients with OAG in comparison to controls (P < 0.001 for all comparisons). There was a positive correlation between mean baseline FBF and HVF mean deviation (r = 0.27, P = 0.03) and between mean baseline FBF and average retinal nerve fiber layer thickness (r = 0.44, P = 0.001). Neither the analysis of ET-1 concentrations (P= 0.71) nor the autoantibodies measurements (P > 0.05, for all) showed any difference between the 2 groups. CONCLUSIONS: Significant peripheral microvascular abnormalities were found in patients with OAG compared to controls, suggesting that microvascular changes might play a role in the pathogenesis of the disease. In addition, part of these peripheral microvascular abnormalities seems to be correlated with both functional and structural glaucomatous damage. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Microparticles: potential new contributors to the pathogenesis of systemic sclerosis?

Abstract Background Microparticles (MPs) are membrane-derived vesicles released from cells undergoing activation or apoptosis with diverse proinflammatory and prothrombotic activities, that have been implicated in the pathogenesis of systemic sclerosis (SSc). We aimed to evaluate the plasma levels of platelet-derived microparticles (PMPs), endothelial cell-derived microparticles (EMPs), and monocyte-derived microparticles (MMPs) in SSc patients, and the association between MPs and the clinical features of SSc. Methods In this cross-sectional study, 70 patients with SSc and 35 age- and sex-matched healthy controls were evaluated. Clinical and nailfold capillaroscopy (NFC) data were obtained from all patients. Plasma levels of PMPs (CD42+/31+), EMPs (CD105+), and MMPs (CD14+) were quantified by flow cytometry. Results Patients were mainly females (90%), with a mean age of 48.9 years old. PMP, EMP, and MMP levels were significantly increased in SSc patients compared to controls (79.2% ± 17.3% vs. 71.0% ± 19.8%, p = 0.033; 43.5% ± 8.7% vs. 37.8% ± 10.4%, p = 0.004; and 3.5% ± 1.3% vs. 1.1% ± 0.5%, p < 0.0001, respectively). PMP levels were significantly higher in patients with positive anti-topoisomerase-I antibodies (p = 0.030) and in patients with a disease duration > 3 years (p = 0.038). EMP levels were lower in patients with a higher modified Rodnan skin score (p = 0.015), and in those with an avascular score > 1.5 in NFC (p = 0.042). Conclusion The increased levels of PMPs, EMPs and MMPs in scleroderma patients might indicate a possible role for these agents in the pathogenesis of this challenging disease.

A cell-based assay for detection of anti-fibrillarin autoantibodies with performance equivalent to immunoprecipitation.

Anti-fibrillarin autoantibodies are useful for the diagnosis and prognosis of systemic sclerosis (SSc). Anti-fibrillarin produces a clumpy nucleolar pattern in indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA). Here we develop and validate a reliable cell-based anti-fibrillarin assay (Fibrillarin/CBA) for use in clinical diagnostic laboratories. A TransMembrane Signal was fused to the human fibrillarin gene (TMS-fibrillarin). HEp-2 cells overexpressing transgenic TMS-fibrillarin at the cytoplasmic membrane were used as IFA substrate in the Fibrillarin/CBA. Sixty-two serum samples with nucleolar pattern in the HEp-2 IFA (41 clumpy; 21 homogeneous/punctate) were tested for anti-fibrillarin using Fibrillarin/CBA, immunoprecipitation (IP), line-blot and ELISA. In addition, samples from 106 SSc-patients were evaluated with Fibrillarin/CBA and the results were correlated with disease phenotypes. Thirty-eight of 41 samples with the clumpy nucleolar pattern (92.7%) were positive in the Fibrillarin/CBA, while all 21 samples with other nucleolar patterns were negative. Fibrillarin/CBA results agreed 100% with IP results. Among the 38 Fibrillarin/CBA-positive samples, only 15 (39.5%) and 11 (29%) were positive for anti-fibrillarin in line-blot and ELISA, respectively. Higher frequency of diffuse cutaneous SSc (dcSSc) phenotype (72.7% vs 36.8%; p=0.022), cardiac involvement (36.4% vs 6.5%; p=0.001) and scleroderma renal crisis (18.2% vs 3.3% p = 0.028) was observed in SSc patients with positive compared to negative Fibrillarin/CBA result. Performance of Fibrillarin/CBA in the detection of anti-fibrillarin autoantibodies was comparable to the gold standard IP. Positive Fibrillarin/CBA results correlated with disease phenotypes known to be associated with anti-fibrillarin autoantibodies, underscoring the clinical validation of this novel assay.

Severity and mortality of COVID-19 in patients with systemic sclerosis: a Brazilian multicenter study.

INTRODUCTION: COVID-19 may be associated with greater severity and mortality in patients with systemic sclerosis (SSc). The present study aimed to evaluate the prevalence, severity and mortality of COVID-19 in a Brazilian cohort of SSc patients. METHODS: This multicenter, retrospective, observational study included 1,042 SSc patients followed in four centers of São Paulo between March 2020 and June 2021. Diagnosis of COVID-19 was established by proper positive RT-PCR testing or by highly suspicious infection. Patients were grouped into mild (outpatient setting treatment and no need for oxygen support) and moderate-to-severe (hospitalization and/or need for oxygen support) COVID-19. RESULTS: Of the 1,042 SSc patients, 118 patients were diagnosed with COVID-19. Interstitial lung disease (SSc-ILD) was present in 65.6% of the total cohort and in 46.3% of SSc patients with COVID-19. There were 78 (66.1%) cases of mild COVID-19, and 40 (33.9%) cases of moderate-to-severe disease, with 6 (5.1%) deaths. By univariate analysis, pulmonary arterial hypertension (OR 9.50, p=0.006), SSc-ILD (OR 3.90, p=0.007), FVC <80% (OR 2.90, p=0.01), cardiac involvement (OR 5.53, p=0.003), and use of rituximab (OR 3.92, p=0.039), but not age, gender, comorbidities or use of corticosteroids, were predictors of worse outcome for COVID-19. Using multivariate analysis, only SSc-ILD was significantly associated to a higher risk of moderate-to-severe COVID-19 (OR 2.73, 95% CI 1.12-6.69, p=0.02). Forty percent of the patients remained with symptoms after presenting COVID-19, predominantly dyspnea and/or cough (17%). CONCLUSION: In this cohort of patients with SSc, those with SSc-ILD were highly impacted by COVID-19, with a higher risk of moderate-to-severe COVID-19 infection and death.

The Role of Autoantibody Testing in Modern Personalized Medicine.

Personalized medicine (PM) aims individualized approach to prevention, diagnosis, and treatment. Precision Medicine applies the paradigm of PM by defining groups of individuals with akin characteristics. Often the two terms have been used interchangeably. The quest for PM has been advancing for centuries as traditional nosology classification defines groups of clinical conditions with relatively similar prognoses and treatment options. However, any individual is characterized by a unique set of multiple characteristics and therefore the achievement of PM implies the determination of myriad demographic, epidemiological, clinical, laboratory, and imaging parameters. The accelerated identification of numerous biological variables associated with diverse health conditions contributes to the fulfillment of one of the pre-requisites for PM. The advent of multiplex analytical platforms contributes to the determination of thousands of biological parameters using minute amounts of serum or other biological matrixes. Finally, big data analysis and machine learning contribute to the processing and integration of the multiplexed data at the individual level, allowing for the personalized definition of susceptibility, diagnosis, prognosis, prevention, and treatment. Autoantibodies are traditional biomarkers for autoimmune diseases and can contribute to PM in many aspects, including identification of individuals at risk, early diagnosis, disease sub-phenotyping, definition of prognosis, and treatment, as well as monitoring disease activity. Herein we address how autoantibodies can promote PM in autoimmune diseases using the examples of systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, idiopathic inflammatory myopathies, autoimmune hepatitis, primary biliary cholangitis, and autoimmune neurologic diseases.

Mortality in Systemic Sclerosis-Associated Interstitial Lung Disease in Brazil: A Real-Life, Long-Term Follow-up Observational Study.

OBJECTIVES: The aim of this study was to identify risk factors associated with mortality in patients with systemic sclerosis (SSc), particularly those with interstitial lung disease (ILD), over a long-term follow-up in a large Brazilian SSc cohort. METHODS: We conducted a medical records review study of 380 scleroderma patients from 1982 to 2019. Systemic sclerosis ILD was considered in those with evidence of ILD on chest high-resolution computed tomography (HRCT). Causes of death were determined. RESULTS: Among the 380 SSc patients, SSc-ILD on chest HRCT was observed in 227 patients (59.7%). Seventy-two patients (18.9%) died during a mean follow-up of 7.2 years since the SSc diagnosis; among them, 57 (79.2%) had SSc-ILD, compared with 15 (20.8%) without SSc-ILD (p < 0.001). Of the 72 deaths, 51.4% were considered related to SSc, and ILD was the leading cause of death. The overall survival rates at 5, 10, and 15 years were 87.9%, 81.5%, and 74.9%, respectively. Kaplan-Meier analysis showed a significantly worse prognosis among patients with SSc-ILD than among those without ILD (p < 0.001). Among patients with SSc-ILD, disease duration of less than 4 years (p < 0.001), forced vital capacity <80% at baseline (p = 0.017), and pulmonary systolic arterial pressure ≥40 mm Hg on echocardiography (p < 0.001) were significantly associated with mortality by multivariate analysis. CONCLUSIONS: In Brazilian SSc patients, the presence of ILD was associated with a worse prognosis. The higher mortality among SSc-ILD patients, especially those with a shorter disease duration and forced vital capacity <80%, highlights the need for early screening and closer monitoring before irreversible lung function deterioration occurs.

Serum BDNF and cognitive dysfunction in SLE: findings from a cohort of 111 patients.

OBJECTIVE: The association between brain-derived neurotrophic factor (BDNF) and neuropsychiatric systemic lupus erythematosus (NPSLE) is controversial in the literature. Cognitive dysfunction (CD) is a common, underdiagnosed NPSLE manifestation, but its pathophysiology is unknown. Thus, we investigate serum BDNF as a potential biomarker of CD in a cohort of SLE patients. METHODS: We included 63 SLE patients, 48 NPSLE, and 57 age- and gender-matched controls (CON). All participants underwent neuropsychological assessment. Data on cardiovascular comorbidities, SLE disease activity index (SLEDAI), and Systemic Lupus International Collaborating Clinics damage index (SLICC-DI) were compiled. Multiple regression analyses evaluated predictors of serum BDNF levels. RESULTS: Serum BDNF levels were lower in SLE and NPSLE patients than in CON (SLE 800.4 ± 502.7 vs. NPSLE 779.7 ± 426.3 vs. CON 1,345.5 ng/mL ± 438.4; p < 0.001). In addition, hypertension (B: - 192.5, SE: 84.3, 95% CI: - 359.7 to - 25.3, p = 0.024) and SLICC-DI score (B: - 75.9, SE: 27.2, 95% CI: - 129.8 to - 22, p = 0.006) were predictors of serum BDNF levels in SLE. There was no relation between BDNF levels and CD. CONCLUSION: BDNF levels are lower in SLE patients than CON and inversely associated with hypertension and SLICC-DI scores. No association between BDNF levels and CD or NPSLE was observed in this cohort. These findings indicate that BDNF may be associated with overall burden in SLE rather than specific manifestations such as cognition impairment. Key Points • BDNF is associated with an overall burden in SLE rather than specific manifestations such as cognition dysfunction. • BDNF levels are reduced in patients with SLE, and higher SLICC-DI scores and hypertension are independent predictors of lower serum BDNF levels. • The cognitive dysfunction rate is elevated (46%) among Brazilian SLE patients.

Structural abnormalities associated with glaucoma using swept-source optical coherence tomography in patients with systemic sclerosis.

PURPOSE: Vasospasm represents an early event in systemic sclerosis (SSc). Ocular vasospasm may induce optic nerve head (ONH) damage and has been involved in the pathogenesis of glaucoma, especially normal-tension glaucoma (NTG). We aimed to investigate the presence of structural abnormalities associated with NTG using swept-source optical coherence tomography (SS-OCT) and to correlate the OCT parameters with clinical, capillaroscopy and digital blood flow measures in patients with SSc. METHODS: In this cross-sectional study, 40 patients with SSc and 23 age-matched controls were included. The following parameters were measured using SS-OCT: mean and sectoral retinal nerve fibre layer (RNFL) thickness, macular ganglion cell layer complex (GCC) thickness and ONH morphology. Nailfold capillaroscopy (NFC) and digital blood flow measurements using laser Doppler imaging (LDI) were performed in all subjects. RESULTS: Patients with SSc showed a thinner temporal RNFL than the controls (69.23 ± 11.74 versus 83.35 ± 20.19 µm, p = 0.001). The other parameters were similar between the two groups. In SSc patients, there was an inverse correlation between the disease duration and the average, superior and inferior RNFL thickness and the GCC thickness and between Raynaud's phenomenon duration and the average RNFL and GCC thickness (p < 0.05). NFC and LDI measurements did not show correlations with OCT parameters. CONCLUSION: A thinner temporal RNFL and the correlation between Raynaud's phenomenon and disease duration and structural abnormalities on OCT suggest the presence of early ganglion cell damage in patients with SSc. Although mild, these findings indicate the need to monitor ocular abnormalities in SSc.

A comprehensive framework for navigating patient care in systemic sclerosis: A global response to the need for improving the practice of diagnostic and preventive strategies in SSc.

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications.

Anti-annexin V autoantibodies and vascular abnormalities in systemic sclerosis: a longitudinal study.

BACKGROUND: Annexins are a group of conserved proteins which exert several regulatory functions on various cellular activities. Increased frequency and levels of antibodies against annexin V have already been observed in several autoimmune diseases including systemic sclerosis (SSc), but their role as a vascular biomarker is unknown. The aim of this study was to determine the serum levels and the dynamical behavior of anti-annexin V antibodies over a 24 months follow-up in patients with SSc. METHODS: In this bicentric cross-sectional study, 70 patients with SSc were consecutively selected from March 2016 to April 2017. Demographic and clinical features, including the presence of active DUs, were collected. Serum anti-annexin V IgG and IgM antibodies were measured at baseline and after 6, 12 and 24 months of follow-up. Videocapillaroscopy was performed in all patients. RESULTS: Among the 70 SSc patients included anti-annexin V IgG was found in 11 patients (15.7%) (range of 15.88-39.48 U/mL) and anti-annexin V IgM in 10 patients (14.3%) (range of 14.16-22.69 U/mL) at baseline. During follow-up, the number of patients who were positive for anti-annexin V IgG and IgM remained stable over 24 months. Among the patients with positive anti-annexin V IgG at baseline the frequency of patients with necrosis or amputation of extremities, forced vital capacity less than 70% and pulmonary arterial hypertension (PAH) was significantly higher than in patients with negative anti-annexin V IgG antibodies. Patients with anti-annexin V IgG had also a higher Raynaud's Condition Score and a higher Health Assessment Questionnaire Disability Index (HAQ-DI) than patients without these antibodies at baseline. Patients with positive anti-annexin V IgM at baseline presented a higher frequency of PAH, compared to those with negative anti-annexin V IgM at baseline. CONCLUSIONS: Anti-annexin V antibodies are stable and do not change their positivity during a 24 month follow-up in SSc patients. Anti-annexin V IgG was associated with more severe interstitial lung involvement and digital microangiopathy, and patients with anti-annexin V IgG or IgM had a higher occurrence of PAH indicating an association of these biomarker with more severe disease.

Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud's phenomenon and systemic sclerosis.

Capillaroscopy is a non-invasive and safe tool which allows the evaluation of the morphology of the microcirculation. Since its recent incorporation in the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for systemic sclerosis together with its assessed role to monitor disease progression, capillaroscopy became a 'mainstream' investigation for rheumatologists. Given its increasing use by a variety of physicians internationally both in daily practice to differentiate primary from secondary Raynaud's phenomenon, as well as in research context to predict disease progression and monitor treatment effects, standardisation in capillaroscopic image acquisition and analysis seems paramount. To step forward to this need, experts in the field of capillaroscopy/microcirculation provide in this very consensus paper their view on image acquisition and analysis, different capillaroscopic techniques, normal and abnormal capillaroscopic characteristics and their meaning, scoring systems and reliability of image acquisition and interpretation.

Anti-annexin V autoantibodies and vascular abnormalities in systemic sclerosis: a longitudinal study

Abstract Background: Annexins are a group of conserved proteins which exert several regulatory functions on various cellular activities. Increased frequency and levels of antibodies against annexin V have already been observed in several autoimmune diseases including systemic sclerosis (SSc), but their role as a vascular biomarker is unknown. The aim of this study was to determine the serum levels and the dynamical behavior of anti-annexin V antibodies over a 24 months follow-up in patients with SSc. Methods: In this bicentric cross-sectional study, 70 patients with SSc were consecutively selected from March 2016 to April 2017. Demographic and clinical features, including the presence of active DUs, were collected. Serum anti-annexin V IgG and IgM antibodies were measured at baseline and after 6, 12 and 24 months of follow-up. Videocapillaroscopy was performed in all patients. Results: Among the 70 SSc patients included anti-annexin V IgG was found in 11 patients (15.7%) (range of 15.88-39.48 U/mL) and anti-annexin V IgM in 10 patients (14.3%) (range of 14.16-22.69 U/mL) at baseline. During follow-up, the number of patients who were positive for anti-annexin V IgG and IgM remained stable over 24 months. Among the patients with positive anti-annexin V IgG at baseline the frequency of patients with necrosis or amputation of extremities, forced vital capacity less than 70% and pulmonary arterial hypertension (PAH) was significantly higher than in patients with negative anti-annexin V IgG antibodies. Patients with anti-annexin V IgG had also a higher Raynaud's Condition Score and a higher Health Assessment Questionnaire Disability Index (HAQ-DI) than patients without these antibodies at baseline. Patients with positive anti-annexin V IgM at baseline presented a higher frequency of PAH, compared to those with negative anti-annexin V IgM at baseline. Conclusions: Anti-annexin V antibodies are stable and do not change their positivity during a 24 month follow-up in SSc patients. Anti-annexin V IgG was associated with more severe interstitial lung involvement and digital microangiopathy, and patients with anti-annexin V IgG or IgM had a higher occurrence of PAH indicating an association of these biomarker with more severe disease.(AU)

Pan-American League of Associations for Rheumatology (PANLAR) capillaroscopy study group consensus for the format and content of the report in capillaroscopy in rheumatology.

OBJECTIVE: The aim of this work was to produce a consensus-based report for capillaroscopy in rheumatology to be used in daily clinical practice. METHODS: A written Delphi questionnaire regarding capillaroscopy report was developed from a literature review and expert consensus. The Delphi questionnaire was sent to an international panel including 25 rheumatologists experts in capillaroscopy, asking them to rate their level of agreement or disagreement with each statement. The exercise consisted of three online rounds and a face-to-face (live meeting) that took place in the PANLAR 2018 congress held in Buenos Aires, Argentina. RESULTS: The participants to the first, second, third, and face-to-face round were 22, 21, 21, and 16 rheumatologists, respectively. Fifty-five items were discussed in the first round, 58 in the second, 22 in the third, and 9 in the face-to-face meeting. At the end of the exercise, 46 recommendations for the capillaroscopy report in rheumatology reached a consensus. CONCLUSION: This is the first consensus-based report in capillaroscopy. It will be useful in daily clinical practice and to address the effort of the standardization in the technique. KEY POINTS: • The current lack of consensus for the capillaroscopy report makes difficult the interpretation of findings as well as follow-up of rheumatic diseases. • This study produced the first international consensus for the format and content of the naifold capillaroscopy report in rheumatology. • The report is an integral part of the capillaroscopy examination and its use in a homogeneous form can help in the correct interpretation of findings in daily practice.

Capillaroscopy changes are associated with disease progression in patients with early systemic sclerosis: A prospective study.

AIM: After the development of the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for systemic sclerosis (SSc), there are still a group of patients affected by early SSc who do not meet the new criteria. This study aimed to evaluate capillaroscopy changes and to identify predictors of progression to definite SSc in patients with early SSc over a 3-year follow-up. METHODS: In this prospective study, 44 patients with early SSc (LeRoy and Medsger 2001 criteria) were included. Clinical evaluation and widefield nailfold capillaroscopy were performed at baseline and after 3 years of follow-up. At the end of follow-up, the fulfilment of the 2013 ACR/EULAR criteria was also assessed. RESULTS: After 3 years, 34 patients with early SSc were re-evaluated. Of these, eight patients (23.5%) developed definite SSc. Worsening of capillaroscopy parameters was observed in 55.9% of patients. An increase in the number of giant capillaries and worsening of the avascular score were more frequent in patients who developed SSc than in those who did not (P = 0.02; P = 0.002, respectively). By multivariate analysis, an active or a late pattern at baseline on capillaroscopy was an independent predictor for the development of definite SSc (odds ratio = 30.0, 95% CI 2.1-421.1). CONCLUSIONS: In this prospective study, worsening in capillaroscopy parameters was observed in early SSc patients. An active or a late pattern on capillaroscopy was an independent predictive risk factor for the development of SSc, suggesting that capillaroscopy might be a useful tool to identify patients with early SSc at risk of disease progression.

Effect of probiotics on gastrointestinal symptoms and immune parameters in systemic sclerosis: a randomized placebo-controlled trial.

OBJECTIVES: Changes in the intestinal microbiota have been associated with the pathogenesis of SSc. Probiotics act by modulating the microbiome and the immune response. This study aimed to evaluate the efficacy of probiotics on gastrointestinal (GI) symptoms and immune responses in SSc patients. METHODS: Patients with SSc with a moderate-severe total score on the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA GIT 2.0) instrument were randomly assigned to receive a daily dose of probiotics (Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus acidophillus and Bifidobacterium lactis, 109 colony-forming units per capsule) or placebo for 8 weeks. The primary endpoint was improvement in the UCLA GIT 2.0 total score after 8 weeks. Secondary outcomes included changes in Th1, Th2, Th17 and regulatory T cell circulating levels and in the HAQ Disability Index (HAQ-DI) score. Parameters were assessed at baseline and after 4 and 8 weeks of treatment. RESULTS: A total of 73 patients were randomized to receive probiotics (n = 37) or placebo (n = 36). After 8 weeks, there was no difference in the UCLA GIT 2.0 score between the two groups. At week 8, the probiotic group showed a significant decrease in the proportion of Th17 cells compared with placebo (P = 0.003). There was no difference in the proportion of Th1, Th2 and regulatory T cells or in the HAQ-DI score between the groups. CONCLUSION: Probiotics did not improve GI symptoms in SSc patients. The reduction in Th17 cell levels suggests an immunomodulatory effect of probiotics on SSc. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov), NCT02302352.

Risk of digital ulcers occurrence in systemic sclerosis: a cross-sectional study.

BACKGROUND/OBJECTIVE: Digital ulcers (DUs) represent a frequent complication of systemic sclerosis (SSc). The aim of this study was to evaluate clinical, serological and capillaroscopy features that are associated with DUs in patients with SSc. METHODS: In this bicentric cross-sectional study, 70 patients with SSc were consecutively selected from March 2016 to April 2017. Demographic and clinical features, including the presence of active DUs, were collected. Videocapillaroscopy was performed in all patients. RESULTS: Among the 70 patients included (mean age of 46.8 years, mean disease duration of 9.41 years), 14 (20%) had active DUs. Based on multivariate analysis, the presence of anti-Scl-70 antibodies, the HAQ-DI score, and the capillary loss score were independently associated with DUs with odds ratios of 7.96 (95% CI 1.32-47.99), 55.77 (95% CI 1.76-1764.28), and 16.66 (95% CI 2.07-133.81), respectively. CONCLUSIONS: The presence of avascular areas in capillaroscopy, elevation of HAQ-DI score and anti-Scl-70 antibodies were independent factors associated with DUs in patients with SSc.