Focus on Filgotinib in Rheumatoid Arthritis: A Trial-Based Review.

Janus kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is involved in pathophysiologic cascade of a notable number of rheumatic diseases. The development of JAK inhibitors has expanded treatment choices in rheumatoid arthritis (RA) with a sustained class-effect efficacy. Filgotinib is a novel selective inhibitor of JAK1 isoform licensed for use in RA and ulcerative colitis. In this review we aim to present an analysis of filgotinib's efficacy and drug-specific safety warnings. Patients with RA with or without concomitant conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) (naïve or experienced) and those who have failed biologic Disease-Modifying Antirheumatic Drugs (bDMARDs) were examined in randomised clinical trials. Filgotinib was also tested against placebo, methotrexate, or adalimumab. Long-term extension trials provide insights for up to four years of continuous filgotinib administration. Beneficial effects are depicted in both disease activity parameters and quality of life indexes in moderate or severe RA with a longitudinal efficacy. In head-to-head comparison with adalimumab, filgotinib 200 mg was non-inferior. Adverse effects alerts are marked by the elevated risk of infectious adverse effects with the exception of herpes zoster infection, which has a low incidence.

Non-Invasive Assessment of Micro- and Macrovascular Function after Initiation of JAK Inhibitors in Patients with Rheumatoid Arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors constitute a novel class of oral biologic disease-modifying antirheumatic drugs for patients with rheumatoid arthritis (RA). However, their use has been associated with increased risk of major cardiovascular events. We investigated whether treatment with JAK inhibitors exerts significant alterations in the micro- and microvasculature in RA patients. METHODS: Thirteen patients with RA initiating treatment with JAK inhibitors were prospectively studied. Eventually, data from 11 patients who completed the study were analyzed. Procedures were performed at baseline and 3 months after treatment. Nailfold videocapillaroscopy was applied to detect alterations of the dermal capillary network. Participants underwent 24 h ambulatory blood pressure monitoring (Mobil-O-Graph device) for the assessment of blood pressure (both brachial and aortic) and markers of large artery stiffening [pulse wave velocity (PWV), augmentation index] throughout the whole 24 h and the respective day- and nighttime periods. Carotid intima-media thickness was assessed with ultrasound. RESULTS: Three-month treatment with JAK inhibitors was not associated with any differences in brachial and aortic blood pressure, arterial stiffness, and carotid atherosclerosis, with the only exception of nighttime PWV, which was significantly elevated at follow-up. However, three-month treatment with JAK inhibitors induced significant microvascular alterations and increased the total number of capillaroscopic abnormalities. CONCLUSIONS: Three-month treatment with JAK inhibitors may exert significant effects on microcirculation as assessed with nailfold videocapillaroscopy, whereas macrovascular structure and function appears largely unaffected. Further research toward this direction may add substantial information to the available literature regarding cardiovascular aspects of JAK inhibitors in RA.

Peripheral nailfold capillary microscopic abnormalities in rheumatoid arthritis are associated with arterial stiffness: Results from a cross-sectional study.

Vascular injury eventually resulting in the establishment of cardiovascular disease is a serious complication in rheumatoid arthritis (RA). Nailfold videocapillaroscopy (NVC) is a non-invasive imaging modality that enables the quantitative and qualitative assessment of the peripheral microvasculature. Nevertheless, capillaroscopic patterns remain inadequately defined in RA, especially regarding their clinical significance as potential markers of systemic vascular impairment. Consecutive RA patients underwent NVC using a standardized protocol, to assess the following parameters: capillary density, avascular areas, capillary dimensions, microhemorrhages, subpapillary venous plexus, and presence of ramified, bushy, crossed and tortuous capillaries. Carotid-femoral pulse wave velocity (PWV) and pulse pressure were measured as well-acknowledged markers of large artery stiffening. The vast majority of our cohort (n = 44) presented a combination of non-specific and abnormal capillaroscopic parameters. Capillary ramification was associated with both PWV and pulse pressure, even after adjustment for cardiovascular risk factors and systemic inflammation. Our study highlights the high prevalence of a wide range of capillaroscopic deviations from the normal patterns in RA. Furthermore, it provides for the first time evidence of an association between structural disorders of the microcirculation and markers of macrovascular dysfunction, suggesting that NVC might have a role as an index of generalised vascular impairment in RA.

Right Ventricular Morphology and Function after Exercise Training in People with Systemic Sclerosis: A Randomized Controlled Pilot Study.

BACKGROUND: Vascular dysfunction and its concomitant multi-organ involvement, including cardiac involvement, affects prognosis in systemic sclerosis (SSc) patients. Regular exercise has demonstrated to be able to improve vascular function in SSc. However, the effects of an exercise program on the heart and specifically in right ventricular (RV) morphology and function in SSc have yet to be explored. The study aimed to examine whether a 3-month combined exercise program can affect RV morphology and function in SSc patients. METHODS: Twenty-eight SSc patients were randomly allocated to either the exercise training (ET) or the control (CON) group. Baseline and follow-up assessments consisted of a cardiopulmonary exercise test along with both a conventional and a two-dimensional speckle tracking echocardiography (2DSTE) focused on RV morphology and function. Following the baseline assessments, Group ET participated in a supervised combined exercise program for 12 weeks, while group CON received their usual care. RESULTS: The ET group demonstrated increases in peak oxygen consumption by 25.1% (p < 0.001), global RV free wall longitudinal systolic strain by 6.69% (p < 0.03), RV free wall longitudinal systolic strain of the basal segment by 13.5% (p < 0.001), and global RV four-chamber longitudinal systolic strain by 6.76% (p < 0.03) following the exercise program. No differences were observed in group CON. CONCLUSIONS: Combined exercise improved cardiorespiratory efficiency and indices of RV systolic function, as assessed by the 2DSTE, in SSc patients.

Understanding and managing cardiac involvement in systemic sclerosis.

INTRODUCTION: Cardiac involvement is common in systemic sclerosis occurring in up to 80% of patients. Primary myocardial dysfunction results from impairment of coronary microvascular circulation, myocardial inflammation and fibrosis with the prevalence of atherosclerosis remaining contradictory. AREAS COVERED: This review presents the various aspects of cardiac involvement in SSc from a pathophysiological, clinical, diagnostic and therapeutic standpoint. Imaging modalities with emerging role in the understanding of mechanisms and prompt diagnosis of myocardial fibrosis namely cardiac magnetic resonance are also discussed. EXPERT OPINION: Cardiac involvement in SSc - and particularly primary myocardial disease - remains a challenge as clinical symptoms manifest in advanced stages of heart failure and convey poor prognosis. Over the last years the introduction of sophisticated imaging methods of myocardial function has resulted in a better understanding of the underlying pathophysiological processes of myocardial damage such as microvasculopathy, inflammation, diffuse or focal fibrosis. Such developments could contribute to the identification of patients at higher risk for subclinical heart involvement for whom diligent surveillance and prompt initiation of therapy with cardioprotective and/or immunosuppressive drugs coupled with invasive interventions namely radiofrequency ablation, implantable cardioverter-defibrillator when indicated, may improve long-term outcomes.

The role of asymmetric dimethylarginine in endothelial dysfunction and abnormal nitric oxide metabolism in systemic sclerosis: results from a pilot study.

INTRODUCTION/OBJECTIVES: Systemic sclerosis (SSc) is characterized by generalized vasculopathy affecting mainly small vessels while macrovascular involvement is less investigated. The aim of this study was to examine associations between asymmetric dimethylarginine (ADMA) - a biomarker of atherosclerosis - and assessments of macrovascular endothelial function in patients with SSc. METHODS: This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA measurement in serum samples was based on an enzyme immunoassay technique. Participants underwent blood pressure measurement according to 2018 ESC/ESH Guidelines, applanation tonometry for the evaluation of arterial stiffness, and carotid ultrasound for the measurement of the intima-media thickness (cIMT). RESULTS: Eighty-one Caucasians (82.3% female) SSc individuals with mean age 55.44 ± 13.4 years were included in this analysis. The correlation analysis of ADMA levels (unadjusted and adjusted values) with functional and morphological parameters of atherosclerosis revealed no statistically significant associations. Subgroup analysis based on disease duration (≤ 4 years), immunologic profile (SCL-70 and ACA antibodies), disease type (limited, diffuse), and inflammatory status (erythrocyte sedimentation rate [ESR] > 25 mm/h and C-reactive protein [CRP] > 5 mg/L) showed no associations, except from a significant positive correlation between ADMA levels and cΙΜΤmean (r = 0.370, p = 0.044) in individuals with early SSc. CONCLUSIONS: The results of the study suggest that ADMA may be related with accelerated atherosclerosis in early stages of the disease. However, the lack of association between other morphological and functional parameters of endothelial dysfunction may suggest that other regulators of nitric oxide metabolism may contribute to macrovascular injury in SSc in various phases of the disease. Key Points • ADMA is a biomarker of atherosclerosis and has been linked with microvascular complications of SSc. •ADMA was not correlated with morphological and functional parameters of atherosclerosis in the population of the study. •The demonstrated association between ADMA and cIMT in patients with early SSc may suggest a role of NO/ADMA pathway in the initiation of macrovascular injury in SSc.

Asymmetric dimethylarginine correlates with worsening peripheral microangiopathy in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease characterized primarily by micro-angiopathy and endothelial dysfunction which stimulate a fibrotic process. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor and represents a novel biomarker for vascular dysfunction. Nailfold video capillaroscopy (NVC) represents a non-invasive and reliable technique for the evaluation of microvasculopathy in SSc. OBJECTIVES: The aim of this study was to examine the possible association between ADMA and microvascular involvement in patients with SSc. METHODS: This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA was measured in serum samples using a commercial enzyme immunoassay. Participants underwent NVC with qualitative and semi-quantitative assessment and all NVC parameters were measured in the distal row of each finger. The findings were classified in one of the three qualitative NVC patterns: early, active, and late. RESULTS: Eighty-one (92,6 % women) SSc individuals with mean age 55.44 ± 13.4 years were included in this analysis. Within-groups comparisons revealed a trend between higher ADMA levels and progressive micro-vasculopathy (1,29 [2,1] vs 1,57 [1,95] vs 2,41 [3,87]; for early, active and late patterns respectively, p = 0.039). Furthermore, ADMA concentration was significantly associated with the number of capillaries/mm (r = -0.235; p = 0.035). CONCLUSIONS: Serum ADMA levels were significantly associated with advancing stages of microcirculatory abnormalities suggesting that ADMA may have a role in promoting microvascular endothelial dysfunction in SSc individuals.

Study of Peripheral Microcirculation Assessed by Nailfold Video-Capillaroscopy and Association with Markers of Endothelial Dysfunction and Inflammation in Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease that primarily affects synovial joints and is associated with increased cardiovascular (CV) mortality and morbidity. This association is only partially attributed to the presence of classic CV disease risk factors, and is strongly associated with characteristics of disease itself namely systemic chronic inflammation and autoimmune activation. Growing evidence suggests that microvascular endothelial dysfunction contributes to the initiation and progression of vascular disease. Nailfold capillaroscopy is a non-invasive method that evaluates the morphology and the structure of nailfold capillaries. Extension of this method is the Nailfold Videocapillaroscopy (NVC), which provides the possibility of combining functional and anatomical study of peripheral microcirculation. The present cross-sectional study aims to evaluate using NVC the peripheral microcirculation in adult patients with RA and investigate the associations between structural and functional indices of digital capillaries with markers of atherosclerosis.

Methotrexate induced neurotoxicity in a patient with rheumatoid arthritis on rituximab therapy: a case-based review.

Rheumatoid arthritis (RA) is a systemic inflammatory disease treated with conventional and biologic disease-modifying drugs. Methotrexate is the anchor drug for the treatment of RA and is also frequently used for various autoimmune diseases. Adverse events are common and generally easy to manage, involving mainly the gastrointestinal tract and the liver function. However, neurotoxicity is very uncommon in adults with rheumatic diseases. B cell depletion with rituximab is another therapy approach particularly in patients with refractory RA. Whistle leukoencephalopathy - namely progressive multifocal leukoencephalopathy-is an infrequent but well-described side effect of rituximab. In contrast, central nervous system toxicity due to methotrexate is extremely rare especially in RA individuals under oral or subcutaneous low dose on weekly basis. We present a challenging case of a RA patient on treatment with methotrexate and rituximab presenting with leukoencephalopathy. The patient was diagnosed with methotrexate-induced leukoencephalopathy which reversed after treatment discontinuation. We comment on the symptoms and diagnostic workout and we review the available literature on this issue based on recommendations for narrative reviews.

JAK Inhibition in Patients with Rheumatoid Arthritis: Haemodynamic Effects and Impact on Micro- and Macrovascular Function. Study Design and Rationale.

Rheumatoid arthritis (RA) is characterised by increased rates of cardiovascular disease (CVD), which represents the leading cause of death. Patients with RA presents increased prevalence of hypertension, which substantially contributes to the increased CVD burden associated with the disease. A solid pathophysiological background supports the presence of microvascular dysfunction in RA even in the absence of established CVD, while macrovascular dysfunction in the form of large artery stiffening has been further described. Janus kinase (JAK) inhibitors constitute a novel class of disease-modifying anti-rheumatic drugs (DMARDs) for the management of rheumatoid arthritis (RA). However, the vascular effects of JAK inhibitors in RA patients remain largely understudied. More recent evidence suggests higher risk of major adverse cardiovascular events with JAK inhibition compared to treatment with a TNF inhibitor, and calls for more careful consideration of potential negative effects on the cardiovascular system. The present prospective observational cohort study aims to investigate the impact of JAK inhibitors on ambulatory blood pressure and haemodynamic profile, as well as markers of micro- and macrovasculopathy among patients with RA.

Cardiovascular complications after COVID-19 in chronic kidney disease, dialysis and kidney transplant patients.

The coronavirus disease 2019 (COVID-19) is associated with increased mortality in patients with chronic kidney disease (CKD), dialysis patients and kidney transplant recipients (KTR). Cardiovascular complications, such as sudden arrhythmias, thromboembolic events, coronary events, cardiomyopathies and heart failure, may present in about 10-20% of patients with COVID-19. Patients with CKD, dialysis patients and KTR are all at increased cardiovascular risk and present with more cardiovascular complications after COVID-19 compared to the general population. During the pandemic, health care giving has rapidly changed by reducing elective outpatient reviews, which may refrain these high-risk patients from the appropriate management of their medical conditions, further increasing cardiovascular risk. Importantly, acute kidney injury (AKI) is another common complication of severe COVID-19 and associates with increased mortality. A large proportion of the AKI patients need renal replacement treatment, while 30% of them may not present renal function recovery and remain dialysis-dependent after discharge, thereby having potentially increased future cardiovascular risk. This review summarizes current knowledge regarding the cardiovascular events and mortality in patients with CKD or undergoing hemodialysis and in KTR.

Non-Invasive Assessment of Endothelial Dysfunction in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterised by an increased pressure in the pulmonary arterial circulation, resulting in the elevation of pulmonary vascular resistance. Pulmonary endothelial dysfunction and inflammation, triggered by shear stress and hypoxia, constitute the hallmarks of pulmonary vasculopathy by promoting endothelial and smooth muscle cells proliferation, vasoconstriction, and thrombosis. While research was predominantly focused on pulmonary vasculature, the investigation of peripheral endothelial damage in different vascular beds has attracted the interest over the last years. As a result, effective non-invasive methods that can assess the endothelial function and the architectural integrity have been utilized for the evaluation of pulmonary and peripheral vasculature. Non-invasive plethysmography, pulmonary flow reserve, nailfold videocapillaroscopy, near-infrared spectroscopy, and imaging techniques such as magnetic resonance angiography and perfusion imaging coupled by a number of biomarkers can be used for the assessment of peripheral vascular function in PAH individuals. In this review, we summarise and critically approach the current evidence of more systemic derangement of vascular function in PAH defined by novel, non-invasive methods employed for functional and morphological assessment of endothelium and microcirculation.

Peripheral microcirculatory abnormalities are associated with cardiovascular risk in systemic sclerosis: a nailfold video capillaroscopy study.

INTRODUCTION: Microvascular dysfunction is the key element in the pathogenesis of systemic sclerosis (SSc), whereas the contribution of large and medium size vessel abnormalities is yet to be established. The aim of the present study is to assess the association between micro- and macrovascular function by utilizing a broad spectrum of assessments of vascular performance. METHODS: We included consecutive, consenting SSc patients who underwent nailfold video capillaroscopy (NVC) for microcirculation evaluation. Peripheral and central systolic and diastolic blood pressure, carotid intima-media thickness (cIMT), aortic augmentation index (AIx) corrected for a heart rate of 75 beats per minute (AIx-75), and carotid-femoral pulse wave velocity (PWV) were also performed to assess macrovascular function. Cardiovascular risk disease (CVD) algorithms were also calculated and included in the analysis. RESULTS: A total of 81 patients (6 males) were studied with mean age 55.44 ± 13.40 years. Reduced capillary density was inversely correlated with arterial stiffness (Alx-75) and augmentation pressure (r = - 0.262, p = 0.018, and r = - 0.249, p = 0.025 respectively). Alx was significantly lower in the early compared to late pattern (28.24 ± 11.75 vs 35.63 ± 10.47, p = 0.036). A significant trend was found among NVC patterns with Alx-75 values being higher with the progression of microangiopathy towards the "late" group (26.36 ± 10.90 vs 30.81 ± 11.59 vs 35.21 ± 7.90, p = 0.027 for trend). Similarly, Framingham risk score and Atherosclerotic Cardiovascular Disease score were progressively higher across the worsening NVC patterns (4.10 ± 4.13 vs 2.99 ± 2.72 vs 6.36 ± 5.65, p = 0.023, and 6.99 ± 7.18 vs 5.63 ± 4.41 vs 12.09 ± 9.90, p = 0.019, respectively, for trends). Finally, QRISK3 (10-year cardiovascular disease risk) and ASCVD (Atherosclerotic Cardiovascular Disease) scores were inversely correlated with the number of capillaries (r = - 0.231, p = 0.048, and r = - 0.260, p = 0.038 respectively). CONCLUSION: These data suggest that CVD risk scores and macrovascular parameters are strongly correlated with microvasculopathy in patients with SSc. Key Points • Microangiopathy is the hallmark of SSc, but the relationship between subclinical atherosclerosis and small vessel disease remains unknown. • Arterial stiffening and CVD risk scores are positively associated with the degree of progression of peripheral microvasculopathy assessed with NVC. • The results of the study suggest an association between NVC abnormalities and higher CVD risk in SSc patients.

Nailfold videocapillaroscopic changes in patients with pulmonary arterial hypertension associated with connective tissue diseases.

Pulmonary arterial hypertension (PAH) represents one of the most devastating complications in connective tissue diseases (CTDs). The aim of this study was to investigate the presence of peripheral microangiopathy in patients with PAH associated with CTDs (CTD-PAH) by exploring nailfold videocapillaroscopic (NVC) changes and identify possible associations of NVC characteristics with markers of disease severity. Α cross-sectional study was performed in 18 CTD-PAH patients [13 PAH due to systemic sclerosis (SSc-PAH) and 5 with other types of CTD-PAH], 14 patients with SSc without PAH (SSc-non-PAH) and 20 healthy controls. NVC quantitative and qualitative parameters were evaluated using Optilia Digital Capillaroscope. To ensure inter-observer repeatability, capillaroscopic images were reviewed by two independent investigators. When compared to healthy controls, patients with CTD-PAH (77.8% women, mean age 65.9 years) presented reduced capillary density (6.5 ± 1.6 loops/mm vs. 9.7 ± 0.7 loops/mm, p < 0.001) and increased capillary loop width (23.3 ± 10.1 µm vs. 11.2 ± 2.5 µm, p < 0.001). SSc-PAH patients presented lower capillary density in comparison with other CTD-PAH patients and SSc-non-PAH subjects and abnormal and disorganized capillaries compared to controls. Patients with other CTD-PAH had also reduced capillary density and increased loop diameter compared to controls. A significant linear correlation was identified between capillary density and estimated glomerular filtration rate in the total CTD-PAH population (r = 0.63, p = 0.007). In SSc-PAH group, capillary loop diameter was positively correlated to cardiac index (r = 0.61, p = 0.02). Significant NVC microvascular changes were detected in patients with various types of CTD-PAH, suggesting an impaired peripheral microcirculation parallel to pulmonary vasculopathy.

Microcirculatory function deteriorates with advancing stages of chronic kidney disease independently of arterial stiffness and atherosclerosis.

Cardiovascular disease is the main cause of mortality in chronic kidney disease (CKD). Endothelial dysfunction and capillary rarefaction are established cardiovascular risk factors. Nailfold video capillaroscopy provides a thorough assessment of capillary density and functional reserve. This study aimed to examine possible differences in structural and functional capillary density in CKD stages 2-4 with nailfold video capillaroscopy. Ninety-six CKD patients, divided into four equally sized groups according to CKD stage (2, 3a, 3b, 4), underwent nailfold video capillaroscopy, during which capillary density was measured at baseline, after 4-min arterial occlusion and after 2-min venous occlusion. Arterial stiffness and wave parameters were measured with applanation tonometry and common carotid intima-media thickness (ccIMT) with ultrasound. Baseline capillary density showed a progressive reduction with advancing CKD stages (stage 2: 32.6 ± 2.8, stage 3a: 31.2 ± 3.8, stage 3b: 32.5 ± 3.3, stage 4: 28.5 ± 3.1, p = 0.011). Similar reductions were observed during postocclusive hyperemia (39.4 ± 3.0, 37.6 ± 4.2, 38.4 ± 3.8, and 33.8 ± 3.3, respectively; p = 0.021) and after venous congestion (41.1 ± 3.1, 39.0 ± 4.4, 39.9 ± 3.5, and 35.2 ± 3.4; p = 0.032). Office PWV and ccIMT showed nonsignificant increasing trends with advancing CKD. In multivariate analysis, eGFR showed a positive association (per ml/min increase; ß: 0.053, 95% CI: 0.004-0.101), whereas diabetes (ß: -1.706, 95% CI: -3.176 to -0.236) and parathyroid hormone (PTH) (per pg/ml increase; ß: -0.022, 95% CI: -0.036 to -0.008) had negative associations with postocclusive capillary density. Both structural and functional capillary density progressively decrease with advancing CKD stages. Apart from reduced eGFR, diabetes and increased PTH levels are independently associated with this reduction. This capillary rarefaction may largely contribute to the increased cardiovascular risk of CKD patients.

Association Between Uric Acid and Worsening Peripheral Microangiopathy in Systemic Sclerosis.

Objective: The key element in the pathogenesis of systemic sclerosis (SSc) is microcirculatory changes in several vascular beds. Uric acid is associated with endothelial dysfunction and therefore, microvascular damage. The aim of this study was to examine the association between uric acid (UA) and peripheral microvascular involvement in patients with SSc. Methods: We included consecutive, consenting patients with SSc. Serum UA, urea and creatinine were measured, and glomerular filtration rate (GFR) was calculated with CKD-EPI. All participants underwent nailfold video-capillaroscopy (NVC) to evaluate the microcirculation. Results: A total of 64 patients (95.3% women) were included in the study. UA levels were significantly associated with the number of avascular areas (r = 0.290; p = 0.020), whereas no correlation was shown for the GFR (r = -0.065; p = 0.609). A significant trend of UA in the three capillaroscopic patterns was shown (3.90 ± 1.52 vs. 4.15 ± 0.98 vs. 5.38 ± 2.26; for early, active, and late patterns respectively, p = 0.028). Multivariate analysis showed that male gender (ß = 3.049; 95% CI = 0.997-5.101) and UA (ß = 0.352; 95% CI = 0.117-0.588) were independently associated with the number of avascular areas. Conclusion: These data suggest that UA levels are significantly associated with the capillaroscopic patterns, reflecting a progressive microvasculopathy.

Arthritis and Myositis in a Patient Treated with Programmed Cell Death-1 (PD-1) Inhibitor Pembrolizumab for Lung Cancer.

Immune checkpoint inhibitors (ICIs) are a new class of drug that have demonstrated efficacy across many cancer types. Because of their nature and mode of action, ICIs unleash immune activation raising concerns as to whether they can be used in patients with concomitant autoimmune or auto-inflammatory diseases. Their usage can lead to the development of autoimmune phenomena known as immune related adverse events (irAEs), virtually affecting every organ. As the use of ICIs is drastically increasing, evidence of irAEs has been accumulating. Herein, we report a case of inflammatory myositis and arthritis 6 months after pembrolizumab therapy, an anti-programmed death-1 (PD1) ICI in a patient with lung cancer, aiming at raising awareness of the diagnostic and clinical challenges clinicians may face when checkpoint inhibitors-related rheumatologic irAEs are developed.

Cancer risk in systemic sclerosis: identifying risk and managing high-risk patients.

Introduction: Systemic sclerosis (SSc) is associated with a heightened cancer risk compared to the general population. Several pathways including immune system upregulation, cumulative inflammation, environmental factors, and genetic predisposition contribute to the development of both cancer and autoimmunity. Areas covered: This paper provides an overview of studies investigating the relationship between SSc and various types of cancer with a special focus on the identification of patients at higher risk for malignancy development. The demographic, serological, clinical, and disease-related characteristics of SSc individuals who are diagnosed with cancer over the course of their disease are discussed to provide a practical guidance for relevant screening strategies. Expert opinion: Several studies have identified subgroups of SSc patients at higher cancer risk based on the immunological profile (anti-RNAPol III positivity), diffuse disease type, and older age at SSc onset. Additionally, a close temporal association between SSc and cancer onset in certain antibody subsets raises the question as to whether more aggressive screening strategies should be considered. Currently, there are no published studies investigating the cost-effectiveness, efficacy, and safety of a targeted cancer-detection program. Screening procedures should at least follow recommendations for the general population with a special focus on patients at higher risk and specific cancer types.

Subclinical atherosclerosis in systemic sclerosis and rheumatoid arthritis: a comparative matched-cohort study.

Systemic autoimmune inflammatory disorders confer a higher risk of cardiovascular (CV) disease leading to increased morbidity and mortality and reduced life expectancy compared to the general population. CV risk in systemic sclerosis (SSc) has not been studied extensively but surrogate markers of atherosclerosis namely carotid intima media thickness (cIMT) and pulse wave velocity (PWV) are impaired in some but not all studies in SSc patients. The aim of this study was to investigate the prevalence of subclinical atherosclerosis assessed by cIMT and PWV between two well-characterized SSc and Rheumatoid Arthritis (RA) cohorts. Consecutive SSc patients attending the Scleroderma Clinic were compared with RA patients recruited in the Dudley Rheumatoid Arthritis Co-morbidity Cohort (DRACCO), a prospective study examining CV burden in RA. Augmentation Index (Aix75) and cIMT were measured in all participants. Propensity score matching was utilised to select patients from the two cohorts with similar demographic characteristics, CV risk factors and inflammatory load. Unpaired analysis was performed using unpaired t test for continuous variables and χ2 test for dichotomous variables. Statistical analysis was repeated using paired t test for continuous normal variables and McNemar's test for dichotomous variables. Fifty five age- and sex-matched SSc and RA patients were included in the analysis. No difference was demonstrated between SSc and RA subjects regarding cIMT (0.66 mm vs 0.63 mm, respectively) and Aix75% measurements (33.4 vs 31.7, respectively) neither in paired (p = 0.623 for cIMT and p = 0.204 for Aix%) nor in unpaired t test analysis (p = 0.137 for cIMT and p = 0.397 for AIx%). The results of this comparative study show that subclinical atherosclerosis is comparable between SSc and RA, a systemic disease with well-defined high atherosclerotic burden. Such findings underscore the importance of CV risk management in SSc in parallel with other disease-related manifestations.

Arterial stiffness correlates with progressive nailfold capillary microscopic changes in systemic sclerosis: results from a cross-sectional study.

BACKGROUND: While microangiopathy is well-documented in systemic sclerosis (SSc), a potential link between SSc and macrovascular disease is highly debated and remains to be established. The aim of the present study is to investigate the association between micro- and macrovascular involvement in the setting of SSc. METHODS: Consecutive, consenting SSc patients were assessed by nailfold video-capillaroscopy (NVC) to evaluate the microcirculation. The number of capillaries per mm2 and the capillaroscopic skin ulcer risk index (CSURI) were measured, and findings were also classified into three scleroderma patterns (i.e., early, active, and late). Carotid intima-media thickness (IMT), aortic augmentation index corrected for a heart rate of 75 beats per minute (AIx-75), carotid-femoral pulse wave velocity (PWV), and central systolic and diastolic blood pressure were also determined to assess macrovascular function. RESULTS: A total of 37 patients were studied. A significant correlation was observed between AIx and the average number of capillaries per mm2 (r = - 0.34, p = 0.047) and between AIx and CSURI (r = 0.35, p = 0.044). Patients with the "early" scleroderma pattern had lower AIx values compared with "active" (20.5 ± 11.4 vs 34.1 ± 11.5%, p = 0.02) and "late" (20.5 ± 11.4 vs 33.4 ± 8.8%, p = 0.05) patterns. No other significant correlations were found between macrovascular biomarkers (PWV, carotid IMT, systolic and diastolic central blood pressure) and the capillaroscopic measurements. CONCLUSIONS: These data suggest that arterial stiffness (as assessed by AIx-75) correlates with microvascular damage in patients with SSc.