JAK Inhibition as a Potential Treatment Target in Systemic Lupus Erythematosus.

Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules responsible for signal transduction of multiple cytokines and growth factors in different cell types, involved in the maintenance of immune tolerance. Thus, the dysregulation of this pathway plays a crucial role in the pathogenesis of multiple autoimmune, inflammatory, and allergic diseases and is an attractive treatment target. JAK inhibitors (JAKinibs) have been approved in the treatment of multiple autoimmune diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (SPA). In SLE, there is a plethora of ongoing trials evaluating their efficacy, with tofacitinib, baricitinib and deucravacitinib showing promising results, without major safety concerns. In this review, we will discuss the rationale of targeting JAKinibs in SLE and summarize the clinical data of efficacy and safety of JAKinibs in SLE patients.

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.

Circulating levels of galectin-3 and coronary microvascular perfusion in rheumatoid arthritis patients with suppressed inflammation.

OBJECTIVE: Cardiovascular manifestations are the leading cause of mortality in rheumatoid arthritis (RA). Galectin-3, a lectin protein with major role in cellular, inflammatory, and fibrotic processes, has been introduced as a novel cardiac biomarker. We hypothesized that patients with RA present increased levels of galectin-3, and investigated potential associations with arterial stiffness and coronary microvascular dysfunction. METHODS: This cross-sectional study enrolled RA patients and non-RA individuals without cardiovascular comorbidities. Galectin-3 and high-sensitivity C-reactive protein (hsCRP) were measured with enzyme-linked immunosorbent assay (ELISA) in serum samples. Subendocardial viability ratio (SEVR), an index of microvascular myocardial perfusion, and pulse wave velocity (PWV), the gold-standard measure of vascular stiffness, were estimated with applanation tonometry. RESULTS: Cardiovascular risk factors and hsCRP were comparable between patients (n = 24) and controls (n = 24). However, galectin-3 was increased [6.9 (6.7) vs 4.6 (4.7)] ng/dl, p = 0.015], and coronary microvascular perfusion was decreased (142.6 ± 22.8 vs 159.7 ± 23.2%, p = 0.028) in RA patients compared to controls, whereas PWV did not significantly differ. Galectin-3 correlated with both PWV and SEVR in univariate analysis. However, after adjustment for cardiovascular risk factors and subclinical inflammation, these associations were rendered non-significant. CONCLUSION: Galectin-3 appears increased in RA, even among patients with suppressed inflammation in the absence of cardiovascular comorbidities. The observed association of galectin-3 with coronary microvascular perfusion in our study was non-significant after adjustment for cardiovascular risk factors and inflammation. The potential role of galectin-3 as a cardiac biomarker in RA warrants further investigation. Key Points • Galectin-3 has emerged as a novel cardiac biomarker but remains understudied in RA. • Patients with RA present elevated levels of galectin-3 and impaired coronary microvascular perfusion compared to non-RA individuals. • These differences were observed in patients with suppressed inflammation, even in the absence of CVD. • The association of galectin-3 with coronary microvascular impairment in RA warrants further investigation.

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.

Nailfold Videocapillaroscopy for the Evaluation of Peripheral Microangiopathy in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic and refractory autoimmune joint disease that affects multiple organs. Several methods have been applied for the study of microvascular endothelial dysfunction, which is considered an important component of vascular disease in RA. Implementation of nailfold videocapillaroscopy (NVC) represents a viable choice, as the skin is an easily accessible window for the non-invasive, real-time assessment of subtle microcirculation abnormalities. Although NVC is routinely used in the rheumatology field, especially for the diagnostic workout of Raynaud's phenomenon, accumulating evidence suggests a role in the evaluation of systemic vasculopathy associated with autoimmune rheumatic disorders. The current paper aims to provide an overview of NVC as a valuable clinical aid for the assessment of peripheral microcirculation in RA. Previous studies characterizing the capillaroscopic pattern in RA are summarized, along with associations with disease-related characteristics. Most available reports have mainly focused on the descriptions of non-specific morphological alterations that may reflect endothelial injury over the course of the disease. Still, the exact pattern of structural and functional capillaroscopic alterations and their clinical significance in RA remains a subject of ongoing research.

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.

Monitoring and Managing Cardiovascular Risk in Immune Mediated Inflammatory Diseases.

Cardiovascular disease (CVD) is common in immune-mediated inflammatory diseases (IMIDs) and it is predominately attributed to the interplay between chronic inflammation and traditional CVD risk factors. CVD has significant impact on the survival of patients with IMIDs as it is associated with increased morbidity and mortality. Despite recommendations for monitoring and managing CVD in patients with IMIDs, the individual CVD risk assessment remains problematic as CVD risk calculators for the general population consistently underestimate the risk in patients with IMIDs. Application of new technologies utilizing artificial intelligence techniques have shown promising potential for tailoring predictive medicine to the individual patient, but further validation of their role in clinical decision-making is warranted. In the meantime, individuals with IMIDs should be encouraged to adopt behavioral interventions targeting at modifiable lifestyle CVD risk factors, whereas rheumatologists need to be well aware of the unfavorable effects of antirheumatic medication on various CVD risk factors and outcomes. In the current paper, we aim to provide an overview of current and emerging strategies for mitigating CVD risk in patients with IMIDs, based on a practical approach.

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.