Gastrointestinal Manifestations of Sarcoidosis: A State-of-the-Art, Comprehensive Review of the Literature-Practical Clinical Insights and Many Unmet Needs on Diagnosis and Treatment.

This comprehensive literature review explores the involvement of the gastrointestinal (GI) tract in sarcoidosis, a multisystem granulomatous disorder of unknown etiology. GI sarcoidosis presents a diagnostic and therapeutic challenge due to its rarity and nonspecific clinical manifestations, including overlap with other gastrointestinal diseases. We conducted a comprehensive screening of articles addressing the clinical features, diagnostic approaches, and treatment strategies for GI sarcoidosis. Our findings reveal that GI sarcoidosis can affect any part of the gastrointestinal tract, with the stomach and small intestine being the most involved. Clinical presentations range from asymptomatic cases to severe complications such as obstruction and perforation, with reflux being a common symptom. Diagnosis is often delayed due to the nonspecific nature of symptoms and the need for histopathological confirmation. Therapeutic approaches are poorly defined, typically involving corticosteroids as the mainstay of treatment. However, the long-term efficacy and safety of these treatments remain uncertain in this patient group, given the significant risks and complications associated with prolonged glucocorticoid therapy. There is a clear need to develop accurate diagnostic protocols to distinguish GI sarcoidosis from other conditions and to establish standardized therapeutic guidelines to optimize patient outcomes. Further research is essential to enhance our understanding and management of this complex condition.

Safety of Nintedanib in a Patient with Chronic Pulmonary Fibrosis and Kidney Disease.

Nintedanib, an intracellular inhibitor that targets multiple tyrosine kinase, is an important drug for the treatment of pulmonary fibrosis. Until now, no studies have been published reporting the nintedanib tolerability or its efficacy in patients with chronic pulmonary lung disease and chronic kidney disease comorbidity. The safety, efficacy and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) and for this reason it is contraindicated in these patients. We describe a case of use of nintedanib in a patient affected by idiopathic pulmonary fibrosis (IPF) who started, from 2022, nintedanib 150 mg twice a day with careful monitoring of liver and kidney function. Due to the onset of stage 3/4 chronic kidney disease associated with proteinuria, nintedanib was suspended for two months, and the patient received Prednisone at a dose of 12.5 mg/day. During the two months of suspension, the renal function did not improve, unlike the respiratory status worsened. In the past a renal biopsy was performed which showed no correlation with nintedanib use. Nintedanib therapy started again following the decline in lung function and desaturation below 90% in the 6-min walking test (6MWT). Patient showed a good tolerability of nintedanib with sporadic episode of diarrhea and an improvement of pulmonary function leading to a stable state of chronic pulmonary fibrosis disease. For this reason, in mutual agreement with the patient, we decided to maintain nintedanib therapy even when the patient required hemodialysis. No toxic effects appeared. This case report revealed the safety of nintedinab in patient with concomitant kidney failure, but more studies are necessary.

Deciphering loop gain complexity: a primer for understanding a pathophysiological trait of obstructive sleep apnea patients.

Loop Gain (LG), a concept borrowed from engineering used to describe the stability of electrical circuits under negative feedback, has emerged as a crucial pathophysiological trait in sleep respiratory disorders. In simple terms, LG measures how the respiratory control system reacts to changes in breathing. A high LG suggests that minor disturbances in breathing prompt exaggerated responses, potentially leading to instability and oscillations in respiratory patterns. Conversely, a low LG implies that the system responds more gently to disturbances, resulting in stable and well-regulated breathing. However, understanding the concept of loop gain presents challenges due to its dynamic nature across various sleep respiratory disorders, sleep stages, positions, and interactions with other pathophysiological traits. Recent efforts have aimed to identify a non-invasive method for assessing LG, with some evidence suggesting that information regarding pathophysiological traits can be extracted from polysomnography. There exists a clinical imperative for physician to unravel the intricacies of LG when managing Obstructive Sleep Apnea (OSA) patients, because LG abnormalities delineate a distinct pathophysiological phenotype of OSA. Specifically, certain patients exhibit a high LG as the primary factor driving sleep apnea, influencing treatment outcomes. For instance, individuals with high LG may respond differently to therapies such as continuous positive airway pressure (CPAP) or oral appliances compared to those with normal LG, or they can be treated with specific drugs or combination therapies. Thus, understanding LG becomes paramount for precise assessment of OSA patients and is fundamental for optimizing a personalized and effective treatment approach.

A versatile role for lung ultrasound in systemic autoimmune rheumatic diseases related pulmonary involvement: a narrative review.

Systemic autoimmune rheumatic diseases (SARDs) related pulmonary disease is highly prevalent, with variable clinical presentation and behavior, and thus is associated with poor outcomes and negatively impacts quality of life. Chest high resolution computed tomography (HRCT) is still considered a fundamental imaging tool in the screening, diagnosis, and follow-up of pulmonary disease in patients with SARDs. However, radiation exposure, economic burden, as well as lack of point-of-care CT equipment limits its application in some clinical situation. Ultrasound has found a place in numerous aspects of the rheumatic diseases, including the vasculature, skin, muscle, joints, kidneys and in screening for malignancies. Likewise it has found increasing use in the lungs. In the past two decades, lung ultrasound has started to be used for pulmonary parenchymal diseases such as pneumonia, pulmonary edema, lung fibrosis, pneumothorax, and pleural lesions, although the lung parenchymal was once considered off-limits to ultrasound. Lung ultrasound B-lines and irregularities of the pleural line are now regarded two important sonographic artefacts related to diffuse parenchymal lung disease and they could reflect the lesion extent and severity. However, its role in the management of SARDs related pulmonary involvement has not been fully investigated. This review article will focus on the potential applications of lung ultrasound in different pulmonary scenarios related with SARDs, such as interstitial lung disease, diffuse alveolar hemorrhage, diaphragmatic involvement, and pulmonary infection, in order to explore its value in clinical daily practice.

Pirfenidone in Idiopathic Pulmonary Fibrosis: Real-World Observation on Efficacy and Safety, Focus on Patients Undergoing Antithrombotic and Anticoagulant.

Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple side effects. The aim of the study was to examine the efficacy and safety profile of pirfenidone in a real-life context, with a focus on the concomitant use of antithrombotic and/or anticoagulant treatments. The clinical and functional data (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], diffusing lung capacity for carbon monoxide [DLCO], and 6 min walking test distance [6MWD]) of all IPF patients treated with pirfenidone and referred to our two centers between 2019 and 2022 were retrospectively analyzed at baseline, 6 and 12 months after the start of treatment. A total of 55 IPF subjects undergoing pirfenidone treatment were included in the analysis (45.5% females, median [IQR] age at disease onset 68.0 [10.0] years, median [IQR] age at baseline 69.0 [10.8] years). Compared to baseline, at 12 months, FVC (86.0% vs. 80.0%; p = 0.023) and DLCO (44.0% vs. 40.0%; p = 0.002) were significantly reduced, while FEV1 (p = 0.304) and 6MWD (p = 0.276) remained stable; no significant change was recorded at 6 months. Most of the reported adverse events were mild or moderate. Gastrointestinal intolerance (9.1%) was the main cause of treatment discontinuation. A total of 5% of patients reported at least one minor bleeding event, although all episodes occurred in those receiving concomitant antithrombotic or anticoagulant. Overall, this real-life experience confirms the efficacy and safety profile of pirfenidone in the case of the concomitant use of antithrombotic and/or anticoagulant drugs.

A novel technique for conducting flexible bronchoscopy cryobiopsy under conscious sedation: An observational study.

Transbronchial lung cryobiopsy (TBCB) is a reliable method for obtaining histopathological findings in interstitial lung diseases. TBCB is traditionally performed during rigid bronchoscopy, positioning an endobronchial balloon blocker to facilitate bleeding management. Therefore, it can be challenging to implement in Centers without access to anesthesiologic support or dedicated beds for endoscopic procedures. We present a series of 11 patients who underwent 12 TBCBs using a flexible bronchoscope and a 5 Fr endobronchial blocker passing through an uncuffed endotracheal tube, under moderate sedation and spontaneous breathing. All procedures were carried out in an endoscopy suite, using fluoroscopy guidance but without requiring anesthesiologic assistance. TBCB was feasible in all cases, and it demonstrated similar or improved diagnostic yield (90.1%) and safety compared to rigid bronchoscopy. In 1 case, it was successfully repeated due to an inconclusive histological definition at the first attempt. The size of the samples was consistent with the literature, as it was the incidence of pneumothorax (16.6%). Four cases of moderate bleeding and 4 cases of severe bleeding were managed without further complications. To our knowledge, this is the first description of a technique allowing to perform TBCB through an artificial airway without need for either rigid bronchoscopy or general anesthesia. We believe this technique could make TBCB faster, cost-effective, and feasible even in resource-limited settings without compromising on safety. However, further studies are needed to validate these findings.

Pirfenidone and Nintedanib in Pulmonary Fibrosis: Lights and Shadows.

Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases (ILD). Both drugs have side effects that affect patients in different ways and have different levels of severity, making treatment even more challenging for patients and clinicians. The present review aims to assess the effectiveness and potential complications of Pirfenidone and Nintedanib treatment regimens across various ILD diseases. A detailed search was performed in relevant articles published between 2018 and 2023 listed in PubMed, UpToDate, Google Scholar, and ResearchGate, supplemented with manual research. The following keywords were searched in the databases in all possible combinations: Nintedanib; Pirfenidone, interstitial lung disease, and idiopathic pulmonary fibrosis. The most widely accepted method for evaluating the progression of ILD is through the decline in forced vital capacity (FVC), as determined by respiratory function tests. Specifically, a decrease in FVC over a 6-12-month period correlates directly with increased mortality rates. Antifibrotic drugs Pirfenidone and Nintedanib have been extensively validated; however, some patients reported several side effects, predominantly gastrointestinal symptoms (such as diarrhea, dyspepsia, and vomiting), as well as photosensitivity and skin rashes, particularly associated with Pirfenidone. In cases where the side effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. However, further research is needed to optimize the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Finally, other studies are requested to establish the treatments that can stop ILD progression.

Vascular Endothelial Damage in COPD: Where Are We Now, Where Will We Go?

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has higher rates among the general population, so early identification and prevention is the goal. The mechanisms of COPD development have not been completely established, although it has been demonstrated that endothelial dysfunction plays an important role. However, to date, the measurement of endothelial dysfunction is still invasive or not fully established. Nailfold video capillaroscopy (NVC) is a safe, non-invasive diagnostic tool that can be used to easily evaluate the microcirculation and can show any possible endothelial dysfunctions early on. The aim of this review is to evaluate if nailfold microcirculation abnormalities can reflect altered pulmonary vasculature and can predict the risk of cardiovascular comorbidities in COPD patients. METHODS: A systematic literature search concerning COPD was performed in electronic databases (PUBMED, UpToDate, Google Scholar, ResearchGate), supplemented with manual research. We searched in these databases for articles published until March 2024. The following search words were searched in the databases in all possible combinations: chronic obstructive pulmonary disease (COPD), endothelial damage, vascular impairment, functional evaluation, capillaroscopy, video capillaroscopy, nailfold video capillaroscopy. Only manuscripts written in English were considered for this review. Papers were included only if they were able to define a relationship between COPD and endothelium dysfunction. RESULTS: The search selected 10 articles, and among these, only three previous reviews were available. Retinal vessel imaging, flow-mediated dilation (FMD), and skin autofluorescence (AF) are reported as the most valuable methods for assessing endothelial dysfunction in COPD patients. CONCLUSIONS: It has been assumed that decreased nitric oxide (NO) levels leads to microvascular damage in COPD patients. This finding allows us to assume NVC's potential effectiveness in COPD patients. However, this potential link is based on assumption; further investigations are needed to confirm this hypothesis.

Oscillometry Longitudinal Data on COVID-19 Acute Respiratory Syndrome Treated with Non-Invasive Respiratory Support.

Background: Oscillometry allows for the non-invasive measurements of lung mechanics. In COVID-19 ARDS patients treated with Non-Invasive Oxygen Support (NI-OS), we aimed to (1) observe lung mechanics at the patients' admission and their subsequent changes, (2) compare lung mechanics with clinical and imaging data, and (3) evaluate whether lung mechanics helps to predict clinical outcomes. Methods: We retrospectively analyzed the data from 37 consecutive patients with moderate-severe COVID-19 ARDS. Oscillometry was performed on their 1st, 4th, and 7th day of hospitalization. Resistance (R5), reactance (X5), within-breath reactance changes (ΔX5), and the frequency dependence of the resistance (R5-R19) were considered. Twenty-seven patients underwent computed tomographic pulmonary angiography (CTPA): collapsed, poorly aerated, and normally inflated areas were quantified. Adverse outcomes were defined as intubation or death. Results: Thirty-two patients were included in this study. At the first measurement, only 44% of them had an abnormal R5 or X5. In total, 23 patients had measurements performed on their 3rd day and 7 on their 7th day of hospitalization. In general, their R5, R5-R19, and ΔX decreased with time, while their X5 increased. Collapsed areas on the CTPA correlated with the X5 z-score (ρ = -0.38; p = 0.046), while poorly aerated areas did not. Seven patients had adverse outcomes but did not present different oscillometry parameters on their 1st day of hospitalization. Conclusions: Our study confirms the feasibility of oscillometry in critically ill patients with COVID-19 pneumonia undergoing NI-OS. The X5 z-scores indicates collapsed but not poorly aerated lung areas in COVID-19 pneumonia. Our data, which show a severe impairment of gas exchange despite normal reactance in most patients with COVID-19 ARDS, support the hypothesis of a composite COVID-19 ARDS physiopathology.

Cardiopulmonary exercise testing complements both spirometry and nuclear imaging for assessing sarcoidosis stage and for monitoring disease activity.

BACKGROUND: Pulmonary sarcoidosis is a systemic disease that can confound established follow-up tools. Pulmonary function tests (PFTs) are recommended in initial and follow-up patient evaluations yet are imperfect predictors of disease progression. The cardiopulmonary exercise test (CPET) is another potentially useful monitoring tool, although previous studies report conflicting findings regarding which variables are altered by the disease. Nuclear imaging tests are also employed to assess inflammatory activity and may be predictive of functional deterioration. AIM: We asked whether PFTs or CPET are more diagnostic of disease stage, which subsets of functional variables are impacted by the disease, and how these relate to nuclear imaging signs of active inflammation. STUDY DESIGN AND METHODS: We collected retrospective data (spirometry, CPET, Gallium-67 scintigraphy, 18F-FDG PET/CT) from 48 patients and 10 controls. Disease severity was assessed following Scadding classification. First, we correlated individual PFTs and CPET parameters to Scadding stage and nuclear imaging data. Next, we performed Principal Component Analysis (PCA) on PFTs and CPET parameters, separated into respiratory, cardiovascular and metabolic subsets. Finally, we constructed multiple regression models to determine which variable subsets were the best predictors of Scadding stage and disease activity. RESULTS: The majority of PFTs and CPET single parameters were significantly correlated with patient stage, while only few correlated with disease activity. Nevertheless, multiple regression models were able to significantly relate PFTs and CPET to both disease stage and activity. Additionally, these analyses highlighted CPET cardiovascular parameters as the best overall predictors of disease stage and activity. CONCLUSIONS: Our results display how CPET and spirometry data complement each other for sarcoidosis disease staging, and how these tests are able to detect disease activity. Our findings suggest that CPET, a repeatable and non-invasive functional test, should be more routinely performed and taken into account in sarcoidosis patient follow-up.

Patients' unmet needs and treatment preferences concerning digital ulcers in systemic sclerosis.

INTRODUCTION: Digital ulcers (DUs) significantly impact on quality of life and function in patients with systemic sclerosis (SSc). The aim of our survey was to explore patients' perspectives and their unmet needs concerning SSc-DUs. MATERIALS: SSc patients were invited through international patient associations and social media to participate in an online survey. RESULTS: 358 responses were obtained from 34 countries: US (65.6%), UK (11.5%) and Canada (4.5%). Recurrent DUs are common: >10 DUs (46.1%), 5-10 DUs (21.5%), 1-5 DUs (28.5%), 1 DU (3.9%). Fingertip DUs were most frequent (84.9%), followed by those overlying the interphalangeal joints (50.8%). The impact of DUs in patients is broad, from broad-ranging emotional impacts to impact on activities of daily living, and personal relationships. Half (51.7%) of respondents reported that they received wound/ulcer care, most often provided by non-specialist wound care clinics (63.8%). There was significant variation in local (wound) DU care, in particular the use of debridement and pain management. DU-related education was only provided to one-third of patients. One-quarter (24.6%) were 'very satisfied' or 'satisfied' that the provided DU treatment(s) relieved their DU symptoms. Pain, limited hand function, and ulcer duration/chronicity were the main reasons for patients to consider changing DU treatment. CONCLUSIONS: Our data show that there is a large variation in DU treatment between countries. Patient access to specialist wound-care services is limited and only a small proportion of patients had their DU needs met. Moreover, patient education is often neglected. Evidence-based treatment pathways are urgently needed for DU management.

A multi-national survey to identify clinicians' perspectives concerning Proton Pump inhibitors in patients with systemic sclerosis.

OBJECTIVES: Proton Pump Inhibitors (PPIs) are widely used in SSc for gastroesophageal reflux disease (GERD). However, there is little evidence to support their empirical use and long-term safety has been questioned. Our objective was to better describe clinicians' attitudes toward PPIs prescription and use in SSc patients. METHODS: Clinicians involved in the care of SSc patients were invited through international physician networks and social media to participate in an online survey. RESULTS: Responses from 227 clinicians from 36 countries were evaluable. The majority 'agreed' (41.4 %) or 'strongly agreed' (45.4 %) that GERD is a major cause of morbidity in SSc. Lifestyle modifications are seldom (16 %) considered effective. Only half 'agreed' (43 %) or 'strongly agreed' (11 %) there is solid evidence supporting PPIs efficacy in SSc. The most common reasons for PPIs prescription were symptomatic GERD unresponsive to lifestyle modification (95 %), objective evidence of GERD (82 %), and hoarseness or respiratory symptoms (71 %). There are variable concerns about PPIs long-term safety in SSc. The three highest (mean) reasons (0-10, here 10 is 'very concerned') were: small intestinal bacterial overgrowth (5.5), osteoporosis (5.4), and drug interactions (5.2). There are significant differences in attitudes towards surgery for refractory GERD, and concerns about potential complications. PPIs may have a putative role for disease modification (e.g., ILD and calcinosis), and the role of immunosuppression is uncertain for GI (gastrointestinal) disease in SSc. CONCLUSION: PPIs are frequently prescribed in SSc. Side effects are a recognized concern, especially regarding long-term therapy. There is significant variation in attitudes towards surgical intervention. Future research and practical treatment recommendation for PPIs in SSc are urgently needed.

Nailfold Capillaroscopy Analysis Can Add a New Perspective to Biomarker Research in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), all of which are characterised by inflammation of small-medium-sized vessels. Progressive understanding of these diseases has allowed researchers and clinicians to start discussing nailfold video capillaroscopy (NVC) as a future tool for many applications in daily practice. Today, NVC plays a well-established and validated role in differentiating primary from secondary Raynaud's phenomenon correlated with scleroderma. Nevertheless, there has not been sufficient attention paid to its real potential in the ANCA-associated vasculitis. In fact, the role of NVC in vasculitis has never been defined and studied in a multicentre and multinational study. In this review, we carried out a literature analysis to identify and synthesise the possible role of capillaroscopy for patients with ANCA-associated vasculitis. METHODS: Critical research was performed in the electronic archive (PUBMED, UpToDate, Google Scholar, ResearchGate), supplemented with manual research. We searched in these databases for articles published until November 2023. The following search words were searched in the databases in all possible combinations: capillaroscopy, video capillaroscopy, nailfold-video capillaroscopy, ANCA-associated vasculitis, vasculitis, granulomatosis with polyangiitis, EGPA, and microscopic polyangiitis. RESULTS: The search identified 102 unique search results. After the evaluation, eight articles were selected for further study. The literature reported that capillaroscopy investigations documented non-specific abnormalities in 70-80% of AAV patients. Several patients showed neoangiogenesis, capillary loss, microhaemorrhages, and bushy and enlarged capillaries as the most frequent findings. Furthermore, the difference between active phase and non-active phase in AAV patients was clearly discernible. The non-active phase showed similar rates of capillaroscopy alterations compared to the healthy subjects, but the active phase had higher rates in almost all common abnormalities instead. CONCLUSIONS: Microvascular nailfold changes, observed in patients affected by vasculitis, may correlate with the outcome of these patients. However, these non-specific abnormalities may help in the diagnosis of vasculitis. As such, new analysis analyses are necessary to confirm our results.

Functional Progression after Dose Suspension or Discontinuation of Nintedanib in Idiopathic Pulmonary Fibrosis: A Real-Life Multicentre Study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with rapidly progressive evolution and an unfavorable outcome. Nintedanib (NTD) is an antifibrotic drug that has been shown to be effective in slowing down the progression of the disease. The aim of our study was to examine the efficacy, especially in terms of the functional decline, and the safety profile of NTD in patients treated with the recommended dose and subjects who reduced or suspended the therapy due to the occurrence of adverse reactions. METHODS: We conducted a real-life retrospective study based on the experience of NTD use in two centers between 2015 and 2022. Clinical data were evaluated at baseline, at 6 and 12 months after the NTD introduction in the whole population and in subgroups of patients who continued the full-dose treatment, at a reduced dosage, and at the discontinuation of treatment. The following data were recorded: the demographic features, IPF clinical features, NTD therapeutic dosage, tolerability and adverse events, pulmonary function tests (PFTs), the duration of treatment upon discontinuation, and the causes of interruption. RESULTS: There were 54 IPF patients who were included (29.6% females, with a median (IQR) age at baseline of 75 (69.0-79.0) years). Twelve months after the introduction of the NTD therapy, 20 (37%) patients were still taking the full dose, 11 (20.4%) had reduced it to 200 mg daily, and 15 (27.8%) had stopped treatment. Gastrointestinal intolerance predominantly led to the dose reduction (13.0%) and treatment cessation (20.4%). There were two deaths within the initial 6 months (3.7%) and seven (13.0%) within 12 months. Compared to the baseline, the results of the PFTs remained stable at 6 and 12 months for the entire NTD-treated population, except for a significant decline in the DLCO (% predicted value) at both 6 (38.0 ± 17.8 vs. 43.0 ± 26.0; p = 0.041) and 12 months (41.5 ± 15.3 vs. 44.0 ± 26.8; p = 0.048). The patients who continued treatment at the full dose or a reduced dosage showed no significant differences in the FVC and the DLCO at 12 months. Conversely, those discontinuing the NTD exhibited a statistically significant decline in the FVC (% predicted value) at 12 months compared to the baseline (55.0 ± 13.5 vs. 70.0 ± 23.0; p = 0.035). CONCLUSIONS: This study highlights the functional decline of the FVC at 12 months after the NTD initiation among patients discontinuing therapy but not among those reducing their dosage.

Robustness of Longitudinal Safety and Efficacy After Paclitaxel-Based Endovascular Therapy for Treatment of Femoro-Popliteal Artery Occlusive Disease: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The aims of this study were: i) to assess fragility indices (FIs) of individual randomized controlled trials (RCTs) that compared paclitaxel-based drug-coated balloons (DCBs) or drug-eluting stents (DESs) versus standard endovascular devices, and ii) to meta-analyze mid-term and long-term safety and efficacy outcomes from available RCT data while also estimating the FI of pooled results. METHODS: This systematic review has been registered in the PROSPERO public database (CRD42022304326 http://www.crd.york.ac.uk/PROSPERO). A query of PubMed (Medline), EMBASE (Excerpta Medical Database), Scopus, and CENTRAL (Cochrane Central Register of Controlled Trials) databases was performed to identify eligible RCTs. Rates of primary patency (PP) and target lesion revascularization (TLR) were assessed as efficacy outcomes, while lower limb amputation (LLA) consisting of major amputation that is. below or above the knee and all-cause mortality were estimated as safety outcomes. All outcomes were pooled with a random effects model to account for any clinical and study design heterogeneity. The analyses were performed by dividing the RCTs according to their maximal follow-up length (mid-term was defined as results up to 2-3 years, while long-term was defined as results up to 4-5 years). For each individual outcome, the FI and reverse fragility index (RFI) were calculated according to whether the outcome results were statistically significant or not, respectively. The fragility quotient (FQ) and reverse fragility quotient (RFQ), which are the FI or RFI divided by the sample size, were also calculated. RESULTS: A total of 2,337 patients were included in the systematic review and meta-analysis. There were 2 RCTs examining DES devices and 14 RCTs evaluating different DCBs. For efficacy outcomes, there was evidence that paclitaxel-based endovascular therapy increased the PP rate and reduced the TLR rate at mid-term, with a calculated pooled risk ratio (RR) of 1.66 for patency (95% CI, 1.55-1.86; P < 0.001), with a corresponding number needed-to-treat (NNT) of 3 patients (95% CI, 2.9-3.8) and RR of 0.44 for TLR (95% CI, 0.35-0.54; P = 0.027), respectively. Similarly, there was evidence that paclitaxel-based endovascular therapy both increased PP and decreased TLR rates at long-term, with calculated pooled RR values of 1.73 (95% CI, 1.12-2.61; P = 0.004) and 0.53 (95% CI, 0.45-0.62; P = 0.82), respectively. For safety outcomes, there was evidence that paclitaxel-based endovascular therapy increased all-cause mortality at mid-term, with a calculated pooled RR of 2.05 (95% CI, 1.21-3.24). However, there was no difference between treatment arms in LLA at mid-term (95% CI, 0.1-2.7; P = 0.68). Similarly, neither all-cause mortality nor LLA at long-term differed between treatment arms, with a calculated pooled RR of 0.66, 1.02 (95% CI, 0.31-3.42) and 1.02 (95% CI, 0.30-5.21; P = 0.22), respectively. The pooled estimates of PP at mid-term were robust (FI = 28 and FQ = 1.9%) as were pooled rates of TLR (FI = 18 and FQ = 0.9%). However, when safety outcomes were analyzed, the robustness of the meta-analysis decreased significantly. In fact, the relationship between the use of paclitaxel-coated devices and all-cause mortality at mid-term showed very low robustness (FI = 4 and FQ = 0.2%). At 5 years, only the benefit of paclitaxel-based devices to reduce TLR remained robust, with an FI of 32 and an FQ of 3.1%. CONCLUSIONS: The data supporting clinical efficacy endpoints of RCTs that examined paclitaxel-based devices in the treatment of femoral-popliteal arterial occlusive disease were robust; however, the pooled safety endpoints were highly fragile and prone to bias due to loss of patient follow-up in the original studies. These findings should be considered in the ongoing debate concerning the safety of paclitaxel-based devices.

A Multinational Survey Investigating the Unmet Needs and Patient Perspectives Concerning Proton Pump Inhibitors in Systemic Sclerosis.

OBJECTIVE: Proton pump inhibitors (PPIs) are widely prescribed to treat gastroesophageal reflux disease (GERD) in Systemic Sclerosis (SSc). However, not all patients adequately respond to the treatment, and there are frequent concerns about the safety of long-term use of PPIs. Our aim was to identify the main problems/complaints of SSc patients on PPIs, as well as understand their unmet needs. METHODS: SSc patients treated with PPIs were invited through international patient associations and social media to participate in an online survey. RESULTS: We gathered 301 valid responses from 14 countries (United Kingdom 19.3% and United States 70.4%). Multiple PPIs use (two: 30% and three: 21% in series) was common. The majority (89%) reported improvement in gastrointestinal symptoms from receiving PPIs. Side effects attributed to receiving PPIs were uncommon (19%); however, most (79%) were potentially concerned. Around half (58%) had received lifestyle information, and most (85%) had searched online for information about PPIs. Only in the minority (12%) had a surgical approach been discussed; however, half (46%) indicated that they would be willing to undergo surgery to resolve their GERD symptoms but had important concerns. CONCLUSION: Despite the frequent use of PPIs in patients with SSc, there is significant heterogeneity in prescription, and combination therapy (PPIs plus other medication for acid reflux) is not uncommon (approximately 40%). Patients have significant concerns about PPIs side effects. Education about PPIs is often neglected, and patients very frequently use online sources to obtain information on drug treatment. A surgical approach is infrequently discussed, and patients fear this potential therapeutic approach.

Biomarkers in Systemic Sclerosis: An Overview.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor ß (TGF-ß) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

Pulmonary Sarcoidosis and Immune Dysregulation: A Pilot Study on Possible Correlation.

BACKGROUND: Sarcoidosis is a systemic inflammatory disease characterized by an altered inflammatory response. OBJECTIVE: The aim of this study was to evaluate whether immune system alterations detected by lymphocyte typing in peripheral blood correlate with the severity of sarcoidosis, calculated according to two separate severity scores proposed by Wasfi in 2006 and Hamzeh in 2010. MATERIALS AND METHODS: Eighty-one patients were recruited, and clinical data and laboratory tests at the time of diagnosis were obtained in order to assess the severity index score and investigate any statistically significant correlation with the cytofluorimetry data. RESULTS: Our data demonstrated that none of the two scores show an association with the level of total lymphocytes or lymphocyte subclasses. LIMITATIONS: First of all, the sample taken into consideration is small. The assessment was performed only at disease onset and not during the disease. Furthermore, the severity scores do not take into account disease activity (measured by PET/CT or gallium scintigraphy). CONCLUSIONS: Lymphocyte subpopulation values at the time of diagnosis do not appear to correlate with disease severity at onset.