Scar sarcoidosis: Clinical features and prognostic significance.

BACKGROUND AND AIM: Only a few series of patients with scar sarcoidosis (SS) have been reported. Our aim was to analyse the clinical features of SS patients and their relationship to the prognosis of sarcoidosis. METHODS: Patients with systemic sarcoidosis with SS diagnosed between 1980-2017 at Bellvitge University Hospital, were enrolled. Their clinical charts were reviewed to collect the following data: age, sex, ethnicity, number of lesions, location of SS, origin of the scar, association with erythema nodosum or other specific cutaneous lesions, radiological stage at diagnosis, chronic systemic sarcoidosis activity. RESULTS: Forty two of 728 patients with systemic sarcoidosis presented SS (31 females and 11 males, mean age 47.71±13.747 years). SS was present at the onset of systemic sarcoidosis in 35/42 cases (83.33%). Twelve patients had simultaneously erythema nodosum. In 14 patients SS was the only specific cutaneous lesion of sarcoidosis. Foreign bodies were observed in 16 of 26 biopsied SS lesions (61.54%). Radiological stage at diagnosis was 0 for 2 patients, I for 22, II for 13, III for 4, and IV for 1. The activity of systemic sarcoidosis persisted for more than 5 years in 16/42 patients with SS (38.1%) vs. 186/686 patients with systemic sarcoidosis (27.11%), However the differences were not significant (p=0.154). CONCLUSIONS: SS was observed in 5.77% of our patients with systemic sarcoidosis. It is usually present at the onset of the disease and is an useful sign for suspicion of a diagnosis of sarcoidosis, but it carries no prognostic significance.

New genetic drivers in hemorrhagic hereditary telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in around 90% of the patients; also 2% of patients harbor pathogenic variants at SMAD4 and GDF2. Importantly, the genetic cause of 8% of patients with clinical HHT remains unknown. Here, we present new putative genetic drivers of HHT. METHODS: To identify new HHT genetic drivers, we performed exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology. We applied a multistep filtration strategy to catalog deleterious variants and prioritize gene candidates based on their known relevance in endothelial cell biology. Additionally, we performed in vitro validation of one of the identified variants. RESULTS: We identified variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT. We have identified the SMAD6 p.(Glu407Lys) variant in one of the families; this is a loss-of-function variant leading to the activation of the BMP/TGFß signaling in endothelial cells. CONCLUSIONS: Variants in these genes should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations.

Aflibercept for Gastrointestinal Bleeding in Hereditary Hemorrhagic Telangiectasia: A Case Report.

Herein, we present the first described hereditary hemorrhagic telangiectasia (HHT) patient treated with aflibercept for severe GI involvement after tachyphylaxis to bevacizumab, with promising results. HHT is a rare genetic disease characterized by systemic vascular malformations. Gastrointestinal telangiectasia is one of the major involvements that can produce chronic severe iron-deficiency anemia. Nowadays, support treatment with iron replacement therapy, red blood cell transfusions, and antiangiogenic drugs-mainly bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF)-are the main therapeutic options for this complication. The evidence of alternative drugs in patients with failure to this approach, such as tachyphylaxis to bevacizumab, is scarce. Aflibercept is a VEGF inhibitor with antiangiogenic properties approved for the treatment of different types of cancer and ocular neovascularization diseases.

Long-term use of somatostatin analogs for chronic gastrointestinal bleeding in hereditary hemorrhagic telangiectasia.

Background: Chronic bleeding due to gastrointestinal (GI) involvement in patients with hemorrhagic hereditary telangiectasia (HHT) can provoke severe anemia with high red blood cells (RBC) transfusion requirements. However, the evidence about how to deal with these patients is scarce. We aimed to assess the long-term efficacy and safety of somatostatin analogs (SA) for anemia management in HHT patients with GI involvement. Methods: This is a prospective observational study including patients with HHT and GI involvement attended at a referral center. SA were considered for those patients with chronic anemia. Anemia-related variables were compared in patients receiving SA before and during treatment. Patients receiving SA were divided into responders (patients with minimal hemoglobin levels improvement >10 g/L and maintaining hemoglobin levels ≥80 g/L during treatment), and non-responders. Adverse effects during follow-up were collected. Results: Among 119 HHT patients with GI involvement, 67 (56.3%) received SA. These patients showed lower minimal hemoglobin levels (73 [60-87] vs. 99 [70.2-122.5], p < 0.001), and more RBC transfusion requirements (61.2% vs. 38.5%, p = 0.014) than patients without SA therapy. Median treatment period was 20.9 ± 15.2 months. During treatment, there was a statistically significant improvement in minimum hemoglobin levels (94.7 ± 29.8 g/L vs. 74.7 ± 19.7, p < 0.001) and a reduction of patients with minimal hemoglobin levels <80 g/L (39 vs. 61%, p = 0.007) and RBC transfusions requirement (33.9% vs. 59.3%, p < 0.001). Sixteen (23.9%) patients showed mild adverse effects, mostly diarrhea or abdominal pain, leading to treatment discontinuation in 12 (17.9%) patients. Fifty-nine patients were eligible for efficacy assessment and 32 (54.2%) of them were considered responders. Age was associated with non-responder patients, OR 95% CI; 1.070 (1.014-1.130), p = 0.015. Conclusion: SA can be considered a long-term effective and safe option for anemia management in HHT patients with GI bleeding. Older age is associated with poorer response.

Perioperative Complications and Long-Term Follow-Up of Liver Transplantation in Hemorrhagic Hereditary Telangiectasia: Report of Three Cases and Systematic Review.

The aim was to describe three patients with hemorrhagic hereditary telangiectasia (HHT) requiring liver transplantation (LT) and to perform a systematic review focusing on surgical complications and long-term follow-up. Unrestricted searches of the Medline and Embase databases were performed through February 2022. Forty-five studies were selected including 80 patients plus the three new reported patients, 68 (81.9%) were female and mean age was 50 (27-72) years. Main indications for LT were high-output cardiac failure (n = 40; 48.2%), ischemic cholangitis (n = 19; 22.9%), and a combination of both conditions (n = 13;15.6%). Mean cold ischemic time and red blood cell units transfused during LT were 554 (300-941) minutes and 11.4 (0-88) units, respectively. Complications within 30 days were described in 28 (33.7%) patients, mainly bleeding complications in 13 patients, hepatic artery (HA) thrombosis in four and hepatic vein thrombosis in one. Mean follow-up was 76.4 (1-288) months, and during it, four new patients developed thrombotic complications in HA, HA aneurysm, celiac artery, and the portal-splenic-mesenteric vein. HHT relapse in the transplant allograft was detected in 13 (17.1%) patients after 1-19 years (including two fatal recurrences). Overall mortality was 12%. In conclusion, previous assessment of HA anatomy and hyperdynamic circulatory state could reduce LT complications. The risk of relapse in the hepatic graft supports a multidisciplinary follow-up for HHT patients with LT.

Catheter-Directed Therapies in Patients with Pulmonary Embolism: Predictive Factors of In-Hospital Mortality and Long-Term Follow-Up.

(1) Background: Catheter-directed therapies (CDT) may be considered for selected patients with pulmonary embolism (PE); (2) Methods: Retrospective observational study including all consecutive patients with acute PE undergoing CDT (mechanical or pharmacomechanical) from January 2010 through December 2020. The aim was to evaluate in-hospital and long-term mortality and its predictive factors; (3) Results: We included 63 patients, 43 (68.3%) with high-risk PE. All patients underwent mechanical CDT and, additionally, 27 (43%) underwent catheter-directed thrombolysis. Twelve (19%) patients received failed systemic thrombolysis (ST) prior to CDT, and an inferior vena cava (IVC) filter was inserted in 28 (44.5%) patients. In-hospital PE-related and all-cause mortality rates were 31.7%; 95% CI 20.6-44.7% and 42.9%; 95% CI 30.5-56%, respectively. In multivariate analysis, age > 70 years and previous ST were strongly associated with PE-related and all-cause mortality, while IVC filter insertion during the CDT was associated with lower mortality rates. After a median follow-up of 40 (12-60) months, 11 more patients died (mortality rate of 60.3%; 95% CI 47.2-72.4%). Long-term survival was significantly higher in patients who received an IVC filter; (4) Conclusions: Age > 70 years and failure of previous ST were associated with mortality in acute PE patients treated with CDT. In-hospital and long-term mortality were lower in patients who received IVC filter insertion.

Satisfactory treatment of mucocutaneous lesions in hereditary hemorrhagic telangiectasia patients with dual pulsed dye laser and neodymium: yttrium-aluminum-garnet.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by telangiectasia and larger arteriovenous malformations (AVM) in different organs. Mucocutaneous telangiectasia can bleed and cause stigmatization, but the best treatment approach has not been defined yet. The aim of the study was to evaluate the efficacy and safety of dual pulsed dye laser and neodymium: yttrium-aluminum-garnet (PDL-Nd:YAG) laser treatment for mucocutaneous telangiectasia in HHT patients. It is a retrospective case series, where clinical files of all HHT patients treated with PDL-Nd:YAG laser at our Department between December 2010 and July 2019 were reviewed. Demographic, clinical, and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners scoring pretreatment and posttreatment pictures on a 5-point scale. Patient satisfaction and procedure pain were assessed using an ordinal scale (0-10). Forty-three treatment areas from 26 patients were analyzed. Lesions were predominantly located on the lower lip and cheeks. The median number of laser sessions per patient was 3 (interquartile range [IQR] 2-4). The median global severity score at baseline was 2 and became 0 at endpoint (p < 0.0001), with a median improvement rate of 4 (IQR 3-4). All patients reported a high degree of satisfaction (median 9) and tolerable pain (median 5). In conclusion, dual PDL-Nd: YAG laser is a convenient, safe, and effective treatment option for mucocutaneous telangiectasia in HHT patients.

Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial.

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients. Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization. Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39-1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360-842] vs. 870 mg [IQR 364-1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00-17.5] vs. 18.5 days [3.00-53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05-2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC. Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19. Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

Non-retrieved inferior vena cava filters: causes and long-term follow-up.

BACKGROUND: Temporary inferior vena cava (IVC) filters are not always retrieved. Information about long-term outcomes of patients with indwelling filters is scarce. Aims of our study were to assess reasons that preclude retrieval of temporary IVC filters and long-term outcomes and causes of death in patients with indwelling filters. MATERIALS AND METHODS: Retrospective observational study including all consecutive patients undergoing IVC filter insertion from January 2009 through December 2018. Patients with permanent filters and those with temporary filters not retrieved were followed from insertion until June 2020. RESULTS: We included 271 patients with a mean age of 63.8 years. The main indication for filter insertion was acute venous thromboembolism and contraindication for anticoagulation (83%). The filter was deemed as permanent in 24.4% of patients and temporary in 75.6%. Sixty six percent of temporary filters were retrieved; the main cause of non-retrieval was lack of planning / follow-up (57.9%). One hundred twelve patients (41.3%) remained with indwelling filters. After follow-up, 54.5% were alive and 45.5% had died, with a median survival time of 6.19 (95% CI, 2.63-9.75) years. The most frequent cause of death during follow-up was cancer (49%). The frequency of anticoagulant therapy was similar in both groups (57.4%% versus 54.9%). CONCLUSIONS: The main preventable cause of non-retrieval of temporary IVC filters was lack of planning / follow-up. Structured follow-up programs should be implemented to increase retrieval rates. In patients with indwelling filters, the main cause of death was cancer and extended anticoagulation was not associated with survival.

Angiogenesis, hereditary hemorrhagic telangiectasia and COVID-19.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth. The evidence about the influence of Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in patients with rare diseases is scarce. We aimed to know the prevalence of coronavirus disease 2019 (COVID-19) in HHT patients. The HHT pathogenic angiogenesis and endothelial injury in COVID-19 are discussed using data from RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry. RiHHTa is an open, multicenter, prospective, observational registry including adult patients with HHT. A 27-item survey that captured clinical data of admitted HHT patients for COVID-19 was distributed to all RiHHTa investigators from June 8th to June 24th 2020. Only one out of 1177 HHT patients was admitted for COVID-19 pneumonia. She is a 74 years-old woman with a pathogenic variant in ACVRL1 gene. Her clinical course did not involve mechanical ventilation or worsening epistaxis, and she was successfully discharged after two weeks. The endothelial damage and the consequent angiogenic process in COVID-19 patients deserve further investigation.

Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis.

BACKGROUND: A higher incidence of thrombotic events, mainly pulmonary embolism (PE), has been reported in hospitalized patients with COVID-19. The main objective was to assess clinical and laboratory differences in hospitalized COVID-19 patients according to occurrence of PE. METHODS: This retrospective study included all consecutive patients hospitalized with COVID-19 who underwent a computed tomography (CT) angiography for PE clinical suspicion. Clinical data and median blood test results distributed into weekly periods from COVID-19 symptoms onset, were compared between PE and non-PE patients. RESULTS: Ninety-two patients were included, 29 (32%) had PE. PE patients were younger (63.9 (SD 13.7) vs 69.9 (SD 12.5) years). Clinical symptoms and COVID-19 CT features were similar in both groups. PE was diagnosed after a mean of 20.0 (SD 8.6) days from the onset of COVID-19 symptoms. Corticosteroid boluses were more frequently used in PE patients (62% vs. 43%). No patients met ISTH DIC criteria. Any parameter was statistically significant or clinically relevant except for D-Dimer when comparing both groups. Median values [IQR] of D-dimer in PE vs non-PE patients were: week 2 (2010.7 [770.1-11208.9] vs 626.0 [374.0-2382.2]; p = 0.004); week 3 (3893.1 [1388.2-6694.0] vs 1184.4 [461.8-2447.8]; p = 0.003); and week 4 (2736.3 [1202.1-8514.1] vs 1129.1 [542.5-2834.6]; p = 0.01). Median fold-increase of D-dimer between week 1 and 2 differed between groups (6.64 [3.02-23.05] vs 1.57 [0.64-2.71], p = 0.003); ROC curve AUC was 0.879 (p = 0.003) with a sensitivity and specificity for PE of 86% and 80%, respectively. CONCLUSIONS: Among hospitalized COVID-19 patients, D-dimer levels are higher at weeks 2, 3 and 4 after COVID-19 symptom onset in patients who develop PE. This difference is more pronounced when the fold increase between weeks 1 and 2 is compared.

Beneficial effect of corticosteroids in preventing mortality in patients receiving tocilizumab to treat severe COVID-19 illness.

OBJECTIVES: To assess the characteristics and risk factors for mortality in patients with severe coronavirus disease-2019 (COVID-19) treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS). METHODS: From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality. RESULTS: A total of 1,092 patients with COVID-19 were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186 patients, 155 (83.3 %) patients were receiving noninvasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (±4.3) and 4.3 days (±3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p < 0.001), chronic heart failure (HR = 4.4, p = 0.003), and chronic liver disease (HR = 4.69, p = 0.004). The use of CS, in combination with TCZ, was identified as a protective factor against mortality (HR = 0.26, p < 0.001) in such severe COVID-19 patients receiving TCZ. No serious superinfections were observed after a 30-day follow-up. CONCLUSIONS: In patients with severe COVID-19 receiving TCZ due to systemic host-immune inflammatory response syndrome, the use of CS in addition to TCZ therapy, showed a beneficial effect in preventing in-hospital mortality.

Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of cases submitted to molecular diagnosis. METHODS: We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain. RESULTS: By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 ± 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients. CONCLUSIONS: ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.

Direct oral anticoagulants versus vitamin K antagonists in antiphospholipid syndrome: A meta-analysis.

BACKGROUND: Anticoagulant treatment is recommended in patients with thrombosis and antiphospholipid syndrome (APS). Conflicting results have been reported on the role of direct oral anticoagulants (DOACs) in these patients. We performed a meta-analysis of randomized controlled trials (RCTs) focused on this issue. METHODS: We searched MEDLINE and EMBASE for RCTs comparing DOACs and vitamin K antagonists (VKAs) for secondary thromboprophylaxis in patients with thrombotic APS. The primary objective was to assess the efficacy of DOACs compared to VKAs to prevent recurrence of thromboembolic events. Risk difference (RD) was reported as weighted RD according to Mantel-Haenszel random-effect method. RESULTS: Three RCTs (426 patients) were included, all comparing rivaroxaban with VKAs. The proportion of recurrences (either arterial or venous) was higher among rivaroxaban patients when compared with those receiving VKAs (9.5% vs 2.8%; RD 6%, 95% CI, -0.05 - 0.18, p=0.29), although non-statistically significant. In patients with an arterial index event, thromboembolic recurrences were more frequent in those treated with rivaroxaban compared to those treated with VKAs (25% vs 6.2%; RD 19%, 95% CI, 0.04 - 0.33; p =0.01; I2 49%). In triple aPL positive patients, rivaroxaban showed higher rates of thromboembolic recurrences compared with VKAs (12% vs 3%; RD 9%, 95% CI, 0.02 - 0.15; p= 0.01; I2 13%). Non-statistically significant differences were observed in major bleeding events or mortality. CONCLUSIONS: The use of rivaroxaban in APS patients is associated with an increased rate of thromboembolic recurrences compared to VKAs, at least in those with arterial index event or triple aPL positivity.

Clinical features and outcomes of asymptomatic pulmonary sarcoidosis. A comparative cohort study.

OBJECTIVE: To evaluate the clinical characteristics and outcomes of patients with asymptomatic pulmonary sarcoidosis (APS) detected incidentally and compare them with symptomatic non-Löfgren sarcoidosis (SnLS) patients. METHODS: Patients diagnosed as having APS at a University hospital in Barcelona, Spain, followed prospectively from 1976 to 2018. APS was defined as the presence of bilateral hilar lymphadenopathy (BHL) with or without lung parenchymal involvement discovered incidentally on chest radiograph or CT scan. APS was compared with SnLS. RESULTS: APS was diagnosed in 50 (13.6%) and SnLS in 317 (86.4%) patients. At diagnosis, stage I chest radiograph was significantly more frequent in APS than in SnLS (p < 0.001) and there were no asymptomatic patients with stages III and IV. SnLS showed more severe impairment in FVC (p = 0.009) and forced expiratory volume in 1st second (FEV1) (p = 0.003) than APS, while DLco was similar in both groups. Extrathoracic involvement at diagnosis and during the follow up was less frequent in APS than in SnLS patients (p < 0.005). Endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS) was the most used diagnostic tool. Treatment was more frequently required in the SnLS than in APS (p < 0.001). At five years, APS patients showed less presence of active disease than SnLS (p = 0.054). CONCLUSIONS: APS showed earlier radiological stages, lesser impairment in lung function, extrapulmonary organ involvement and need for treatment than SnLS. EBUS was the most useful diagnostic tool. In spite of its benign presentation, around one third of patients evolved to persistent disease but usually with mild clinical and functional impairment.

PI3K (Phosphatidylinositol 3-Kinase) Activation and Endothelial Cell Proliferation in Patients with Hemorrhagic Hereditary Telangiectasia Type 1.

Hemorrhagic hereditary telangiectasia (HHT) type 2 patients have increased activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in telangiectasia. The main objective is to evaluate the activation of the PI3K pathway in cutaneous telangiectasia of HHT1 patients. A cutaneous biopsy of a digital hand telangiectasia was performed in seven HHT1 and eight HHT2 patients and compared with six controls. The study was approved by the Clinical Research Ethics Committee of our center. A histopathological pattern with more dilated and superficial vessels that pushed up the epidermis was identified in HHT patients regardless of the type of mutation and was associated with older age, as opposed to the common telangiectasia pattern. The mean proliferation index (Ki-67) was statistically higher in endothelial cells (EC) from HHT1 than in controls. The percentage of positive EC for pNDRG1, pAKT, and pS6 in HHT1 patients versus controls resulted in higher values, statistically significant for pNDRG1 and pS6. In conclusion, we detected an increase in EC proliferation linked to overactivation of the PI3K pathway in cutaneous telangiectasia biopsies from HHT1 patients. Our results suggest that PI3K inhibitors could be used as novel therapeutic agents for HHT.

Gastrointestinal Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia: Risk Factors and Endoscopic Findings.

BACKGROUND: We aimed to describe risk factors for gastrointestinal (GI) bleeding and endoscopic findings in patients with hereditary hemorrhagic telangiectasia (HHT). METHODS: This is a prospective study from a referral HHT unit. Endoscopic tests were performed when there was suspicion of GI bleeding, and patients were divided as follows: with, without, and with unsuspected GI involvement. RESULTS: 67 (27.9%) patients with, 28 (11.7%) patients without, and 145 (60.4%) with unsuspected GI involvement were included. Age, tobacco use, endoglin (ENG) mutation, and hemoglobin were associated with GI involvement. Telangiectases were mostly in the stomach and duodenum, but 18.5% of patients with normal esophagogastroduodenoscopy (EGD) had GI involvement in video capsule endoscopy (VCE). Telangiectases ≤ 3 mm and ≤10 per location were most common. Among patients with GI disease, those with hemoglobin < 8 g/dL or transfusion requirements (65.7%) were older and had higher epistaxis severity score (ESS) and larger telangiectases (>3 mm). After a mean follow-up of 34.2 months, patients with GI involvement required more transfusions and more emergency department and hospital admissions, with no differences in mortality. CONCLUSIONS: Risk factors for GI involvement have been identified. Patients with GI involvement and severe anemia had larger telangiectases and higher ESS. VCE should be considered in patients with suspicion of GI bleeding, even if EGD is normal.

Multidisciplinary approach and long-term follow-up in a series of 640 consecutive patients with sarcoidosis: Cohort study of a 40-year clinical experience at a tertiary referral center in Barcelona, Spain.

Cohort studies of large series of patients with sarcoidosis over a long period of time are scarce. The aim of this study is to report a 40-year clinical experience of a large series of patients at Bellvitge University Hospital, a tertiary university hospital in Barcelona, Spain. Diagnosis of sarcoidosis required histological confirmation except in certain specific situations. All patients underwent a prospective study protocol. Clinical assessment and follow-up of patients were performed by a multidisciplinary team.From 1976 to 2015, 640 patients were diagnosed with sarcoidosis, 438 of them (68.4%) were female (sex ratio F/M 2:1). The mean age at diagnosis was 43.3 ±â€Š13.8 years (range, 14-86 years), and 613 patients (95.8%) were Caucasian. At diagnosis, 584 patients (91.2%) showed intrathoracic involvement at chest radiograph, and most of the patients had normal pulmonary function. Erythema nodosum (39.8%) and specific cutaneous lesions (20.8%) were the most frequent extrapulmonary manifestations, but there was a wide range of organ involvement. A total of 492 patients (76.8%) had positive histology. Follow-up was carried out in 587 patients (91.7%), over a mean of 112.4 ±â€Š98.3 months (range, 6.4-475 months). Corticosteroid treatment was administered in 255 patients (43.4%), and steroid-sparing agents in 49 patients (7.7%). Outcomes were as follows: 111 patients (18.9%) showed active disease at the time of closing this study, 250 (42.6%) presented spontaneous remission, 61 (10.4%) had remission under treatment, and 165 (28.1%) evolved to chronic sarcoidosis; among them, 115 (19.6%) with mild disease and 50 (8.5%) with moderate to severe organ damage. A multivariate analysis showed that at diagnosis, age more than 40 years, the presence of pulmonary involvement on chest radiograph, splenic involvement, and the need of treatment, was associated with chronic sarcoidosis, whereas Löfgren syndrome and mediastinal lymphadenopathy on chest radiograph were indicators of good outcome.Sarcoidosis is a multisystem disease with protean clinical-radiographic manifestations. Although almost half of patients follow a spontaneous resolution or under treatment, a significant number of them may have several degrees of organ damage. This study emphasizes the value of a multidisciplinary approach and long-term follow-up by specialized teams in sarcoidosis.