NMR-based metabolomic signature: An important tool for the diagnosis and study of pathogenesis of autoimmune hepatitis.

BACKGROUND AND AIMS: Metabolomics is used to predict, diagnose, and monitor metabolic disorders but altered metabolomic signatures have also been reported in diverse diseases, including autoimmune disorders. However, the metabolomic profile in autoimmune hepatitis (AIH) has not been investigated in depth. Therefore, we investigated the metabolomic signature of AIH and its significance as a diagnostic and pathogenetic tool. APPROACH AND RESULTS: Metabolites in plasma samples from 50 patients with AIH at diagnosis, 43 healthy controls, 72 patients with primary biliary cholangitis (PBC), 26 patients with metabolic dysfunction-associated liver disease, and 101 patients with chronic viral hepatitis were determined by 1 H NMR (nuclear magnetic resonance) spectroscopy. Fifty-two metabolites were quantified, and metabolic pathway analysis was performed. Multivariate analysis revealed that AIH could be differentiated from healthy controls and each of the disease controls ( p <0.001). Fifteen metabolites differentiated AIH from disease controls (PBC+chronic viral hepatitis+metabolic dysfunction-associated liver disease) (95% sensitivity and 92% specificity). Ten distinct metabolic pathways were altered in AIH compared to disease controls. The metabolic pathway of branched-chain amino acids (lower valine, leucine, and isoleucine levels and their catabolic intermediates in PBC), methionine (lower methionine, 2-aminobutyrate, and 2-hydroxybutyrate levels in PBC), alanine-aspartate-glutamate (lower metabolites in PBC), and that of metabolites associated with gut microbiota (lower choline, betaine, and dimethylamine levels in PBC) were significantly different between AIH and PBC ( p <0.01). CONCLUSIONS: 1 H NMR spectroscopy could be a promising novel tool to diagnose and study AIH pathogenesis as there is no need for much sample handling, is highly reproducible with high sensitivity and specificity, and low cost.

HERACLIS-HDV cohort for the factors of underdiagnosis and prevalence of hepatitis D virus infection in HBsAg-positive patients.

BACKGROUND AND AIMS: Hepatitis D virus (HDV) underdiagnosis remains common. We assessed the HDV screening and prevalence rates in HBsAg-positive patients seen at tertiary liver centres throughout Greece as well as factors affecting HDV diagnosis. METHODS: All adult HBsAg-positive patients seen within the last 5 years were included. Non-screened patients who visited or could be recalled to the clinics over a 6-month period were prospectively tested for anti-HDV. RESULTS: Of 5079 HBsAg-positive patients, 53% had anti-HDV screening (41% before and 12% after study initiation). Pre-study (8%-88%) and total screening rates (14%-100%) varied widely among centres. Screening rates were associated with older age, known risk group, elevated ALT, centre location and size and period of first visit. Anti-HDV prevalence was 5.8% without significant difference in patients screened before (6.1%) or after study initiation (4.7%, p = 0.240). Anti-HDV positivity was associated with younger age, parenteral drug use, born abroad, advanced liver disease and centre location. Overall, HDV RNA detectability rate was 71.6% being more frequent in anti-HDV-positive patients with elevated ALT, advanced liver disease and hepatitis B therapy. CONCLUSIONS: Anti-HDV screening rates and recall capabilities vary widely among Greek liver clinics being higher in HBsAg-positive patients of known risk group with active/advanced liver disease seen at smaller centres, while non-medical factors are also important. Anti-HDV prevalence varies throughout Greece being higher in patients born abroad with younger age, parenteral drug use and advanced liver disease. Viremia is more frequently but not exclusively detected in anti-HDV-positive patients with elevated ALT and advanced liver disease.

Vasopressin during Laparoscopic Myomectomy: Does It Really Extend Its Limits?

STUDY OBJECTIVE: Τo investigate whether the use of vasopressin played an important role in the safe expansion of the indications of laparoscopic myomectomy in our practice. DESIGN: A retrospective comparison of prospectively collected data (Canadian Task Force classification II2). SETTING: A gynecologic endoscopy unit in a tertiary university hospital. PATIENTS: One hundred fifty patients undergoing laparoscopic myomectomy; 50 were treated without the use of any vasoconstrictive agent (group 1), and 100 were treated with intraoperative intramyometrial injection of dilute vasopressin (20 IU/100 mL normal saline) (group 2). INTERVENTIONS: Laparoscopic myomectomy. MEASUREMENTS AND MAIN RESULTS: We compared the 2 groups in terms of size, number, and type of myomas; estimated blood loss (EBL); procedure length; transfusion rates; laparoconversion rates; and rates of complications. Two cases in group 1 (4%) were laparoconverted versus none (0%) in group 2. Overall, the mean EBL was 321.8 ± 246.0 mL in group 1 compared with 147.8 ± 171.8 mL in group 2, respectively (p <.001). Additionally, EBL was significantly lower in the vasopressin group in all of the study's subgroups of patients stratified according to the size and number of myomas. Procedure length did not differ significantly between the 2 groups (130.8 ± 49.5 vs 115.6 ± 49.4 minutes, p = .078). The risk factors for prolongation of the procedure included size and number of myomas independently of vasopressin. The rates of hypercapnea and subcutaneous emphysema were higher in group 1. The risk factors for hypercapnea and subcutaneous emphysema included the size and intramural position of the largest myoma. Vasopressin was not associated with serious cardiovascular adverse events. CONCLUSIONS: Vasopressin is effective in reducing blood loss during laparoscopic myomectomy. Although experienced surgeons may achieve comparable operation times without vasopressin, even in the most challenging cases, blood loss may still be considerable. The occurrence of hypercapnea is higher in untreated cases and may contribute to laparoconversion.

The "1-3-5 cough test": comparing the severity of urodynamic stress incontinence with severity measures of subjective perception of stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: The purpose of the study was to examine whether a test performed during urodynamics, the "1-3-5 cough test", could determine the severity of urodynamic stress incontinence (USI). METHODS: We included women referred for urodynamics who were diagnosed with USI. The "1-3-5 cough test" was performed to grade the severity of USI at the completion of filling cystometry. A diagnosis of "severe", "moderate" or "mild" USI was given if urine leakage was observed after one, three or five consecutive coughs respectively. We examined the associations between grades of USI severity and measures of subjective perception of stress urinary incontinence (SUI): International Consultation of Incontinence Modular Questionnaire-Female Lower Urinary Tract Symptom (ICIQ-FLUTS), King's Health Questionnaire (KHQ), Urinary Distress Inventory-6 (UDI-6), Urinary Impact Questionnaire-7 (UIQ-7). RESULTS: A total of 1,181 patients completed the ICIQ-FLUTS and KHQ and 612 completed the UDI-6 and UIQ-7 questionnaires. There was a statistically significant association of higher grades of USI severity with higher scores of the incontinence domain of the ICIQ-FLUTS. The scores of the UDI-6, UIQ-7 and of all KHQ domains (with the exception of general health perception and personal relationships) had statistically significant larger mean values for higher USI severity grade. Groups of higher USI severity had statistically significant associations with higher scores of most of the subjective measures of SUI. CONCLUSIONS: Severity of USI, as defined by the "1-3-5 cough test", was associated with the severity of subjective measures of SUI. This test may be a useful tool for the objective interpretation of patients with SUI who undergo urodynamics.

Calprotectin serum levels on admission and during follow-up predict severity and outcome of patients with COVID-19: A prospective study.

BACKGROUND & AIMS: Calprotectin reflects neutrophil activation and is increased in various inflammatory conditions including severe COVID-19. However, serial serum calprotectin measurements in COVID-19 patients are limited. We assessed prospectively, calprotectin levels as biomarker of severity/outcome of the disease and a COVID-19 monitoring parameter in a large cohort of consecutive COVID-19 patients. METHODS: Calprotectin serum levels were measured in 736 patients (58.2 % males; median age 63-years; moderate disease, n = 292; severe, n = 444, intubated and/or died, n = 50). Patients were treated with combined immunotherapies according to our published local algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF)/COVID-19-related mortality. RESULTS: Median (interquartile range) calprotectin levels were significantly higher in patients with severe disease [7(8.2) vs. 6.1(8.1)µg/mL, p = 0.015]. Calprotectin on admission was the only independent risk factor for intubation/death (HR=1.473, 95 %CI=1.003-2.165, p = 0.048) even after adjustment for age, sex, body mass index, comorbidities, neutrophils, lymphocytes, neutrophil to lymphocytes ratio, ferritin, and CRP. The area under the curve (AUC, 95 %CI) of calprotectin for prediction of intubation/death was 0.619 (0.531-0.708), with an optimal cut-off at 13 µg/mL (sensitivity: 44 %, specificity: 79 %, positive and negative predictive values: 13 % and 95 %, respectively). For intubated/died patients, paired comparisons from baseline to middle of hospitalization and subsequently to intubation/death showed significant increase of calprotectin (p = 0.009 and p < 0.001, respectively). Calprotectin alteration had the higher predictive ability for intubation/death [AUC (95 %CI):0.803 (0.664-0.943), p < 0.001]. CONCLUSIONS: Calprotectin levels on admission and their subsequent dynamic alterations could serve as indicator of COVID-19 severity and predict the occurrence of SRF and mortality.

Midurethral slings for women with urodynamic mixed incontinence: what to expect?

INTRODUCTION AND HYPOTHESIS: We assessed the efficacy of midurethral slings (MUS) in women with urodynamically proven mixed incontinence (UMI). METHODS: A prospective study was carried out in women with UMI in whom conservative treatment failed and who underwent MUS. Pre- and postoperative assessment included: completion of the validated ICIQ-FLUTS questionnaire, POP-Q examination and urodynamics (UDS). The primary outcome was the assessment of symptoms at 12 months. Secondary outcomes included assessment of postoperative UDS findings and evaluation of differences in symptoms and UDS diagnosis between the TVT and TVT-O groups. RESULTS: Eighty-five women were included; 44 (49.2%) underwent TVT and 41 (51.8%) underwent TVT-O. Concomitant prolapse surgery was performed in 65 out of 85 patients (76.5%). At 12 months' follow-up there was a statistically significant reduction in stress urinary incontinence (p < 0.001), urge urinary incontinence (p < 0.001), urgency (p = 0.021) and frequency (p = 0.014). Depending on the symptom 10.6% to 24.7% of women reported deterioration of symptoms. UDS at 12 months revealed the absence of urodynamic stress incontinence (USI) in 82.4% of patients and no evidence of detrusor overactivity (DO) in 35.3%. No differences in symptoms were found between the TVT and TVT-O group, but the absence of DO was more common in the TVT group (48.5% vs 22.7%, p = 0.014). CONCLUSIONS: Placement of MUS alleviates incontinence and overactive bladder symptoms in patients with UMI. TVT causes similar subjective improvement to TVT-O, but resulted in higher resolution of DO. Our study provides data that could be helpful in informing patients preoperatively of the potential impact that the MUS may have on each individual symptom separately, including the likelihood of symptom deterioration.

Translation and psychometric evaluation of the Greek short forms of two condition-specific quality of life questionnaires for women with pelvic floor disorders: PFDI-20 and PFIQ-7.

INTRODUCTION AND HYPOTHESIS: The aim of this study was the cross-cultural adaptation, validation, and psychometric evaluation in the Greek language of two self-reported instruments used for patients with pelvic floor disorders (PFDs): the Pelvic Floor Distress Inventory (PFDI-20) and the Pelvic Floor Impact Questionnaire (PFIQ-7). METHODS: For the cross-cultural adaptation, a multistep forward-back translation protocol was utilized. Evaluation of the psychometric properties of the questionnaires involved the assessment of validity, stability, internal consistency, and responsiveness. Validity, stability, and internal consistency were evaluated in women presenting with PFDs (group A), whereas responsiveness was assessed in women undergoing pelvic floor surgery (group B). RESULTS: A total of 100 women presenting with PFDs were included in Group A. A near excellent content/face validity was confirmed as assessed by the missing values criterion (0-5 %). Stability, as assessed by the intraclass correlation coefficient, showed almost perfect agreement with a mean ICC of 0.850 (PFDI-20) and 0.840 (PFIQ-7). Internal consistency was found to be high for both questionnaires (Cronbach's alpha > 0.8). Finally, 85 women underwent pelvic floor repair surgery and were included for the assessment of responsiveness (group B). Good to excellent responsiveness was found for the prolapse and urinary subscales of the questionnaires. However, poor responsiveness was found for the colorectal-anal scale of the PFDI-20, whereas the colorectal-anal scale of the PFIQ-7 proved to be nonresponsive to change. CONCLUSIONS: The Greek versions of PFDI-20 and PFIQ-7 were found to be comprehensible, valid, reliable, and responsive to use with patients complaining of PFDs.

FibroMeter scores are predictive noninvasive markers of advanced and significant liver fibrosis in patients with chronic viral hepatitis or metabolic dysfunction-associated steatotic liver disease.

Background: FibroMeter and FibroMeter vibration-controlled transient elastography (FibroMeter VCTE) were assessed in a Greek cohort of patients with chronic viral hepatitis (CVH) B and C or metabolic dysfunction-associated steatotic liver disease (MASLD) to evaluate their accuracy in predicting advanced liver fibrosis against other well-validated noninvasive markers. Methods: Group 1: n=83 CVH and group 2: n=38 MASLD patients underwent liver biopsy and transient elastography (TE) on the same day as sera collection. FibroMeter scores APRI and FIB-4 were calculated in all 121 patients, while MASLD fibrosis score (MFS) was also calculated in group 2. Results: In CVH, FibroMeter VCTE performed equivalently to TE and better than the other markers in predicting advanced (≥F3) and significant (≥F2) fibrosis (area under the receiver operating characteristic curve [AUC] 0.887, P<0.001 for F3; AUC 0.766 P<0.001 for F2). FibroMeter Virus (cutoff 0.61) had lower sensitivity (20%) but performed equivalently to APRI and FIB-4. In MASLD, all markers but APRI performed equivalently in predicting advanced fibrosis. FibroMeter VCTE >0.2154 had the same sensitivity (100%) and specificity (81%) as TE (cutoff >7.1 kPa). FibroMeter MASLD >0.25 performed equivalently to MFS and FIB4, but with higher specificity (100%). Both FibroMeter and FibroMeter VCTE correlated with liver histology but not with liver enzymes. Conclusions: FibroMeter VCTE predicts accurately advanced fibrosis in CVH and MASLD, irrespectively of transaminase levels. FibroMeter Virus can be applied only as an alternative marker in CVH, while FibroMeter MASLD performs equally to TE and calculated scores (MFS, FIB-4) in predicting advanced fibrosis in MASLD patients.

The validation of international consultation on incontinence questionnaires in the Greek language.

AIMS: The objective of this study was to validate four specific International Consultation on Incontinence Questionnaires (ICIQ) modules in the Greek language: (i) the ICIQ-FLUTS long form (ICIQ-FLUTS-LF), (ii) the ICIQ-FLUTS, (iii) the ICIQ-FLUTS-SEX, and (iv) the ICIQ-Vaginal Symptoms Questionnaire (ICIQ-VS), originally validated in English. METHODS: The English questionnaires were initially translated into Greek, then back-translated into English and final modifications were made after testing the questionnaires on a sample of patients. To validate the translated questionnaires, the following tests were undertaken: Content/face validity, internal consistency (reliability) and stability (test-retest reliability). RESULTS: A total of 122 women participated in the study. Eighty-nine presented with pelvic organ prolapse (POP) and/or urinary incontinence (UI) symptoms and 33 attended an outpatient gynecological clinic without POP/UI symptoms. All modules showed excellent content/face validity (missing values 0-2.5%). Cronbach's alpha test for internal consistency showed satisfactory to excellent reliability (0.876 for ICIQ-FLUTS-LF, 0.85 for ICIQ-FLUTS, and 0.83 for ICIQ-VS), with the exception ICIQ-FLUTS-SEX which was 0.69. The test-retest reliability showed moderate to near-perfect agreement (weighted kappa value 0.52-0.99). CONCLUSIONS: The Greek versions of the ICIQ-FLUTS-LF, ICIQ-FLUTS, and ICIQ-VS questionnaires were successfully validated. Our data showed that the ICIQ FLUTS-SEX questionnaire, as it stands in its current English version, cannot be reliably used to assess sex symptoms in the Greek female population.

Long-term results of mycophenolate mofetil vs. azathioprine use in individuals with autoimmune hepatitis.

Background & Aims: We have shown previously that mycophenolate mofetil (MMF) might be used as first-line treatment instead of azathioprine (AZA) in individuals with autoimmune hepatitis (AIH). Herein, we present our long-term prospective data on response and outcome after first-line therapy with MMF in treatment-naïve individuals with AIH, as similar data are missing. Methods: During the 21 years of the study, 292 individuals with AIH were included (females: 213; median age: 59 [17-85] years). Patients received either prednisolone 0.5-1 mg/kg/day alone (n = 19) or in combination with AZA 1-2 mg/kg/day (n = 64) or MMF (n = 183). The tapering schedule of prednisolone was identical between groups. We assessed the rates of complete biochemical response (CBR) at 6 months, 12 months, and the end of follow-up; non-response (4 weeks of treatment); CBR off prednisolone; adverse effects; CBR off treatment; histological remission; and overall and liver-related mortality between the AZA and MMF groups. Results: The MMF group had lower non-response (p = 0.02) and higher CBR rates at 12 months (86 vs. 71.8%; p <0.05) and the end of follow-up (96 vs. 87.2%; p = 0.03) than the AZA group. Treatment change was more frequent in the AZA group (43.7 vs. 11%; p <0.001), mostly because of intolerance, whereas MMF was proven safe (serious complications 3.8 vs. 18.8%; p = 0.0003). MMF-treated patients were more frequently eligible to stop immunosuppression according to the guidelines (p <0.05). Cirrhosis at diagnosis, age at diagnosis >60 years, and longer disease duration were independent predictors of liver-related mortality. Conclusions: MMF seems an efficient alternative first-line treatment option for AIH, bearing lower non-response at 4 weeks and higher CBR rates at 12 months and the end of follow-up than AZA. In addition, MMF was proven to be safe, leading more frequently to the eligibility for stopping immunosuppression according to the guidelines. Impact and implications: For more than 40 years, azathioprine (AZA) has been considered the standard treatment for induction and maintenance of response in autoimmune hepatitis (AIH). However, treatment usually needs to be maintained for life, as relapses are common after AZA cessation. Therefore, alternative treatment options are needed. Herein, we showed that the use of mycophenolate mofetil (MMF) as an alternative first-line immunosuppressant was much more efficient in the long-term than AZA as attested by the lower non-response rates at 4 weeks and higher response rates at 12 months and the end of follow-up. Moreover, AZA-treated patients were more prone to change treatment because of intolerance, whereas MMF-treated patients were more often eligible to achieve treatment withdrawal.

Soluble IL-2R Levels at Baseline Predict the Development of Severe Respiratory Failure and Mortality in COVID-19 Patients.

Risk stratification of coronavirus disease-19 (COVID-19) patients by simple markers is critical to guide treatment. We studied the predictive value of soluble interleukin-2 receptor (sIL-2R) for the early identification of patients at risk of developing severe clinical outcomes. sIL-2R levels were measured in 197 patients (60.9% males; median age 61 years; moderate disease, n = 65; severe, n = 132, intubated and/or died, n = 42). All patients received combined immunotherapies (anakinra ± corticosteroids ± intravenous immunoglobulin ± tocilizumab) according to our local treatment algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF) or mortality. Median (interquartile range) sIL-2R levels were significantly higher in patients with severe disease, compared with those with moderate disease (6 (6.2) vs. 5.2 (3.4) ng/mL, p = 0.017). sIL-2R was the strongest laboratory predictive factor for intubation/death (hazard ratio 1.749, 95%CI 1.041-2.939, p = 0.035) after adjustment for other known risk factors. Youden's index revealed optimal sIL-2R cut-off for predicting intubation/death at 9 ng/mL (sensitivity: 67%; specificity: 86%; positive and negative predictive value: 57% and 91%, respectively). Delta sIL-2R between the day of event or discharge minus admission date was higher in patients that intubated/died than in those who did not experience an event (2.91 (10.42) vs. 0.44 (2.88) ng/mL; p = 0.08)). sIL-2R on admission and its dynamic changes during follow-up may reflect disease severity and predict the development of SRF and mortality.

Serum Cartilage Oligomeric Matrix Protein and Golgi Protein-73: New Diagnostic and Predictive Tools for Liver Fibrosis and Hepatocellular Cancer?

The cartilage oligomeric matrix protein (COMP) and Golgi-protein-73 (GP73) have been proposed as markers of liver fibrosis and hepatocellular carcinoma (HCC). Our aim was to assess the performance of the combination of these markers in diagnosing cirrhosis and predicting HCC development. Sera from 288 consecutive patients with chronic liver diseases were investigated by using COMP and GP73-ELISAs. Dual positivity for COMP (>15 U/L) and GP73 (>20 units) was observed in 24 (8.3%) patients, while 30 (10.4%) were GP73(+)/COMP(-), 37/288 (12.8%) GP73(-)/COMP(+), and 197 (68.5%) GP73(-)/COMP(-). Positivity for both markers was associated with cirrhosis [23/24 (95.8%) for GP73(+)/COMP(+) vs. 22/30 (73.3%) for GP73(+)/COMP(-) vs. 25/37 (67.6%) for GP73(-)/COMP(+) vs. 46/197 (23.4%) for GP73(-)/COMP(-); P < 0.001]. The combination of GP73, COMP, the aspartate aminotransferase/platelets ratio index, and the Fibrosis-4 score had even higher diagnostic accuracy to detect the presence of cirrhosis [AUC (95% CI): 0.916 (0.878-0.946)] or significant liver fibrosis (METAVIR ≥ F2) [AUC (95% CI): 0.832 (0.768-0.883)] than each marker alone. Kaplan-Meier analysis showed that positivity for both GP73 and COMP was associated with higher rates of HCC development (P < 0.001) and liver-related deaths (P < 0.001) during follow-up. In conclusion, the combination of GP73 and COMP seems efficient to detect cirrhosis and predict worse outcomes and the development of HCC in patients with chronic liver diseases.

Lessons from pathophysiology: Use of individualized combination treatments with immune interventional agents to tackle severe respiratory failure in patients with COVID-19.

Aims Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may lead to the development of severe respiratory failure. In hospitalized-patients, prompt interruption of the virus-driven inflammatory process by using combination treatments seems theoretically of outmost importance. Our aim was to investigate the hypothesis of multifaceted management of these patients. Methods A treatment algorithm based on ferritin was applied in 311 patients (67.2% males; median age 63-years; moderate disease, n=101; severe, n=210). Patients with ferritin <500ng/ml received anakinra 2-4mg/kg/day ± corticosteroids (Arm A, n=142) while those with ≥500ng/ml received anakinra 5-8mg/kg/day with corticosteroids and γ-globulins (Arm B, n=169). In case of no improvement a single dose of tocilizumab (8mg/kg; maximum 800mg) was administered with the potential of additional second and/or third pulses. Treatment endpoints were the rate of the development of respiratory failure necessitating intubation and the SARS-CoV-2-related mortality. The proposed algorithm was also validated in matched hospitalized-patients treated with standard-of-care during the same period. Results In overall, intubation and mortality rates were 5.8% and 5.1% (0% in moderate; 8.6% and 7.6% in severe). Low baseline pO2/FiO2 and older age were independent risk factors. Comparators had significantly higher intubation (HR=7.4; 95%CI: 4.1-13.4; p<0.001) and death rates (HR=4.5, 95%CI: 2.1-9.4, p<0.001). Significant adverse events were rare, including severe secondary infections in only 7/311 (2.3%). Conclusions Early administration of personalized combinations of immunomodulatory agents may be life-saving in hospitalized-patients with COVID-19. An immediate intervention (the sooner the better) could be helpful to avoid development of full-blown acute respiratory distress syndrome and improve survival.

Belimumab is a promising third-line treatment option for refractory autoimmune hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a disease of unknown aetiology with a favourable response to immunosuppression. However, in the clinic, it appears that <50% of patients achieve complete response on standard treatment. Serum B cell-activating factor (BAFF) levels are elevated in patients with AIH and are likely to contribute to disease pathogenesis. Given that belimumab, a BAFF inhibitor, has been shown to be effective in other autoimmune diseases, we investigated its use as a third-line add-on treatment option in patients with advanced AIH who did not respond to conventional treatment. METHODS: Herein, we report for the first time two patients, a 27-year-old female and a 58-year-old male, both with AIH-related compensated cirrhosis at diagnosis, who were refractory to standard immunosuppressive therapies and received add-on third-line therapy with belimumab. RESULTS: Both patients achieved a complete response and remained in remission while receiving low-dose corticosteroids. No adverse events related to belimumab and/or disease decompensation were observed. CONCLUSIONS: These preliminary findings indicate belimumab as a promising treatment option for patients with AIH and refractory and advanced liver-related fibrosis. LAY SUMMARY: A small proportion of patients with autoimmune hepatitis (AIH) are refractory to standard treatments; these patients bear the highest probability of developing decompensated cirrhosis and hepatocellular carcinoma because third-line treatment options are not well established. In this case study, we showed that third-line add-on therapy with belimumab, a B cell-activating factor inhibitor, could be an alternative and promising treatment option in patients with advanced AIH who did not respond to conventional treatment.

Severe Pharyngodynia Followed by Migratory Polyarthritis and High Fever in Young Immigrants: Remember That Rheumatic Fever Is Still Relevant in 2020!

Acute rheumatic fever (ARF) is the immune-mediated sequelae of untreated group-A streptococcal infection. In this regard, rheumatic heart disease is the most prominent manifestation with devastating long-term complications. In the postantibiotic era, ARF is extremely rare in high-income countries; thus, its diagnosis might escape the clinicians' notice. However, its incidence remains high not only in certain low- and middle-income regions with poor public health systems but also in socioeconomically vulnerable populations residing in high-income countries. Herein, we report two cases of ARF in young immigrant adults in order to highlight the need for increased clinical suspicion to establish a prompt and timely diagnosis of ARF and describe in detail its differential diagnosis and approach to treatment.