Risk of rituximab-induced hepatitis B flare after antiviral discontinuation in rheumatic patients with chronic hepatitis B virus.

OBJECTVES: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents. METHODS: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed. RESULTS: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate. CONCLUSIONS: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

Pre-existing and new-onset metabolic dysfunctions increase cirrhosis and its complication risks in chronic hepatitis B.

INTRODUCTION: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing among the chronic hepatitis B (CHB) population. This study aimed to explore the impact of metabolic dysfunction (MD) on cirrhosis and cirrhotic complication risks in CHB. METHODS: Patients with CHB were consecutively recruited between 2006-2021. The presence of MD was based on the five cardiometabolic criteria specified in the MASLD definition. Patients were categorized into MD/non-MD groups based on these criteria. RESULTS: 11,502 treatment-naïve non-cirrhotic CHB patients were included with a median follow-up of 5.3 years. Patients in the MD group (n=7314) were older and had lower HBV DNA levels than non-MD patients (n=4188). After adjustment for clinical and viral factors, MD patients had significantly higher risks of cirrhosis (adjusted hazard ratio [aHR]: 1.82, 95% confidence interval [CI]: 1.40-2.37, p<0.001) and cirrhotic complications (aHR: 1.30 per MD, 95% CI 1.03-1.63, p=0.025) in a dose-dependent manner. Furthermore, new-onset diabetes mellitus during the follow-up aggravated the risk of cirrhotic complications (aHR: 2.87, 95% CI: 1.34-6.11, p=0.006). Hepatic steatosis was associated with lower risks of cirrhosis (aHR: 0.57 within five years, 95% CI: 0.44-0.74, p<0.001) and cirrhotic complications (aHR: 0.45, 95% CI 0.23-0.88, p=0.020). Among individuals with hepatic steatosis, MASLD patients exhibited a higher cirrhosis risk than non-MD patients. CONCLUSION: Concurrent and new-onset MD increase the risks of cirrhosis and cirrhotic complications in CHB patients, independent of hepatic steatosis. Proactively investigating metabolic comorbidities in CHB is critical to stratify the risk of liver disease progression.

Metabolic Dysfunction-Associated Steatotic Liver Disease Facilitates Hepatitis B Surface Antigen Seroclearance and Seroconversion.

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear. METHODS: Patients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups. RESULTS: From 2006 to 2021, 4084 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n = 887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n = 3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.10-1.85; P = .007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR, 1.37; 95% CI, 1.00-1.86; P = .049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virologic profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR, 1.41; 95% CI, 1.09-1.84; P = .010). CONCLUSIONS: In untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB.

The significance of dense fine speckled pattern in antinuclear antibody-associated rheumatic disease and coexisting autoantibodies: A propensity score-matched cohort study.

AIM: To investigate the relationship between the prevalence of antinuclear antibody (ANA) -associated rheumatic diseases (AARD) and the presence of dense fine speckled (DFS) and homogeneous patterns in ANA tests. METHODS: This retrospective study enrolled adult patients with either a DFS or homogeneous pattern in their ANA test. A mixed pattern was defined as the presence of more than one pattern reported in the test. The presence of anti-DFS70 antibodies and other common autoantibodies were detected using EUROLINE ANA Profile 23. A 1:2 propensity score matching was applied to control for demographic and other interfering factors. RESULTS: A total of 59 patients with a DFS pattern were enrolled and compared with a matched homogeneous group. The DFS group had a significantly lower prevalence of AARD (3.4% vs. 16.9%, p = .008) and the subgroup with anti-DFS70 antibodies showed an even lower prevalence (2% vs. 20%, p = .002). Among the 33 patients with monospecific anti-DFS70 antibodies, five had a mixed pattern, and all patients with common autoantibodies had an isolated DFS pattern. CONCLUSIONS: The findings of this study suggest that patients with a DFS pattern in their ANA test may have a lower prevalence of AARD compared with those with a homogeneous pattern. However, an isolated DFS pattern in ANA testing does not necessarily indicate the presence of monospecific anti-DFS70 antibodies or AARD. Confirmatory testing for the monospecific anti-DFS70 antibody is mandatory to exclude AARD.

Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B.

OBJECTIVE: Chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) are the leading causes of hepatocellular carcinoma (HCC). We aim to explore the impact of concurrent MAFLD on the risk of HCC in CHB. METHODS: Patients with CHB were consecutively recruited from 2006 to 2021. MAFLD was defined by steatosis and either obesity, diabetes mellitus, or other metabolic abnormalities. The cumulative incidence of HCC and associated factors were compared between the MAFLD and non-MAFLD groups. RESULTS: 10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1 years. CHB patients with MAFLD (n = 2212) had fewer hepatitis B e antigen (HBeAg)-positivity, lower HBV DNA levels, and Fibrosis-4 index compared with the non-MAFLD group (n = 8334). MAFLD was independently associated with a 58% reduced risk of HCC (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.25-0.68, p < 0.001). Furthermore, steatosis and metabolic dysfunction had distinct effects on HCC. Steatosis was protective against HCC (aHR 0.45, 95% CI 0.30-0.67, p < 0.001), while a greater burden of metabolic dysfunction increased the risk (aHR 1.40 per dysfunction increase, 95% CI 1.19-1.66, p < 0.001). The protective effect of MAFLD was further confirmed in analysis with inverse probability of treatment weighting (IPTW), patients who had undergone antiviral therapy, those with probable MAFLD, and after multiple imputation for missing data. CONCLUSIONS: Concurrent hepatic steatosis is independently associated with a lower risk of HCC, whereas the increasing burden of metabolic dysfunction aggravates the risk of HCC in untreated CHB patients.

Risk of Hepatitis B Virus (HBV) Reactivation in HBsAg-Negative, Anti-HBc-Negative Patients Receiving Rituximab for Autoimmune Diseases in HBV Endemic Areas.

Background/Aims: Rituximab is known to be associated with high hepatitis B virus (HBV) reactivation rate in patients with resolved HBV infection and hematologic malignancy. However, data regarding HBV reactivation (HBVr) in rheumatic patients receiving rituximab is limited. To assess the HBVr rate in hepatitis B surface antigen (HBsAg)-negative patients receiving rituximab for autoimmune diseases in a large real-world cohort. Methods: From March 2006 to December 2019, 900 patients with negative HBsAg receiving at least one cycle of rituximab for autoimmune diseases in a tertiary medical center in Taiwan were retrospectively reviewed. Clinical outcome and factors associated with HBVr were analyzed. Results: After a median follow-up period of 3.3 years, 21 patients developed HBVr, among whom 17 patients were positive for hepatitis B core antibody (anti-HBc) and four were negative. Thirteen patients had clinical hepatitis flare, while eight patients had HBsAg seroreversion without hepatitis. Old age, anti-HBc positivity, undetectable serum hepatitis B surface antibody level at rituximab initiation and a higher average rituximab dose were associated with a higher HBVr rate. There was no significant difference in the HBVr risk between rheumatoid arthritis and other autoimmune diseases. Among anti-HBc-negative patients, subjects without HBV vaccination at birth had an increased risk of HBVr (4/368, 1.1%) compared with those who received vaccination (0/126, 0%). Conclusions: In HBV endemic areas where occult HBV is prevalent, anti-HBc-negative patients, may still be at risk for HBVr after rituximab exposure. HBVr may still be considered in HBsAg-negative patients developing abnormal liver function after rituximab exposure, even in patients with negative anti-HBc.

Characteristics and Potential Risk Factors of Hydroxychloroquine Retinopathy in Patients with Systemic Lupus Erythematosus: Focusing on Asian Population.

Purpose: Hydroxychloroquine (HCQ) would cause irreversible retinal damage, despite its pivotal role in treatment of systemic lupus erythematosus (SLE). This study aims to reassess the characteristics and risk factors of HCQ retinopathy. Methods: This study included patients with SLE who had used HCQ for >5 years and received ophthalmologic examinations during November 2017 to December 2020 in a tertiary hospital in Taiwan. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) were performed in all patients. Visual field assessment and/or multifocal electroretinography were done if suspicious findings were noted by SD-OCT or FAF. Clinical features and dosing details of HCQ were recorded by chart review. Results: Ninety-two patients were included, with the median duration of drug exposure of 11.2 years [interquartile range (IQR) 9.4-12.7 years], median daily dose of 6.9 mg/kg (IQR 6.1-7.7 mg/kg), and cumulative dose of 1,503.6 g (IQR 1,257.7-1,805.9 g). HCQ retinopathy was diagnosed in 10.9% of patients (10 of 92), and in 20.8% of patients (5 of 24) who complained about blurred vision. High myopia [odds ratio (OR) 5.03; 95% confidence interval (CI) 1.29-24.79; P = 0.03] and lower body weight (OR 0.88; 95% CI 0.78-0.97; P = 0.03) were significantly associated with HCQ retinopathy. Conclusions: Long-term HCQ users may suffer from retinal toxicity. Since there is no optimal substitute for HCQ, careful retinal evaluation is needed to avoid unnecessary drug discontinuation. In addition, an association between high myopia and HCQ retinopathy was noted. More investigation is needed to clarify this association.

Extracorporeal Membrane Oxygenation in Immunocompromised Patients With Acute Respiratory Distress Syndrome-A Retrospective Cohort Study.

Objective: Although the negative impact of immunosuppression on survival in patients with acute respiratory distress syndrome (ARDS) treated by extracorporeal membrane oxygenation (ECMO) is well known, short-term outcomes such as successful weaning rate from ECMO and subgroups benefit most from ECMO remain to be determined. The aims of this study were (1) to identify the association between immunocompromised status and weaning from ECMO in patients of ARDS, and (2) to identify subgroups of immunocompromised patients who may benefit from ECMO. Methods: This retrospective cohort study enrolled patients who received ECMO for ARDS from 2010 to 2020. Immunocompromised status was defined as having a hematological malignancy, active solid tumor, solid organ transplant, or autoimmune disease. Results: This study enrolled 256 ARDS patients who received ECMO, of whom 68 were immunocompromised. The multivariable analysis showed that immunocompromised status was not independently associated with failure to wean from ECMO. In addition, the patients with an autoimmune disease (14/24, 58.3%) and organ transplantation (3/3, 100%) had a numerically higher weaning rate from ECMO than other immunocompromised patients. For causes of ARDS, most patients with pulmonary hemorrhage (6/8, 75%) and aspiration (5/9, 55.6%) could be weaned from ECMO, compared to only a few of the patients with interstitial lung disease (2/9, 22.2%) and sepsis (1/4, 25%). Conclusions: Immunocompromised status was not an independent risk factor of failure to wean from ECMO in patients with ARDS. For patients with pulmonary hemorrhage and aspiration-related ARDS, ECMO may be beneficial as bridge therapy.

Anti-DFS70 Antibodies for Differentiating Systemic Autoimmune Rheumatic Disease in Patients with Positive ANA Tests: A Systematic Review and Meta-Analysis.

Anti-DFS70 antibodies have been proposed as a marker to exclude systemic autoimmune rheumatic disease (SARD). We conducted this systematic diagnostic test accuracy review and meta-analysis to determine the performance of anti-DFS70 antibodies in patients with a positive anti-nuclear antibody (ANA) test result to exclude SARD. We searched PubMed, Embase, Web of Science, Scopus and the Cochrane Library up to 22 February 2021, and included studies examining the diagnostic accuracy of anti-DFS70 antibodies in patients with a positive ANA test result. The results were pooled using a hierarchical bivariate model and plotted in summary receiver operating characteristic curves. R software and Stata Statistical Software were used for the statistical analysis. Eight studies with 4168 patients were included. The summary sensitivity was 0.19 (95% confidence interval: 0.12-0.28) and the specificity was 0.93 (95% confidence interval: 0.88-0.96). The area under the curve was 0.69 (95% confidence interval: 0.64-0.72). The meta-regression analysis showed that targeting only ANA-associated rheumatic disease was associated with higher specificity. In addition, the studies with a non-SARD prevalence of <80% and using a chemiluminescence assay were associated with higher specificity. Anti-DFS70 antibodies have high specificity for the exclusion of SARD among patients presenting with a positive ANA test, but the sensitivity is low.

Pregnancy outcomes in patients treated with belimumab: Report from real-world experience.

OBJECTIVE: To investigate the neonatal and maternal outcomes of patients treated with belimumab during pregnancy. MATERIALS AND METHODS: We retrospectively collected patients who were treated with belimumab during pregnancy from January 2018 to October 2020 in a tertiary referral hospital in Taiwan. All patients had clinical and serological features of systemic lupus erythematosus or antiphospholipid syndrome and had been treated accordingly. The patients' medical and obstetric history, obstetric complications and fetal outcomes were collected by chart review. RESULTS: A total of 13 pregnancies in 13 patients were included. The median age was 38 years (interquartile range 32-41 years), 46.2% had a history of recurrent pregnancy loss, and the median number of treatment courses with belimumab (400 mg per dose) was two. There were 11 live births (84.6%, 11 of 13). One episode of omphalitis was noted in one fetus, who recovered well with antibiotic treatment. No fetus had leukopenia, lymphopenia, neutropenia, or thrombocytopenia in the days after birth. No fetal anomalies were found in this series. Among the six patients with a past history of recurrent pregnancy loss, four had live births. CONCLUSION: This study provides new evidence for the use of belimumab in pregnant patients. No increase in the risk of fetal anomalies or severe infection was noted in the patients who were exposed to belimumab during pregnancy. Cautious monitoring is necessary if belimumab is used in pregnant patients, and more data are still needed to validate its safety.

Progressive multifocal leukoencephalopathy in systemic lupus erythematosus managed with pembrolizumab: A case report with literature review.

Progressive multifocal leukoencephalopathy (PML) is one of the rare but lethal infectious complication in patients with SLE, manifesting progressive central nervous demyelination caused by JC virus (JCV). There have been no effective antiviral agents so far; however, immune checkpoint inhibitors (ICI) have been demonstrated as potential treatments by reinvigorating antiviral T-cell activity against JC virus. To date, sixteen PML cases treated with anti-PD-1 have been reported; however, there was no report addressing the use of ICI in patients with concomitant PML and rheumatic disease, possibly due to the concern for possible autoimmune disease flare-up. In addition, treatment outcomes of these ICI-treated cases were heterogeneous. Experiences from these cases suggested that high disease burden, JC viral load in CSF, and severe immunosuppression status at baseline may predict poor response to treatment. Our case, a 62-year-old woman with long-standing SLE, turned out to have a delayed but effective response to prolonged ICI treatment despite of her high JC viral load and immunosuppressed status caused by high-dose steroid and rituximab. To our knowledge, this is the first case report with SLE complicated with PML clinically improved by pembrolizumab treatment without consequent immune related adverse events (irAE). Considering the lethal nature of PML and absence of effective medication, ICI is a reasonable consideration in patients with SLE and progressive PML.

Experience of the use of hydroxychloroquine on patients with COVID-19: A perspective on viral load and cytokine kinetics.

Until now, there are no approved treatment against COVID-19. Hydroxychloroquine (HCQ) was hypothesized to be active against SARS-CoV2 via antiviral and anti-inflammatory effect; however, HCQ for COVID-19 in clinical use remained debating. In this preliminary report, we presented six patients with mild to moderate COVID-19. They were treated with HCQ for 14 days from the day of COVID-19 diagnosis. Serial viral load from respiratory specimens were performed every other day. Cytokine profile was checked before HCQ initiation and on the 14th day of HCQ treatment. All patients receiving HCQ completed 14-day course without complication. Among the six patients, the mean duration from symptom onset to last detectable viral load was 34 ± 12 days, which was similar to those without specific treatment in previous reports. Low level of interferon-gamma was noted in all patients of different stage of infection and three patients had elevation of IL-17 level. Prolonged virus shedding is still observed regardless HCQ. The impact of HCQ on cytokine kinetics remained unclear; however, IL-17 could be an inflammatory marker for disease status monitor and a potential therapeutic target.