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.

Tissue microenvironment dictates inflammation and disease activity in rheumatoid arthritis.

The recent advance in treatments for rheumatoid arthritis (RA) has significantly improved the prognosis of RA patients. However, these novel therapies do not work well for all RA patients. The unmet need suggests that the current understanding about how inflammatory response arises and progresses in RA is limited. Recent accumulating evidence reveals an important role for the tissue microenvironment in the pathogenesis of RA. The synovium, the main tissue where the RA activity occurs, is composed by a unique extracellular matrix (ECM) and residing cells. The ECM molecules provide environmental signals that determine programmed site-specific cell behavior. Improved understanding of the tissue microenvironment, especially how the synovial architecture, ECM molecules, and site-specific cell behavior promote chronic inflammation and tissue destruction, will enhance deciphering the pathogenesis of RA. Moreover, in-depth analysis of tissue microenvironment will allow us to identify potential therapeutic targets. Research is now undertaken to explore potential candidates, both cellular and ECM molecules, to develop novel therapies. This article reviews recent advances in knowledge about how changes in cellular and ECM factors within the tissue microenvironment result in propagation of chronic inflammation in RA.

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.

Combined intravenous immunoglobulin and baricitinib treatment for severe COVID-19 with rhabdomyolysis: A case report.

Since December 2019, the outbreak of coronavirus disease 2019 (COVID-19) has spread rapidly around the world. The severity of COVID-19 ranges from asymptomatic carriers to severe acute respiratory distress syndrome (ARDS). Accumulating evidence has shown that COVID-19 may be associated with multiple organ complications including cardiac injury, viral myositis and neurological deficits. Numerous laboratory biomarkers including lymphocytes, platelets, lactate dehydrogenase and creatine kinase (CK) have been associated with the prognostic outcomes of patients with COVID-19. However, dynamic correlations between levels of biomarkers and clinical course have not been studied. Herein, we report a 74-year-old female patient with severe COVID-19 which progressed to ARDS requiring intubation and mechanical ventilation. The laboratory findings showed lymphopenia, hypogammaglobulinemia, and elevated inflammatory biomarkers and CK. She received intensive therapy with hydroxychloroquine, lopinavir/ritonavir, and azithromycin with limited effects. Immunomodulatory treatments with high dose intravenous immunoglobulin and baricitinib were prescribed with satisfactory biochemical, radiographic and clinical recovery. We found an interesting correlation between serum CK elevation and inflammatory biomarkers, which reflected clinical improvement. This case demonstrates that inflammatory biomarkers, cytokines, and CK level correlated with disease severity and treatment response, and combined use of intravenous immunoglobulin and baricitinib is a potential treatment in patients with severe COVID-19.

Anti-Cyclic Citrullinated Peptide Antibodies Correlate to Ultrasound Synovitis in Rheumatoid Arthritis Better Than C-Reactive Protein.

OBJECTIVES: The aim of this study was to compare ultrasound (US) grading and laboratory measures in patients with rheumatoid arthritis. METHODS: Two-hundred four patients with rheumatoid arthritis who received US evaluation for synovitis were included after excluding those using tocilizumab. Ultrasound grading of synovial hypertrophy (SH) and power Doppler (PD) at the most severe site were recorded. An assessment of the correlation of laboratory measures and US grading was conducted by reviewing the electronic medical records. RESULTS: High-titer anti-cyclic citrullinated peptide (anti-CCP) antibodies positivity was associated with SH grade ≥2 (odds ratio [OR], 6.00; 95% confidence interval [CI], 1.78-20.2) and PD grade ≥2 (OR, 5.56; 95% CI, 1.82-16.9). Recent C-reactive protein (CRP) levels ≥0.3 mg/dL were associated with SH grade ≥2 (OR, 3.13; 95% CI, 1.38-7.10) and PD grade ≥2 (OR, 2.38; 95% CI, 1.31-4.31). Anti-CCP antibody levels correlated with US scores better than the levels of CRP with higher Spearman ρ correlation coefficients. Most of the patients with recent CRP levels <0.3 mg/dL had US synovitis. In logistic regression, high levels of anti-CCP antibodies and CRP were both independently associated with SH grade ≥2 and PD grade ≥2. CONCLUSIONS: Higher levels of anti-CCP antibodies and CRP may predict synovitis on US, whereas discrepancies existed between inflammatory markers and US grading. These findings suggest that US has a role in the comprehensive assessment of disease activity, especially for patients with high-titer positive anti-CCP antibodies.

Progressive multifocal leukoencephalopathy in a 27-year-old lady with systemic lupus erythematosus - rheumatoid arthritis overlap syndrome.

Progressive multifocal leukoencephalopathy (PML) is a rare viral demyelinating disease of central nervous system. Immunosuppression is a significant risk factor for the disease. Previously, PML developed more commonly in patients of hematological malignancy and acquired immune deficiency syndrome (AIDS). In the era of biological disease modifying anti-rheumatic drugs, PML is more frequently reported in patients of autoimmune diseases. However, for its rarity and unspecific clinical presentations, accurate diagnosis and immediate immune restoration might be difficult in clinical practice, and the outcome might thus be miserable. Herein we present a 27-year-old lady of systemic lupus erythematosus (SLE) - rheumatoid arthritis overlap syndrome with suspected involvement of central nervous system. Neuropsychiatric SLE was suspected first. However, after intensive immunosuppressive treatment, the condition kept deteriorating. An alternative diagnosis was thus considered. PML was suspected for her immunosuppressive status and suggestive radiological findings, and the diagnosis was confirmed by a polymerase chain reaction of JC virus from cerebrospinal fluid. After restoring the immune status by decreasing the dose of immunosuppressants, the condition of the patient improved significantly. We report this case to raise the importance of clinical alertness for the rare but possibly underdiagnosed disease.

Weaning outcome of solid cancer patients requiring mechanical ventilation in the intensive care unit.

BACKGROUND: Whether the weaning outcome of solid cancer patients receiving mechanical ventilation (MV) in the intensive care unit (ICU) is comparable to that in non-cancer patients is unknown. The aim of this study was to compare the weaning outcomes between non-cancer patients and patients with different types of cancer. METHODS: We studied patients requiring MV during ICU stay for medical reasons between 2012 and 2014. Cancer patients were grouped into those with lung cancer (LC), head and neck cancer (HNC), hepatocellular carcinoma (HCC), and other cancers (OC). The primary endpoint was successful weaning at day 90 after the initiation of MV, and the main secondary endpoints were 28-day and 90-day mortality after ICU admission. RESULTS: Five hundred and eighteen patients with solid cancers and 1362 non-cancer patients were recruited. The rate of successful weaning at day 90 was 57.9% in cancer patients, which was lower than 68.9% in non-cancer patients (p < 0.001). Compared to non-cancer patients, LC was associated with a lower probability of weaning at day 90 (hazard ratio 0.565, 95% CI 0.446 to 0.715), while HNC, HCC, and OC had similar probabilities. The 28-day and 90-day mortality rates were higher in cancer patients than in non-cancer patients (45.2% vs. 29.4%, and 65.6% vs. 37.7%, respectively, both p < 0.001). CONCLUSION: Among mechanically ventilated patients in the ICU, those with LC were associated with a lower probability of weaning at day 90 compared to non-cancer patients.

Ultrasound characteristics of soft tissues near sacroiliac joints and in the lumbar region of patients with ankylosing spondylitis.

AIMS: To investigate the musculoskeletal morphomechanical properties (i.e., the thickness and elastic modulus) and the total count of power Doppler signals near the sacroiliac joints in patients with ankylosing spondylitis (AS) and non-AS individuals. MATERIAL AND METHODS: Twenty participants with AS [median age (interquartile range): 31.7 (11.04) years] and 19 controls [36.3 (10.5) years] with no AS history were recruited. Bilateral ultrasound image acquisition was performed, including the short posterior sacroiliac ligament, interosseous sacroiliac ligament, long posterior sacroiliac ligament, iliolumbar ligament, proximal piriformis muscle, and sacrotuberous ligament. The intraclass correlation coefficients (ICC) of ultrasound parameters, laboratory test results of human leukocyte antigen B27, C-reactive protein, and erythrocyte sedimentation rate, and self-reported physical and disease activity scores were also obtained. RESULTS: The ligaments and piriformis muscle were thicker and stiffer (greater elastic modulus) in participants with AS than in non-AS participants (all p<0.01). The measurements showed good or excellent reliability (all ICC(3,1) >0.85). The numbers of power Doppler signals detected in the iliolumbar ligament, proximal piriformis muscle, and sacrotuberous ligament were higher in participants with AS than in non-AS participants (all p<0.001). A correlation was identified between disease duration and the elastic modulus of the piriformis muscle (r=0.640, p=0.003). CONCLUSION: We conclude that the ligaments and proximal piriformis muscle of AS participants have increased thickness, elastic modulus, and power Doppler signal than those of non-AS individuals. These reliable findings may serve as potential markers for the early diagnosis of AS and for assessing medication effects.

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.

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.

Clinical features and prognostic predictors in patients with rheumatic diseases complicated by Pneumocystis pneumonia.

OBJECTIVES: To investigate the clinical outcomes and risk factors of mortality in patients with rheumatic diseases complicated by Pneumocystis pneumonia (PCP). METHODS: Between November 2015 and April 2021, patients with rheumatic diseases with PCP in a tertiary referral hospital were retrospectively enrolled. The diagnosis of PCP requires the fulfillment of clinical, radiographic, and microbiological criteria. Factors associated with in-hospital, 30-day, and 90-day mortality were evaluated. RESULTS: A total of 128 patients with rheumatic diseases who had a positive quantitative polymerase chain reaction assay for Pneumocystis jirovecii were screened, and 72 patients were included in the final analysis. The median (interquartile range [IQR]) pneumonia severity index (PSI) was 101.5 (77.0-132.0). The median (IQR) adjunctive corticosteroid dosage was 0.6 (0.4-0.9) mg/kg/day prednisolone equivalent. The receiver operating characteristic curve analysis showed that the optimal cutoff point of median adjunctive corticosteroid dosage was 0.6 mg/kg/day to predict in-hospital, 30-day, and 90-day mortality. In the multivariable logistic regression analysis, median adjunctive corticosteroid dosage ≥0.6 mg/kg/day and PSI >90 were independent factors of in-hospital, 30-day, and 90-day mortality. CONCLUSION: A median adjunctive corticosteroid dosage of ≥0.6 mg/kg/day might be associated with mortality in patients with rheumatic diseases complicated by PCP.

Association between SLICC/ACR damage index and outcomes for lupus patients after cardiac valve surgery.

Systemic lupus erythematosus (SLE) is associated with multi-organ damage including cardiac valve, which may need valvular operation. However, methods for outcome prediction and prosthetic valve selection are unclear in SLE patients undergoing cardiac valve surgery. Twenty-five SLE patients receiving valvular operation in a single institute between 2002 and 2020 were enrolled. Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR damage index, SDI) was applied to evaluate the damage severity. Clinical outcomes were compared between patients with different SDI. The hospital survival rate was 88%, and long-term survival rate was 59.5% and 40.2% at 5 and 10 years. The median SDI was 4 (interquartile range 3-6) in our study, patients were then grouped into higher SDI (defined as SDI ≥ 5, n = 11) and lower SDI group (defined as SDI < 5, n = 14). The in-hospital survival rate (72.2% vs 100%, P = 0.074) and 5-year survival rate (18.2% vs 92.9%, P < 0.001) were lower in higher SDI group, compared to lower SDI group. SDI score was associated with long-term outcome for SLE patients receiving cardiac valve surgery. SDI ≥ 5 was associated with very poor long-term outcomes. This finding implicates that xenograft might be a reasonable choice for SLE patients with SDI ≥ 5.

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.

Serum C-Reactive Protein and Interleukin-6 Levels as Biomarkers for Disease Severity and Clinical Outcomes in Patients with Idiopathic Granulomatous Mastitis.

Idiopathic granulomatous mastitis (IGM) is a rare inflammatory breast disease mimicking breast cancer. Limited research has been conducted on the application of serum biomarkers. This study aims to investigate the association of serum biomarkers with disease severity in patients with IGM. From November 2011 to March 2020, medical records of patients with IGM were reviewed. Serum cytokine levels were measured in patients and healthy controls between July 2018 and March 2020. A total of 41 patients with histologically proven IGM were found. Serum interleukin (IL)-6 level was significantly higher in patients with IGM (n = 11) than healthy controls (n = 7). Serum IL-6 and C-reactive protein (CRP) levels were significantly higher in patients with severe disease than mild and moderate disease. Serum IL-6 (Spearman's ρ = 0.855; p < 0.001) and CRP (Spearman's ρ = 0.838; p = 0.001) levels were associated with time to resolution. A higher serum CRP level was associated with a longer time to resolution (B = 0.322; p < 0.001) in multiple linear regression analysis. Serum IL-6 and CRP levels can be used as biomarkers for the evaluation of disease severity in IGM. IL-6 may play a crucial role in the immunopathology of IGM.

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.

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.