Tocilizumab in the treatment of hyperferritinemic syndrome and capillary leak syndrome secondary to rheumatoid arthritis: Case report and literature review.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is mainly characterized by joint swelling, pressure pain and joint destruction. Some patients may suffer from a variety of serious complications, which require prompt diagnosis and treatment. Otherwise, the patient condition may deteriorate rapidly, leading to premature death. OBJECTIVE: We reported a case of RA combined with hyperferritinemic syndrome and capillary leak syndrome (CLS) that was successfully treated with tocilizumab (TCZ), with the aim of improving diagnostic ideas for clinicians and consequently improving the diagnosis and treatment of the hyperferritinemic syndrome and CLS. CASE SUMMARY: A 55-year-old female patient was admitted to the Department of Infectious Diseases of our hospital due to "recurrent fever for more than 1 month and aggravation for 3 days." The patient was diagnosed with fever of unknown origin (lung infection?) and received anti-infective therapy with large encirclement of anti-bacterial, antifungal and empirical anti-tuberculosis successively during hospitalization in the Department of Infectious Diseases. Yet her condition continues to progress. The patient was eventually diagnosed with RA combined with hyperferritinemic syndrome and CLS. Then she received glucocorticoids (GC) (160 mg qd) combined with intravenous immunoglobulin (IVIG, 20 g/d, for 3 days). We considered that the patient also had an overwhelming proinflammatory cytokine storm, so she received a strong anti-inflammatory treatment with TCZ (400 mg qm). The patient symptoms and follow-up chest CT showed significant improvement following treatment. CONCLUSION: TCZ has good efficacy in the treatment of RA combined with hyperferritinemic syndrome and CLS and is expected to be a promising treatment.

Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial.

OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).

Elevated serum creatinine levels and risk of cognitive impairment in older adults with diabetes: a NHANES study from 2011-2014.

Background: The brain and kidney have similar microvascular structure, which makes them susceptible to certain common pathophysiological processes. In this study, we examined several indicators of kidney injury/function associated with cognitive function in older diabetic patients in the hope of finding effective markers for detecting cognitive impairment (CI). Methods: A total of 2209 older participants (aged ≥60 years) from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) were analyzed for the association between diabetes and CI using a multiple linear regression analysis model. Using the same approach, we also analyzed the relationship between indicators of kidney injury/function and cognitive function (Animal Fluency Test, Digit Symbol Substitution Test) in the diabetic population. Results: Diabetes was associated with CI. In age-adjusted model, older diabetics performed significantly poorer on tests of cognitive function compared to normoglycaemic individuals (1.145 points lower on the Animal Fluency Test (P = 0.005) and 7.868 points reduced on the Digit Symbol Substitution Test (P < 0.001)). In diabetics, we found elevated serum creatinine (SCr) (especially at SCr≥300uM) was associated with lower scores on cognitive function tests after strict adjustment for potential influences on cognitive function. While, albumin/creatinine ratio (ACR) was only associated with Digit Symbol Substitution score (DSS) not Animal Fluency score (AFS), and estimated glomerular filtration rate (eGFR) was only associated with CI (AFS and DSS) at the end-stage renal disease. Conclusion: SCr, as a sensitive indicator of kidney injury, was significantly associated with CI and can potentially be used as an effective marker for screening CI in older diabetics.

Role of CD19+ CD5+ CD1d+ Bregs in maintaining the Th17/Treg balance in mice with systemic lupus erythematosus complicated with atherosclerosis.

OBJECTIVE: In this study, we aimed to investigate Bregs, their regulatory effects on Th17/Treg cell balance, and the release of downstream inflammatory factors in a mouse model of low-density lipoprotein receptor (LDLr)-/- + Pristane. METHODS: After the establishment of the mouse model of systemic lupus erythematosus (SLE) complicated with atherosclerosis (AS), 8-week-old LDLr-/- + Pristane mice (n = 10) were included in the SLE + AS group. Furthermore, 8-week-old MRL/lpr and C57 mice were used as the SLE and normal control groups, respectively (n = 10 per group). After feeding the mice a high-fat diet for 14 weeks, peripheral blood and spleen of mice were collected, and Bregs, Th17, and Treg cells and related inflammatory factors were detected by flow cytometry, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction. RESULTS: The number of Bregs and Tregs in spleen lymphocytes of SLE + AS mice significantly decreased compared with the C57 group (p < .05), whereas the number of Th17 cells significantly increased (p = .000). Furthermore, the proportion of Bregs showed a negative correlation with the Th17/Treg ratio (p = .03). Mice in the SLE + AS group showed higher serum interleukin (IL)-10, IL-17, and tumor necrosis factor-α levels than those in the SLE and C57 groups (p < .05). Furthermore, IL-35 and transforming growth factor (TGF)-ß expression was reduced in the SLE + AS group compared with the C57 group (p < .05). CONCLUSIONS: The proportion of Breg decreases was negatively associated with increased Th17/Treg which was increased in SLE + AS mice, indicating that Bregs may regulate Th17/Treg cell homeostasis and cytokine release via IL-35 and TGF-ß production.

Risk of hepatitis B reactivation in HBsAg-/HBcAb+ patients after biologic or JAK inhibitor therapy for rheumatoid arthritis: A meta-analysis.

BACKGROUND: The risk of hepatitis B virus (HBV) reactivation after biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) therapy in patients with rheumatoid arthritis (RA) combined with HBsAg-/HBcAb+ is still inconsistent. METHODS: We conducted a systematic review of existing databases from 1977 to August 22, 2021. Studies of RA patients combined with HBsAg-/HBcAb +, treated with b/tsDMARDs and the reported number of HBV reactivation were included. RESULTS: We included 26 studies of 2252 HBsAg-/HBcAb+ RA patients treated with b/tsDMARDs. The pooled HBV reactivation rate was 2.0% (95% confidence interval [CI]: 0.01-0.04; I2 = 66%, p < .01). In the subgroup analysis, the HBV reactivation rate of rituximab (RTX), abatacept, and inhibitors of Janus kinase (JAK), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were 9.0% (95% CI: 0.04-0.15; I2 = 61%, p = .03), 6.0% (95% CI: 0.01-0.13; I2 = 40%, p = .19), 1.0% (95% CI: 0.00-0.03; I2 = 41%, p = .19), 0.0% (95% CI: 0.00-0.02; I2 = 0%, p = .43), 0.0% (95% CI: 0.00-0.01; I2 = 0%, p = .87), respectively. While HBsAb- patients have a significant risk of reactivation (odds ratio [OR] = 4.56, 95% CI = 2.45-8.48; I2 = 7%, p = .37), low HBsAb+ group also display a significant risk of reactivation (OR = 5.45, 95% CI: 1.35-21.94; I2 = 0%, p = .46). CONCLUSIONS: This meta-analysis demonstrates the highest potential risk of HBV reactivation in HBsAg-/HBcAb+ RA patients receiving RTX treatment, especially HBsAb- patients. Our study furthers the understanding of the prophylactic use of anti-HBV drugs in such patients. However, it is relative safety to use the inhibitors of IL-6, TNF-α, and JAK in these patients.

Favorable pregnancy outcomes in two patients with systemic lupus erythematosus treated with belimumab.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with poor pregnancy outcomes and complications. Belimumab can significantly improve disease activity in patients with SLE. However, there is insufficient evidence to prove the absolute safety of belimumab treatment during pregnancy. CASE SUMMARY: A 37-year-old woman was diagnosed with SLE after a renal puncture biopsy in 2012. The other patient was a 25-year-old woman. She was diagnosed with SLE at 19 years of age. They were treated by standard therapy in the early stage of treatment. The first patient has multiple histories of miscarriages or abortions at different gestational ages caused by SLE activity. The other patient also has persistent thrombocytopenia due to SLE flare. In our patients, SLE was poorly controlled by standard therapy. We initiated belimumab treatment during pregnancy because the benefits of treating SLE outweighed the risks to the fetus. The first patient was admitted to the first belimumab infusion at approximately 14 weeks of gestation. The other patient was admitted to the first belimumab infusion at approximately 12 weeks of gestation. Although our patients did not show complete disease remission during belimumab treatment, neither had serious adverse reactions or adverse pregnancy events, and their babies were in good conditions at birth. CONCLUSION: We present 2 cases of pregnant women with SLE who were treated with belimumab. Both were able to deliver their babies successfully without any complications.

Increased Risk of Retinal Vasculitis in Patients With Systemic Lupus Erythematosus: A Nationwide Population-Based Cohort Study.

Objectives: To evaluate the relationship between systemic lupus erythematosus (SLE) and the risk of retinal vasculitis (RV) using a population-based database. Methods: Using the 1997-2013 Taiwanese National Health Insurance Database, we identified newly diagnosed SLE patients between 2001 and 2012 as the SLE group. We matched the SLE group with non-SLE individuals selected from a representative one million sample of the population in a 1:20 ratio for age, sex, and the year of the index date. After adjusting for potential confounders, including urbanization of the patient's residence, the level of the payroll-related insured amount, and selected comorbidities, we examined the association between SLE and the risk of RV using the Cox proportional hazard model shown as hazard ratios (HRs) with 95% confidence intervals (CIs). Sensitivity analyses were conducted using various definitions of RV. Results: We included 11,586 patients with SLE and 231,720 matched non-SLE individuals. The mean age of the study participants was 36.7 ± 16.9 years, and the female-to-male ratio was 6.8:1. The incidence rates of RV were 56.39 cases per 100,000 person-years and 2.45 cases per 100,000 person-years, respectively. After adjusting for potential confounders, the incidence rate of RV in the SLE cohort was 22.99 times higher than that in the non-SLE cohort (56.39 vs. 2.45 per 100,000 person-years). The adjusted HR for RV in the SLE group was 23.61 (95% CI, 14.94-37.32). The results remained robust in the sensitivity analysis. Conclusion: This nationwide population-based study revealed that SLE patients had a significantly higher risk of RV than non-SLE individuals.

Transbronchial lung cryobiopsy for connective tissue disease-related interstitial lung disease and interstitial pneumonia with autoimmune features: a single center retrospective case series.

OBJECTIVE: Transbronchial lung cryobiopsy (TBLC) has been recently introduced for diagnosing interstitial lung diseases. We aimed to assess the effectiveness and safety of TBLC by identifying the specific patterns of histology in the diagnosis of connective tissue disease-related interstitial lung disease (CTD-ILD) and interstitial pneumonia with autoimmune features (IPAF). METHODS: The clinical-radiological-pathological data from the Affiliated Hospital of Guilin Medical University between July 1, 2017, and October 31, 2020, of patients whose clinical-radiological or clinical-radiological-pathological diagnosis was CTD-ILD or IPAF and who underwent TBLC, transbronchial lung biopsy (TBLB), or surgical lung biopsy were retrospectively analyzed and summarized with review. The size of biopsy samples, complications, and diagnostic yield were compared. RESULTS: Fourteen patients met the inclusion criteria, of whom 12 underwent TBLC, 1 underwent TBLB, and 1 underwent each procedure at different times. Compared to the size of TBLB specimens (5.625 ± 0.479 mm2), the size of TBLC specimens (12.00 (12.00, 15.00) mm2) was much larger (Z = - 3.262, P = 0.001). The diagnostic yields of TBLC and TBLB were 100.00% (13/13) and 0.00% (2/2), respectively (P = 0.0095). The most frequent complication was mild bleeding. The risk of bleeding between TBLB (1/2, 50.00%) and TBLC (10/13, 76.92%) did not differ significantly (P = 0.469). CONCLUSION: TBLC can add extra diagnostic value by effectively identifying specific types of histology for patients with suspected CTD-ILD or IPAF, with a procedure that is safe from adverse events. Key Points • Transbronchial lung cryobiopsy has been introduced recently for diagnosing interstitial lung disease. • Transbronchial lung cryobiopsy was found to be effective and safe in the diagnosis for patients with suspected interstitial lung disease. It can be used as a preferred method for biopsy when the clinical-radiological diagnosis is uncertain.

Effectiveness of methotrexate in combination therapy in a rat collagen-induced arthritis model.

This study was to investigate the effect of methotrexate in combination therapy by the characteristic cytokine in Th17 cells and the frequency of Tregs, which involved in the induction and pathological progress of rheumatoid arthritis (RA). The collagen-induced arthritis rats were treated with methotrexate + prednisone, methotrexate + disease-modifying rheumatic drugs (DMARDs) and methotrexate + TNFi, respectively. The following parameters were observed to evaluate three treatments: the frequency and function of Th17 cells and Tregs, the scores of X-rays, H&E staining and immunohistochemistry. For rats starting methotrexate + prednisone (low doses), the frequency and suppressive function of Th17 cells decreased while the frequency of Tregs increased, which were the same in methotrexate + TNFi. Immunohistochemical in the pathological sections of ankle joint showed the same results. The effect of methotrexate + DMARDs treatment was slightly inferior to the other combination therapies. In summary, rats treated with methotrexate + prednisone can achieve high level of Tregs and low level of Th17 cells and IL-17. Low doses of glucocorticoid suggesting a critical role in the pathogenesis of rheumatoid arthritis may have the similar effect as DMARDs.

Artesunate influences Th17/Treg lymphocyte balance by modulating Treg apoptosis and Th17 proliferation in a murine model of rheumatoid arthritis.

CD4+ regulatory T (Treg) cells and T-helper 17 (Th17) cells have been shown to have important roles in rheumatoid arthritis (RA). In our previous study, it was demonstrated that artesunate was able to alter the Treg/Th17 ratio in patients with RA; however, the underlying mechanisms remain unclear. The present study established a male Sprague Dawley (SD) rat model of type II collagen-induced arthritis (CIA). SD rats were divided into normal control, CIA model and artesunate-treated (5, 10 or 20 mg/kg/day) groups. Treg and Th17 cells were detected in the synovium by immunohistochemical analysis of forkhead/winged helix transcription factor (Foxp3) and interleukin (IL)-17 expression. Subsequently, lymphocytes were extracted from the rat spleens, and the proportions of Treg/Th17 cells were detected by flow cytometry. The results demonstrated that the expression levels of Foxp3 were significantly decreased, and those of IL-17 were significantly increased, in the CIA model group, as compared with the normal control group. The results demonstrated that artesunate decreased the frequency of Th17 cells and increased the frequency of Treg cells in CIA rats in a dose-dependent manner. In conclusion, the present study suggested that artesunate may regulate the Th17/Treg balance by inducing Th17-mediated apoptosis. Therefore, artesunate may be considered a novel therapeutic agent for the treatment of patients with RA.

TRAF6 regulates the effects of polarized maturation of tolerability: Marrow-derived dendritic cells on collagen-induced arthritis in mice.

The study aimed to investigate the relationship between tumor necrosis factor receptor-associated factor 6 (TRAF6) and a differentially mature dendritic cell (mDC) in collagen-induced arthritis (CIA) mice and to determine whether or not TRAF6 regulates the activation of an immature dendritic cell (iDC) and inhibits iDC maturation to induce immune tolerance. The mouse bone marrow stem cells were induced with recombinant granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and recombinant interleukin-4 (rmIL-4) to differentiate immature dendritic cells (DCs), which were divided into four groups with different maturation states: rmGM-CSF, rmIL-4; TNF-α; LPS; and FK506 group. The levels of the cell surfaces of CD80, CD86, and MHI-II were analyzed by flow cytometry to prove DCs at different levels of maturity. The expression of IL-12 in DCs at different maturation states was detected by enzyme-linked immunosorbent assay (ELISA). The expression of TRAF6 mRNA and protein in each group of DCs was detected by a reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. The results revealed that the differentiation of bone marrow cells into iDCs was significantly induced by cytokines (rmGM-CSF, IL-4). CD80, CD86, MHC-II were expressed in the four groups, and the difference between them was statistically significant (P<0.05). A higher degree of DC differentiation led to a gradual increase of IL-12 secretion in the four groups. The difference was statistically significant (P<0.05) for this secretion (group D, 10,620.73±276.73 pg/ml). The expression levels of TRAF6 mRNA were significantly higher in group D than those in the other three groups (P<0.01). Although there was no significant difference in the expression levels of TRAF6 mRNA between groups B and C, the expression levels of TRAF6 mRNA between groups B and C were higher than those of the control group. The TRAF6 protein expression was higher in group D than that in the other three groups (P<0.01), and the difference was statistically significant. There was a statistically significant difference in the TRAF6 protein expression between group A and groups B and C, but the expression in group C was higher than that in group B (P<0.01). In conclusion, the expression of co-stimulatory molecules gradually increased in the DCs of different maturation states, and the expression of IL-12, TRAF6 mRNA, and TRAF6 protein positively correlated with the degree of DC maturation. TRAF6 is important in iDC polarity and maturation.

Artesunate interfere in modulation of Foxp3 expression in synovial cells in collagen-induced arthritis rats.

OBJECTIVE: To investigate the expression and significance of forkhead/winged helix (Foxp3) in rat synovial cells in collagen-induced arthritis rats after artesunate interventions. METHODS: A male Wistar rat model of type II collagen-induced arthritis (CIA) was established. The synovia was removed, and synovial cells were cultured for 5-7 generations. The cells were divided into a normal control group, a CIA model group, artesunate groups at different concentrations (5, 10, and 20 ng/mL), and a hydroxychloroquine group. The expressions of the Foxp3 gene in the groups were detected by reverse transcription polymerase chain reaction, and their protein expressions were detected by western blotting. RESULTS: In the drug intervention and CIA model groups, Foxp3 gene and protein expressions increased. The Foxp3 gene and protein expressions in the drug intervention groups were higher than those in the CIA model group, and fiber-like synovial cells numbers decreased. Foxp3 in the artesunate group was expressed at a greater level than the levels expressed in the control groups (P<0.05). Significantly increased of expression was observed in the 20 ng/mL artesunate group compared with the model group (P<0.05). CONCLUSIONS: Artesunate could increase the expression of Foxp3 in a dose-dependent manner, and thus reduce pannus formation and erosion of cartilage and bone to prevent lesions from rheumatoid arthritis.

Autoimmunity and dysmetabolism of human acquired immunodeficiency syndrome.

Acquired immunodeficiency syndrome (AIDS) remains ill-defined by lists of symptoms, infections, tumors, and disorders in metabolism and immunity. Low CD4 cell count, severe loss of body weight, pneumocystis pneumonia, and Kaposi's sarcoma are the major disease indicators. Lines of evidence indicate that patients living with AIDS have both immunodeficiency and autoimmunity. Immunodeficiency is attributed to deficits in the skin- and mucosa-defined innate immunity, CD4 T cells and regulatory T cells, presumably relating human immunodeficiency virus (HIV) infection. The autoimmunity in AIDS is evident by: (1) overproduction of autoantibodies, (2) impaired response of CD4 cells and CD8 cells, (3) failure of clinical trials of HIV vaccines, and (4) therapeutic benefits of immunosuppression following solid organ transplantation and bone marrow transplantation in patients at risk of AIDS. Autoantibodies are generated in response to antigens such as debris and molecules de novo released from dead cells, infectious agents, and catabolic events. Disturbances in metabolic homeostasis occur at the interface of immunodeficiency and autoimmunity in the development of AIDS. Optimal treatments favor therapeutics targeting on the regulation of metabolism to restore immune homeostasis.