Serum IgG4 Concentration is a Potential Predictive Biomarker in Glucocorticoid Treatment for Idiopathic Retroperitoneal Fibrosis

Objectives: To evaluate the management and outcome of idiopathic retroperitoneal fibrosis (iRPF) in Japan, and identify its clinical biomarker. Methods: We retrospectively analyzed 129 patients with iRPF treated between January 2008 and May 2018 at 12 university and related hospitals. Patients treated with glucocorticoid were analyzed to identify a predictive biomarker. These patients were classified into three groups according to overall effectiveness (no change: NC, complete response: CR and partial response groups: PR), and each parameter was compared statistically.Results: Male-female ratio was 5: 1, and median age at diagnosis was 69 (33-86) years. Smoking history was reported in 59.6% of the patients. As treatment, 95 patients received glucocorticoid therapy with an overall response rate of 84%. As a result, serum concentration of IgG4 was significantly decreased in NC group compared with the other two groups (56.6mg/dL vs 255mg/dL, 206mg/dL, P=0.0059 and 0.0078). ROC analysis was performed between the non-responder (NC) and responder groups (CR+PR) to identify the cut-off value of serum IgG4 as a predictive marker. As a result, AUC was 0.793 and the values of sensitivity and specificity were 0.85 and 0.64, respectively, under the cut-off values of 67.6mg/dL. Conclusions: In the majority of iRPF patients, glucocorticoid therapy resulted in a favorable response. Pre-treatment serum IgG4 concentration may have potential as a predictive biomarker of steroid treatment.

Primary Toxoplasma gondii infection-associated with hemophagocytic syndrome in a man with HIV infection: a case report

Background Reactivation of latent Toxoplasma gondii (T. gondii) infection is more common than primary infection in patients with human immunodeficiency virus (HIV). We report a rare case of primary T. gondii infection-associated hemophagocytic syndrome (HPS). Case presentation A man with HIV infection presented with fever, dyspnea and pancytopenia. He was diagnosed with primary T. gondii infection by the seroconversion from single-positive IgM antibody to double-positive IgM and IgG antibody. Metagenomic next-generation sequencing (mNGS) of a plasma sample yielded high reads of T. gondii DNA. He responded well to combined anti-Toxoplasma medicines and glucocorticoid treatment. Conclusions In patients with HPS and positive T. gondii IgM antibody, mNGS analysis of a peripheral blood sample is helpful in diagnosing disseminated T. gondii infection. The dynamic changes by serological detection for IgM and IgG of T. gondii further supported the inference that the patient has experienced a primary T. gondii infection.

Triamcinolone Acetonide-Loaded Nanoparticles Encapsulated By CD90+ MCSs-Derived Microvesicles Drive Anti-Inflammatory Properties and Promote Cartilage Regeneration After Osteoarthritis

Background: Osteoarthritis (OA) is a highly prevalent human degenerative joint disorder that has long plagued patients. Glucocorticoid injection into the intra-articular (IA) cavity provides potential short-term analgesia and anti-inflammation, but long-term IA causes loss of cartilage content. Synovial mesenchymal stem cells (MSCs) reportedly promote cartilage proliferation and increase cartilage content. Methods: The CD90+ MCSs-derived micro-vesicle (CD90@MV)-coated nanoparticle (CD90@NP) was developed. CD90+ MCSs were extracted from human synovial tissue. Cytochalasin B (CB) relaxed the interaction between the cytoskeleton and the cell membranes of CD90+ MCSs, stimulating CD90@MV secretion. The poly (lactic-co-glycolic acid) (PLGA) nanoparticle was coated with CD90@MV, and a model glucocorticoid, triamcinolone acetonide (TA), was encapsulated in CD90@NP (T-CD90@NP). Results: CD90@MV membrane proteins were similar to CD90+ MCSs, indicating that the CD90@MV bio-activity is similar to the cartilage proliferation-inducing CD90+ MCSs. The CD90@NP binding to injury cartilage primary cells was significantly stronger than the erythrocyte membrane-coated nanoparticles (RNP). In the rabbit OA model, long-term IA of T-CD90@NP showed significantly enhanced repair of damaged cartilage than TA and CD90+ MCSs treatments. In the rat OA model, short-term IA of T-CD90@NP showed effective anti-inflammatory ability similar to TA treatment. Moreover, long-term IA of T-CD90@NP induced cartilage to restart the cell cycle and reduced cartilage apoptosis. T-CD90@NP promotes regeneration of chondrocytes, reduces apoptosis via the FOXO pathway, and influences type 2 macrophage polarization to regulate inflammation through IL-10. Conclusion: This study confirms that T-CD90@NP promotes chondrocyte proliferation and anti-inflammation, improving the clinical glucocorticoid treatment plan.

A multi-professional approach for transition of care at discharge in hyperglycemic inpatients with covid-19: a single center study

Background: The discharge from hospital of insulin-treated hyperglycemic patients is always challenging. This is even more so in patients requiring glucocorticoid treatment, such as those with COVID-19. Patients and method: A retrospective monocentric study of 23 inpatients with newly diagnosed or already known diabetes mellitus (DM) who were naïve to insulin treatment, , and who were hospitalized with COVID-19 in non-critical settings and then discharged. Patients were followed-up for one month after discharge for the management of insulin treatment by a multi-professional team through phone consultations. Results: Insulin prescriptions at discharge were 24.6 ± 14 U/day injected in 2 ± 1.5 daily shots. A mean of three phone consultations were required. One month later, the mean insulin reduction was 1.5 ± 1.3 shots and 6 ± 5 U/day. All patients reached their glycemic target without hypoglycemic events, drop-outs, or readmissions. Conclusion: This study demonstrates the feasibility, efficacy, and safety of a multi-professional approach through telemedicine for managing DM patients after discharge during COVID-19.

Glucocorticoid-Induced Hypokalemic Periodic Paralysis after Short-Term Use of Tenofovir with Hypophosphatemia: A Case Report

Hypokalemic periodic paralysis (HPP) is a neuromuscular disorder associated with muscular dysfunction caused by hypokalemia. There are various causes of HPPs and rarely, HPP appears to be relevant to tenofovir or glucocorticoid treatment. There have been several case reports of tenofovir-related nephrotoxicity or tenofovir-induced HPP. However, a case report of glucocorticoid-induced HPP in a patient using tenofovir temporarily has not been reported. Herein, we report a case of glucocorticoid-induced HPP with short-term use of tenofovir. A 28-year-old man visited the emergency room with decreased muscle power in all extremities (2/5 grade). In their past medical history, the patient was treated with tenofovir for two months for a hepatitis B virus infection. At the time of the visit, the drug had been discontinued for four months. The day before visiting the emergency room, betamethasone was administered at a local clinic for herpes on the lips. Laboratory tests showed hypokalemia, hypophosphatemia, and mild metabolic acidosis. However, urinalysis revealed no abnormal findings. Consequently, it can be postulated that this patient developed HPP by glucocorticoids after taking tenofovir temporarily. This is the first case report of glucocorticoid-induced HPP in a patient using tenofovir. Clinicians who prescribe tenofovir should be aware of HPP occurring when glucocorticoids are used.

Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

Glucocorticoids are potent anti-inflammatory drugs; however, their molecular mode of action remains complex and elusive. They bind to the glucocorticoid receptor (GR), a nuclear receptor that controls gene expression in almost all tissues in a cell type-specific manner. While GR’s transcriptional targets mediate beneficial reactions in immune cells, they also harbor the potential of adverse metabolic effects in other cell types such as hepatocytes. Here, we have profiled nascent transcription upon glucocorticoid stimulation in LPS-activated primary murine macrophages using 4sU-seq. We compared our results to publicly available nascent transcriptomics data from murine liver and bioinformatically identified non-coding RNAs transcribed from intergenic GR binding sites in a tissue-specific fashion. These tissue-specific enhancer RNAs (eRNAs) correlate with target gene expression, reflecting cell type-specific glucocorticoid responses. We further associate GR-mediated eRNA expression with changes in H3K27 acetylation and BRD4 recruitment in inflammatory macrophages upon glucocorticoid treatment. In summary, we propose a common mechanism by which GR-bound enhancers regulate target gene expression by changes in histone acetylation, BRD4 recruitment and eRNA expression. We argue that local eRNAs are potential therapeutic targets downstream of GR signaling which may modulate glucocorticoid response in a cell type-specific way.

A hybrid soluble gp130/spike-nanobody fusion protein simultaneously blocks IL-6 trans-signaling and cellular infection with SARS-CoV2

SARS-CoV2 infection can induce mild to life threatening symptoms. Especially individuals over 60 years of age or with underlying co-morbidities including heart or lung disease, and diabetes or immune compromised patients are at higher risk. Fatal multi-organ damage in COVID19 patients can be attributed to Interleukin (IL-)6 dominated cytokine storm. Consequently, IL-6R monoclonal antibody treatment for severe COVID19 cases has been approved for therapy. High concentrations of soluble IL-6R were found in COVID19 intensive care unit patients suggesting the involvement of IL-6 trans-signaling in disease pathology. Here, in analogy to bispecific antibodies (bsAbs), we developed the first bispecific IL-6 trans-signaling inhibitor c19s130Fc which blocks viral infection and IL-6 trans-signaling. c19s130Fc is a designer protein of the IL-6 trans-signaling inhibitor cs130 fused to a single domain nanobody directed against the receptor binding domain (RBD) of the SARS-CoV2 spike protein. c19s130Fc binds with high affinity to IL-6:sIL6R complexes as well as the spike protein of SARS-CoV2 as shown by surface plasmon resonance. Using cell-based assays, we demonstrate that c19s130Fc blocks IL-6 trans-signaling-induced proliferation and STAT3 phosphorylation of Ba/F3-gp130 cells as well as SARS-CoV2 infection and STAT3 phosphorylation in Vero cells. Taken together, c19s130Fc represents a new class of bispecific inhibitors consisting of a soluble cytokine receptor fused to anti-viral nanobodies and principally demonstrates the multi-functionalization of trans-signaling inhibitors. Importance The availability of effective SARS-CoV2 vaccines is a big step forward in managing the pandemic situation. In addition, therapeutic options e.g. monoclonal antibodies to prevent viral cell entry and anti-inflammatory therapies including glucocorticoid treatment are currently developed or in clinical use utilized to treat already infected patients. Here we report a novel dual-specific inhibitor to simultaneously target SARS-Cov2 infection and virus induced hyper-inflammation. This was achieved by fusing an inhibitor of viral cell entry with a molecule blocking IL-6, a key mediator of SARS-CoV2 induced hyper-inflammation. Through this dual action, this molecule may have the potential to efficiently ameliorate symptoms of COVID19 in infected individuals.

A Clinical Retrospective Study of Recurrent Painful Ophthalmoplegic Neuropathy in Adults

Introduction. Recurrent painful ophthalmoplegic neuropathy (RPON) is quite rare and usually occurs in children. In this report, we describe the clinical features, diagnosis, and treatment of RPON in adults. Methods. A retrospective review was conducted of all RPON cases seen and treated at the Zhongshan Ophthalmic Center of Sun Yat-sen University and the Department of Neurology of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, over the period from January 2016 to May 2020. Results. A total of 8 patients (3 males and 5 females) with a mean age of 42.9 years (range: 23–64 years) met the diagnostic criteria of RPON. Headaches were present prior to the onset of ophthalmoplegic neuropathy in 50% of these patients, while in the remaining 50%, headaches occurred simultaneously with eye symptoms. The degree of these headaches was described as being mild or moderate. Abnormalities involving cranial nerve III were the most frequently reported pathologies (6 cases, 75%), followed by nerve VI (4 cases, 50%) and then nerve IV (1 case, 12.5%) (more than one nerve was affected in some cases). Following either with glucocorticoid treatment or with observation only, symptoms and signs within all 8 patients completely dissipated within 3–28 days. Conclusions. All adult cases of RPON along with their clinical features as reported here were similar to those of children.

Validation of the Southend Giant Cell Arteritis Probability Score in a Scottish single centre fast-track pathway

Objective To externally validate the Southend GCA Probability Score (GCAPS) in patients attending a GCA Fast-Track Pathway (GCA FTP) in NHS Lanarkshire. Methods Consecutive GCA FTP patients between November 2018 and December 2020 underwent GCAPS assessment as part of routine care. GCA diagnoses were supported by USS +/- TAB and confirmed at 6 months. Percentages of patients with GCA according to GCAPS risk group, performance of total GCAPS in distinguishing GCA/non-GCA final diagnoses, and test characteristics using different GCAPS binary cut-offs, were assessed. Associations between individual GCAPS components and GCA, and the value of USS and TAB in the diagnostic process, were also explored. Results 44/129 patients were diagnosed with GCA, including 0/41 GCAPS low risk patients (GCAPS <9), 3/40 medium risk (GCAPS 9–12), and 41/48 high risk (GCAPS >12). Overall performance of GCAPS in distinguishing GCA/non-GCA was excellent [ROC AUC 0.976 (95% CI 0.954–0.999)]. GCAPS cut-off ≥10 had 100.0% sensitivity and 67.1% specificity for GCA. GCAPS cut-off ≥13 had highest accuracy (91.5%), with 93.2% sensitivity and 90.6% specificity. Several individual GCAPS components were associated with GCA. Sensitivity of USS increased by ascending GCAPS risk group (nil, 33.3%, 90.2% respectively). TAB was diagnostically useful in cases where USS was inconclusive. Conclusion This is the first published study describing application of GCAPS outside the specialist centre where it was developed. Performance of GCAPS as a risk stratification tool was excellent. GCAPS may have additional value for screening GCA FTP referrals and guiding empirical glucocorticoid treatment.