LncRNAs and Rheumatoid Arthritis: From Identifying Mechanisms to Clinical Investigation

Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix destruction caused by immune system abnormalities are the main features of RA. The use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) has achieved great advances in the therapy of RA. Yet there are still patients facing the problem of poor response to drug therapy or drug intolerance. Current therapy methods can only moderate RA progress, but cannot stop or reverse the damage it has caused. Recent studies have reported that there are a variety of long non-coding RNAs (LncRNAs) that have been implicated in mediating many aspects of RA. Understanding the mechanism of LncRNAs in RA is therefore critical for the development of new therapy strategies and prevention strategies. In this review, we systematically elucidate the biological roles and mechanisms of action of LncRNAs and their mechanisms of action in RA. Additionally, we also highlight the potential value of LncRNAs in the clinical diagnosis and therapy of RA.

Incidence and Clinical Management of Atrial Arrhythmias in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome characterized by adrenergically-triggered ventricular arrhythmias, syncope, and sudden cardiac death. Several small studies suggest that atrial arrhythmias (AAs) are common in patients with CPVT. Objective: To determine the incidence and type of AAs observed within a large, single-center cohort of CPVT cases as well as the efficacy and durability of AA-directed management. Methods: In this retrospective study, the electronic medical record of 129 patients (52% female; average age at diagnosis 20.8  15.3 years) with CPVT (95% with a putative CPVT1-causative RYR2 variant) between 01/2000 and 09/2019 were reviewed for electrocardiographic evidence of AAs. Clinical features and efficacy of pharmacologic and ablation therapy were assessed. Results: Overall, 10/129 (7.8%) CPVT patients, all RYR2 variant-positive, had evidence of an AA (atrial fibrillation/flutter in 6, atrial tachycardia in 3, and supraventricular tachycardia in 1). The median age at AA diagnosis was 23 (14.2-35.5) years. 8/10 of patients experienced symptoms attributed to their AA, including inappropriate shocks. All patients were trialed on anti-arrhythmics, including -blockers, and/or flecainide. Owing to drug failure (1/10), drug intolerance (1/10), or patient preference (2/10); 4/10 patients received an ablation. Over a median follow-up of 23.5 (4.5-63) months, no AA recurrences were observed. Conclusion: Compared to prior studies, the incidence of AAs in this large, single-center referral cohort of CPVT patients was substantially lower (7.8% vs. 26%-35%). Although larger multi-center studies are needed to confirm, this study suggests that ablation is efficacious and durable in CPVT-associated AAs.

Drug Intolerance: Age Related Aspects

Aim: Identification of age-specific drug intolerance. Materials and methods: The study was conducted over the period from 2017 to 2020 and included 200 outpatient medical history forms of people diagnosed as having an unspecified pathological reaction to a drug or medication. All drug reactions are reported by patients own statements and were allocated to dichotomous variables. The results were analyzed by nonparametric statistics. Results: Three groups of patients: 18-44 years (n=49); 45-60 years (n=60); 61 and over (n=91). The odds of incomprehensible reactions were 2.2 times higher in patients in group 3 than in patients in the other groups. Group 3 patients were 12 times more likely to have an itchy reaction to medications than patients in the other groups. Group 1 patients were 3 times more likely to have urticaria than patients in groups 2 and 3. The odds of drug intolerance to ACE inhibitors were 2.6 times higher in group 3 patients than in patients in other groups. When comparing clinical manifestations of drug intolerance to penicillin- and cephalosporin-type antibiotics, no significant differences were found in all patients. The presence of allergies and somatic pathology of 3 or more systems did not significantly affect the possibility of reactions of varying severity to 3 or more drugs in these groups. Conclusions: Patients age has no effect on the possibility of reactions to certain groups of drugs. The exception was ACE inhibitors, which is most likely due to the higher frequency of prescribing antihypertensive therapy in patients in this age group. The aggravation of clinical manifestations and the occurrence of polypharmacy are not associated with age and comorbid background. It should be noted that correlation between age and non-life-threatening clinical manifestations of drug intolerance was revealed, which indicates the absence of reliable effect of age on the possibility of anaphylactic shock or angioedema.

Update on the Management of Uveitic Macular Edema

Uveitic macular edema (ME) is a frequent complication in 8.3% of uveitis patients and is a leading cause of serious visual impairment in about 40% of cases. Despite the numerous available drugs for its treatment, at least a third of patients fail to achieve satisfactory improvement in visual acuity. First-line drugs are steroids administered by various routes, but drug intolerance or ineffectiveness occur frequently, requiring the addition of other groups of therapeutic drugs. Immunomodulatory and biological drugs can have positive effects on inflammation and often on the accompanying ME, but most uveitic randomized clinical trials to date have not aimed to reduce ME; hence, there is no clear scientific evidence of their effectiveness in this regard. Before starting therapy to reduce general or local immunity, infectious causes of inflammation should be ruled out. This paper discusses local and systemic drugs, including steroids, biological drugs, immunomodulators, VEGF inhibitors, and anti-infection medication.

Acute Q fever in third trimester pregnancy

A 29-year-old gravida 2 para 1 woman presented at 29 weeks gestation with fevers, back pain, thrombocytopenia and hepatitis. PCR testing of blood samples detected Coxiella burnetii and paired serology later confirmed the diagnosis of acute Q fever in pregnancy. The patient was treated empirically with oral clarithromycin and experienced a symptomatic and biochemical improvement. Therapy was changed to oral trimethoprim/sulphamethoxazole but was complicated by a delayed cutaneous reaction, prompting recommencement of clarithromycin. Therapy continued until delivery of a healthy girl at 39 weeks and 3 days. Q fever in pregnancy is likely under-reported and is associated with the development of chronic infection and obstetric complications. Treatment with clarithromycin is an alternative to trimethoprim/sulphamethoxazole in the setting of drug intolerance.

Validation of a Brief Screening Instrument for Chemical Intolerance in a large U.S. National Sample

Keywords: Chemical Intolerance, Drug Intolerance, Food Intolerance, QEESI, BREESI, Multiple Chemical Sensitivity, Toxicant-induced Loss of Tolerance, Prevalence

High SVR12 With 8-Week Course of Direct-Acting Antivirals in Adolescents and Children With Chronic Hepatitis C: A Comprehensive Analysis

Direct-acting antiviral (DAA) treatment for 8 weeks has a sustained virological response rate in adults with chronic hepatitis C. We have conducted a systematic review and meta-analysis to compare the efficacy and safety of the 8-week vs. 12/24-week DAA treatment in adolescents and children with CHC. The PubMed, Web of Science, and Cochrane databases were searched for the relevant articles from January 1, 2017 to August 28, 2020 and further screened for literature reviews on April 1, 2021. Pool proportions with 95% CIs for SVR12 were summarized with fixed/random effects models using Freeman–Tukey double arcsine transformation. Subgroup analysis was used to explore the source of heterogeneity. Thirty-six relevant publications were identified. For adolescents aged 12–17 years old, the pooled SVR12 and AE rate were 99.4% (95% CI: 98.7–99.9) and 34.7% (95% CI: 31.9–37.6). No one discontinued treatment due to drug intolerance. In addition, the SVR12 adolescents treated for 12 and 8/24 weeks were 99.3% (95% CI: 98.4–99.9) and 100%, respectively. The pooled SVR12 rate, AEs, and SAEs for children younger than 12 years were 98.9% (95% CI: 97.3–99.8), 51.6% (95% CI: 47.0–56.2), and 1.1% (95% CI: 0.4–2.5), respectively. The most common AE was fatigue (28.4%). The SVR12 was 98.8% (95% CI: 97.1–99.8) and 100% for the pediatric patients treated for 12 weeks and 8/24 weeks, respectively. Taken together, DAAs are generally effective against CHC and well-tolerated by the adolescents and children. A treatment duration of 8 weeks is equally effective and safe as 12/24 weeks in this demographic group.

Fibroblast growth factor receptor (FGFR) inhibitor rogaratinib in patients with advanced pretreated squamous-cell non-small cell lung cancer over-expressing FGFR mRNA: The SAKK 19/18 phase II study.

e21119 Background: A substantial proportion of patients with squamous lung cell carcinoma (SQCLC) (46%) exhibit tumor overexpression of fibroblast growth factor receptor (FGFR) messenger ribonucleic acid (mRNA). Rogaratinib is a novel pan-FGFR inhibitor with anti-tumor activity in pre-clinical models as a single agent in FGFR pathway-addicted tumor models. Phase I data showed promising activity and good safety profile. The objective of the SAKK 19-18 trial was to determine clinical activity and safety of rogaratinib in patients with advanced SQCLC overexpressing tumor FGFR1-3 mRNA. Methods: Patients with metastatic SQCLC, previously treated with systemic treatment, overexpressing tumour FGFR mRNA were treated with rogaratinib 600 mg BID until progression of disease or drug intolerance. A rate ≤15% of PFS at 6 months was considered uninteresting, whereas a PFS rate at 6 months ≥38% was considered promising. Ten patients were needed in the first stage with at least 2 achieving 6 months PFS in order to continue the accrual. Results: Between May and November 2020, 49 patients were screened and 20 were classified FGFR positive. Among them15 patients were registered in the trial and the first 10 were assessed for the first stage analysis. Most commons treatment related adverse events (TRAEs) were hyperphosphatemia (60%), diarrhoea (20%), and dry mouth (20%). Grade ≥3 TRAEs occurred in 50% of the patents with Hypercalcemia being the most frequent one (20%). Among 10 first patients only 1 achieved 6 months PFS while 2 was the boundary required for continuing this trial. Conclusions: Despite preliminary signal of activity, rogaratinib failed to improve PFS in patients overexpressing tumor FGFR mRNA. Further studies on a more reliable biomarker are needed, the development of rogaratinib in SQCLC has been put on hold by Bayer and the SAKK 19/18 study was terminated early due to lack of efficacy. Clinical trial information: NCT03762122.

Real-world experience of using ciclosporin-A 0.1% (Ikervis) in the management of ocular surface inflammatory diseases

PurposeTo report the real-world experience of using topical ciclosporin, Ikervis, in the management of ocular surface inflammatory diseases (OSIDs).MethodsThis was a retrospective study of patients treated with Ikervis for OSIDs at the Queen’s Medical Centre, Nottingham, between 2016 and 2019. Relevant data, including demographics, indications, clinical parameters, outcomes and adverse events, were collected and analysed for patients who had completed at least 6 months follow-up. For analytic purpose, clinical outcome was categorised as ‘successful’ (resolved or stable disease), ‘active disease’ and ‘drug intolerance’.Results463 patients were included; mean age was 51.1±21.6 years, with a 59.0% female predominance. Mean follow-up was 14.6±9.2 months. The most common diagnosis was dry eye disease (DED; 322, 69.5%), followed by allergic eye disease (AED; 53, 11.4%) and ocular mucous membrane pemphigoid/Steven-Johnson syndrome (OMMP/SJS; 38, 8.2%). Successful treatment was achieved in 343 (74.1%) patients, with 44 (9.5%) requiring additional treatment and 76 (16.4%) reporting drug intolerance. The efficacy of Ikervis was highest in DED (264, 82.0%), followed by OMMP/SJS (25, 65.8%) and post-keratoplasty (7, 50.0%; p<0.001). Logistic regression analysis demonstrated age <70 years (p=0.007), AED (p=0.002) and OMMP/SJS (p=0.001) as significant predictive factors for Ikervis intolerance. AED and post-keratoplasty were 8.16 times (95% CI, 2.78 to 23.99) and 13.98 times (95% CI, 4.22 to 46.28), respectively, more likely to require additional treatment compared with DED.ConclusionsIkervis is a useful steroid-sparing topical treatment for managing OSIDs in the real-world setting. Preparations with improved tolerability are needed to benefit a larger number of patients.