Challenges to Vaccination against SARS-CoV-2 in Patients with Immune-Mediated Diseases

Aberrant deployment of the immune response is a hallmark pathogenic feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19), possibly accounting for high morbidity and mortality, especially in patients with comorbidities, including immune-mediated disorders. Immunisation with SARS-COV-2 vaccines successfully instructs the immune system to limit viral spread into tissues, mitigate COVID-19 manifestations and prevent its most detrimental inflammatory complications in the general population. Patients with immune-mediated diseases have been excluded from vaccine registration trials, foreclosing the acquisition of specific efficacy and safety data. In this review, we aimed to summarise and critically discuss evidence from real-world studies addressing this issue to provide a comprehensive view of the impact of vaccination practices in patients with allergy, autoimmunity or immunodeficiency. We analysed clinical and laboratory data from 34 studies involving more than 13,000 subjects with various immune disorders who were vaccinated with mRNA- DNA- or inactivated viral particle-based vaccines. These data globally support the safe and effective use of SARS-CoV-2 vaccines in patients with immune-mediated diseases, although patient-tailored strategies to determine vaccination timing, vaccine choice and background therapy management are warranted to optimise vaccination outcomes. More data are needed regarding patients with primary immunodeficiencies.

Rilonacept: A Newly Approved Treatment for Recurrent Pericarditis

Objective To review the pharmacology, efficacy, and safety of rilonacept for the prevention and treatment of recurrent pericarditis (RP). Data Sources A MEDLINE search was conducted between January 2006 and April 2021 using the following terms: rilonacept, pharmacology, pericarditis, recurrent pericarditis, interleukin (IL) antagonist, and pharmacology; prescribing information was also used. Study Selection and Data Extraction English-language studies assessing pharmacology, efficacy, and safety of IL antagonists were reviewed. Data Synthesis Rilonacept traps IL-1α and IL-1β. In the Phase III trial, rilonacept was associated with a lower risk of recurrence, more persistent clinical response, and higher amount of days with no or minimal pericarditis symptoms, compared with placebo. The median time to pain response was 5 days, and median time to normalization of C-reactive protein was 7 days with rilonacept. All patients receiving rilonacept during the run-in period were able to be weaned off of standard background therapy, leading to transition to rilonacept monotherapy. The most common adverse effects were upper respiratory tract infections and injection site reactions. Relevance to Patient Care and Clinical Practice Rilonacept may be used for the prevention and treatment of multiple recurrences in patients receiving background therapy for RP, and reduction in risk of recurrence in adults and adolescents ≥12 years with elevated C-reactive protein. Rilonacept may be considered to wean patients from standard background therapy. Conclusion Rilonacept is a safe, once weekly, subcutaneously administered IL-1 “trap,” indicated for the treatment of RP, and reduction in risk of recurrent pericarditis in adults and children ≥12 years of age.

Case Report and Review of the Literature: Bullous Skin Eruption After the Booster-Dose of Influenza Vaccine in a Pediatric Patient With Polymorphic Maculopapular Cutaneous Mastocytosis

Vaccination is a well-known trigger for mast cell degranulation in subjects affected by mastocytosis. Nevertheless, there is no exact standardized protocol to prevent a possible reaction after a vaccine injection, especially for patients who have already presented a previous vaccine-related adverse event, considering that these patients frequently tolerate future vaccine doses. For this reason, we aim to share our experience at Meyer Children’s University Hospital in Florence to raise awareness on the potential risk for future vaccinations and to discuss the valuable therapeutic strategies intended to prevent them, taking into account what is proposed by experts in literature. We describe the case of an 18-month-old female affected by a polymorphic variant of maculopapular cutaneous mastocytosis that presented an extensive bullous cutaneous reaction 24 hours after the second dose (booster dose) of inactivated-tetravalent influenza vaccine, treated with a single dose of oral corticosteroid therapy with betamethasone (0.1 mg/kg) and an oral antihistamine therapy with oxatomide (1 mg/kg/daily) for a week, until resolution. To the best of our knowledge, in the literature, no documented case of reaction to influenza vaccine in maculopapular cutaneous mastocytosis is described. Subsequently, the patient started a background therapy with ketotifen daily (0.05 mg/kg twice daily), a non-competitive H1-antihistamine, and a mast cell stabilizer (dual activity). A non-standardized pharmacological premedication protocol with an H1-receptor antagonist (oxatomide, 0.5 mg/kg) administered 12 hours before the immunizations, and a single dose of betamethasone (0.05 mg/kg) together with another dose of oxatomide (0.5 mg/kg) administered 2 hours before the injections was followed to make it possible for the patient to continue with the scheduled vaccinations. Indeed, no reactions were subsequently reported. Thus, in our experience, a background therapy with ketotifen associated with a premedication protocol made by two doses of oxatomide and a single dose of betamethasone was helpful to make possible the execution of the other vaccines. We suggest how in these children, it could be considered the idea of taking precaution when vaccination is planned, regardless of the kind of vaccine and if a dose of the same vaccine was previously received. However, international consensus needs to be reached to manage vaccinations in children with mastocytosis and previous adverse reactions to vaccines.

Echohysterosalpingography: pros and cons. A systematic review

Background. Infertility is becoming ever more pressing a problem by year in Russia and worldwide. Tubal-peritoneal infertility is most frequent, with the prevalence of 42.5-80.5% in various estimates. Echohysterosalpingography is considered the today’s “gold standard” in tubal-peritoneal infertility diagnosis in women. This method is known to possess a series of limitations and adverse consequences due to painful sensations during and after check-ups that psychologically afflict women.Objectives. An overview of current methods for inspecting fallopian tubes in reproductively impaired patients to inform promising diagnostic research.Methods. Publications were mined and analysed in the PubMed, eLibrary, Web of Science, Cochrane Library and Cyberleninka electronic databases. The query terms were: echohysterosalpingography [эхогистеросальпингография], echohysterography [эхогистерография], infertility [бесплодие], pregnancy planning [планирование беременности], fallopian patency [проходимость маточных труб], ultrasonic diagnosis [ультразвуковая диагностика], submucous myomatous node [субмукозный миоматозный узел], incompetent uterine scar [несостоятельный рубец на матке], niche [ниша]. The topic selected was female infertility, particularly, the use of echohysterosalpingography in fallopian diagnosis in reproductively impaired women.Results. The review covers 52 sources of the total 118 analysed. Current published evidence and its review identify a notable success of imaging techniques in the fallopian tube diagnosis in women with reproductive problems. The continually developing echohysterosalpingography technique is considered more promising for routine use. Techniques gain more value in analyses of implantation failures. The main challenges in current radiodiagnosis and monitoring of fallopian lesions at a background therapy are the inspection standardisation, disease classification, imaging diagnostic accuracy and prognostic value evaluation in patients with reproductive loss and infertility.Conclusion. The prospective routes of research comprise the definition of optimal check-up terms, echohysterography and echohysterosalpingography diagnostic criteria descriptiveness, improving prognosis in the carrying of pregnancy and treatment efficacy control. A timely and accurate diagnosis of uterus and fallopian tubes is of paramount importance to sustain the women’s reproductive health.

Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials

The goal of clinical research is to improve clinical practice. In progressive neurodegenerative conditions without any disease-slowing therapies, this will result in eventual approval of a first disease-modifying treatment. Clinical trials will still be needed to discover treatments that are more effective, safer, or more convenient. This will generate controversies over how to design these trials, specifically, controversies about the use of a placebo control. We consider ethical guidance for these studies with attention to three designs: placebo-controlled trials in the absence of the new drug, placebo-controlled trials with the approved drug as background therapy, and trials with the new drug as an active-control. To understand the practical implications of these designs, we examine experiences in drug development in Multiple Sclerosis (MS). We conclude by contemplating the future of clinical trials in Alzheimer’s disease (AD).

Clinical Effectiveness and Safety of Gliclazide MR and Linagliptin Combination in the Management of Patients With T2DM and Chronic Kidney Disease (CKD) Switched From Glimepiride - a Real-World, Retrospective, Observational Study

Background: Type 2 diabetes (T2DM) patients are at high risk of developing to CKD and progressing to adverse outcomes vs Nondiabetics. The aim was to evaluate the effectiveness and safety of gliclazide MR switched from glimepiride in combination with linagliptin considering their associated potential benefits in albuminuria reduction and delaying progression of adverse renal outcomes in T2DM patients with kidney disease as shown in previous data. Methodology: The medical study database of the author’s hospital identified T2DM patients with stage 1–3 CKD with mean eGFR of 50.4 ± 8.56 ml/min/1.73 m2 and were inadequately controlled with glimepiride (mean dose 3.24mg) for the last 3 months. These patients were switched to gliclazide MR with appropriate equivalent dose while DPP-4 inhibitors like linagliptin (5 mg OD) (79%), sitagliptin (14%), vildagliptin (7%), were continued as background therapy. About 59.35% of subjects were on glimepiride 2 mg, 21.93% subjects on glimepiride 3 mg and 18.7% on glimepiride 4 mg. The gliclazide dose was up titrated by 30 mg every 15 days to achieve a target post-prandial glucose (PPG) ≤180 mg/dL. The average dose of gliclazide MR during the study was 44 mg; approximately two-thirds of patients 61% were on 60 mg, 22% on 90mg, and 7% on 30 mg. Patients were counselled to recognize the symptoms and record the hypoglycemic episodes. The statistical analysis included the analysis of changes in glycemic control, risk of hypoglycemia & renal function parameters. The patients were followed up for 24 weeks duration. Results: A total 218 eligible patients (110 female & 108 male) with CKD (stages 1–3) were included. The mean age, body weight, baseline HbA1c, FPG, PPG levels, mean eGFR, and UACR (urine albumin creatinine ratio) were 62.94 ± 8.72 years, 67.9 ± 9.33 kg, 8.51 ±0.81%, 148.53 ± 16.72, 202 ± 18.45 mg/dL, 50.49 ± 8.56 ml/min/1.73 m2 and 154.34 mg/g respectively. Gliclazide MR was initiated substituting glimepiride with appropriate dosing determined by the physician. Two subjects discontinued the therapy due to intolerability. At 24 weeks follow up, HbA1c, FPG, PPG level was reduced by -0.63, -10.33, -30.04%, respectively (p< 0.001). There was a significant reduction in events of overall hypoglycemia (22.25%). Improvement in renal function with respect to eGFR level (+1.77 ml/min/1.73 m2) and albuminuria reduction (-45.56 mg/g) were also observed in patients. Conclusion: This study demonstrates the clinical effectiveness and safety of gliclazide MR with the combination of DPP-4is like linagliptin as an alternate option to glimepiride in diabetes patients with chronic kidney disease.

Osteoarthritis background therapy: current view on the glucosamine and chondroitin therapy

The article highlights the current status of symptomatic slow-acting drugs (SYSADOA) in osteoarthritis (OA). Mechanism of action, clinical studies data on the effectiveness of glucosamine (GA) and chondroitin sulfate (CS) and their combinations in OA, their positive symptomatic and structural-modifying effects, are described. The article provides the latest recommendations for the OA treatment with these two drugs and presents an argument for the combination therapy with both drugs as a background therapy in the earliest stages of OA. It is indicated that such therapy should be long-term due to its high safety and possible reduction of cardiovascular accidents risk as well. It is noted that therapeutic doses of CS and GA are ≥1500 and ≥800 mg per day, respectively, and encapsulated forms of SYSADOAs have advantages due to their pharmacokinetic features.

Diagnosis and Management of Severe Asthma in Switzerland: Analysis of Survey Results Conducted with Specialists and General Practitioners

<b><i>Background:</i></b> Severe asthma commonly affects 5–10% of the asthmatic population and accounts for approximately 50% of the overall asthma costs. <b><i>Objective:</i></b> This analysis investigated how severe asthma is diagnosed, treated, and managed by specialists and general practitioners (GPs) in Switzerland. <b><i>Methods:</i></b> Two surveys, one each among specialists (<i>N</i> = 44) and GPs (<i>N</i> = 153), were conducted to understand their self-perception on diagnosis, treatment, and management of severe asthma. <b><i>Results:</i></b> Fifty-five percent of the specialists felt very confident and 43% confident in recognizing the symptoms of severe asthma and diagnosing severe asthma. In contrast, 9% of the GPs were very confident and 59% confident in diagnosing severe asthma. More specific diagnostic tests for severe asthma, like total and specific immunoglobulin E levels and measurement of the fraction of exhaled nitric oxide, were run by specialists (χ² = 171.4; df = 15, <i>p</i> &#x3c; 0.001). GPs and specialists were using different measurements to assess severe asthma (χ² = 385.2; df = 13, <i>p</i> &#x3c; 0.001) and their prescribing patterns differed significantly (χ² = 189.8; df = 10, <i>p</i> &#x3c; 0.001). GPs referred patients with severe asthma if the diagnosis was unclear (24%), if treatment failure occurred (26%), and if the patients were at high risk (41%). <b><i>Conclusions:</i></b> Oral corticosteroids (OCSs) are considered as background therapy for severe asthma by GPs and specialists. In order to reduce the OCS burden, there is a need to improve the awareness for other add-on therapies. A joint collaboration between GPs and specialists is the key to leverage therapeutic strategies together.