Steroid treatment suppresses the CD4+ T-cell response to the third dose of mRNA COVID-19 vaccine in systemic autoimmune rheumatic disease patients.

Prolonged steroid treatment has a suppressive effect on the immune system, however, its effect on the cellular response to mRNA vaccine is unknown. Here we assessed the impact of prolonged steroid treatment on the T-cell and humoral response to the SARS-CoV-2 spike (S) peptide following the third dose of the BNT162b2 vaccine in systemic autoimmune rheumatic disease patients. We found that CD4 T-cell response to the S peptide in patients on high-dose long-term steroid treatment showed significantly less S-peptide specific response, compare to low-dose or untreated patients. Remarkably, these results were not reflected in their humoral response, since almost all patients in the cohort had sufficient antibody levels. Moreover, S-peptide activation failed to induce significant mRNA levels of IFNγ and TNFα in patients receiving high-dose steroids. RNA-sequencing datasets analysis implies that steroid treatments' inhibitory effect of nuclear factor kappa-B signaling may interfere with the activation of S-specific CD4 T-cells. This reveals that high-dose steroid treatment inhibits T-cell response to the mRNA vaccine, despite having sufficient antibody levels. Since T-cell immunity is a crucial factor in the immune response to viruses, our findings highlight the need for enhancing the efficiency of vaccines in immune-suppressive patients, by modulation of the T-cell response.

Immunogenicity and safety of the mRNA-based BNT162b2 vaccine in systemic autoimmune rheumatic diseases patients.

BACKGROUND: The COVID-19 outbreak has led to the rapid development and administration of the COVID-19 vaccines worldwide. Data about the immunogenicity and adverse effects of the vaccine on patients with systemic autoimmune rheumatic diseases (SARDs) is emerging. AIM: To evaluate Pfizer/BioNTech (BNT162b2) mRNA-based vaccine second-dose immunogenicity and safety, and the relation between them, in patients with SARDs. METHODS: A total of one hundred forty tow adults who received two doses of the BNT162b2 vaccine were included in the study. The SARDs group included Ninety-nine patients and the control group (forty-three participants) comprised a mixture of healthy participants and patients who were seen at the rheumatology clinic for non-SARDs. Anti-SARS-CoV-2 IgG antibodies against the Spike protein were evaluated using a SARS-CoV-2 IgG immunoassay. A level of > 150 AU/mL was considered positive. An adverse effects questionnaire was given to the participants upon their first visit to the clinic after their BNT162b2 vaccination. RESULTS: Of the 142 participants, 116 were seropositive (81.7%) and 26 (18.3%) were seronegative. Of the seronegative participants, 96.2% were SARDs patients. The proportion of seropositivity in the SARDs patients treated with any immunosuppressant was significantly lower (69.9%) compared to the control group and SARDs patients not receiving immunosuppressants (96.8%). A significant negative correlation between seronegativity and treatment with rituximab, mycophenolate mofetil (MMF), and prednisone was found in the SARDs group (p = 0.004, 0.044, 0.007 respectively). No fever was observed following the BNT162b2 vaccine in seronegative patients, and the frequency of musculoskeletal adverse effects upon the second dose of the BNT162b2 vaccine was significantly higher in seropositive compared to seronegative patients and in the control group compared to the SARDs patients (p = 0.045, p = 0.02 respectively). CONCLUSION: A decline in the immunogenicity to the second dose of BNT162b2 mRNA is seen in patients with SARDs, especially in patients treated with rituximab, MMF, and prednisone. Adverse effects of the vaccine including fever and musculoskeletal symptoms might be a signal for the acquisition of immunity in those patients. KEY POINTS: • BNT162b2 mRNA vaccine is less immunogenic in SARDs patients compared to the control group. • Rituximab, prednisone, and mycophenolate mofetil significantly reduced immunogenicity to the vaccine. • There is a correlation between immunogenicity and adverse effects of the vaccine.

A Study of the Efficacy and Safety of Subcutaneous Injections of Tocilizumab in Adults with Rheumatoid Arthritis.

BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.

CHA2DS2-VASc score and clinical outcomes of patients with acute coronary syndrome.

BACKGROUND: The CHA2DS2-VASc score has been recommended for the assessment of thromboembolic risk in patients with atrial fibrillation. HYPOTHESIS: The CHA2DS2-VASc score may be associated with adverse outcomes in patients with ACS. METHODS: Included were patients with ACS enrolled in the Acute Coronary Syndrome Israeli biennial Surveys (ACSIS) during 2000-2013. Patients were divided into 4 groups according to their CHA2DS2-VASc score (0 or 1, 2 or 3, 4 or 5, and >5). The primary endpoint was 1-year all-cause mortality. RESULTS: The 13,422 patients had a mean age of 63.5±13years and included 25.8% females. Higher CHA2DS2-VASc score was associated with a significant increase in 1-year mortality. Patients with a CHA2DS2-VASc score >5 had the highest 1-year mortality risk that was 6-fold higher compared to patients with a score of 0 to 1 (hazard ratio=6, 95% CI=4.1-8.8, p<0.0001). However, even an intermediate CHA2DS2-VASc score of 2-3 was associated with a significant 2.6-fold increase in 1-year mortality. Patients with a higher CHA2DS2-VASc score were less frequently selected for an invasive strategy with an early coronary angiogram and subsequent angioplasty and were less commonly treated with the guideline-based medications. However, differences in outcomes remained significant following a multivariate analysis suggesting that these variations in therapy can only partially explain the differences in outcomes. CONCLUSIONS: Higher CHA2DS2-VASc score identifies high-risk patients that may be overlooked by existing scores. Further studies are needed in order to evaluate whether the CHA2DS2-VASc score may be used together with the GRACE score for an improved risk assessment of ACS patients.

Chronic urticaria and autoimmunity: associations found in a large population study.

BACKGROUND: Chronic urticaria (CU) is a common disease in which most cases were considered to be idiopathic. Recent evidence indicates that at least a subset of cases of chronic idiopathic urticaria are autoimmune in origin. OBJECTIVE: We aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inflammatory serologic markers in a large unselected population. METHODS: Data on 12,778 patients given a diagnosis of CU by either allergy or dermatology specialists during 17 years in a large health maintenance organization in Israel were collected. For each patient, we collected information on diagnosis of major, well-defined autoimmune diseases and autoimmunity- and inflammatory-related serologic markers. Similar data were collected for a control group comprised of 10,714 patients who visited dermatologists, family physicians, or allergy specialists and had no indication of CU. RESULTS: Having CU was associated with an increased odds ratio for hypothyroidism, hyperthyroidism, and antithyroid antibodies. Female patients with CU had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus, mostly diagnosed during the 10 years after the diagnosis of CU. High mean platelet volume, positive rheumatoid factor, and antinuclear antibodies were all significantly more prevalent in patients with CU. CONCLUSIONS: A strong association was found between CU and major autoimmune diseases. A common pathogenic mechanism is implied by the high prevalence of autoantibodies and the existence of a chronic inflammatory process expressed by the high mean platelet volume. These findings have implications for the diagnosis, management, and prognosis of patients with CU.

[Does the transition to clinical training change students' perception of career choice, physician's character and preclinical studies?].

BACKGROUND: In Israel, the transition to clinical training in hospitals is the first direct encounter of the medical student with the reality of the profession. This is a significant socialization step for his upcoming professional decisions. AIMS: This study aimed to identify how this encounter influences students' perceptions of career choice, physician's character and preclinical studies. METHODS: Fourth year Israeli medical students at the Tel Aviv University voluntarily completed a questionnaire before and after their first clinical clerkship. The questionnaire was comprised of 30 5-point Likert scale statements and 3 multiple choice questions with the possibility to add remarks. RESULTS: The random response rate was 90% (81/90) before the clerkship and 82% (90/110) at its end. Results indicate that the students are satisfied with their medical studies at both junctures. However, after the clerkship, 23% of the students consider alternatives to clinical medicine compared with only 6% before, and 16% would rethink studying medicine. Physicians are perceived as professional, compassionate, respectful to colleagues and actively participating in students' education. Physicians' levels of workload and bitterness are evaluated as high and moderate, respectively, while their levels of reward and satisfaction with medicine are evaluated as low and moderate, respectively. Their evaluation of the contribution of preclinical studies as preparation for clinical studies had not changed after the clerkship and was moderate, and earlier exposure to patients and clinical relevancy of the learned subjects were preferred. SUMMARY AND DISCUSSION: The students enter the medical world highly satisfied, and this feeling shall be maintained until the stage of being independent physicians and choosing their specialties. The picture that evolved, in which a high proportion of the students consider alternatives to clinical medicine, is disappointing. Educators should be aware of their role model function not only in knowledge and skills, but also in behavior and communication with patients. The students pointed to necessary changes in the medical curriculum to make basic sciences more relevant to clinical medicine. A broader study at different stages of studies in the rest of the medical faculties in Israel may be needed.

Prevalence and risk factors of atherosclerosis in patients with psoriatic arthritis.

OBJECTIVES: To evaluate the extent of subclinical atherosclerosis by measuring the intima-media wall thickness (IMT) of the common carotid artery in patients with psoriatic arthritis (PsA) and to identify vascular risk factors associated with PsA. METHODS: Forty-seven patients with PsA were compared with 100 allegedly healthy subjects. Carotid duplex scanning was used to measure common carotid artery IMT. Traditional risk factors, such as gender, age, body mass index (BMI), hypertension, smoking, and lipids were checked. Assessment of PsA activity included clinical patterns of involvement, degree of severity, duration of morning stiffness, number of tender and swollen joints, degree of pain and fatigue, the Bath Ankylosing Spondylitis Disease Activity Index, the Psoriasis Area and Severity Index, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fibrinogen. RESULTS: The average IMT (mean +/- standard deviation) for PsA patients was significantly higher compared with controls (0.76 +/- 0.11 versus 0.64 +/- 0.27, respectively, P < 0.00001) for the whole group and after adjustment for age, gender, BMI, hypertension, and hyperlipidemia. The PsA subjects had significantly higher levels of hypertension, hyperlipidemia, ESR, CRP, and fibrinogen, and their average IMT significantly correlated with age, BMI, duration of skin and joint disease, spine involvement, ESR, and fibrinogen. IMT did not correlate with the presence of oligo- or polyarthritis but was increased in patients with clinical spinal involvement. IMT was not associated with the degree of severity or the use of different therapies for PsA, including methotrexate or tumor necrosis factor-alpha-blocking agents. CONCLUSIONS: PsA patients exhibited greater IMT than healthy controls. Increased IMT independently correlated with parameters of disease activity and conventional risk factors of atherosclerosis.

The effect of fermented yogurt on the prevention of diarrhea in a healthy adult population.

BACKGROUND: Probiotic dairy products are increasingly gaining popularity. Although the role of probiotic bacteria in the prevention and treatment of pediatric and antibiotic associated diarrhea is fairly well established, their role in the prevention of adult infectious diarrhea has not been well investigated. METHODS: Five hundred forty-one, young male military recruits were enrolled and randomly assigned to receive a yogurt containing Lactobacillus casei (n = 275) or a nonprobiotic yogurt (n = 266). The incidence and duration of diarrhea were documented and stool samples examined for bacteria and parasites. RESULTS: Five hundred and two participants were eligible for final analysis, 254 receiving probiotic yogurt and 248 in the control group. Seventy-one participants (14.14%) experienced diarrhea during the study period. The incidence of diarrhea in the probiotic group and the control group was 12.2% and 16.1%, respectively (P = .207). The mean duration of diarrhea was 3 +/- 1.95 days in the probiotic group and 2.6 +/- 1.08 days in the control group (P = .276). CONCLUSION: Our study demonstrated a nonsignificant trend for reduction of the incidence of diarrhea among healthy young adults consuming yogurt containing Lactobacillus casei . Further study is needed to evaluate the role of probiotics in adults.