BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major public health issues. Although the primary and secondary prevention of RHD through appropriate management of bacterial pharyngitis and ARF are well-described in the literature, few studies address the knowledge, attitude, and practice (KAP) of developing countries. We aimed to evaluate the KAP of the frontline physicians in Egyptian university hospitals regarding pharyngitis and ARF.
METHODS: We employed a cross-sectional design between September 1st, 2022, and January 31st, 2023 using a self-administered questionnaire in 21 Egyptian universities. The questionnaire was developed based on previous studies and recent guidelines and included four domains: sociodemographic data, knowledge, attitude, and practice regarding pharyngitis and ARF. We utilized both online (Google Forms) and paper surveys. Frontline physicians, including interns, residents, and assistant lecturers, were conveniently invited to participate. Furthermore, with the help of participating phycisians in recruiting their colleagues, we utilized the snowball method. Data were analyzed using IBM SPSS version 27 software.
RESULTS: The final analysis included 629 participants, of whom 372 (59.1%) were males and 257 (40.9%) had direct contact with ARF patients. Most participants (61.5%) had a fair knowledge level while 69.5% had a fair level of practice regarding ARF and pharyngitis. Higher satisfactory knowledge levels were noted regarding pharyngitis (17.1% vs. 11.3%; p-value: 0.036) and ARF (26.8% vs. 18%; p-value: 0.008) among physicians dealing directly with ARF cases compared to physicians in departments not dealing directly with ARF cases. Physicians in Cairo region universities had significantly higher levels of satisfactory knowledge about ARF compared to Delta and Upper Egypt region universities (p = 0.014). Delta region universities showed significantly lower levels of practice compared to Cairo and Upper Egypt region universities (p = 0.027). The most frequently recognized barriers against health promotion were low socioeconomic status (90.3%) and lack of adequate public education (85.8%).
CONCLUSIONS: Despite the fair knowledge and practice levels towards bacterial pharyngitis and ARF among participants, many gaps were still identified that might contribute to RHD prevalence. Educational interventions should be implemented by updating the local guidelines in Egypt for diagnosis and management based on the most recent guidelines.

BACKGROUND: Four-weekly intramuscular (IM) benzathine penicillin G (BPG) injections to prevent acute rheumatic fever (ARF) progression have remained unchanged since 1955. A Phase-I trial in healthy volunteers demonstrated the safety and tolerability of high-dose subcutaneous infusions of BPG which resulted in a much longer effective penicillin exposure, and fewer injections. Here we describe the experiences of young people living with ARF participating in a Phase-II trial of SubCutaneous Injections of BPG (SCIP).
METHODS: Participants (n = 20) attended a clinic in Wellington, New Zealand (NZ). After a physical examination, participants received 2% lignocaine followed by 13.8mL to 20.7mL of BPG (Bicillin-LA®; determined by weight), into the abdominal subcutaneous tissue. A Kaupapa Māori consistent methodology was used to explore experiences of SCIP, through semi-structured interviews and observations taken during/after the injection, and on days 28 and 70. All interviews were recorded, transcribed verbatim, and thematically analysed.
RESULTS: Low levels of pain were reported on needle insertion, during and following the injection. Some participants experienced discomfort and bruising on days one and two post dose; however, the pain was reported to be less severe than their usual IM BPG. Participants were \'relieved\' to only need injections quarterly and the majority (95%) reported a preference for SCIP over IM BPG.
CONCLUSIONS: Participants preferred SCIP over their usual regimen, reporting less pain and a preference for the longer time gap between treatments. Recommending SCIP as standard of care for most patients needing long-term prophylaxis has the potential to transform secondary prophylaxis of ARF/RHD in NZ and globally.

Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited. The objective was to explore the antibody response including response to omicron virus subvariants (sBA.1 and sBS.2) after third and fourth COVID-19 vaccine doses in Swedish IRD patients treated with immunomodulating drugs compared to controls. Antibody levels to spike wild-type antigens (full-length protein and S1) and the omicron variants sBA.1 and sBA.2 (full-length proteins) were measured. A positive response was defined as having antibody levels over cut-off or ≥fourfold increase in post-vaccination levels for both antigens. Patients with arthritis, vasculitis, and other autoimmune diseases (n = 414), and controls (n = 61) receiving biologic/targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) with or without conventional synthetic DMARDs participated. Of these, blood samples were available for 370 patients and 52 controls after three doses, and 65 patients and 15 controls after four doses. Treatment groups after three vaccine doses were rituximab (n = 133), abatacept (n = 22), IL6r inhibitors (n = 71), JAnus Kinase inhibitors (JAK-inhibitors) (n = 56), tumor necrosis factor inhibitor (TNF-inhibitors) (n = 61), IL12/23/17 inhibitors (n = 27), and controls (n = 52). The percentage of responders after three and four vaccine doses was lower in rituximab-treated patients (59% and 57%) compared to controls (100%) (P < 0.001). After three doses, the percentage of responders in all other groups was 100%, including response to omicron sBA.1 and sBA.2. In rituximab-treated patients, higher baseline immunoglobulin G (IgG) and longer time-period between rituximab and vaccination predicted better response. In this Swedish nationwide study including IRD patients three and four COVID-19 vaccine doses were immunogenic in patients treated with IL6r inhibitors, TNF-inhibitors, JAK-inhibitors, and IL12/23/17-inhibitors but not in rituximab. As >50% of rituximab patients responded to vaccines including omicron subvariants, these patients should be prioritized for additional vaccine doses.
OBJECTIVE: Results from this study provide further evidence that additional doses of COVID-19 vaccines are immunogenic and result in satisfactory antibody response in a majority of patients with inflammatory rheumatic diseases (IRD) receiving potent immunomodulating treatments such as biological or targeted disease-modifying anti-rheumatic drugs (DMARDs) given as monotherapy or combined with traditional DMARDs. We observed that rituximab treatment, both as monotherapy and combined with csDMARDs, impaired antibody response, and only roughly 50% of patients developed a satisfactory antibody response including response to omicron subvariants after the third vaccine. In addition, higher IgG levels at the last rituximab course before the third vaccine dose and a longer time after the last rituximab treatment increased the chance of a satisfactory antibody response. These results indicate that rituximab-treated patients should be prioritized for additional vaccine doses.
RESULTS: EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with number 2021-000880-63.

Recent studies have demonstrated an increased incidence of ischemic stroke among patients with certain autoimmune inflammatory rheumatic diseases (AIIRDs). However, the associations between young stroke and AIIRDs have not been fully investigated. This study aimed to evaluate the risk of ischemic stroke among young patients with AIIRDs.
The National Health Insurance Research Database in Taiwan was utilized to establish cohorts of patients with AIIRDs diagnosed between 2004 and 2015, who were compared with 1,000,000 control participants. Cox proportional hazards regression models were used to calculate the hazard ratio of ischemic stroke and young ischemic stroke for individual AIIRDs after adjustment for relative risk factors.
During the study period, a total of 64,120 patients with AIIRDss and 1,000,000 control patients were identified. The overall mean follow-up time was 5.33 years. There were 223 (0.8%) and 1,923 (0.3%) young ischemic stroke-related hospitalizations among patients with AIIRDs and controls, respectively. The incidence rate of young ischemic stroke was 0.08 in patients with rheumatoid arthritis, 0.08 in patients with Sjögren\'s syndrome, 0.26 in patients with systemic lupus erythematosus, 0.17 in patients with idiopathic inflammatory myositis, 0.24 in patients with systemic sclerosis, 0.05 in patients with Behçet\'s disease, and 0.44 in patients with systemic vasculitis, versus 0.05 per 100 person-years in the general population. The adjusted hazard ratios for young ischemic stroke were 1.07 (95% CI 0.70-1.43) for rheumatoid arthritis, 1.39 (95% CI 0.94-2.06) for Sjögren\'s syndrome, 5.79 (95% CI 4.68-7.17) for systemic lupus erythematosus, 2.07 for idiopathic inflammatory myositis (95% CI 0.98-4.38), 2.79 for systemic sclerosis (95% CI 1.38-5.63), 0.82 for Behçet\'s disease (95% CI 0.26-2.55), and 4.15 (95% CI 1.96-8.82) for systemic vasculitis.
Patients younger than 50 years with systemic lupus erythematosus, systemic sclerosis, or systemic vasculitis have a significantly elevated risk of developing ischemic stroke. Further research is needed to elucidate the pathogenesis of accelerated atherosclerosis in these AIIRDs.

BACKGROUND: Rheumatic heart disease is the largest contributor to cardiac-related mortality in children worldwide. Outcomes in endemic settings after its antecedent illness, acute rheumatic fever, are not well understood. We aimed to describe 3-5 year mortality, acute rheumatic fever recurrence, changes in carditis, and correlates of mortality after acute rheumatic fever.
METHODS: We conducted a prospective cohort study of Ugandan patients aged 4-23 years who were diagnosed with definite acute rheumatic fever using the modified 2015 Jones criteria from July 1, 2017, to March 31, 2020, enrolled at three rheumatic heart disease registry sites in Uganda (in Mbarara, Mulago, or Lira), and followed up for at least 1 year after diagnosis. Patients with congenital heart disease were excluded. Patients underwent annual review, most recently in August, 2022. We calculated rates of mortality and acute rheumatic fever recurrence, tabulated changes in carditis, performed Kaplan-Meier survival analyses, and used Cox regression models to identify correlates of mortality.
RESULTS: Data were collected between Sept 1 and Sept 30, 2022. Of 182 patients diagnosed with definite acute rheumatic fever, 156 patients were included in the analysis. Of these 156 patients (77 [49%] male and 79 (51%) female; data on ethnicity not collected), 25 (16%) died, 21 (13%) had a cardiac-related death, and 17 (11%) had recurrent acute rheumatic fever over a median of 4·3 (IQR 3·0-4·8) years. 16 (24%) of the 25 deaths occurred within 1 year. Among 131 (84%) of 156 survivors, one had carditis progression by echo. Moderate-to-severe carditis (hazard ratio 12·7 [95% CI 3·9-40·9]) and prolonged PR interval (hazard ratio 4·4 [95% CI 1·7-11·2]) at acute rheumatic fever diagnosis were associated with increased cardiac-related mortality.
CONCLUSIONS: These are the first contemporary data from sub-Saharan Africa on medium-term acute rheumatic fever outcomes. Mortality rates exceeded those reported elsewhere. Most decedents already had chronic carditis at initial acute rheumatic fever diagnosis, suggesting previous undiagnosed episodes that had already compounded into rheumatic heart disease. Our data highlight the large burden of undetected acute rheumatic fever in these settings and the need for improved awareness of and diagnostics for acute rheumatic fever to allow earlier detection.
BACKGROUND: Strauss Award at Cincinnati Children\'s Hospital, American Heart Association, and Wellcome Trust.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.

To investigate the association between chronic inflammatory rheumatic diseases (CIRD) and drug use disorder (DUD). Individuals aged ≥ 30 years in 2009 that met the following conditions were included: residing in the Skåne region, Sweden, with at least one healthcare contact in person and no history of DUD (ICD-10 codes F11-F16, F18-F19) during 1998-2009 (N = 649,891). CIRD was defined as the presence of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), or systemic lupus erythematosus. Treating CIRD as a time-varying exposure, we followed people from January 1, 2010 until a diagnosis of DUD, death, relocation outside the region, or December 31, 2019, whichever occurred first. We used flexible parametric survival models adjusted for attained age, sociodemographic characteristics, and coexisting conditions for data analysis. There were 64 (95% CI 62-66) and 104 (88-123) incident DUD per 100,000 person-years among those without and with CIRD, respectively. CIRD was associated with an increased risk of DUD in age-adjusted analysis (hazard ratio [HR] 1.77, 95% CI 1.49-2.09). Almost identical HR (1.71, 95% CI 1.45-2.03) was estimated after adjustment for sociodemographic characteristics, and it slightly attenuated when coexisting conditions were additionally accounted for (1.47, 95% CI 1.24-1.74). Fully adjusted HRs were 1.49 (1.21-1.85) for RA, 2.00 (1.38-2.90) for AS, and 1.58 (1.16-2.16) for PsA. More stringent definitions of CIRD didn\'t alter our findings. CIRD was associated with an increased risk of DUD independent of sociodemographic factors and coexisting conditions. Key Points • A register-based cohort study including 649,891 individuals aged≥30 residing in the Skåne region, Sweden, was conducted. • Chronic inflammatory rheumatic diseases were associated with higher risks of drug use disorder independent of sociodemographic factors and coexisting conditions.

Familial Mediterranean Fever (FMF) is the most frequent monogenic autoinflammatory disease (AID). Some patients have persistent symptoms despite colchicine intake. Mast cells (MC) are innate immune cells involved in inflammatory conditions including AID. Their activation is responsible for various symptoms such as abdominal pain, bloating and pruritus.
Our objective was to evaluate features of a systemic MC activation in FMF adult patients.
FMF adult patients prospectively filled a MC activation survey and usual MC mediators (tryptase and histamine in whole blood, plasma and urine) were measured. They were compared with a healthy control group (HC) and a systemic mastocytosis (SM) group. When digestive biopsies were realized during follow-up, MC infiltration in digestive mucosa was analyzed in FMF, in comparison with SM, Crohn disease (CD) and normal biopsies.
Forty-four FMF patients, 44 HC and 44 SM patients were included. Thirty-one (70%) FMF patients had symptoms of mast cell activation, versus 14 (32%) in the HC group (p = 0.0006). Thirty (68%) FMF patients had at least one elevated MC mediator: mainly whole blood histamine, in 19 (43%) and urinary histamine, in 14 (32%), which were significantly higher than in HC subjects. MC infiltration was comparable in FMF digestive biopsies, biopsies of CD and normal biopsies but was lower than in SM biopsies.
FMF patients show frequent symptoms of MC activation and an increase of blood or urinary histamine never described before in this disease. This suggests an implication of MC and possibly basophils in FMF pathophysiology.

OBJECTIVE: To assess knowledge and practices associated with rheumatic fever among medical practitioners in an urban setting.
METHODS: The cross-sectional study was conducted at five major hospitals in Karachi from August to November 2019, and comprised house officers, postgraduate trainees, and general physicians of either gender. The subjects were given a questionnaire assessing their knowledge and perception regarding acute rheumatic fever as well as prophylaxis. Data was analysed using SPSS 25.
RESULTS: Of the 247 respondents, 173(70%) were house officers, 31(13%) were postgraduate trainees and 43(17%) were general physicians. Overall, 202(82%) subjects were associated with some teaching hospital. Significantly more postgraduate trainees and general physicians answered correctly when asked to identify clinical and laboratory findings suggestive of Group A streptococcal throat infection than house officers (p<0.001). Among the house officers 49(28.3%), and among the postgraduate trainees 11(35.4%) knew the correct way to prescribe penicillin to prevent rheumatic fever. Among the general physicians, 20(46.5%) had accurate knowledge regarding the prescription.
CONCLUSIONS: Knowledge and practices of medical practitioners regarding rheumatic fever were less than ideal and may play a part in misdiagnoses of Group A streptococcal infections and, hence, prophylaxis.

UNASSIGNED: Group A Streptococcus (GAS) causes pharyngitis (sore throat) and impetigo (skin sores) GAS pharyngitis triggers rheumatic fever (RF) with epidemiological evidence supporting that GAS impetigo may also trigger RF in Australian Aboriginal children. Understanding the concurrent burden of these superficial GAS infections is critical to RF prevention. This pilot study aimed to trial tools for concurrent surveillance of sore throats and skins sore for contemporary studies of RF pathogenesis including development of a sore throat checklist for Aboriginal families and pharynx photography.
UNASSIGNED: Yarning circle conversations and semi-structured interviews were performed with Aboriginal caregivers and used to develop the language and composition of a sore throat checklist. The sore throat story checklist was combined with established methods of GAS pharyngitis and impetigo surveillance (examination, bacteriological culture, rapid antigen detection and serological tests) and new technologies (photography) and used for a pilot cross-sectional surveillance study of Aboriginal children attending their health clinic for a routine appointment. Feasibility, acceptability, and study costs were compiled.
UNASSIGNED: Ten Aboriginal caregivers participated in the sore-throat yarning circles; a checklist was derived from predominant symptoms and their common descriptors. Over two days, 21 Aboriginal children were approached for the pilot surveillance study, of whom 17 were recruited; median age was 9 years [IQR 5.5-13.5], 65% were female. One child declined throat swabbing and three declined finger pricks; all other surveillance elements were completed by each child indicating high acceptability of surveillance assessments. Mean time for screening assessment was 19 minutes per child. Transport of clinical specimens enabled gold standard microbiological and serological testing for GAS. Retrospective examination of sore throat photography concorded with assessments performed on the day.
UNASSIGNED: Yarning circle conversations were effective in deriving culturally appropriate sore throat questionnaires for GAS pharyngitis surveillance. New and established tools were feasible, practical and acceptable to participants and enable surveillance to determine the burden of superficial GAS infections in communities at high risk of RF. Surveillance of GAS pharyngitis and impetgio in remote Australia informs primary RF prevention with potential global translation.