Long-term antibiotic prophylaxis for prevention of rheumatic fever recurrence and progression to rheumatic heart disease.

BACKGROUND: Rheumatic fever is a non-suppurative, inflammatory sequela of group A Streptococcus pharyngitis that can occur at two to four weeks after infection. Following an episode of rheumatic fever, there is a risk of developing rheumatic heart disease (RHD) later in life that carries significant risk of morbidity and mortality. RHD remains the largest global cause of cardiovascular disease in the young (age < 25 years). The historical literature provides inconclusive evidence that antibiotic prophylaxis is beneficial in reducing the risk of recurrence of rheumatic fever and development of RHD. Antibiotics are thought to work by reducing the carriage of group A Streptococcus and thus reducing the risk of infection. This review was commissioned by the World Health Organization (WHO) for an upcoming guideline. OBJECTIVES: 1. To assess the effects of long-term antibiotics versus no antibiotics (control) for secondary prevention of rheumatic fever recurrence and associated sequelae in people with previous rheumatic fever or RHD. 2. To assess the effects of long-term intramuscular penicillin versus long-term oral antibiotics for secondary prevention of rheumatic fever recurrence and associated sequelae in people with previous rheumatic fever or RHD. SEARCH METHODS: We systematically searched CENTRAL, MEDLINE, Embase, Conference Proceedings Citation Index-Science, clinical trial registers, ISRCTN.com and reference lists without restrictions on language or date up to 10 March 2024. SELECTION CRITERIA: We sought randomised controlled trials or quasi-randomised trials, described in any language, including participants with previous rheumatic fever and/or RHD of any age, based in community or hospital settings. Studies were included if they compared firstly antibiotic prophylaxis with no antibiotic prophylaxis, and, secondly, intramuscular penicillin prophylaxis versus oral antibiotic prophylaxis. DATA COLLECTION AND ANALYSIS: We used standardised methodological, Cochrane-endorsed procedures and performed meta-analyses with risk ratios (RR) and Peto odds ratios (Peto OR). Our primary outcomes were recurrence of rheumatic fever, progression or severity of RHD and cardiac complications. Our secondary outcomes were obstetric complications (maternal and foetal events), mortality, treatment adherence, adverse events and acceptability to participants. We performed comprehensive assessments of risk of bias and certainty of evidence, applying the GRADE methodology. MAIN RESULTS: We included 11 studies (seven RCTs and four quasi-randomised trials) including 3951 participants. The majority of the included studies were conducted in the USA, UK and Canada during the 1950s to 1960s. Most participants with previous rheumatic fever had been diagnosed using the modified Jones criteria (mJC) (four studies), were an average of 12.3 years of age and 50.6% male. We assessed the majority of the included studies to be at high risk of bias, predominantly relating to blinding and attrition bias. Comparison one: antibiotics versus no antibiotics Pooled meta-analysis of six RCTs provides moderate-certainty evidence that antibiotics overall (oral or intramuscular) probably reduce the risk of recurrence of rheumatic fever substantially (0.7% versus 1.7%, respectively) (risk ratio (RR) 0.39, 95% confidence interval (CI) 0.22 to 0.69; 1721 participants). People with early or mild RHD likely have the greatest capacity to benefit from intramuscular antibiotic prophylaxis (8.1%) compared to no antibiotics (0.7%) (RR 0.09, 95% CI 0.03 to 0.29; 1 study, 818 participants; moderate-certainty evidence). Antibiotics may not affect mortality in people with late-stage RHD (RR 1.23, 95% CI 0.78 to 1.94; 1 study, 994 participants; low-certainty evidence). Antibiotics may not affect the risk of anaphylaxis (Peto odds ratio (OR) 7.39, 95% CI 0.15 to 372; 1 study, 818 participants; low-certainty evidence) or sciatic nerve injury (Peto OR 7.39, 95% CI 0.15 to 372; 1 study, 818 participants; low-certainty evidence) compared with no antibiotics, but probably have an increased risk of hypersensitivity reactions (RR 137, 8.51 to 2210; 2 studies, 894 participants; moderate-certainty evidence) and local reactions (RR 29, 1.74 to 485; 1 study, 818 participants; moderate-certainty evidence). Comparison two: intramuscular antibiotics versus oral antibiotics Pooled analysis of two RCTs showed that prophylactic intramuscular benzathine benzylpenicillin likely reduces recurrence of rheumatic fever substantially when compared to oral antibiotics (0.1% versus 1%, respectively) (RR 0.07, 95% CI 0.02 to 0.26; 395 participants; moderate-certainty evidence). Furthermore, it is unclear whether intramuscular benzyl penicillin is superior to oral antibiotics in reducing the risk of mortality in the context of RHD (Peto OR 0.22, 95% CI 0.01 to 4.12; 1 study, 431 participants; very low-certainty evidence). There were no data available on progression of latent RHD or adverse events including anaphylaxis, sciatic nerve injury, delayed hypersensitivity/allergic reactions and local reactions to injection. AUTHORS' CONCLUSIONS: This review provides evidence that antibiotic prophylaxis likely reduces the risk of recurrence of rheumatic fever compared to no antibiotics, and that intramuscular benzathine benzylpenicillin is probably superior to oral antibiotics (approximately 10 times better). Moreover, intramuscular benzathine benzylpenicillin likely reduces the risk of progression of latent RHD. Evidence is scarce, but antibiotics compared with no antibiotics may not affect the risk of anaphylaxis or sciatic nerve injury, but probably carry an increased risk of hypersensitivity reactions and local reactions. Antibiotics may not affect all-cause mortality in late-stage RHD compared to no antibiotics. There is no evidence available to comment on the effect of intramuscular penicillin over oral antibiotics for progression of latent RHD and adverse events, and little evidence for all-cause mortality. It is important to interpret these findings in the context of major limitations, including the following: the vast majority of the included studies were conducted more than 50 years ago, many before contemporary echocardiographic studies; methodology was often at high risk of bias; outdated treatments were used; only one study was in latent RHD; and there are concerns regarding generalisability to low socioeconomic regions. This underlines the need for ongoing research to understand who benefits most from prophylaxis.

Therapeutic consequences in patients with both inflammatory rheumatic diseases and multiple sclerosis.

Dealing with patients with both multiple sclerosis (MS) and inflammatory rheumatic disorders (IRDs) is not uncommon for a rheumatologist, as there is a statistical association between SpA and MS. As several CNS demyelinating events have been reported in patients treated with TNF inhibitor (TNFi), the pre-existing demyelinating disease was considered a contraindication for TNFi. However, this contraindication is mainly based on a randomized controlled trial in MS and not on large epidemiological studies. According to the last epidemiological studies, TNFi might not be an inducer of MS. Moreover, there are no clear recommendations on the use of the other DMARDs in patients suffering from an IRD and MS. In this review, we summarize the link between MS and IRDs and the impact of DMARDs on MS, especially TNFi. We also look at the impact of disease-modifying drugs for adults with MS and IRDs.

Sydenham chorea in the top end of Australia's Northern Territory: A 20-year retrospective case series.

AIM: Sydenham chorea is an immune-mediated neuropsychiatric condition, and a major criterion for diagnosis of acute rheumatic fever (ARF). Children in remote Northern Australia experience disproportionately high rates of ARF, yet studies looking at the epidemiology, clinical presentation and management of Sydenham chorea are limited in this population. METHODS: We conducted a retrospective case series from January 2002 to April 2022 of all paediatric patients aged ≤18 years admitted to Royal Darwin Hospital with Sydenham chorea. Cases were identified using the hospital's clinical coding system (ICD10). Medical records were reviewed and data on demographics, clinical presentation, investigation results, treatment and outcome were extracted, deidentified and analysed. RESULTS: One hundred ten presentations of Sydenham chorea occurred between 2002 and 2022, 109 (99%) of these were in First Nations children, with 85% residing in very remote locations. Most commonly, chorea presented as a generalised movement disorder affecting all four limbs (49%). Neuropsychiatric symptoms were reported in 33 (30%), and there was evidence of rheumatic heart disease on echocardiogram in 86 (78%) at presentation. All patients received benzathine penicillin, but there was significant variation in management of chorea, ranging from supportive management, to symptomatic management with anticonvulsants, to immunomodulatory medications including corticosteroids. CONCLUSION: This case series highlights the significant burden of Sydenham chorea among First Nations children living in Northern Australia and demonstrates wide variation in treatment approaches. High-quality clinical trials are required to determine the best treatment for this disabling condition.

Perioperative management of patients with inflammatory rheumatic diseases : Updated recommendations of the German Society for Rheumatology.

BACKGROUND: Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014. METHODS: After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added. RESULTS: The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case <10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing. CONCLUSION: Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.

Population pharmacokinetic study of benzathine penicillin G administration in Indigenous children and young adults with rheumatic heart disease in the Northern Territory, Australia.

BACKGROUND: Benzathine penicillin G (BPG) is the cornerstone of secondary prophylaxis to prevent Streptococcus pyogenes infections, which precede acute rheumatic fever (ARF). The paucity of pharmacokinetic (PK) data from children and adolescents from populations at the highest risk of ARF and rheumatic heart disease (RHD) poses a challenge for determining the optimal dosing and frequency of injections and undermines efforts to develop improved regimens. METHODS: We conducted a 6 month longitudinal PK study of young people receiving BPG for secondary prophylaxis. Throat and skin swabs were collected for microbiological culture along with dried blood spot (DBS) samples for penicillin concentrations. DBSs were assayed using LC-MS/MS. Penicillin concentration datasets were analysed using non-linear mixed-effects modelling and simulations performed using published BMI-for-age and weight-for-age data. RESULTS: Nineteen participants provided 75 throat swabs, 3 skin swabs and 216 penicillin samples. Throat cultures grew group C and G Streptococcus. Despite no participant maintaining penicillin concentration >20 ng/mL between doses, there were no S. pyogenes throat infections and no ARF. The median (range) observed durations >20 ng/mL for the low- and high-BMI groups were 14.5 (11.0-24.25) and 15.0 (7.5-18.25) days, respectively. CONCLUSIONS: Few patients at highest risk of ARF/RHD receiving BPG for secondary prophylaxis maintain penicillin concentrations above the target of 20 ng/mL beyond 2 weeks during each monthly dosing interval. These PK data suggest that some high-risk individuals may get inadequate protection from every 4 week dosing. Future research should explore this gap in knowledge and PK differences between different populations to inform future dosing schedules.

[Management of inflammatory rheumatic diseases during and after malignancies]. / Management von entzündlich rheumatischen Erkrankungen während und nach Malignomen.

The management of inflammatory rheumatic diseases in patients with a simultaneous or previous malignant disease is associated with complex questions. Difficulties and possible solutions in the interpretation of meaningful studies are presented. Recommendations in guidelines on this topic are discussed. National registries and health insurance databases were examined with respect to the risk of tumor recurrence under disease-modifying antirheumatic drugs; however, these analyses mainly refer to tumor necrosis factor (TNF) inhibitors and rituximab. Data on tumor incidence and, if available, risk of tumor recurrence are summarized for commonly used disease-modifying antirheumatic drugs. Finally, an attempt is made to formulate proposals for rheumatological treatment in patients with a history of malignancy.

Structured review of primary interventions to reduce group A streptococcal infections, acute rheumatic fever and rheumatic heart disease.

Rheumatic heart disease (RHD) is a large, preventable, global public health burden. In New Zealand (NZ), acute rheumatic fever (ARF) and RHD rates are highest for Maori and Pacific children. This structured review explores the evidence for primary prevention interventions to diagnose and effectively treat group A Streptococcus (GAS) pharyngitis and skin infections to reduce rates of ARF and RHD. Medline, EMBASE and Scopus databases were searched as well as other electronic publications. Included were 50 publications from 1980 onwards. This review has identified that there is little available evidence for effective primary prevention strategies to reduce ARF rates in NZ. However, two primary intervention strategies that should be considered by communities at high-risk of ARF are: the use of school-based clinics to identify and treat GAS pharyngitis and GAS skin infections; and intramuscular benzathine penicillin G with lignocaine analgesia in children who present with a GAS positive throat.

Adherence rates and risk factors for suboptimal adherence to secondary prophylaxis for rheumatic fever.

AIM: Secondary prophylaxis with 3-4 weekly benzathine penicillin G injections is necessary to prevent disease morbidity and cardiac mortality in patients with acute rheumatic fever (ARF) and rheumatic heart disease (RHD). This study aimed to determine secondary prophylaxis adherence rates in the Far North Queensland paediatric population and to identify factors contributing to suboptimal adherence. METHODS: A retrospective analysis of data recorded in the online RHD register for Queensland, Australia, was performed for a 10-year study period. The proportion of benzathine penicillin G injections delivered within intervals of ≤28 days and ≤35 days was measured. A multi-level mixed model logistic regression assessed the influence of age, gender, ethnicity, suburb, Accessibility and Remoteness Index of Australia class, number of people per dwelling, Index of Relative Socio-economic Advantage and Disadvantage, Index of Education and Occupation, year of inclusion on an ARF/RHD register and individual effect. RESULTS: The study included 277 children and analysis of 7374 injections. No children received ≥80% of recommended injections within a 28-day interval. Four percent received ≥50% of injections within ≤28 days and 46% received ≥50% of injections at an extended interval of ≤35 days. Increasing age was associated with reduced delivery of injections within 35 days. Increasing year of inclusion was associated with improved delivery within 28 days. The random effect of individual patients was significantly associated with adherence. CONCLUSIONS: Improved timely delivery of secondary prophylaxis for ARF and RHD is needed as current adherence is very low. Interventions should focus on factors specific to each individual child or family unit.

Acute Rheumatic Fever.

The incidence of acute rheumatic fever (ARF) is 8 to 51 per 100,000 people worldwide. It most commonly affects children 5 to 15 years of age after a group A streptococcal infection. Overcrowding and poor socioeconomic conditions are directly proportional to the incidence of ARF. Rheumatic carditis is a manifestation of ARF that may lead to rheumatic heart disease (RHD). Timely treatment of group A streptococcal infection can prevent ARF, and penicillin prophylaxis can prevent recurrence of ARF. Prevention of recurrent ARF is the most effective way to prevent RHD. ARF is diagnosed using the 2015 modified Jones criteria. There is no gold standard laboratory test. Therefore, clinicians need to be aware of the clinical signs and symptoms of ARF to include in their differential diagnosis when seeing such patients. Secondary prophylaxis with benzathine penicillin G has been shown to decrease the incidence of RHD and is key to RHD control. Clinicians need to understand the implications of secondary prophylaxis for ARF. There is also a need to improve ARF diagnosis, to find novel therapies to reduce the incidence of ARF, and to reduce the prevalence of RHD. RHD research is neglected and underfunded. Thus, there is also a need for RHD advocacy and public health awareness to increase research on RHD.

The Role of Thiocyanate in Modulating Myeloperoxidase Activity during Disease.

Thiocyanate (SCN-) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F-, Br-, I-) as substrates for myeloperoxidase by undergoing two-electron oxidation with hydrogen peroxide. This forms their respective hypohalous acids (HOX where X- = halides) and in the case of thiocyanate, hypothiocyanous acid (HOSCN), which is also a bactericidal oxidative species involved in the regulation of commensal and pathogenic microflora. Disease may dysregulate redox processes and cause imbalances in the oxidative profile, where typically favoured oxidative species, such as hypochlorous acid (HOCl), result in an overabundance of chlorinated protein residues. As such, the pharmacological capacity of thiocyanate has been recently investigated for its ability to modulate myeloperoxidase activity for HOSCN, a less potent species relative to HOCl, although outcomes vary significantly across different disease models. To date, most studies have focused on therapeutic effects in respiratory and cardiovascular animal models. However, we note other conditions such as rheumatic arthritis where SCN- administration may worsen patient outcomes. Here, we discuss the pathophysiological role of SCN- in diseases where MPO is implicated.

Osteoporosis therapy in patients with inflammatory rheumatic diseases and osteonecrosis of the jaw.

BACKGROUND AND OBJECTIVES: The aim of the present study was to assess the prevalence of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients suffering from inflammatory rheumatic diseases, as well as to assess the prevalence of relevant dental, behavioral, and medical risk factors for MRONJ. MATERIALS AND METHODS: A total of 198 patients with inflammatory rheumatic diseases and osteoporosis therapy were recruited from a tertiary rheumatological/immunological referral center between June 2015 and September 2016. They were assessed using a structured interview. A maxillofacial surgeon later examined patients complaining of possible symptoms of osteonecrosis. In cases of osteonecrosis, dental records were obtained and evaluated. Preventive measures taken and dental as well as other clinical risk factors were evaluated. RESULTS: Of the 198 patients, three suffered from osteonecrosis of the jaw, none of whom had any history of malignant disease or radiation therapy, resulting in a prevalence of 1.5%. Of these three patients, only one was given bisphosphonates intravenously (i.v.), whereas all three had been treated orally. All three diagnoses of MRONJ had been previously known to the patients and their maxillofacial surgeons. Two of the patients had rheumatoid arthritis, and one patient suffered from large vessel vasculitis. Long anti-osteoporotic treatment duration, low functional status, and low bone density of the femur were significantly associated with MRONJ development. CONCLUSION: Inflammatory rheumatic diseases constitute a risk factor for MRONJ in patients treated with bisphosphonates for osteoporosis. Patients should be counseled accordingly and should be offered dental screening and regular dental check-ups.

Clonidine for pain-related distress in Aboriginal children on a penicillin regimen to prevent recurrence of rheumatic fever.

CONTEXT: Indigenous children and adolescents in Australia and globally bear the burden of acute rheumatic fever (ARF). It has been virtually eliminated in well-resourced, developed settings. ARF is an autoimmune response to infection with group A Streptococcus. The mainstay of management is long-acting intramuscular penicillin injections to prevent recurrence of ARF and development of rheumatic heart disease (RHD), comprising valvular pathology and attendant complications. In Australia, penicillin injections are currently prescribed every 28 days for 5-10 years after diagnosis of ARF, depending on cardiac involvement. Adherence to this regimen reduces ARF recurrences and RHD progression. 'Days at risk' of ARF recurrence are calculated as the number of days after day 28 that an injection is not received. Adherence to the injection schedule has been reported as difficult in most global locations due to the painful nature of the injections, the long timeframes of the prescription, young age of patients, access problems and costs in some locations. The newly updated Australian guideline on the prevention, diagnosis and management of ARF and RHD has a chapter dedicated to secondary prophylaxis. This chapter takes into account cultural considerations and advises on ways to minimise pain and distress of injections in children such as pain gate strategies, distraction techniques and concurrent injection of local anaesthetic. ISSUES: Some children continue to find the injection regimen traumatising despite strategies to reduce pain and fear. Clinicians providing the injections to children also find the injecting episodes distressing if pain is not effectively minimised. An Aboriginal Community Controlled Health Service in a remote setting in northern Australia addressed the issue of severe trauma of injection episodes experienced by an Aboriginal boy aged 7 years. Usual strategies were not effective, so advice was sought from an expert anaesthetist at a tertiary hospital. As a result, oral clonidine 3 µg/kg was trialled 45 minutes prior to the penicillin injection. Procedural coaching and monitoring protocols specific to administration of clonidine in children under their care were created by the health service. The initial dose of clonidine was delivered with the child as an inpatient. LESSONS LEARNED: Clonidine was successful in reducing pain related distress and facilitating adherence to the penicillin regimen. Subsequent doses were delivered and monitored in a remote setting by nurses. After 18 months, the boy no longer required clonidine due to his increased coping capacity. A second child was recognised with similar trauma and has been taking clonidine for pre-procedural sedation for 6 months with good effect and no adverse effects. An additional child was similarly prescribed clonidine without success. Failure in that instance was attributed to lack of procedural coaching and receiving the initial dose of clonidine in an emergency department in hurried circumstances. Individualised child-focused and culturally appropriate care in remote settings is feasible: in this instance team planning for use of clonidine and procedural coaching when other measures have failed. However, for children with RHD, or other comorbidities, advice from the child's treating cardiologist is required prior to prescribing clonidine due to possible adverse consequences. These include hypotension and atrioventricular block, which could lead to haemodynamic compromise in the setting of moderate to severe RHD.

Carditis in Acute Rheumatic Fever in a High-Income and Moderate-Risk Country.

OBJECTIVE: To describe clinical presentation, electrocardiographic, and echocardiographic characteristics of carditis at the time of diagnosis of acute rheumatic fever (ARF) over a 13-year period. STUDY DESIGN: A single-center retrospective chart analysis was conducted involving all consecutive patients diagnosed with ARF between 2003 and 2015. Patient age, sex, clinical characteristics, recent medical history for group A streptococcal pharyngotonsillitis and antibiotic treatment, and laboratory, echocardiographic, and electrocardiographic findings were recorded. RESULTS: Of 98 patients (62 boys, mean age 8.81 ± 3.04 years), 59 (60.2%) reported a positive history of pharyngotonsillitis; 48 (49%) had received antibiotic (mean duration of treatment of 5.9 ± 3.1 days), and, among these, 28 (58.3%) had carditis. Carditis was the second most frequent finding, subclinical in 27% of patients. Mitral regurgitation was present in 49 of 56 patients (87.5%) and aortic regurgitation in 36/56 (64.3%) no stenosis was documented. CONCLUSIONS: ARF is still present in high-income countries and can develop despite primary prophylaxis, especially when given for a short course. Our findings highlight the need for 10 days of antistreptococcal treatment to prevent ARF. Echocardiography is important because 27% of cases with carditis were subclinical.

Biosimilars in rheumatology.

Biotechnologicals are an invaluable resource in the treatment of patients with inflammatory rheumatic diseases (IRD) non-responsive or intolerant to conventional therapies. However, they are the main driver for increase in direct costs and represent a significant economic burden to healthcare systems worldwide. Since biosimilars are similar and more affordable versions of previously licenced biotechnologicals, they are expected to contribute to healthcare system sustainability and reduce inequities in treatment access. The landmark approval of CT-P13 as the first infliximab biosimilar paved the way for new infliximab but also etanercept, adalimumab and rituximab biosimilars. In Europe, North America and some countries of Asia, development is strictly regulated and only those presenting a totality-of-evidence dossier with highly similar physicochemical, biological and clinical performances are endorsed by regulatory agencies as biosimilars. The current article addresses the importance of biosimilar medicines in the treatment of IRD, as well as their innovative development and regulatory pathways, clinical evidence of similarity and challenges that may undermine their widespread use and success.

Understanding group A streptococcal pharyngitis and skin infections as causes of rheumatic fever: protocol for a prospective disease incidence study.

BACKGROUND: Group A Streptococcal (GAS) infections cause the autoimmune disease acute rheumatic fever (ARF), which can progress to chronic rheumatic heart disease (RHD). Treating pharyngitis caused by GAS with antibiotics is important in preventing ARF. However, it is difficult to distinguish these infections from GAS carriers. There is growing evidence for GAS skin infections as a cause of ARF. This study will identify the incidence of true GAS pharyngitis and serological responses to GAS skin infections. The effectiveness of antibiotics for these conditions will be explored, and modifiable risk factors. Serum antibody titres indicating the upper limits of normal (ULN for ASO/ADB antibodies) will be established alongside carriage rates in asymptomatic children. METHODS: This is a prospective disease incidence study, with an associated case-control study. The study population includes 1000 children (5-14 years) from Auckland, New Zealand, 800 of whom have visited their healthcare professional, resulting in a throat or skin swab for GAS, and 200 who are asymptomatic. The conditions of interest are GAS throat swab positive pharyngitis (n = 200); GAS carriage (n = 200); GAS negative throat swab (n = 200); GAS skin infections (n = 200); and asymptomatic controls (n = 200). All participants, except asymptomatic controls, will have acute and convalescent serological testing for ASO/ADB titres (collected < 9 days, and 2-4 weeks following symptom onset, respectively), alongside viral PCR from throat swabs. Asymptomatic controls will have ASO/ADB titres measured in one blood specimen and a throat swab for microbial culture. Caregivers of children will be interviewed using a questionnaire and any GAS isolates identified will be emm typed. The persistence of GAS antibodies will also be investigated. DISCUSSION: Findings from this study will fill critical gaps in scientific knowledge to better understand the pathophysiology of ARF, improve clinical management of GAS infections, and design more effective ARF prevention programmes. In particular it will measure the incidence of true, serologically confirmed GAS pharyngitis; assess the immune response to GAS skin infections and its role as a cause of ARF; examine the effectiveness of oral antibiotics for treating GAS pharyngitis and carriage; and identify whether risk factors for GAS infections might provide intervention points for reducing ARF.

Efficacy of an incentive intervention on secondary prophylaxis for young people with rheumatic fever: a multiple baseline study.

BACKGROUND: Acute rheumatic fever in New Zealand persists and is a barometer of equity as its burden almost exclusively falls on Maori and Pacific Island populations. The primary objective of this study is to determine whether an incentive programme will result in increased secondary prophylaxis injections over a one-year period compared to a baseline period prior to the intervention. METHODS: The evaluation used a multiple baseline study to determine whether an incentive consisting of a mobile phone and monthly "top-up" (for data/calls) resulted in increased injections, increased texts/calls with nurses, reduced number of visits to get a successful injection, less medicine wasted, and increased nurse satisfaction. Participants were 77 young people (aged 14-21) on an acute rheumatic fever registry in Waikato region, New Zealand classified as either fully adherent (all injections received and no more than one late) or partially adherent based on injections at baseline. RESULTS: There was a sharp increase in injections for intermittent patients post-intervention and then a slight decrease overtime, while fully adherent patients maintained their high rate of injections (p = .003). A similar pattern for nurse satisfaction emerged (p = .001). The number of calls/texts increased for all patients (p = .003). The number of visits went down for partially adherent patients and up for fully adherent patients (p = .012). The overall incremental cost-effectiveness was $989 per extra successful injection although costs increased sharply toward the end of the intervention. CONCLUSIONS: Incentivising secondary prophylaxis appears to have a strong impact for partially adherent patients, particularly during the early periods following the initiation of the intervention. Enhancing communication with patients who returned to care may result in more sustainable adherence. TRIAL REGISTRATION: Retrospectively registered: Australia New Zealand Clinical Trials Registry ACTRN12618001150235 , 12 July 2018.

Report: Metformin potential in predisposing arthralgia, type II cross reactivity secondary to group A streptococcus infection & other comorbidities in treating PCOS.

One of the most common endocrinological disorder affecting women in adolescence is Polycystic Ovarian Syndrome (PCOS). Women suffering from PCOS diagnosed with follicles in ovaries show enlarged reproductive organs with small filled follicles. Unusual bleeding, prolonged menstruation, unwanted hair growth, accumulation of fat and acne are the most common problems experienced by adolescents with PCOS. Nowadays, PCOS is treated successfully with the oral antidiabetic drug, metformin and hormone replacement therapy. Its off-label use is still controversial with unknown mechanisms due to patient risk versus benefit hypothesis by practitioners as they successfully treat PCOS in adolescents with metformin. But in few reported cases metformin has potential to induce back pain and swollen joints less frequently with rare cases of behavior alteration. Penicillin belongs to the beta-lactam antibiotics and is most commonly used to treat rheumatic fever although it has potential to cause allergic reactions affecting 10% of patients who exhibit IgE-mediated immunological reactions. Here, we present a case of a female diagnosed with PCOS who after treatment with metformin for more than two years, reported with hyperuricemia, migraine, neurological pain, severe joint and knee pains on shoulders and legs, and rheumatic fever. After treatment with benzathine benzyl penicillin for rheumatic fever, the patient also exhibited Type IV delayed hypersensitivity reaction.

Statins, metformin, proprotein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors and sex hormones: Immunomodulatory properties?

The immune system is closely intertwined with the endocrine system. Many effects of medications used for various clinical endocrine conditions such as the metabolic syndrome, hypercholesterolemia, diabetes mellitus, hypertension, Graves' disease and others also have an impact on the immune system. Some drugs including statins, metformin, angiotensin converting enzyme and proprotein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors and sex hormones are known to have immunomodulatory properties. We here review the literature on this topic and provide some clinical examples including the use of statins in Graves' orbitopathy, rheumatoid arthritis, multiple sclerosis, and adult-onset Still's disease. In that context, we introduce a special immunodiagnostics method developed at the Institute of  Diabetes "Gerhardt Katsch" in Karlsburg, Germany, to not only measure but also monitor immune disease activity.

Poststreptococcal Illness: Recognition and Management.

Group A beta-hemolytic streptococcus can cause several postinfectious, nonsuppurative immune- mediated diseases including acute rheumatic fever, poststreptococcal reactive arthritis, pediatric autoimmune neuropsychiatric disorders, and poststreptococcal glomerulonephritis. Except for sporadic outbreaks, poststreptococcal autoimmune syndromes occur most commonly in sub-Saharan Africa, India, Australia, and New Zealand. Children younger than three years are rarely affected by group A streptococcus pharyngitis or rheumatic fever, and usually do not require testing. Rheumatic fever is a rare condition that presents as a febrile illness characterized by arthritis, carditis or valvulitis, and neurologic and cutaneous disease, followed many years later by acquired valvular disease. Recurrence rates are high. In addition to evidence of recent streptococcal infection, two major or one major and two minor Jones criteria are required for diagnosis. Electrocardiography, chest radiography, erythrocyte sedimentation rate, and an antistreptolysin O titer are the most useful initial tests. Echocardiography is recommended to identify patients with subclinical carditis. The arthritis usually responds within three days to nonsteroidal anti-inflammatory drugs. Poststreptococcal reactive arthritis is nonmigratory, can affect any joint, and typically does not respond to aspirin. Pediatric autoimmune neuropsychiatric disorders affect the basal ganglia and are manifested by obsessive-compulsive and tic disorders. The presentation of poststreptococcal glomerulonephritis ranges from asymptomatic microscopic hematuria to gross hematuria, edema, hypertension, proteinuria, and elevated serum creatinine levels.

Wolff-Parkinson-White syndrome presenting with steroid-induced bradycardia in a patient with acute rheumatic fever.

Steroids are used in the treatment of acute rheumatic fever with moderate-to-severe carditis. Corticosteroids have several cardiovascular side affects that are more common in adults than in children. Corticosteroid-related bradycardia is a rarely seen side effect. Children with bradycardia following oral corticosteroid use are rarely reported previously. We present a child who developed bradycardia after oral corticosteroid treatment and concurrent Wolff-Parkinson-White pattern.