"Hurts less, lasts longer"; a qualitative study on experiences of young people receiving high-dose subcutaneous injections of benzathine penicillin G to prevent rheumatic heart disease in New Zealand.

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). METHODOLOGY: 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 Maori 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. PRINCIPAL FINDINGS: 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.

Trends in penicillin dispensing during an acute rheumatic fever prevention programme.

AIM: Acute rheumatic fever (ARF), a serious inflammatory condition, often leads to rheumatic heart disease (RHD). Between 2011 and 2016, Aotearoa New Zealand implemented a rheumatic fever prevention programme (RFPP) to reduce high rates of ARF through improved community access to timely diagnosis and early treatment of group A streptococcal (GAS) pharyngitis, which has been shown to prevent subsequent ARF. This study aimed to quantify the change in penicillin antibiotic dispensing rates among children aged 18 years or younger during the RFPP. METHOD: This retrospective analysis utilised administrative data from the National Pharmaceutical Collection. Using a controlled, interrupted time series analysis, the effect of the RFPP on antibiotic dispensing rates was explored. Poisson regression models were used to assess the change in dispensing rates during the RFPP among control regions (those not in the RFPP) and regions participating in the RFPP. The primary measure was rate ratio (RR) for the difference between the observed versus counterfactual rates of penicillin dispensing. RESULT: A total of 12,154,872 dispensing records between 2005 and 2018 were included. Amoxicillin was the most frequently dispensed penicillin (57.7%), followed by amoxicillin-clavulanate (23.4%). Amoxicillin dispensing increased by 4.3% in regions operating the RFPP compared to the increase in control regions (p<0.001). The overall rate of penicillin dispensing decreased, driven by a rapid decline in amoxicillin-clavulanate dispensing. CONCLUSION: During the RFPP an increase in amoxicillin dispensing was seen in regions participating in the programme and regions outside of the programme, indicating the programmatic approach led to improved adherence to recommended first-line antibiotics.

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.

Development of a sustained release implant of benzathine penicillin G for secondary prophylaxis of rheumatic heart disease.

BACKGROUND: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3-4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. METHODS: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. RESULTS: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. CONCLUSION: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.

Coexistence of Graves' disease with acute rheumatic fever treated as thyroid storm in young Thai patient.

OBJECTIVES: This report presents a case of acute onset of chorea, concurrent Graves' disease, and acute rheumatic fever in an 8-year-old female patient. CASE PRESENTATION: The child had intermittent involuntary movement of all extremities and both eyes for 4 days, with a previous history of increased appetite, weight lost, and heat intolerance over a period of two months. Physical examination revealed fever, tachycardia, exophthalmos, eyelid retraction, as well as diffused thyroid enlargement. Initial clinical features and thyroid function testing suggested a thyroid storm due to Graves' disease. Methimazole, propranolol, potassium iodide (SSKI), and dexamethasone were prescribed. Congestive heart failure developed after propranolol and cardiovascular re-evaluation and Revised Jones criteria suggested acute rheumatic fever. Chorea was successfully treated with pulse methylprednisolone. CONCLUSIONS: We reported Graves' disease patients with acute rheumatic fever simulating a thyroid storm. The underlying cardiac disease must be considered, especially where chorea and congestive heart failure are present.

[Gender-specific differences in the diagnosis and treatment of inflammatory rheumatic diseases]. / Geschlechtsspezifische Unterschiede in Diagnostik und Therapie entzündlich-rheumatischer Erkrankungen.

BACKGROUND: Gender differences in the diagnosis and treatment of various diseases are increasingly being researched with the aim of optimizing treatment strategies and improving individual treatment success. METHODS: This paper summarizes the existing literature for gender differences in inflammatory rheumatic diseases. RESULTS: Many, but not all, inflammatory rheumatic diseases occur more frequently in women than in men. Women more often have a longer duration of symptoms until diagnosis than men, which may be due to different clinical and radiological presentations. Across diseases, women more often have lower remission and treatment response rates to antirheumatic medication compared to men. Discontinuation rates are also higher in women than in men. Whether women are more likely to develop anti-drug antibodies to biologic disease-modifying antirheumatic drugs is still unclear. For Janus kinase inhibitors, there is no evidence of differential treatment response to date. CONCLUSION: Whether individual dosing regimens and gender-adapted remission criteria are also required in rheumatology cannot be deduced from the evidence available to date.

Effects of biologic and target synthetic disease-modifying anti-rheumatic drugs on sarcopenia in spondyloarthritis and rheumatoid arthritis: a systematic review and meta-analysis.

Sarcopenia is a syndrome defined by generalized and progressive loss of skeletal muscle mass, strength, and function. Besides affecting elderly population, it is actually common among inflammatory rheumatic diseases (IRD) patients. We performed a systematic literature review with a meta-analysis to investigate the influence of biologic and target synthetic disease-modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) on sarcopenia in IRD. A systematic search has been performed on Pubmed, Scopus, and Web of science. Studies characteristics were collected. Assessment tools were body composition (total lean mass (TLM) and percentage, appendicular skeletal mass (ASM), fat-free mass and index (FFM and FFMI), skeletal mass index (SMI) and segmental lean mass (SLM)), and muscle strength and physical performance tests. Treatment effect defined the difference in change from baseline to the end of follow-up treatment was divided by the pooled SD of the difference. Twenty-two studies on 778 patients receiving bDMARDs/tsDMARDs and 157 controls were reviewed. They investigated rheumatoid arthritis (RA) (N = 14), spondyloarthritis (SpA) (N = 6), psoriatic arthritis (N = 1), and both RA and SpA (N = 1). tsDMARDs were used in one study with no effect on sarcopenia. Ten studies demonstrated that bDMARDs increased significantly muscle measures in 347 patients (44.6%) with a significant increase in TLM (6/15 studies; 57.4%), FFMI (4/6 studies; 59.9%), ASM (2/5 studies; 17.6%), SMI (2/5 studies; 18.1%), and SLM (2/2 studies; 3.6%). bDMARDs showed also a positive effect on handgrip strength in 1/3 of studies (45.2%) and on physical performance in 1/2 of studies (61%). In 1/5 of comparative studies, IRD patients on bDMARDs showed significantly higher increase of TLM in comparison to controls naïve bDMARDs. Regarding diagnosis, positive effect of bDMARDs was seen in 67.4% in SpA versus 49.3% in RA, with a significant increase of TLM, ASM and FFMI in 59.4%, 100%, and 65.2% in SpA versus 54.9%, 24.1%, and 54.8% in RA, respectively. Meta-analysis assessed the effect of bDMARD on TLM in 10 studies. There was no statistically significant difference [SMD - 0.10 (95% Confidence Interval - 0.26 - 0.06; tau2 = 0). Heterogeneity across studies was null, and the 95% confidence interval (index of precision) was equal to the 95% predictive interval. The first systematic literature review showed that bDMARDs have a significant improve effect in nearly half of RA and SpA patients on muscle mass and muscle strength, assessed separately. However, the meta-analysis concluded that bDMARDs have no significant effect on TLM.

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.

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.

Research opportunities for the primordial prevention of rheumatic fever and rheumatic heart disease-streptococcal vaccine development: a national heart, lung and blood institute workshop report.

Streptococcus pyogenes, also known as group A streptococcus (StrepA), is a bacterium that causes a range of human diseases, including pharyngitis, impetigo, invasive infections, and post-infection immune sequelae such as rheumatic fever and rheumatic heart disease. StrepA infections cause some of the highest burden of disease and death in mostly young populations in low-resource settings. Despite decades of effort, there is still no licensed StrepA vaccine, which if developed, could be a cost-effective way to reduce the incidence of disease. Several challenges, including technical and regulatory hurdles, safety concerns and a lack of investment have hindered StrepA vaccine development. Barriers to developing a StrepA vaccine must be overcome in the future by prioritising key areas of research including greater understanding of StrepA immunobiology and autoimmunity risk, better animal models that mimic human disease, expanding the StrepA vaccine pipeline and supporting vaccine clinical trials. The development of a StrepA vaccine is a complex and challenging process that requires significant resources and investment. Given the global burden of StrepA infections and the potential for a vaccine to save lives and livelihoods, StrepA vaccine development is an area of research that deserves considerable support. This report summarises the findings of the Primordial Prevention Working Group-VAX, which was convened in November 2021 by the National Heart, Lung, and Blood Institute. The focus of this report is to identify research gaps within the current StrepA vaccine landscape and find opportunities and develop priorities to promote the rapid and successful advancement of StrepA vaccines.

[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.

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.

Revisiting QT prolongation in acute rheumatic fever - Relevance for hydroxychloroquine treatment.

In-vitro evidence suggests hydroxychloroquine could be a potential immunomodulator for the inflammatory carditis of acute rheumatic fever (ARF). Hydroxychloroquine used as an anti-inflammatory agent has a low side effect profile but its use in the Covid-19 pandemic raised concerns about QTc interval prolongation and cardiac arrhythmias. The prolongation of QTc in ARF appears benign but has not been widely studied. We aim to report QTc intervals in a contemporary ARF population and consider implications for hydroxychloroquine use in ARF. The study cohort was 197 children <15 years of age with a clinical diagnosis of ARF. The QTc mean (SD) was 445 msec (28), range 370-545 msec. Eighteen percent of the cohort had a QTc > 99th percentile for normal by age and 8 patients (4%) had a QTc over 500 msec. There was no difference of QTc by age or gender. Inter-observer repeatability for QTc (n = 33) was 35 msec. The QTc is often prolonged in the early phase of ARF, meaning that QT prolonging medications should be used with caution in this setting. Serial ECG monitoring of the QT interval is recommended if hydroxycholoroquine is used in ARF.

Adherence to secondary prevention of rheumatic fever and rheumatic heart disease in young people: an 11-year retrospective study.

OBJECTIVES: To evaluate the secondary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in the Townsville region, Australia. METHODS: Adherence to benzathine benzylpenicillin G (BPG) was determined for 196 children and young adults aged under 22 years between January 2009 and December 2019, and factors associated with BPG adherence were analysed. Secondary outcomes included attendance at specialist reviews and echocardiograms. RESULTS: Adequate adherence (80%) to regular BPG injections was met by 51.1% of the cohort. Adequate BPG adherence more likely occurred for those that attended the Paediatric Outreach Clinic (OR4.15, 95%CI:2.13-8.05) or a school delivery program (OR1.87, 95%CI:1.11-3.45). People with moderate/severe RHD had greater BPG adherence (OR1.76,95%CI:1.00-3.10). People in rural/remote areas were less likely to have adequate BPG adherence compared to urban counterparts (OR0.31, 95%CI:0.15-0.65). Adherence to echocardiography was 66% and specialist review attendance was 12.5-50%. CONCLUSION: Half of the cohort in the Townsville region received adequate BPG prophylaxis to prevent ARF/RHD. Although rates were relatively higher than those reported in other Australian regions, health delivery goals should be close to 100%. Low attendance at specialist services was reported. Implication for public health: Delivery models with dedicated services, case management and family support could improve BPG adherence in individuals with ARF/RHD. Further resources in rural and remote areas are needed.

What is the optimal strategy for managing primary care patients with an uncomplicated acute sore throat? Comparing the consequences of nine different strategies using a compilation of previous studies.

OBJECTIVE: Identifying optimal strategies for managing patients of any age with varying risk of acute rheumatic fever (ARF) attending for an apparently uncomplicated acute sore throat, also clarifying the role of point-of-care testing (POCT) for presence of group A beta-haemolytic Streptococcus (GABHS) in these settings. DESIGN: We compared outcomes of adhering to nine different strategies for managing these patients in primary healthcare. SETTING AND PARTICIPANTS: The nine strategies, similar to guidelines from several countries, were tested against two validation data sets being constructs from seven prior studies. MAIN OUTCOME MEASURES: The proportion of patients requiring a POCT, prescribed antibiotics, prescribed antibiotics having GABHS and finally having GABHS not prescribed antibiotics, if different strategies had been adhered to. RESULTS: In a scenario with high risk of ARF, adhering to existing guidelines would risk many patients ill from GABHS left without antibiotics. Hence, using a POCT on all of these patients minimised their risk. For low-risk patients, it is reasonable to only consider antibiotics if the patient has more than low pain levels despite adequate analgesia, 3-4 Centor scores (or 2-3 FeverPAIN scores or 3-4 McIsaac scores) and a POCT confirming the presence of GABHS. This would require testing only 10%-15% of patients and prescribing antibiotics to only 3.5%-6.6%. CONCLUSIONS: Patients with high or low risk for ARF needs to be managed very differently. POCT can play an important role in safely targeting the use of antibiotics for patients with an apparently uncomplicated acute sore throat.

Predictors of rheumatic fever in sore throat patients: a systematic review and meta-analysis.

BACKGROUND: Concerns about rheumatic fever (RF) drive antibiotic prescriptions for sore throat (ST) in endemic areas. Better guidance is needed on which patients are likely to develop RF in order to avoid misuse and overuse of antibiotics. Our aim was to identify predictive factors for RF in ST patients. METHODS: Multiple databases were searched to identify cohort, case-control, cross-sectional or randomised controlled trials that measured RF incidence in ST patients. An inverse variance random effects model was used to pool the data and calculate odds ratios (ORs). RESULTS: Seven studies with a total of 6890 participants were included: three RCTs and four observational studies. Factors significantly associated with RF development following ST were positive group A streptococcal (GAS) swab (OR 1.74 [95% confidence interval {CI} 1.13 to 2.69]), previous RF history (OR 13.22 [95% CI 4.86 to 35.93]) and a cardiac murmur (OR 3.55 [95% CI 1.81 to 6.94]). Many potential risk factors were not reported in any of the included studies, highlighting important evidence gaps. CONCLUSIONS: ST patients in endemic areas with a positive GAS swab, previous RF history and a cardiac murmur are at increased risk of developing RF. This review identifies vital gaps in our knowledge of factors predicting RF development in ST patients. Further research is needed to develop better clinical prediction tools and rationalise antibiotic use for ST.

Secondary Prevention of Rheumatic Heart Disease in Nepal: Are We Going Backward?

A secondary level of prophylaxis has proven to be the most successful in Nepal, a country with an endemic rate of rheumatic heart disease, in combating the severe issues associated with rheumatic heart disease. The use of benzathine penicillin G in secondary prophylaxis of rheumatic heart disease, recommended by several guidelines, has been increasingly abandoned in Nepal due to a lack of national guidelines and the termination of the prior programs. The use of oral penicillin and alternative oral antibiotics, which are less effective in preventing the recurrence of acute rheumatic fever, is on the rise. Nepal urgently needs to develop new national guidelines and ensure their effective implementation in order to slow the increase in the number of rheumatic heart disease patients. In this article, we explore the limitations, challenges, and advantages of using the consensus-supported intramuscular benzathine penicillin G as the first-line drug for the secondary prevention of rheumatic heart disease.