RARE DISEASE
Rheumatic fever
Rheumatic fever
Rheumatic fever
Synonyms: Acute rheumatic fever
Synonyms: Acute rheumatic fever
Synonyms: Acute rheumatic fever
Drug discovery
0
drugs
With orphan designations
Overview
Rheumatic fever (RF) is an autoimmune sequela of group A streptococcal pharyngitis, predominantly affecting children aged 5-15 years. It manifests with migratory polyarthritis, carditis, chorea, erythema marginatum, or subcutaneous nodules, diagnosed via modified Jones criteria [1][6]. Management includes antibiotic eradication of streptococcal infection, anti-inflammatory agents (NSAIDs/corticosteroids), and long-term penicillin prophylaxis to prevent recurrent attacks and rheumatic heart disease (RHD), a major cause of acquired valvular disease in resource-limited settings [1][3][17].
Therapies
Acute management: Penicillin G for streptococcal eradication; NSAIDs (naproxen) or aspirin for arthritis; corticosteroids for moderate-severe carditis [1][3][6].
Secondary prophylaxis: Monthly intramuscular benzathine penicillin G for ≥5-10 years post-episode, extending to age 21+ if cardiac involvement exists [1][3][13].
Surgical intervention: Valve repair/replacement for advanced RHD-related complications [1][13].
Categories: rare systemic and rheumatological diseases
Research Papers
1,012 drug discovery papers about Rheumatic fever, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,012 drug discovery papers about Rheumatic fever, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Whitia Kia Ora: a culturally responsive model of Bicillin L-A® delivery for people with rheumatic fever in the Waikato region of Aotearoa New Zealand.
Acute rheumatic fever (ARF) is an autoimmune response to group A Streptococcus (Strep A) infection that can lead to rheumatic heart disease (RHD). To prevent Strep A infection for people with ARF or RHD, clinical guidelines recommend monthly intramuscular penicillin (Bicillin L-A®) injections for at least 10 years. However, multiple barriers to accessing healthcare affect adherence. This research aimed to improve adherence by developing a Māori and Pacific-centred model of care. Qualitative, Kaupapa Māori and Kakala methodology underpinned the research. Data collection from people in the Waikato region with ARF, their whānau and healthcare providers included interviews, wānanga and fono. Data were analysed using a general inductive approach. Forty-seven participants were included: nine people with ARF, 10 whānau, eight health professionals and 21 whānau navigators. Three themes were identified: impacts of a colonial health system on Indigenous whānau; life defined by a disease status; and catalysts of healthcare engagement. A community informed, Whānau Ora model of care was also developed. Indigenous methodologies are effective methods to develop community informed, culturally responsive models of care. Although designed for ARF in Waikato, there is potential to adapt this approach for other health conditions and different regions of Aotearoa New Zealand.
2026-08-07 | Acute Rheumatic Fever Without Pharyngitis: A Case Report.
An 18-year-old man presented with fatigue and polyarthralgia refractory to nonsteroidal anti-inflammatory drugs (NSAIDs). He had no history of sore throat or other upper respiratory symptoms. Reactive arthritis was initially suspected. However, persistent symptoms, fever, polyarthritis, a cardiac murmur, atrioventricular block, and an elevated antistreptolysin O titer (739 IU/mL) suggested acute rheumatic fever. He met the revised Jones criteria for acute rheumatic fever. Treatment with amoxicillin and corticosteroids rapidly resolved his symptoms and electrocardiographic abnormalities.
2026-08-03 | Epidemiological Characteristics of Acute Rheumatic Fever and Chronic Rheumatic Heart Disease in the Russian Federation and Moscow, 2012–2024
Relevance. Acute rheumatic fever (ARF) and chronic rheumatic heart disease (CRHD) remain important medical and social problems despite a declining prevalence in most developed countries. These conditions are late complications of group A streptococcal infection and are associated with chronic valvular heart disease, disability, and premature mortality. Current evidence indicates persistent regional disparities in disease distribution and possible underestimation of the true disease burden. Aim . To assess long-term trends in the incidence, prevalence, and mortality of ARF and CRHD in the Russian Federation and Moscow during 2012–2024 and to evaluate age-specific and territorial characteristics of disease distribution. Materials and Methods . A retrospective descriptive epidemiological study was conducted. Data were obtained from Federal Statistical Reporting Forms No. 12 and No. 14. Analyses were performed for the total population and for the following age groups: children aged 0–14 years, adolescents aged 15–17 years, adults aged ≥ 18 years, working-age population, and older-than-working-age population. Incidence, prevalence, and mortality rates per 100,000 population, average long-term rates (ALR), average annual growth rates (AAGR), and trend significance coefficients (t) were calculated. Time-series analysis was performed using the least-squares method with trend-line construction. Results. A total of 24,815 cases of acute rheumatic fever (ARF) and 110,255 newly diagnosed cases of chronic rheumatic heart disease (CRHD) were registered in the Russian Federation between 2012 and 2024. A statistically significant decline in the main epidemiological indicators was observed. The incidence of ARF decreased 4.3-fold, from 1.76 to 0.41 per 100,000 population (AAGR = -9.6 %; p < 0.001). The incidence of CRHD decreased 1.8-fold, from 7.31 to 4.09 per 100,000 population (AAGR = -6.2 %; p < 0.001), while the prevalence of CRHD decreased 2.0-fold, from 130.88 to 66.06 per 100,000 population (AAGR = -5.8 %; p < 0.001). Mortality from ARF decreased 9.7-fold, from 0.03 to 0.003 per 100,000 population, whereas mortality from CRHD decreased 1.8-fold, from 1.09 to 0.60 per 100,000 population. The highest ARF incidence (ALR = 5.06 per 100,000 population), CRHD incidence (ALR = 13.67 per 100,000 population), and CRHD prevalence (ALR = 194.68 per 100,000 population) were observed in the North Caucasian Federal District. The highest ARF incidence was recorded among adolescents aged 15–17 years (ALR = 3.62 per 100,000 population), whereas CRHD predominantly affected individuals older than working age, with average long-term incidence and prevalence rates of 8.27 and 210.53 per 100,000 population, respectively. In Moscow, the main epidemiological indicators of ARF and CRHD were lower than the national averages and also demonstrated statistically significant declines over the study period. Conclusion . A decrease in the incidence, prevalence, and mortality associated with ARF and CRHD was observed in the Russian Federation and Moscow during 2012–2024. However, pronounced territorial disparities and age-related differences in disease distribution persist. These findings highlight the need for further improvement of epidemiological surveillance, prevention of group A streptococcal infection and its complications, and early detection of post-streptococcal diseases.
2026-07-30 | The Shared Role of Molecular Mimicry in the Immunopathogenesis of Rheumatic Fever and Toxoplasmosis
Molecular mimicry is considered to be one of the key mechanisms that connects infectious diseases with the onset and progression of autoimmune diseases. This review outlines its contribution to the pathogenesis of acute rheumatic fever (ARF) and Toxoplasma gondii infection, in focusing on the ability of protective immune responses against microbial antigens to target structurally homologous host proteins. In ARF, the infection with Group A Streptococcus (GAS) leads to the activation of cross-reactive autoantibodies and autoreactive T lymphocytes, which mediate inflammatory injury systemically, primarily involving the myocardium, joints, skin and central nervous system. Several streptococcal virulence factors, such as M protein, lipoteichoic acid, hyaluronic acid capsule and secreted exotoxins, are important in the initiation and maintenance of these immune-mediated cascades. Likewise, molecular mimicry, chronic antigenic stimulation and epitope spreading have all been linked to T. gondii infection as a cause of autoimmune pathology which results in the chronic activation of autoreactive immune cell populations. Host immune status plays a significant role in determining clinical manifestations as toxoplasmosis can be asymptomatic and latent in immunocompetent hosts or severe and life-threatening in immunocompromised hosts. These common immunopathological pathways are key to understanding infection-induced autoimmunity and developing specific prevention, diagnosis, and treatment strategies.
2026-07-16 | Targeting canonical TGFβ/SMAD3 and ERK1/2 signaling in human valve interstitial cells to modulate immune-fibrotic responses in rheumatic heart disease.
Rheumatic heart disease (RHD) is a chronic sequel of acute rheumatic fever characterized by sustained inflammation, fibrosis, and valve degeneration; however, the underlying processes remain unclear. To identify dysregulated molecular pathways, we conducted LC-MS/MS-based proteomic profiling of RHD mitral valve tissue compared with ischemic controls and validated systemic inflammation in RHD patients through peripheral blood analysis. Proteomic analysis revealed upregulation of immune response proteins, TGFβ signaling, and extracellular matrix (ECM) regulators. Notably, proteins associated with innate immune activation and macrophage-related pro- and anti-inflammatory responses were found to be enriched. Peripheral blood analysis further confirmed elevated levels of IL6, TNFα, and TIMP1, indicating systemic inflammation. To investigate the underlying mechanisms, we isolated human valve interstitial cells (hVICs) and treated them with proinflammatory stimuli (TNFα, IFNγ) and profibrotic/ anti-inflammatory (TGFβ) stimulation. TGFβ induced morphological changes within 24 h, consistent with fibrotic transformation, and upregulated fibrotic markers (ACTA2, COL1A1, COL1A2, TIMP1, CTGF, MMP2, and TGFβ) along with increased collagen deposition. In contrast, TNFα and IFNγ suppressed fibrotic gene expression while upregulating TIMP1. Notably, TGFβ induced canonical Smad3 phosphorylation, whereas TNFα and IFNγ did not find, any change. Further, macrophage-hVIC interactions were evaluated using conditioned media from M1 [LPS (100 ng/ml) + TNFα (10 ng/ml)] and M2c [TGFβ (10 ng/ml)] polarized macrophages. M2c macrophage-conditioned media enhanced profibrotic gene expression, whereas M1-conditioned media suppressed it, highlighting the role of immune-fibrotic crosstalk in valvular fibrosis. Notably, the 5-HT₂B receptor antagonist SB204741 and tadalafil effectively inhibited TGFβ-induced Smad3 phosphorylation in hVICs, thereby reducing fibrotic signaling. In addition, tadalafil selectively suppressed ERK1/2-mediated non-canonical signaling, while no significant changes were observed in the STAT3, p38 MAPK and JNK pathways. Collectively, these findings identify immune-fibrotic crosstalk and selective activation of canonical TGFβ/Smad3 and ERK1/2-mediated non-canonical signaling pathways as important contributors to valvular fibrosis in rheumatic heart disease and suggest that targeting these pathways may provide potential therapeutic approaches to limit disease progression.
antibodies
2026-06-29 | <b>Post-Infectious Autoimmunity: Why a Sore Throat or a Stomach Bug Can Lead to Lifelong Self-AttackA Unified “Three-Hit” Framework from Rheumatic Fever to Long‑COVID</b>
Post‑infectious autoimmune diseases affect millions worldwide, yet the transition from a seemingly trivial sore throat or gastrointestinal upset to a chronic, often lifelong, self‑directed immune attack remains one of medicine’s most unsettling paradoxes. This review synthesises over a century of clinical observation and mechanistic immunology into a unified model—the Three‑Hit Framework—comprising (i) a pathogen‑encoded molecular mimic or innate danger signal, (ii) infection‑driven tissue damage that releases cryptic self‑antigens, and (iii) a permissive genetic background that fails to extinguish autoreactive lymphocytes. We dissect the conserved rules of molecular mimicry, bystander activation, and epitope spreading, tracing them from classical prototypes (rheumatic fever, Guillain–Barré syndrome) through contemporary entities (PANDAS, long‑COVID‑associated autoantibodies). By framing autoimmunity as an evolutionary collision between host defence and self‑tolerance, we highlight rational early‑interruption strategies: rapid pathogen clearance, targeted dampening of innate inflammation at the critical “checkpoint” between infection and autoreactivity, and restoration of regulatory networks. This narrative not only offers a mechanistic scaffold for researchers and clinicians but also provides a deeply human explanation for patients seeking to understand how a mild bug turned their immune system into a lifelong foe.
2026-01-07 | Sydenham Chorea With Elevated Interleukin-12 Levels Responsive to Plasmapheresis and Immunotherapy.
Sydenham chorea (SC) presents with random abnormal involuntary movements that occur after an autoimmune reaction to a prior group A beta-hemolytic streptococcal infection. While most cases resolve spontaneously, some cases have a prolonged duration of symptoms and recurrences. We discuss a 22-year-old woman who presented with a two-month history of involuntary, brief, random, and irregular movements of the limbs. She had a history of multiple streptococcal throat infections. At age two, she had scarlet fever. After ruling out other causes of chorea, she was diagnosed with Sydenham chorea. She was treated with intravenous immunoglobulin, oral prednisone, and amantadine, resulting in full symptom resolution. Interleukin-12 (IL-12) was elevated approximately seven months after hospital discharge. Chronic elevation of IL-12 differs from previously published findings, which describe elevation only during the acute phase of the disease. Intensive immunosuppressive treatment during the acute phase, along with adherence to antibiotic therapy, may have contributed to the full resolution of her chorea.
2025-12-26 | Resurgence of rheumatic fever among Pacific peoples in Aotearoa New Zealand: A 2010-2023 analysis of hospitalisation data with implications for equity policy.
The objective of this study was to assess ethnic, geographic and socioeconomic patterns in acute rheumatic fever and rheumatic heart disease hospitalisations in New Zealand (2010-2023), evaluate the impact of public health interventions and identify gaps in national surveillance. National hospitalisation and mortality data were analysed by ethnicity, socioeconomic deprivation and geography, including Counties Manukau and the Ōtara-Papatoetoe Locality. Negative binomial models estimated adjusted risk differences across three time periods. Acute rheumatic fever was disproportionately concentrated among Māori and Pacific peoples in the most socioeconomically deprived areas, with Pacific populations-particularly in Counties Manukau-experiencing the highest burden. Acute rheumatic fever declined among Māori during the Rheumatic Fever Prevention Programme but not among Pacific peoples. A sharp, temporary decline in acute rheumatic fever and rheumatic heart disease hospitalisations occurred among Pacific populations during the COVID-19 pandemic, followed by resurgence by 2023. Persistent ethnic and geographic inequities in acute rheumatic fever and rheumatic heart disease reflect ongoing surveillance gaps, inconsistent notification practices and uneven implementation of interventions. National targets remain unmet, and inequities are widening for some groups. Robust, standardised surveillance systems and equity-focused interventions-particularly for Pacific communities in Counties Manukau-are essential to reducing the preventable burden of acute rheumatic fever and rheumatic heart disease in Aotearoa New Zealand.
2025-11-03 | Abstract 4359896: Interleukin-1 Blockade for Rheumatic Fever Pericarditis in a Steroid-Intolerant Patient: A Case Report
Introduction: In developed nations, acute rheumatic fever (ARF) is a rare cause of pancarditis, including pericarditis. Corticosteroids, though second-line agents for pericarditis, are frequently used to treat the cardiac and joint manifestations of ARF. Interleukin-1 (IL-1) inhibitors offer targeted therapy in recurrent idiopathic pericarditis, yet their role in ARF-related pericarditis remains undefined. We describe the application of IL-1 blockade to post-streptococcal, autoimmune-mediated pericarditis in a patient intolerant to corticosteroids. Case Report: A 38-year-old man with pre-diabetes, hyperlipidemia, and recent upper respiratory infection presented with acute right hip arthritis and elevated inflammatory markers (CRP 190.6 mg/L, ESR 108 mm/hr). Arthrocentesis yielded inflammatory synovial fluid without infection. Symptoms resolved with NSAIDs, prompting discharge. Four days later, he returned with high-grade fevers and diffuse polyarthralgia involving his wrists, hands, ankles, and feet. Exam uncovered migratory arthritis of the right hip and bilateral wrists. Labs showed CRP > 500 mg/L, high-titer antistreptolysin-O, leukocytosis, and acute kidney injury (AKI) with active urinary sediment. The presentation met Jones criteria for adult-onset ARF. Prednisone was started instead of NSAIDs for polyarthritis due to his AKI (figure 1). Following renal recovery with supportive care, he developed pleuritic chest pain, a precordial friction rub, and a HS-troponin peak of 195 ng/L. ECG demonstrated diffuse ST elevations, PR depression, and Spodick’s sign. Echocardiography revealed a small-moderate pericardial effusion. Cardiac MRI showed no myocardial involvement but increased T2 signal and late gadolinium enhancement consistent with pericarditis. Colchicine and high-dose aspirin were initiated, which improved his chest pain and CRP (62 mg/L). However, prednisone taper triggered rebound chest pain, arthritis, and CRP elevation (348 mg/L). He declined a prolonged course of high-dose steroids due to anxiety and hyperglycemia. Anakinra was added, resulting in symptom relief and CRP reduction (2 mg/L). He was transitioned to weekly rilonacept at discharge. Conclusion: This case highlights IL-1 inhibition as a promising therapy in rare presentations of ARF-induced pericarditis, especially when corticosteroids are not tolerated. Using anakinra as a bridge to outpatient rilonacept may offer a targeted, steroid-sparing strategy in persistent pericarditis from ARF.
2025-10-01 | Identification of therapeutic targets for rheumatic heart valve disease based on systematic druggable genome wide Mendelian randomization.
Rheumatic heart valve disease (RHD) is a chronic immune valvular heart disease caused by rheumatic fever, primarily affecting the mitral and aortic valves. It often leads to atrial fibrillation, heart failure, and even premature death. Currently, there are no effective therapeutic drugs available, partially due to the lack of appropriate therapeutic targets. To identify therapeutic targets for RHD, we employed a 2-sample Mendelian randomization approach integrating identified druggable genomics to assess the causal effect of expression quantitative trait loci of druggable genes in the blood on RHD. Subsequently, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses on the druggable genes. We used colocalization analysis to test whether the risk of RHD and gene expression are driven by common single nucleotide polymorphisms. Additionally, the Comparative Toxicogenomics Database was utilized to evaluate the impact of environmental exposures on druggable genes, and molecular docking was conducted to identify potential small molecule interactions. A total of 6888 druggable genes were collected. After conducting various Mendelian randomization analyses and applying false discovery rate correction, we identified 13 drug targets for RHD: TFRC, FMO4, CA2, HLA-DPB2, OXTR, GRAMD1B, PNP, HLA-DPB1, leukocyte immunoglobulin-like receptor B1 (LILRB1), TUBB, LGR6, F13A1, and LPL. These targets were found to be closely related to immune regulation and inflammatory response in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Bayesian colocalization analysis established an interaction between LILRB1 and RHD, with a PP.H4 >0.5, LILRB1 demonstrated a protective effect in RHD (OR = 0.833, 95% confidence interval, 0.699-0.993). Comparative Toxicogenomics Database analysis identified several small molecules influencing LILRB1 mRNA expression, with lipopolysaccharide showing excellent binding affinity in molecular docking with LILRB1 against available structural data for drugs and proteins. Based on a cohort of European ancestry, this study reveals 13 potential therapeutic targets for RHD, with LILRB1 showing particularly promising prospects as a future therapeutic target for RHD.
vaccines
2026-04-18 | A non-conjugated peptide-adjuvant system of synthetic peptide-vaccine elicited potent antibody response and opsonic protection against clinical GAS strains.
Group A Streptococcus (GAS) is a causative agent of life-threatening infections, including pharyngitis, rheumatic fever, and rheumatic heart disease. Currently, no commercial vaccines are licenced to prevent GAS infections. Synthetic peptide-based subunit vaccines composed of minimal antigenic fragments derived from the pathogenic M-protein, represent an attractive approach for mitigating GAS infection transmission. However, such small antigens are poorly immunogenic, necessitating their co-administration with strong immunostimulatory agents (adjuvants). Herein, we proposed the use of self-assembled peptides as the adjuvant by developing non-conjugated peptide-adjuvant system of GAS synthetic peptide-based vaccine in which a synthetic GAS antigen PADRE-J8 (composed of B cell epitope J8 and the universal T-helper epitope PADRE) was physically mixed with a lipopeptide TLR2 agonist (KKSS-C16-C16) and self-assembled peptides. In mice, all vaccine candidates induced antigen-specific systemic immunoglobulin G (IgG) antibodies after subcutaneous immunisation. Among them, a physical mixture of a self-assembled peptide Nap-GFFY, lipopeptide KKSS-C16-C16, and PADRE-J8 antigen (SPV-5) induced the highest antibodies production and produced antibodies were opsonic against GAS clinical isolates. The vaccine formulation lacking the lipopeptide KKSS-C16-C16 (SPV-5(-)) generated J8-specific antibodies; however, their opsonization capacity was poor, indicating that both the self-assembled peptide and the lipopeptide were essential for eliciting strong opsonic responses against bacteria.
2026-03-16 | Early rheumatic heart disease is a recognized intermediate on the pathway to advanced rheumatic heart disease.
Rheumatic heart disease is a major cause of premature cardiovascular morbidity and mortality globally. Over the past decade, echocardiographic screening has changed our understanding of the natural history of RHD, revealing a high burden of clinically silent, mild RHD among people who cannot recall a history of preceding acute rheumatic fever. This viewpoint outlines the evidence that this earliest form of rheumatic heart disease, only detectable through echocardiographic screening, is an intermediate stage that many, but not all, individuals may pass through on the pathway to advanced rheumatic heart disease. This shift in understanding has important clinical and research implications, including introducing a new and more pragmatic target for Streptococcus pyogenes vaccine trials for the indication of rheumatic heart disease prevention.
2025-11-04 | No compelling evidence that vaccination with streptococcus pyogenes group A carbohydrate elicits cross-reactive rheumatic fever autoantibodies.
We reviewed 70 years of research defining the specificity of anti-group A carbohydrate (GAC) monoclonal and polyclonal antibodies and antibodies raised against other S. pyogenes components reacting with GAC. While some rheumatic fever associated autoantibodies react with N-Acetyl-β-D-glucosamine sidechains of GAC and cross-react with tissues, these appear to be a consequence, not the cause, of autoimmunity. We propose GAC be considered further as a broadly protective group A streptococcal vaccine. (70 words).
2025-05-16 | Household Molecular Epidemiology of Streptococcus pyogenes Carriage and Infection in The Gambia.
Africa experiences a high burden of Streptococcus pyogenes disease but has limited epidemiological data. We characterized emm types and emm clusters associated with carriage and disease in The Gambia, a setting with a high rheumatic heart disease burden. A 1-year household cohort study (2021-2022) recruited 442 participants from 44 households to assess S. pyogenes carriage and noninvasive infection. Pharyngeal and skin swab samples were collected to detect carriage, and pharyngitis and pyoderma swab samples were taken to assess infection. Cultured isolates underwent emm typing and were compared with previous collection from the same region. A total of 221 cultured isolates showed 52 different emm types and 16 emm clusters. Strain diversity was high (Simpson reciprocal index, 29.3 [95% confidence interval, 24.8-36.0]), with the highest diversity seen in pyoderma and the lowest in pharyngitis. Based on available cross-opsonization data, the 30-valent M-protein vaccine candidate would cover 50.8% of the isolates, but cross-opsonization data are unknown for 38.5% of them. The emm clusters showed lower diversity and were stable over time, with 4 clusters defining 65.2% of the isolates; 68% of isolates were collected from skin sites (carriage and pyoderma), with evidence of skin-to-throat transmission in the same host. This study provides a unique molecular analysis of skin and throat isolates prospectively collected from persons with carriage and noninvasive infection in Africa. Despite high strain diversity, 4 clusters included two-thirds of the isolates, representing antigen priorities for broad vaccine coverage. In this rheumatic fever-endemic setting, pyoderma and skin carriage represent an important S. pyogenes reservoir and should be included in further surveillance studies and public health interventions. NCT05117528.
2025-04-12 | The epidemiology of repeatedly positive bacterial skin infections in Auckland children, New Zealand.
Māori and Pacific New Zealanders are disproportionately affected by Acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Repeated S. pyogenes skin infections in childhood are thought to increase the risk of developing ARF/RHD. This study investigated the epidemiology of repeated bacterial skin infections within Auckland, New Zealand. Microbiology results from wound swabs collected in primary care between 2010 and 2020 were used to estimate the rate of repeatedly positive infections, along with rate ratios and 95% CIs, across demographic groups. S. aureus infections impacted all groups; but Māori (Rate Ratio: 10.0, 95% CI: 8.5-11.6) and Pacific children (Rate Ratio: 14.6, 95% CI: 12.6-17.0) under 10 years of age were at a greater risk of repeated S. pyogenes infections compared to their non-Māori/non-Pacific counterparts. The relative risk of subsequent S. pyogenes infection was 4.1 times higher (95% CI: 4.0-4.3) following an initial S. pyogenes infection compared to those negative for S. pyogenes. Māori and Pacific children's heightened vulnerability to repeated S. pyogenes skin infections supports the immune priming theory of ARF/RHD. Targeted public health initiatives, primary care interventions and Group A Streptococcal vaccine are crucial to reduce repeated S. pyogenes exposure and potentially lower ARF risks.
proteins
2026-07-08 | Inflammatory and hormonal crosstalk linking rheumatic fever to chronic valvular heart disease.
Rheumatic heart disease (RHD) is a chronic, immune-mediated valvular disorder triggered by Group A β-hemolytic streptococcal infection. Persistent inflammation and immune-mediated tissue injury are central features of disease progression, whereas the roles of hormonal and metabolic regulatory pathways remain less well defined. Emerging evidence suggests that inflammatory signaling may intersect with hormonal and metabolic pathways during the transition from rheumatic fever to chronic valvular disease. Pro-inflammatory mediators have been associated with immune activation and extracellular matrix remodeling, with potential involvement of pathways such as nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and the NOD-like receptor protein 3 inflammasome. Chronic inflammation may also be accompanied by altered neuroendocrine anti-inflammatory feedback, including changes in glucocorticoid receptor signaling and hypothalamic-pituitary-adrenal axis regulation. In addition, sex hormones, thyroid hormones, and metabolic hormones may be linked to immune-cell differentiation, endothelial function, and valvular cell phenotypes, suggesting a possible inflammatory-endocrine regulatory loop that remains insufficiently validated in RHD-specific studies. These relationships may provide a context for understanding valvular interstitial cell activation, endothelial dysfunction, endothelial-mesenchymal transition, metabolic reprogramming, energy imbalance, fibrosis, and calcification, but direct causal evidence remains limited. Future dual-target strategies addressing both inflammatory and hormonal signaling may provide a theoretical framework for individualized intervention; however, their efficacy and safety require rigorous RHD-specific validation. This review summarizes current evidence and discusses the inflammatory-hormonal network as a hypothesis-generating framework for understanding chronic rheumatic valvular remodeling.
2025-08-22 | Low-Dose Interleukin-2 Therapy: A Transformative Approach for the Management of Autoimmune Complications Associated with Streptococcus pyogenes Infections
Acute rheumatic fever is an autoimmune inflammatory reaction to Streptococcus pyogenes infections, leading to progressive heart valve damage and rheumatic heart disease (RHD) [...]
2025-02-25 | Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease.
Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T cells targeting the group A Streptococcus (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD) and Sydenham's chorea. Long-term monthly penicillin injections are recognized as a cornerstone of public health programs to prevent Strep A reinfection and progression of ARF. However, compliance is poor, and better tools are required to slow disease progression. Preclinical evidence suggests that this can be achieved. Using a rat model that replicates post-streptococcal autoimmune complications, we explored the potential of low-dose interleukin-2 (LD-IL-2) as an immunotherapeutic intervention for ARF/RHD. In this model, injections of recombinant M protein from Strep A type 5 (rM5) to Lewis rats induce cardiac tissue inflammation, conduction abnormalities, and cross-reactive antibodies against cardiac and brain proteins central to disease pathogenesis. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes was observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies raised against host proteins and significantly increased regulatory T cells in the mediastinal lymph nodes. These novel findings suggest that LD-IL-2 will be an effective immunotherapeutic agent for treating ARF and has the potential to replace the standard monthly penicillin injections. Post-streptococcal autoimmune syndromes, including acute rheumatic fever, rheumatic heart disease, and Sydenham's chorea, represent a significant yet often under-recognized health and economic burden. This is especially true in low-income countries and among Indigenous populations in high-income nations, where the disease burden is most severe. These conditions arise from an autoimmune response to group A Streptococcus infections, leading to long-term health complications, disability, and premature death. Despite their widespread impact, no vaccine is currently available to prevent reinfections, and no specific therapy exists to treat the resulting autoimmune process. This study uses a rat model of rheumatic heart disease to evaluate the potential of low-dose interleukin 2 therapy in improving clinical outcomes and reducing the incidence of autoimmune diseases triggered by streptococcal infections.
2024-08-12 | Immunotherapeutic strategy to prevent progression and complications of acute rheumatic fever
Abstract Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T-cells targeting the Group A streptococcal (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD). Long-term antibiotic therapy is recognized as a cornerstone of public health programs to prevent reinfection and progression of ARF. However, better tools to slow disease progression, and mitigate its lifelong consequences are required. Evidence obtained in a preclinical model suggests that this can be achieved. Using the rat autoimmune valvulitis model, we explored the potential of low-dose interleukin 2 (LD-IL-2) as an immunotherapeutic intervention. In this model injection of recombinant Strep A M5 protein (rM5) to Lewis rats induce autoimmune complications, cardiac tissue inflammation and conduction abnormalities. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes were observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies against cardiac tissue and induced a significant increase in classical regulatory T-cells (Treg) and CD8 + Tregs in the mediastinal (heart-draining) lymph nodes. These novel findings suggest LD-IL-2 will be an effective immunotherapeutic agent for treating ARF/RHD.
2021-02-25 | Nonimmune antibody interactions of Group A Streptococcus M and M-like proteins
M and M-like proteins are major virulence factors of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes . These proteins confer resistance against innate and adaptive immune responses by recruiting specific human proteins to the streptococcal surface. Nonimmune recruitment of immunoglobulins G (IgG) and A (IgA) through their fragment crystallizable (Fc) domains by M and M-like proteins was described almost 40 years ago, but its impact on virulence remains unresolved. These interactions have been suggested to be consequential under immune conditions at mucosal surfaces and in secretions but not in plasma, while other evidence suggests importance in evading phagocytic killing in nonimmune blood. Recently, an indirect effect of Fc-binding through ligand-induced stabilization of an M-like protein was shown to increase virulence. Nonimmune recruitment has also been seen to contribute to tissue damage in animal models of autoimmune diseases triggered by S . pyogenes infection. The damage was treatable by targeting Fc-binding. This and other potential therapeutic applications warrant renewed attention to Fc-binding by M and M-like proteins.
other
2026-05-25 | The "Cairo Accord"- towards the eradication of RHD: revisited (2026).
Rheumatic heart disease (RHD) continues to be a significant global health burden, particularly in resource-limited regions of the world. This preventable and often neglected disease affects predominantly children and young adults, leading to considerable morbidity and mortality. In this article, we revisit the Cairo Accord that aims to address the challenges of RHD and set policy priorities for its eradication. We highlight the most remarkable progress in the field since the 2021 update, formulating updated recommendations. These include enhancing disease registries and echocardiographic screening, advance research on host and streptococcal strains genetics, biomarkers, vaccines, pharmaceuticals and penicillin prophylaxis, accelerate the development of regional Centers of Excellence, promoting MV repair and the development of tissue-engineered valve substitutes.
2024-09-02 | Immunogenicity of a 30-valent M protein mRNA group A Streptococcus vaccine.
Group A Streptococcus (Strep A) causes both uncomplicated and severe invasive infections, as well as the post-infection complications acute rheumatic fever and rheumatic heart disease. Despite the high global burden of disease resulting from Strep A infections, there is not a licensed vaccine. A 30-valent M protein-based vaccine has previously been shown to be immunogenic in animal models and in a Phase I clinical trial (NCT02564237). Here, we assessed the immunogenicity of a 30-valent messenger (m)RNA vaccine designed to express the same M peptide targets as the 30-valent protein vaccine and compared it with the protein vaccine. Female New Zealand white rabbits were immunized with one of four vaccine formulations (3 doses of each formulation at days 1, 28, and 56): soluble mRNA (100 μg/animal), C-terminal transmembrane mRNA (100 μg/animal), protein vaccine (400 μg/animal), or a non-translatable RNA control (100 μg/animal). Serum was collected one day prior to the first dose and on days 42 and 70. Rabbit serum samples were assayed for antibody levels against synthetic M peptides by ELISA. HL-60 opsonophagocytic killing (OPK) assays were performed to assess functional antibody levels. Serum IgG levels were similar for the mRNA and protein vaccines. The CtTM version of the mRNA vaccine elicited slightly higher antibody levels than the mRNA designed to express soluble proteins. OPK activity was similar for the mRNA and protein vaccines, regardless of M type. The total antibody responses and functional antibody levels elicited by the 30-valent mRNA Strep A vaccines were similar to those observed following immunization with the analogous protein vaccine. The mRNA vaccine platform provides potential advantages to protein-based vaccines including inherent adjuvant activity, increased production efficiency, lower cost, and the potential to rapidly change epitopes/peptides, all of which are important considerations related to multivalent Strep A vaccine development.
2021-11-23 | Recent Progress Toward Clinical Translation of Tissue-Engineered Heart Valves.
Surgical replacement remains the primary option to treat the rapidly growing number of patients with severe valvular heart disease. Although current valve replacements-mechanical, bioprosthetic, and cryopreserved homograft valves-enhance survival and quality of life for many patients, the ideal prosthetic heart valve that is abundantly available, immunocompatible, and capable of growth, self-repair, and life-long performance has yet to be developed. These features are essential for pediatric patients with congenital defects, children and young adult patients with rheumatic fever, and active adult patients with valve disease. Heart valve tissue engineering promises to address these needs by providing living valve replacements that function similarly to their native counterparts. This is best evidenced by the long-term clinical success of decellularised pulmonary and aortic homografts, but the supply of homografts cannot meet the demand for replacement valves. A more abundant and consistent source of replacement valves may come from cellularised valves grown in vitro or acellular off-the-shelf biomaterial/tissue constructs that recellularise in situ, but neither tissue engineering approach has yet achieved long-term success in preclinical testing. Beyond the technical challenges, heart valve tissue engineering faces logistical, economic, and regulatory challenges. In this review, we summarise recent progress in heart valve tissue engineering, highlight important outcomes from preclinical and clinical testing, and discuss challenges and future directions toward clinical translation.
2004-04-01 | Acute rheumatic fever: a chink in the chain that links the heart to the throat?
Acute rheumatic fever (ARF) remains a major problem in tropical regions, resource-poor countries, and minority indigenous communities. It has long been thought that group A streptococcal (GAS) pharyngitis alone was responsible for acute rheumatic fever; this belief has been supported by laboratory and epidemiological evidence gathered over more than 60 years, mainly in temperate climates where GAS skin infection is uncommon. GAS strains have been characterised as either rheumatogenic or nephritogenic based on phenotypic and genotypic properties. Primary prevention strategies and vaccine development have long been based on these concepts. The epidemiology of ARF in Aboriginal communities of central and northern Australia challenges this view with reported rates of ARF and rheumatic heart disease (RHD) that are among the highest in the world. GAS throat colonisation is uncommon, however, and symptomatic GAS pharyngitis is rare; pyoderma is the major manifestation of GAS infection. Typical rheumatogenic strains do not occur. Moreover, group C and G streptococci have been shown to exchange key virulence determinants with GAS and are more commonly isolated from the throats of Aboriginal children. We suggest that GAS pyoderma and/or non-GAS infections are driving forces behind ARF in these communities and other high-incidence settings. The question needs to be resolved as a matter of urgency because current approaches to controlling ARF/RHD in Aboriginal communities have clearly been ineffective. New understanding of the pathogenesis of ARF would have an immediate effect on primary prevention strategies and vaccine development.
1967-01-16 | Therapeutic Surgical Division of the Human Conduction System
A 51-year-old woman was severely incapacitated because of intractable supraventricular tachycardias and rheumatic heart disease involving the aortic and mitral valves. The arrhythmias were not prevented by a variety of drug regimens, and over 200 cardioversions were done. It was believed that the arrhythmias had to be positively controlled if valvular surgery was to be successful. At open-heart surgery the aortic and mitral valves were replaced with ball-valve prostheses and the conduction bundle was divided in the region of the atrioventricular (AV) node. Permanent pacemaker leads were attached to the epicardium. Early postoperatively there was complete AV dissociation with a ventricular rate of 60 beats per minute. Later the ventricular rate slowed to 48 and a pacemaker was connected to the implanted leads for permanent ventricular pacing at 75 beats per minute.
small molecules
2026-08-13 | Whitia Kia Ora: a culturally responsive model of Bicillin L-A® delivery for people with rheumatic fever in the Waikato region of Aotearoa New Zealand.
Acute rheumatic fever (ARF) is an autoimmune response to group A Streptococcus (Strep A) infection that can lead to rheumatic heart disease (RHD). To prevent Strep A infection for people with ARF or RHD, clinical guidelines recommend monthly intramuscular penicillin (Bicillin L-A®) injections for at least 10 years. However, multiple barriers to accessing healthcare affect adherence. This research aimed to improve adherence by developing a Māori and Pacific-centred model of care. Qualitative, Kaupapa Māori and Kakala methodology underpinned the research. Data collection from people in the Waikato region with ARF, their whānau and healthcare providers included interviews, wānanga and fono. Data were analysed using a general inductive approach. Forty-seven participants were included: nine people with ARF, 10 whānau, eight health professionals and 21 whānau navigators. Three themes were identified: impacts of a colonial health system on Indigenous whānau; life defined by a disease status; and catalysts of healthcare engagement. A community informed, Whānau Ora model of care was also developed. Indigenous methodologies are effective methods to develop community informed, culturally responsive models of care. Although designed for ARF in Waikato, there is potential to adapt this approach for other health conditions and different regions of Aotearoa New Zealand.
2026-08-07 | Acute Rheumatic Fever Without Pharyngitis: A Case Report.
An 18-year-old man presented with fatigue and polyarthralgia refractory to nonsteroidal anti-inflammatory drugs (NSAIDs). He had no history of sore throat or other upper respiratory symptoms. Reactive arthritis was initially suspected. However, persistent symptoms, fever, polyarthritis, a cardiac murmur, atrioventricular block, and an elevated antistreptolysin O titer (739 IU/mL) suggested acute rheumatic fever. He met the revised Jones criteria for acute rheumatic fever. Treatment with amoxicillin and corticosteroids rapidly resolved his symptoms and electrocardiographic abnormalities.
2026-08-03 | Epidemiological Characteristics of Acute Rheumatic Fever and Chronic Rheumatic Heart Disease in the Russian Federation and Moscow, 2012–2024
Relevance. Acute rheumatic fever (ARF) and chronic rheumatic heart disease (CRHD) remain important medical and social problems despite a declining prevalence in most developed countries. These conditions are late complications of group A streptococcal infection and are associated with chronic valvular heart disease, disability, and premature mortality. Current evidence indicates persistent regional disparities in disease distribution and possible underestimation of the true disease burden. Aim . To assess long-term trends in the incidence, prevalence, and mortality of ARF and CRHD in the Russian Federation and Moscow during 2012–2024 and to evaluate age-specific and territorial characteristics of disease distribution. Materials and Methods . A retrospective descriptive epidemiological study was conducted. Data were obtained from Federal Statistical Reporting Forms No. 12 and No. 14. Analyses were performed for the total population and for the following age groups: children aged 0–14 years, adolescents aged 15–17 years, adults aged ≥ 18 years, working-age population, and older-than-working-age population. Incidence, prevalence, and mortality rates per 100,000 population, average long-term rates (ALR), average annual growth rates (AAGR), and trend significance coefficients (t) were calculated. Time-series analysis was performed using the least-squares method with trend-line construction. Results. A total of 24,815 cases of acute rheumatic fever (ARF) and 110,255 newly diagnosed cases of chronic rheumatic heart disease (CRHD) were registered in the Russian Federation between 2012 and 2024. A statistically significant decline in the main epidemiological indicators was observed. The incidence of ARF decreased 4.3-fold, from 1.76 to 0.41 per 100,000 population (AAGR = -9.6 %; p < 0.001). The incidence of CRHD decreased 1.8-fold, from 7.31 to 4.09 per 100,000 population (AAGR = -6.2 %; p < 0.001), while the prevalence of CRHD decreased 2.0-fold, from 130.88 to 66.06 per 100,000 population (AAGR = -5.8 %; p < 0.001). Mortality from ARF decreased 9.7-fold, from 0.03 to 0.003 per 100,000 population, whereas mortality from CRHD decreased 1.8-fold, from 1.09 to 0.60 per 100,000 population. The highest ARF incidence (ALR = 5.06 per 100,000 population), CRHD incidence (ALR = 13.67 per 100,000 population), and CRHD prevalence (ALR = 194.68 per 100,000 population) were observed in the North Caucasian Federal District. The highest ARF incidence was recorded among adolescents aged 15–17 years (ALR = 3.62 per 100,000 population), whereas CRHD predominantly affected individuals older than working age, with average long-term incidence and prevalence rates of 8.27 and 210.53 per 100,000 population, respectively. In Moscow, the main epidemiological indicators of ARF and CRHD were lower than the national averages and also demonstrated statistically significant declines over the study period. Conclusion . A decrease in the incidence, prevalence, and mortality associated with ARF and CRHD was observed in the Russian Federation and Moscow during 2012–2024. However, pronounced territorial disparities and age-related differences in disease distribution persist. These findings highlight the need for further improvement of epidemiological surveillance, prevention of group A streptococcal infection and its complications, and early detection of post-streptococcal diseases.
2026-07-30 | The Shared Role of Molecular Mimicry in the Immunopathogenesis of Rheumatic Fever and Toxoplasmosis
Molecular mimicry is considered to be one of the key mechanisms that connects infectious diseases with the onset and progression of autoimmune diseases. This review outlines its contribution to the pathogenesis of acute rheumatic fever (ARF) and Toxoplasma gondii infection, in focusing on the ability of protective immune responses against microbial antigens to target structurally homologous host proteins. In ARF, the infection with Group A Streptococcus (GAS) leads to the activation of cross-reactive autoantibodies and autoreactive T lymphocytes, which mediate inflammatory injury systemically, primarily involving the myocardium, joints, skin and central nervous system. Several streptococcal virulence factors, such as M protein, lipoteichoic acid, hyaluronic acid capsule and secreted exotoxins, are important in the initiation and maintenance of these immune-mediated cascades. Likewise, molecular mimicry, chronic antigenic stimulation and epitope spreading have all been linked to T. gondii infection as a cause of autoimmune pathology which results in the chronic activation of autoreactive immune cell populations. Host immune status plays a significant role in determining clinical manifestations as toxoplasmosis can be asymptomatic and latent in immunocompetent hosts or severe and life-threatening in immunocompromised hosts. These common immunopathological pathways are key to understanding infection-induced autoimmunity and developing specific prevention, diagnosis, and treatment strategies.
2026-07-16 | Targeting canonical TGFβ/SMAD3 and ERK1/2 signaling in human valve interstitial cells to modulate immune-fibrotic responses in rheumatic heart disease.
Rheumatic heart disease (RHD) is a chronic sequel of acute rheumatic fever characterized by sustained inflammation, fibrosis, and valve degeneration; however, the underlying processes remain unclear. To identify dysregulated molecular pathways, we conducted LC-MS/MS-based proteomic profiling of RHD mitral valve tissue compared with ischemic controls and validated systemic inflammation in RHD patients through peripheral blood analysis. Proteomic analysis revealed upregulation of immune response proteins, TGFβ signaling, and extracellular matrix (ECM) regulators. Notably, proteins associated with innate immune activation and macrophage-related pro- and anti-inflammatory responses were found to be enriched. Peripheral blood analysis further confirmed elevated levels of IL6, TNFα, and TIMP1, indicating systemic inflammation. To investigate the underlying mechanisms, we isolated human valve interstitial cells (hVICs) and treated them with proinflammatory stimuli (TNFα, IFNγ) and profibrotic/ anti-inflammatory (TGFβ) stimulation. TGFβ induced morphological changes within 24 h, consistent with fibrotic transformation, and upregulated fibrotic markers (ACTA2, COL1A1, COL1A2, TIMP1, CTGF, MMP2, and TGFβ) along with increased collagen deposition. In contrast, TNFα and IFNγ suppressed fibrotic gene expression while upregulating TIMP1. Notably, TGFβ induced canonical Smad3 phosphorylation, whereas TNFα and IFNγ did not find, any change. Further, macrophage-hVIC interactions were evaluated using conditioned media from M1 [LPS (100 ng/ml) + TNFα (10 ng/ml)] and M2c [TGFβ (10 ng/ml)] polarized macrophages. M2c macrophage-conditioned media enhanced profibrotic gene expression, whereas M1-conditioned media suppressed it, highlighting the role of immune-fibrotic crosstalk in valvular fibrosis. Notably, the 5-HT₂B receptor antagonist SB204741 and tadalafil effectively inhibited TGFβ-induced Smad3 phosphorylation in hVICs, thereby reducing fibrotic signaling. In addition, tadalafil selectively suppressed ERK1/2-mediated non-canonical signaling, while no significant changes were observed in the STAT3, p38 MAPK and JNK pathways. Collectively, these findings identify immune-fibrotic crosstalk and selective activation of canonical TGFβ/Smad3 and ERK1/2-mediated non-canonical signaling pathways as important contributors to valvular fibrosis in rheumatic heart disease and suggest that targeting these pathways may provide potential therapeutic approaches to limit disease progression.
antibodies
2026-06-29 | <b>Post-Infectious Autoimmunity: Why a Sore Throat or a Stomach Bug Can Lead to Lifelong Self-AttackA Unified “Three-Hit” Framework from Rheumatic Fever to Long‑COVID</b>
Post‑infectious autoimmune diseases affect millions worldwide, yet the transition from a seemingly trivial sore throat or gastrointestinal upset to a chronic, often lifelong, self‑directed immune attack remains one of medicine’s most unsettling paradoxes. This review synthesises over a century of clinical observation and mechanistic immunology into a unified model—the Three‑Hit Framework—comprising (i) a pathogen‑encoded molecular mimic or innate danger signal, (ii) infection‑driven tissue damage that releases cryptic self‑antigens, and (iii) a permissive genetic background that fails to extinguish autoreactive lymphocytes. We dissect the conserved rules of molecular mimicry, bystander activation, and epitope spreading, tracing them from classical prototypes (rheumatic fever, Guillain–Barré syndrome) through contemporary entities (PANDAS, long‑COVID‑associated autoantibodies). By framing autoimmunity as an evolutionary collision between host defence and self‑tolerance, we highlight rational early‑interruption strategies: rapid pathogen clearance, targeted dampening of innate inflammation at the critical “checkpoint” between infection and autoreactivity, and restoration of regulatory networks. This narrative not only offers a mechanistic scaffold for researchers and clinicians but also provides a deeply human explanation for patients seeking to understand how a mild bug turned their immune system into a lifelong foe.
2026-01-07 | Sydenham Chorea With Elevated Interleukin-12 Levels Responsive to Plasmapheresis and Immunotherapy.
Sydenham chorea (SC) presents with random abnormal involuntary movements that occur after an autoimmune reaction to a prior group A beta-hemolytic streptococcal infection. While most cases resolve spontaneously, some cases have a prolonged duration of symptoms and recurrences. We discuss a 22-year-old woman who presented with a two-month history of involuntary, brief, random, and irregular movements of the limbs. She had a history of multiple streptococcal throat infections. At age two, she had scarlet fever. After ruling out other causes of chorea, she was diagnosed with Sydenham chorea. She was treated with intravenous immunoglobulin, oral prednisone, and amantadine, resulting in full symptom resolution. Interleukin-12 (IL-12) was elevated approximately seven months after hospital discharge. Chronic elevation of IL-12 differs from previously published findings, which describe elevation only during the acute phase of the disease. Intensive immunosuppressive treatment during the acute phase, along with adherence to antibiotic therapy, may have contributed to the full resolution of her chorea.
2025-12-26 | Resurgence of rheumatic fever among Pacific peoples in Aotearoa New Zealand: A 2010-2023 analysis of hospitalisation data with implications for equity policy.
The objective of this study was to assess ethnic, geographic and socioeconomic patterns in acute rheumatic fever and rheumatic heart disease hospitalisations in New Zealand (2010-2023), evaluate the impact of public health interventions and identify gaps in national surveillance. National hospitalisation and mortality data were analysed by ethnicity, socioeconomic deprivation and geography, including Counties Manukau and the Ōtara-Papatoetoe Locality. Negative binomial models estimated adjusted risk differences across three time periods. Acute rheumatic fever was disproportionately concentrated among Māori and Pacific peoples in the most socioeconomically deprived areas, with Pacific populations-particularly in Counties Manukau-experiencing the highest burden. Acute rheumatic fever declined among Māori during the Rheumatic Fever Prevention Programme but not among Pacific peoples. A sharp, temporary decline in acute rheumatic fever and rheumatic heart disease hospitalisations occurred among Pacific populations during the COVID-19 pandemic, followed by resurgence by 2023. Persistent ethnic and geographic inequities in acute rheumatic fever and rheumatic heart disease reflect ongoing surveillance gaps, inconsistent notification practices and uneven implementation of interventions. National targets remain unmet, and inequities are widening for some groups. Robust, standardised surveillance systems and equity-focused interventions-particularly for Pacific communities in Counties Manukau-are essential to reducing the preventable burden of acute rheumatic fever and rheumatic heart disease in Aotearoa New Zealand.
2025-11-03 | Abstract 4359896: Interleukin-1 Blockade for Rheumatic Fever Pericarditis in a Steroid-Intolerant Patient: A Case Report
Introduction: In developed nations, acute rheumatic fever (ARF) is a rare cause of pancarditis, including pericarditis. Corticosteroids, though second-line agents for pericarditis, are frequently used to treat the cardiac and joint manifestations of ARF. Interleukin-1 (IL-1) inhibitors offer targeted therapy in recurrent idiopathic pericarditis, yet their role in ARF-related pericarditis remains undefined. We describe the application of IL-1 blockade to post-streptococcal, autoimmune-mediated pericarditis in a patient intolerant to corticosteroids. Case Report: A 38-year-old man with pre-diabetes, hyperlipidemia, and recent upper respiratory infection presented with acute right hip arthritis and elevated inflammatory markers (CRP 190.6 mg/L, ESR 108 mm/hr). Arthrocentesis yielded inflammatory synovial fluid without infection. Symptoms resolved with NSAIDs, prompting discharge. Four days later, he returned with high-grade fevers and diffuse polyarthralgia involving his wrists, hands, ankles, and feet. Exam uncovered migratory arthritis of the right hip and bilateral wrists. Labs showed CRP > 500 mg/L, high-titer antistreptolysin-O, leukocytosis, and acute kidney injury (AKI) with active urinary sediment. The presentation met Jones criteria for adult-onset ARF. Prednisone was started instead of NSAIDs for polyarthritis due to his AKI (figure 1). Following renal recovery with supportive care, he developed pleuritic chest pain, a precordial friction rub, and a HS-troponin peak of 195 ng/L. ECG demonstrated diffuse ST elevations, PR depression, and Spodick’s sign. Echocardiography revealed a small-moderate pericardial effusion. Cardiac MRI showed no myocardial involvement but increased T2 signal and late gadolinium enhancement consistent with pericarditis. Colchicine and high-dose aspirin were initiated, which improved his chest pain and CRP (62 mg/L). However, prednisone taper triggered rebound chest pain, arthritis, and CRP elevation (348 mg/L). He declined a prolonged course of high-dose steroids due to anxiety and hyperglycemia. Anakinra was added, resulting in symptom relief and CRP reduction (2 mg/L). He was transitioned to weekly rilonacept at discharge. Conclusion: This case highlights IL-1 inhibition as a promising therapy in rare presentations of ARF-induced pericarditis, especially when corticosteroids are not tolerated. Using anakinra as a bridge to outpatient rilonacept may offer a targeted, steroid-sparing strategy in persistent pericarditis from ARF.
2025-10-01 | Identification of therapeutic targets for rheumatic heart valve disease based on systematic druggable genome wide Mendelian randomization.
Rheumatic heart valve disease (RHD) is a chronic immune valvular heart disease caused by rheumatic fever, primarily affecting the mitral and aortic valves. It often leads to atrial fibrillation, heart failure, and even premature death. Currently, there are no effective therapeutic drugs available, partially due to the lack of appropriate therapeutic targets. To identify therapeutic targets for RHD, we employed a 2-sample Mendelian randomization approach integrating identified druggable genomics to assess the causal effect of expression quantitative trait loci of druggable genes in the blood on RHD. Subsequently, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses on the druggable genes. We used colocalization analysis to test whether the risk of RHD and gene expression are driven by common single nucleotide polymorphisms. Additionally, the Comparative Toxicogenomics Database was utilized to evaluate the impact of environmental exposures on druggable genes, and molecular docking was conducted to identify potential small molecule interactions. A total of 6888 druggable genes were collected. After conducting various Mendelian randomization analyses and applying false discovery rate correction, we identified 13 drug targets for RHD: TFRC, FMO4, CA2, HLA-DPB2, OXTR, GRAMD1B, PNP, HLA-DPB1, leukocyte immunoglobulin-like receptor B1 (LILRB1), TUBB, LGR6, F13A1, and LPL. These targets were found to be closely related to immune regulation and inflammatory response in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Bayesian colocalization analysis established an interaction between LILRB1 and RHD, with a PP.H4 >0.5, LILRB1 demonstrated a protective effect in RHD (OR = 0.833, 95% confidence interval, 0.699-0.993). Comparative Toxicogenomics Database analysis identified several small molecules influencing LILRB1 mRNA expression, with lipopolysaccharide showing excellent binding affinity in molecular docking with LILRB1 against available structural data for drugs and proteins. Based on a cohort of European ancestry, this study reveals 13 potential therapeutic targets for RHD, with LILRB1 showing particularly promising prospects as a future therapeutic target for RHD.
vaccines
2026-04-18 | A non-conjugated peptide-adjuvant system of synthetic peptide-vaccine elicited potent antibody response and opsonic protection against clinical GAS strains.
Group A Streptococcus (GAS) is a causative agent of life-threatening infections, including pharyngitis, rheumatic fever, and rheumatic heart disease. Currently, no commercial vaccines are licenced to prevent GAS infections. Synthetic peptide-based subunit vaccines composed of minimal antigenic fragments derived from the pathogenic M-protein, represent an attractive approach for mitigating GAS infection transmission. However, such small antigens are poorly immunogenic, necessitating their co-administration with strong immunostimulatory agents (adjuvants). Herein, we proposed the use of self-assembled peptides as the adjuvant by developing non-conjugated peptide-adjuvant system of GAS synthetic peptide-based vaccine in which a synthetic GAS antigen PADRE-J8 (composed of B cell epitope J8 and the universal T-helper epitope PADRE) was physically mixed with a lipopeptide TLR2 agonist (KKSS-C16-C16) and self-assembled peptides. In mice, all vaccine candidates induced antigen-specific systemic immunoglobulin G (IgG) antibodies after subcutaneous immunisation. Among them, a physical mixture of a self-assembled peptide Nap-GFFY, lipopeptide KKSS-C16-C16, and PADRE-J8 antigen (SPV-5) induced the highest antibodies production and produced antibodies were opsonic against GAS clinical isolates. The vaccine formulation lacking the lipopeptide KKSS-C16-C16 (SPV-5(-)) generated J8-specific antibodies; however, their opsonization capacity was poor, indicating that both the self-assembled peptide and the lipopeptide were essential for eliciting strong opsonic responses against bacteria.
2026-03-16 | Early rheumatic heart disease is a recognized intermediate on the pathway to advanced rheumatic heart disease.
Rheumatic heart disease is a major cause of premature cardiovascular morbidity and mortality globally. Over the past decade, echocardiographic screening has changed our understanding of the natural history of RHD, revealing a high burden of clinically silent, mild RHD among people who cannot recall a history of preceding acute rheumatic fever. This viewpoint outlines the evidence that this earliest form of rheumatic heart disease, only detectable through echocardiographic screening, is an intermediate stage that many, but not all, individuals may pass through on the pathway to advanced rheumatic heart disease. This shift in understanding has important clinical and research implications, including introducing a new and more pragmatic target for Streptococcus pyogenes vaccine trials for the indication of rheumatic heart disease prevention.
2025-11-04 | No compelling evidence that vaccination with streptococcus pyogenes group A carbohydrate elicits cross-reactive rheumatic fever autoantibodies.
We reviewed 70 years of research defining the specificity of anti-group A carbohydrate (GAC) monoclonal and polyclonal antibodies and antibodies raised against other S. pyogenes components reacting with GAC. While some rheumatic fever associated autoantibodies react with N-Acetyl-β-D-glucosamine sidechains of GAC and cross-react with tissues, these appear to be a consequence, not the cause, of autoimmunity. We propose GAC be considered further as a broadly protective group A streptococcal vaccine. (70 words).
2025-05-16 | Household Molecular Epidemiology of Streptococcus pyogenes Carriage and Infection in The Gambia.
Africa experiences a high burden of Streptococcus pyogenes disease but has limited epidemiological data. We characterized emm types and emm clusters associated with carriage and disease in The Gambia, a setting with a high rheumatic heart disease burden. A 1-year household cohort study (2021-2022) recruited 442 participants from 44 households to assess S. pyogenes carriage and noninvasive infection. Pharyngeal and skin swab samples were collected to detect carriage, and pharyngitis and pyoderma swab samples were taken to assess infection. Cultured isolates underwent emm typing and were compared with previous collection from the same region. A total of 221 cultured isolates showed 52 different emm types and 16 emm clusters. Strain diversity was high (Simpson reciprocal index, 29.3 [95% confidence interval, 24.8-36.0]), with the highest diversity seen in pyoderma and the lowest in pharyngitis. Based on available cross-opsonization data, the 30-valent M-protein vaccine candidate would cover 50.8% of the isolates, but cross-opsonization data are unknown for 38.5% of them. The emm clusters showed lower diversity and were stable over time, with 4 clusters defining 65.2% of the isolates; 68% of isolates were collected from skin sites (carriage and pyoderma), with evidence of skin-to-throat transmission in the same host. This study provides a unique molecular analysis of skin and throat isolates prospectively collected from persons with carriage and noninvasive infection in Africa. Despite high strain diversity, 4 clusters included two-thirds of the isolates, representing antigen priorities for broad vaccine coverage. In this rheumatic fever-endemic setting, pyoderma and skin carriage represent an important S. pyogenes reservoir and should be included in further surveillance studies and public health interventions. NCT05117528.
2025-04-12 | The epidemiology of repeatedly positive bacterial skin infections in Auckland children, New Zealand.
Māori and Pacific New Zealanders are disproportionately affected by Acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Repeated S. pyogenes skin infections in childhood are thought to increase the risk of developing ARF/RHD. This study investigated the epidemiology of repeated bacterial skin infections within Auckland, New Zealand. Microbiology results from wound swabs collected in primary care between 2010 and 2020 were used to estimate the rate of repeatedly positive infections, along with rate ratios and 95% CIs, across demographic groups. S. aureus infections impacted all groups; but Māori (Rate Ratio: 10.0, 95% CI: 8.5-11.6) and Pacific children (Rate Ratio: 14.6, 95% CI: 12.6-17.0) under 10 years of age were at a greater risk of repeated S. pyogenes infections compared to their non-Māori/non-Pacific counterparts. The relative risk of subsequent S. pyogenes infection was 4.1 times higher (95% CI: 4.0-4.3) following an initial S. pyogenes infection compared to those negative for S. pyogenes. Māori and Pacific children's heightened vulnerability to repeated S. pyogenes skin infections supports the immune priming theory of ARF/RHD. Targeted public health initiatives, primary care interventions and Group A Streptococcal vaccine are crucial to reduce repeated S. pyogenes exposure and potentially lower ARF risks.
proteins
2026-07-08 | Inflammatory and hormonal crosstalk linking rheumatic fever to chronic valvular heart disease.
Rheumatic heart disease (RHD) is a chronic, immune-mediated valvular disorder triggered by Group A β-hemolytic streptococcal infection. Persistent inflammation and immune-mediated tissue injury are central features of disease progression, whereas the roles of hormonal and metabolic regulatory pathways remain less well defined. Emerging evidence suggests that inflammatory signaling may intersect with hormonal and metabolic pathways during the transition from rheumatic fever to chronic valvular disease. Pro-inflammatory mediators have been associated with immune activation and extracellular matrix remodeling, with potential involvement of pathways such as nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and the NOD-like receptor protein 3 inflammasome. Chronic inflammation may also be accompanied by altered neuroendocrine anti-inflammatory feedback, including changes in glucocorticoid receptor signaling and hypothalamic-pituitary-adrenal axis regulation. In addition, sex hormones, thyroid hormones, and metabolic hormones may be linked to immune-cell differentiation, endothelial function, and valvular cell phenotypes, suggesting a possible inflammatory-endocrine regulatory loop that remains insufficiently validated in RHD-specific studies. These relationships may provide a context for understanding valvular interstitial cell activation, endothelial dysfunction, endothelial-mesenchymal transition, metabolic reprogramming, energy imbalance, fibrosis, and calcification, but direct causal evidence remains limited. Future dual-target strategies addressing both inflammatory and hormonal signaling may provide a theoretical framework for individualized intervention; however, their efficacy and safety require rigorous RHD-specific validation. This review summarizes current evidence and discusses the inflammatory-hormonal network as a hypothesis-generating framework for understanding chronic rheumatic valvular remodeling.
2025-08-22 | Low-Dose Interleukin-2 Therapy: A Transformative Approach for the Management of Autoimmune Complications Associated with Streptococcus pyogenes Infections
Acute rheumatic fever is an autoimmune inflammatory reaction to Streptococcus pyogenes infections, leading to progressive heart valve damage and rheumatic heart disease (RHD) [...]
2025-02-25 | Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease.
Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T cells targeting the group A Streptococcus (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD) and Sydenham's chorea. Long-term monthly penicillin injections are recognized as a cornerstone of public health programs to prevent Strep A reinfection and progression of ARF. However, compliance is poor, and better tools are required to slow disease progression. Preclinical evidence suggests that this can be achieved. Using a rat model that replicates post-streptococcal autoimmune complications, we explored the potential of low-dose interleukin-2 (LD-IL-2) as an immunotherapeutic intervention for ARF/RHD. In this model, injections of recombinant M protein from Strep A type 5 (rM5) to Lewis rats induce cardiac tissue inflammation, conduction abnormalities, and cross-reactive antibodies against cardiac and brain proteins central to disease pathogenesis. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes was observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies raised against host proteins and significantly increased regulatory T cells in the mediastinal lymph nodes. These novel findings suggest that LD-IL-2 will be an effective immunotherapeutic agent for treating ARF and has the potential to replace the standard monthly penicillin injections. Post-streptococcal autoimmune syndromes, including acute rheumatic fever, rheumatic heart disease, and Sydenham's chorea, represent a significant yet often under-recognized health and economic burden. This is especially true in low-income countries and among Indigenous populations in high-income nations, where the disease burden is most severe. These conditions arise from an autoimmune response to group A Streptococcus infections, leading to long-term health complications, disability, and premature death. Despite their widespread impact, no vaccine is currently available to prevent reinfections, and no specific therapy exists to treat the resulting autoimmune process. This study uses a rat model of rheumatic heart disease to evaluate the potential of low-dose interleukin 2 therapy in improving clinical outcomes and reducing the incidence of autoimmune diseases triggered by streptococcal infections.
2024-08-12 | Immunotherapeutic strategy to prevent progression and complications of acute rheumatic fever
Abstract Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T-cells targeting the Group A streptococcal (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD). Long-term antibiotic therapy is recognized as a cornerstone of public health programs to prevent reinfection and progression of ARF. However, better tools to slow disease progression, and mitigate its lifelong consequences are required. Evidence obtained in a preclinical model suggests that this can be achieved. Using the rat autoimmune valvulitis model, we explored the potential of low-dose interleukin 2 (LD-IL-2) as an immunotherapeutic intervention. In this model injection of recombinant Strep A M5 protein (rM5) to Lewis rats induce autoimmune complications, cardiac tissue inflammation and conduction abnormalities. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes were observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies against cardiac tissue and induced a significant increase in classical regulatory T-cells (Treg) and CD8 + Tregs in the mediastinal (heart-draining) lymph nodes. These novel findings suggest LD-IL-2 will be an effective immunotherapeutic agent for treating ARF/RHD.
2021-02-25 | Nonimmune antibody interactions of Group A Streptococcus M and M-like proteins
M and M-like proteins are major virulence factors of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes . These proteins confer resistance against innate and adaptive immune responses by recruiting specific human proteins to the streptococcal surface. Nonimmune recruitment of immunoglobulins G (IgG) and A (IgA) through their fragment crystallizable (Fc) domains by M and M-like proteins was described almost 40 years ago, but its impact on virulence remains unresolved. These interactions have been suggested to be consequential under immune conditions at mucosal surfaces and in secretions but not in plasma, while other evidence suggests importance in evading phagocytic killing in nonimmune blood. Recently, an indirect effect of Fc-binding through ligand-induced stabilization of an M-like protein was shown to increase virulence. Nonimmune recruitment has also been seen to contribute to tissue damage in animal models of autoimmune diseases triggered by S . pyogenes infection. The damage was treatable by targeting Fc-binding. This and other potential therapeutic applications warrant renewed attention to Fc-binding by M and M-like proteins.
other
2026-05-25 | The "Cairo Accord"- towards the eradication of RHD: revisited (2026).
Rheumatic heart disease (RHD) continues to be a significant global health burden, particularly in resource-limited regions of the world. This preventable and often neglected disease affects predominantly children and young adults, leading to considerable morbidity and mortality. In this article, we revisit the Cairo Accord that aims to address the challenges of RHD and set policy priorities for its eradication. We highlight the most remarkable progress in the field since the 2021 update, formulating updated recommendations. These include enhancing disease registries and echocardiographic screening, advance research on host and streptococcal strains genetics, biomarkers, vaccines, pharmaceuticals and penicillin prophylaxis, accelerate the development of regional Centers of Excellence, promoting MV repair and the development of tissue-engineered valve substitutes.
2024-09-02 | Immunogenicity of a 30-valent M protein mRNA group A Streptococcus vaccine.
Group A Streptococcus (Strep A) causes both uncomplicated and severe invasive infections, as well as the post-infection complications acute rheumatic fever and rheumatic heart disease. Despite the high global burden of disease resulting from Strep A infections, there is not a licensed vaccine. A 30-valent M protein-based vaccine has previously been shown to be immunogenic in animal models and in a Phase I clinical trial (NCT02564237). Here, we assessed the immunogenicity of a 30-valent messenger (m)RNA vaccine designed to express the same M peptide targets as the 30-valent protein vaccine and compared it with the protein vaccine. Female New Zealand white rabbits were immunized with one of four vaccine formulations (3 doses of each formulation at days 1, 28, and 56): soluble mRNA (100 μg/animal), C-terminal transmembrane mRNA (100 μg/animal), protein vaccine (400 μg/animal), or a non-translatable RNA control (100 μg/animal). Serum was collected one day prior to the first dose and on days 42 and 70. Rabbit serum samples were assayed for antibody levels against synthetic M peptides by ELISA. HL-60 opsonophagocytic killing (OPK) assays were performed to assess functional antibody levels. Serum IgG levels were similar for the mRNA and protein vaccines. The CtTM version of the mRNA vaccine elicited slightly higher antibody levels than the mRNA designed to express soluble proteins. OPK activity was similar for the mRNA and protein vaccines, regardless of M type. The total antibody responses and functional antibody levels elicited by the 30-valent mRNA Strep A vaccines were similar to those observed following immunization with the analogous protein vaccine. The mRNA vaccine platform provides potential advantages to protein-based vaccines including inherent adjuvant activity, increased production efficiency, lower cost, and the potential to rapidly change epitopes/peptides, all of which are important considerations related to multivalent Strep A vaccine development.
2021-11-23 | Recent Progress Toward Clinical Translation of Tissue-Engineered Heart Valves.
Surgical replacement remains the primary option to treat the rapidly growing number of patients with severe valvular heart disease. Although current valve replacements-mechanical, bioprosthetic, and cryopreserved homograft valves-enhance survival and quality of life for many patients, the ideal prosthetic heart valve that is abundantly available, immunocompatible, and capable of growth, self-repair, and life-long performance has yet to be developed. These features are essential for pediatric patients with congenital defects, children and young adult patients with rheumatic fever, and active adult patients with valve disease. Heart valve tissue engineering promises to address these needs by providing living valve replacements that function similarly to their native counterparts. This is best evidenced by the long-term clinical success of decellularised pulmonary and aortic homografts, but the supply of homografts cannot meet the demand for replacement valves. A more abundant and consistent source of replacement valves may come from cellularised valves grown in vitro or acellular off-the-shelf biomaterial/tissue constructs that recellularise in situ, but neither tissue engineering approach has yet achieved long-term success in preclinical testing. Beyond the technical challenges, heart valve tissue engineering faces logistical, economic, and regulatory challenges. In this review, we summarise recent progress in heart valve tissue engineering, highlight important outcomes from preclinical and clinical testing, and discuss challenges and future directions toward clinical translation.
2004-04-01 | Acute rheumatic fever: a chink in the chain that links the heart to the throat?
Acute rheumatic fever (ARF) remains a major problem in tropical regions, resource-poor countries, and minority indigenous communities. It has long been thought that group A streptococcal (GAS) pharyngitis alone was responsible for acute rheumatic fever; this belief has been supported by laboratory and epidemiological evidence gathered over more than 60 years, mainly in temperate climates where GAS skin infection is uncommon. GAS strains have been characterised as either rheumatogenic or nephritogenic based on phenotypic and genotypic properties. Primary prevention strategies and vaccine development have long been based on these concepts. The epidemiology of ARF in Aboriginal communities of central and northern Australia challenges this view with reported rates of ARF and rheumatic heart disease (RHD) that are among the highest in the world. GAS throat colonisation is uncommon, however, and symptomatic GAS pharyngitis is rare; pyoderma is the major manifestation of GAS infection. Typical rheumatogenic strains do not occur. Moreover, group C and G streptococci have been shown to exchange key virulence determinants with GAS and are more commonly isolated from the throats of Aboriginal children. We suggest that GAS pyoderma and/or non-GAS infections are driving forces behind ARF in these communities and other high-incidence settings. The question needs to be resolved as a matter of urgency because current approaches to controlling ARF/RHD in Aboriginal communities have clearly been ineffective. New understanding of the pathogenesis of ARF would have an immediate effect on primary prevention strategies and vaccine development.
1967-01-16 | Therapeutic Surgical Division of the Human Conduction System
A 51-year-old woman was severely incapacitated because of intractable supraventricular tachycardias and rheumatic heart disease involving the aortic and mitral valves. The arrhythmias were not prevented by a variety of drug regimens, and over 200 cardioversions were done. It was believed that the arrhythmias had to be positively controlled if valvular surgery was to be successful. At open-heart surgery the aortic and mitral valves were replaced with ball-valve prostheses and the conduction bundle was divided in the region of the atrioventricular (AV) node. Permanent pacemaker leads were attached to the epicardium. Early postoperatively there was complete AV dissociation with a ventricular rate of 60 beats per minute. Later the ventricular rate slowed to 48 and a pacemaker was connected to the implanted leads for permanent ventricular pacing at 75 beats per minute.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.