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:
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.
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.
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