Rheumatic fever (RF) is a nonsuppurative late autoimmune inflammatory complication of
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombotic events and/or recurrent abortions in the presence of antiphospholipid antibodies (aPLs) [
On the other hand, when the scientific literature is analyzed, the relationship between APS and RF has been little studied, and there is no article which conducted a review about this association. Therefore, the aim of this study was to evaluate the clinical associations between rheumatic fever and antiphospholipid syndrome and the impact of coexistence of these two diseases in an individual.
This is a systematic review of scientific papers that deal with the relationship between rheumatic fever and antiphospholipid syndrome. A search was performed in electronic databases: PubMed, MEDLINE, LILACS, SciELO, and Cochrane Database, regarding the period from 1983 (when the antiphospholipid syndrome was described) to October 2012. A combination of the keywords “Rheumatic Fever,” “Antiphospholipid Syndrome,” “Antiphospholipid Antibody Syndrome,” and their respective translations was used. Articles in English, Portuguese, and Spanish were considered. There was no restriction about the study design.
The combination search of keywords was performed by two authors independently and showed 22 scientific articles. A full reading of each of these papers and their references reduced the universe of work for 11 articles that evaluated the relationship of antiphospholipid syndrome with rheumatic fever. Of these, only 7 showed clinical cases of association between APS and RF, being composed of 2 cross-sectional studies and 5 case reports. However, we have used only one cross sectional study since they describe the same patients.
Therefore 11 cases described in the literature about the association of rheumatic fever and antiphospholipid syndrome were identified [
The demographic, clinical, and laboratorial data of patients are summarized in Table
11 cases published in the literature about the association between antiphospholipid syndrome and rheumatic fever.
References | Number of cases | Age, years | Female sex | Color | Disease duration, years | RF manifestations | APS manifestations | SLE associated | ASO | Antiphospholipid antibody | RF prophylaxis |
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Soeiro et al., 2012 [ |
1 | 30 | 100% | Brown | 1.5 RF-APS | Carditis: + (with mitral valve replacement, right bundle branch block) |
Arterial: embolic stroke, AMI |
Yes | 786 UI/mL | aCL IgM: + (14 MPL) | Penicillin G benzathine 100% |
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Camargo et al., 2012 [ |
73 APS, 5 RF-APS | 37.4 | 100% | 100% white | 5.6 RF |
Carditis (ECO abnormal): 100% |
Arterial: stroke 4/5 |
No | Increased in acute phase: 100% | aCL IgG: 2/5 |
Penicillin G benzathine 100% |
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Alcock et al., 2011 [ |
1 | 44 | 100% | — | 27 RF |
Carditis: + (ECG: block first degree |
Arterial: stroke |
No | 883 UI/mL, Anti-DNAase B: 960 UI/mL | aCL: + |
Penicillin 100% |
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Izhevsky et al., 2004 [ |
1 | 29 | 0% | — | -RF9 APS | Carditis: + |
Arterial: AMI (with CRA and successful resuscitation) |
No | Increased | aCL IgG: + |
Penicillin G benzathine 100% |
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Amital et al., 1999 [ |
1 | 45 | 100% | — | 35 RF |
Carditis: + (admitted for mitral valve replacement) |
Arterial: stroke, splenic infarction |
Yes | — | LAC: + | Prophylaxis with antibiotic |
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Fung et al., 1998 [ |
2 | Case 1: 22 |
100% | 1 white, |
Case 1: − |
Case 1: |
Cases 1 and 2: |
Case 1: anti-dsDNA positive (35%) |
Case 1: normal, anti-DNAase B: 1280 UI/mL |
Case 1: aCL IgM: + (14 MPL) |
Case 1: oral penicillin |
AMI: acute myocardial infarction; AV: atrioventricular; CRA: cardiorespiratory arrest; DVT: deep vein thrombosis; ECG: electrocardiogram; ECO: echocardiogram.
The age of patients with APS and RF ranged from 22 to 45 years, with a predominance of females (10/11 patients) and white (6/7). The duration of illness ranged to APS from 5.6 to 24 years and for rheumatic fever from 1.5 to 35 years.
Clinical presentation of rheumatic fever was characterized by the predominance of carditis (11/11) and chorea (7/11). Arthritis was observed in 3 of 11 patients and only one individual presented subcutaneous nodule (9%). No patient had erythema marginatum. Serum levels of ASO (antistreptolysin-O) were elevated in most cases (9/11), with values ranging from 451 to 883 UI/m. In patients in whom it was studied for antiDNAse, this antibody was also positive and with high titers. The prophylaxis for rheumatic fever was reported in all cases, being the benzathine penicillin used as the first choice (8/11), followed by sulfadiazine (1/11) and oral penicillin (1/11).
Regarding the manifestations of APS, stroke was observed in 7/11 (63.6%), being one of them from probable embolic origin. Three of eleven (27.3%) patients had venous event characterized by deep vein thrombosis (DVT). Thrombocytopenia was observed in 3 of 11 cases and no article described the presence of livedo reticularis. Abortion was described in only 1 of 10 individuals. Acute myocardial infarction (AMI) was present in 2 of 10 patients, also being reported the occurrence of splenic infarction in one patient. The antibodies research showed that anticardiolipin (aCL) IgM was the most found antibody and was positive in 5/7 patients, followed by anti-
In only two cases manifestations of systemic lupus erythematosus (SLE) were presented, characterized by pericarditis and positive antibodies (ANA and anti-dsDNA). In two of the patients the presence of anti-dsDNA (antidouble stranded DNA) without other manifestations of SLE and other presented positive ANA (antinuclear antibody) was reported singly. There was no report of another autoimmune disease, besides RF, APS, or SLE.
Common clinical manifestations of APS and RF were distributed as follows: carditis with valvular disease in 100% of cases, chorea in 63.6%, and arthritis in 18.2%.
The present work performed the first systematic review of all clinical cases published in the literature which presented an association between APS and RF.
The major advantage of the present study was carrying out an extensive and complete literature review, for the first time, on the main world databases (PubMed, MEDLINE, LILACS, SciELO, and Cochrane) regarding the period of 1983 to October 2012, with the total of 11 cases of association between APS and RF.
In the scientific literature, there is some evidence of the relationship between APS and RF. In fact, the clinical and experimental study published by Blank et al., which evaluated the serum of 90 patients with RF and of 42 patients with APS, showed that 24% of patients with rheumatic heart disease had positivity for anti-
The study by Figueroa et al. showed that during the active phase of FR, 80% of patients had positive anticardiolipin antibodies (aCL). On the other hand, during the inactive phase of the disease, only 40% of these patients had such antibodies [
This systematic review has highlighted that all patients with APS and RF had carditis, constituting the most frequent manifestation. In fact, the literature indicates that about 30–45% of patients with RF develop carditis, its most serious complication, responsible for permanent valvular lesions [
Regarding chorea, whose prevalence in the APS is around 1.3% [
One feature that caught the attention in APS manifestations of this study was the prevalence of stroke, present in 63.6% of cases. This finding is confirmed in the literature by the work of Camargo et al., where they compared 5 patients with APS associated with RF with 68 patients presented with primary APS. Remarkably, the presence of stroke was significantly higher in the first group (80% versus 25%); however, the echocardiogram in these patients showed no intracardiac thrombi. These results suggest a possible formation of thrombus in situ [
The achievement of this paper has made the design of the profile of a patient with APS and RF possible. This individual is typically female, white, and aged between 22 and 45 years. The duration of disease in this patient is around 5 years for APS and can vary from 1.5 to 35 for RF, and usually the FR appears as the first manifestation. In relation to clinical manifestations of RF, these individuals will follow the pattern of involvement of this condition; in other words, they will have more carditis and chorea with high ASO and will receive antibiotic prophylaxis. However, for the manifestations of APS, interestingly, arterial thrombosis was more common than vein thrombosis, as discussed above. DVT, as main venous event of this syndrome, which afflicts about 55% of patients [
This study provides information that the association between SAF and FR is quite rare, however, is of great clinical importance because the isolated treatment of one of these diseases, such as lack of anticoagulation in an individual with APS hidden and lack of prophylaxis of streptococcal infection in an individual with RF undiagnosed, can lead to serious consequences. This study also warns the doctors who deal with the RF, condition still very common in our environment, such as rheumatologists, pediatricians, cardiologists, cardiac surgeons, and general practitioner, to include in their differential diagnosis the APS, especially in the presence of stroke in patients with RF and whose echocardiogram did not show intracavitary thrombi.
The relationship between APS and RF has been little studied. 11 cases described in the literature about the association of rheumatic fever and antiphospholipid syndrome were identified. Common clinical manifestations of APS and RF were distributed as follows: carditis with valvular disease in 100% of cases, chorea in 63.6%, and arthritis in 18.2%. Previous study showed that 24% of patients with rheumatic heart disease had positivity for anti- This systematic review has highlighted that all patients with APS and RF had carditis, constituting the most frequent manifestation. Regarding chorea, whose prevalence in the APS is around 1.3% [ About APS manifestations, interestingly, arterial thrombosis was more common than vein thrombosis. This study provides information that the association between SAF and FR is quite rare, however, is of great clinical importance. This study warns clinicians to include in their differential diagnosis the APS, especially in the presence of stroke in patients with RF and whose echocardiogram did not show intracavitary thrombi.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter.
Jozélio de Carvalho received Grants from Federico Foundation and CNPq (300665/2009-1).