Differentation of Post-Streptococcal Reactive Arthritis from Acute Rheumatic Fever JUDITH BARASH, MD, ERAN MASHIACH, MD, PNINA NAVON-ELKAN, MD, YACKOV BERKUN, MD, LIORA HAREL, MD, TSIVIA TAUBER, MD, SHAI PADEH, MD, PHILIP J. HASHKES, MD, MSC, AND YOSEF UZIEL, MD, FOR THE PEDIATRIC RHEUMATOLOGY STUDY GROUP OF ISRAEL Objective To perform a retrospective study comparing clinical and laboratory aspects of patients with acute rheumatic fever (ARF) and patients with post-streptococcal reactive arthritis (PSRA), to discern whether these are 2 separate entities or varying clinical manifestations of the same disease. Study design We located the records of 68 patients with ARF and 159 patients with PSRA, whose diseases were diagnosed with standardized criteria and treated by 8 pediatric rheumatologists in 7 medical centers, using the Israeli internet-based pediatric rheumatology registry. The medical records of these patients were reviewed for demographic, clinical, and laboratory variables, and the data were compared and analyzed with univariate, multivariate, and discriminatory analysis. Results Four variables were found to differ significantly between ARF and PSRA and serve also as predictors: sedimentation rate, C-reactive protein, duration of joint symptoms after starting anti-inflammatory treatment, and relapse of joint symptoms after cessation of treatment. A discriminative equation was derived that enabled us to correctly classify >80% of the patients. Conclusion On the basis of simple clinical and laboratory variables, we were able to differentiate ARF from PSRA and correctly classify >80% of the patients. It appears that ARF and PSRA are distinct entities. (J Pediatr 2008;153:696-9) P ost-streptococcal reactive arthritis (PSRA) is defined as arthritis of 1 joints, associated with a recent group A streptococcal infection in a patient who does not fulfill the Jones criteria for the diagnosis of acute rheumatic fever (ARF). 1,2 Although other definitions have been suggested, mainly for adult cases, this definition is the most accepted and used by most investigators. Some authors consider PSRA to be part of the spectrum of ARF, whereas other authors consider it to be a different entity. Authors who consider PSRA to be part of the ARF spectrum refer mainly to a small number of cases in which PSRA has been diagnosed and in which carditis suggestive of ARF subsequently developed. 3,4 In 1993, Deighton 5 proposed the following as distinguishing features of PSRA: 1) onset within 10 days of group A streptococcal infection, as opposed to 2 to 3 weeks in ARF; 2) Prolonged or recurrent arthritis, in contrast to ARF, in which the arthritis lasts a few days to 3 weeks; 3) Slow and partial response to aspirin, whereas in ARF the response to aspirin is usually dramatic. The following diagnostic criteria for PSRA have been proposed by Ayoub and Ahmed based on these clinical features 6 : 1) Arthritis of acute onset, symmetric or asymmetric, usually non-migratory, can affect any joint, persistent or recurrent. The arthritis is at best only poorly responsive to salicylates or nonsteroidal anti-inflammatory drugs; 2) Evidence of antecedent group A streptococcal infection; and 3) Failure to fulfill the modified Jones criteria for the diagnosis of ARF. 2 The question whether PSRA is a distinct entity from ARF has not yet been answered. Our objective was to search for differences in these 2 entities in a well-defined, large cohort. We attempted to discern whether they are 2 separate entities or varying ARF Acute rheumatic fever PSRA Post-streptococcal reactive arthritis From the Pediatric Day Care and Pediatric Rheumatology service (J.B.), and Depart- ment of Pediatrics (E.M.), Kaplan Medical Center, Rehovot, affiliated to the Hadassah Medical School, the Hebrew University Jerusalem, Israel; Pediatric Day Hospital, Shaarei Zedek Medical Center, Jerusalem, af- filiated to the Hadassah Medical School, the Hebrew University, Jerusalem Israel (P.N.-E.); Department of Pediatrics, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (Y.B., S.P.); Schneider Chil- dren Hospital, Petah Tikva, affiliated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (L.H.); Pediatric Day Care, Assaf Harofeh Medical Center, Zrifin, affili- ated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (T.T.); Section of Pediatric Rheumatology, Cleveland Clinic, affiliated to the Cleveland Clinic Lerner School of Medicine of Case Western Uni- versity, Cleveland, OH (P.H.); and Depart- ment of Pediatrics, Meir Medical Center, Kfar Saba, affiliated to the Sackler Medical School Tel Aviv University, Tel Aviv, Israel (Y.U.). Drs Hashkes and Uziel have contributed equally to this study. The authors declare no potential conflict of interest. Submitted for publication Dec 2, 2007; last revision received Mar 31, 2008; accepted May 21, 2008. Reprint requests: Judith Barash, MD, Pediatric Day Care, Kaplan Medical Center, PO Box 1, Rehovot 76100, Israel. E-mail: judith_b@ clalit.org.il; [email protected]. 0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.05.044 696
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doi:10.1016/j.jpeds.2008.05.044a l
Differentation of Post-Streptococcal Reactive Arthritis from Acute Rheumatic Fever
JUDITH BARASH, MD, ERAN MASHIACH, MD, PNINA NAVON-ELKAN, MD, YACKOV BERKUN, MD, LIORA HAREL, MD, TSIVIA TAUBER, MD, SHAI PADEH, MD, PHILIP J. HASHKES, MD, MSC, AND YOSEF UZIEL, MD, FOR THE PEDIATRIC RHEUMATOLOGY STUDY GROUP OF ISRAEL
bjective To perform a retrospective study comparing clinical and laboratory aspects of patients with acute rheumatic fever ARF) and patients with post-streptococcal reactive arthritis (PSRA), to discern whether these are 2 separate entities or varying linical manifestations of the same disease.
tudy design We located the records of 68 patients with ARF and 159 patients with PSRA, whose diseases were diagnosed ith standardized criteria and treated by 8 pediatric rheumatologists in 7 medical centers, using the Israeli internet-based ediatric rheumatology registry. The medical records of these patients were reviewed for demographic, clinical, and laboratory ariables, and the data were compared and analyzed with univariate, multivariate, and discriminatory analysis.
esults Four variables were found to differ significantly between ARF and PSRA and serve also as predictors: sedimentation ate, C-reactive protein, duration of joint symptoms after starting anti-inflammatory reatment, and relapse of joint symptoms after cessation of treatment. A discriminative quation was derived that enabled us to correctly classify >80% of the patients.
onclusion On the basis of simple clinical and laboratory variables, we were able to ifferentiate ARF from PSRA and correctly classify >80% of the patients. It appears that RF and PSRA are distinct entities. (J Pediatr 2008;153:696-9)
ost-streptococcal reactive arthritis (PSRA) is defined as arthritis of 1 joints, associated with a recent group A streptococcal infection in a patient who does not fulfill the Jones criteria for the diagnosis of acute rheumatic fever (ARF).1,2
lthough other definitions have been suggested, mainly for adult cases, this definition is he most accepted and used by most investigators. Some authors consider PSRA to be part f the spectrum of ARF, whereas other authors consider it to be a different entity.
Authors who consider PSRA to be part of the ARF spectrum refer mainly to a small umber of cases in which PSRA has been diagnosed and in which carditis suggestive of RF subsequently developed.3,4
In 1993, Deighton5 proposed the following as distinguishing features of PSRA: ) onset within 10 days of group A streptococcal infection, as opposed to 2 to 3 weeks in RF; 2) Prolonged or recurrent arthritis, in contrast to ARF, in which the arthritis lasts
few days to 3 weeks; 3) Slow and partial response to aspirin, whereas in ARF the esponse to aspirin is usually dramatic.
The following diagnostic criteria for PSRA have been proposed by Ayoub and hmed based on these clinical features6: 1) Arthritis of acute onset, symmetric or
symmetric, usually non-migratory, can affect any joint, persistent or recurrent. The rthritis is at best only poorly responsive to salicylates or nonsteroidal anti-inflammatory rugs; 2) Evidence of antecedent group A streptococcal infection; and 3) Failure to fulfill he modified Jones criteria for the diagnosis of ARF.2
The question whether PSRA is a distinct entity from ARF has not yet been nswered. Our objective was to search for differences in these 2 entities in a well-defined, arge cohort. We attempted to discern whether they are 2 separate entities or varying
From the Pediatric Day Care and Pediatric Rheumatology service (J.B.), and Depart- ment of Pediatrics (E.M.), Kaplan Medical Center, Rehovot, affiliated to the Hadassah Medical School, the Hebrew University Jerusalem, Israel; Pediatric Day Hospital, Shaarei Zedek Medical Center, Jerusalem, af- filiated to the Hadassah Medical School, the Hebrew University, Jerusalem Israel (P.N.-E.); Department of Pediatrics, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (Y.B., S.P.); Schneider Chil- dren Hospital, Petah Tikva, affiliated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (L.H.); Pediatric Day Care, Assaf Harofeh Medical Center, Zrifin, affili- ated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (T.T.); Section of Pediatric Rheumatology, Cleveland Clinic, affiliated to the Cleveland Clinic Lerner School of Medicine of Case Western Uni- versity, Cleveland, OH (P.H.); and Depart- ment of Pediatrics, Meir Medical Center, Kfar Saba, affiliated to the Sackler Medical School Tel Aviv University, Tel Aviv, Israel (Y.U.).
Drs Hashkes and Uziel have contributed equally to this study.
The authors declare no potential conflict of interest.
Submitted for publication Dec 2, 2007; last revision received Mar 31, 2008; accepted May 21, 2008.
Reprint requests: Judith Barash, MD, Pediatric Day Care, Kaplan Medical Center, PO Box 1, Rehovot 76100, Israel. E-mail: judith_b@ clalit.org.il; [email protected].
0022-3476/$ - see front matter
RF Acute rheumatic fever PSRA Post-streptococcal reactive arthritis
d f p w t 2 a a
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linical manifestations of the same disease and, if possible, to ffer a simple clinical tool to differentiate between them.
METHODS We located patients, 16 years old, who received a
iagnosis and were treated by 8 pediatric rheumatologists rom 7 centers who participated in the Israeli internet-based ediatric rheumatology registry.7 We searched for patients in hom ARF was diagnosed with joint involvement and pa-
ients with a diagnosis of PSRA between the years 1996 and 005 (most after 2001). A total of 159 patients with PSRA nd 68 patients with ARF for whom there was sufficient nalyzable data were found.
ARF was diagnosed according to the revised Jones riteria,2 and PSRA was diagnosed in cases of arthritis in- olving 1 joints associated with proven group A streptococ- al infection in a patient not fulfilling the Jones criteria. The edical charts of these patients were reviewed by a single
hysician, and all demographic, clinical, and laboratory data ere summarized. The characteristics of ARF and PSRA ere compared with 2-sample t tests (for continuous vari-
bles) and 2 tests (for categorical variables). Multivariate ackwards stepwise logistic regression analysis was used to odel the probability of ARF versus PSRA. A prediction
quation was calculated by using discriminant analysis.8 The tudy was approved by each center’s ethical committee.
RESULTS There was no significant difference in the 2 groups in
able I. Clinical and laboratory data of patients ith acute rheumatic fever and post-streptococcal
eactive arthritis
P value
ever °C (SD) 38.3 (0.4) 38.3 (0.5) NS with Fever 38 66 16 .0004 umber of active joints (SD)
2.5 (1.2) 1.8 (1.3) .0004
igratory arthritis % 79 33 .004 ymetrical arthritis % 40 22 .05 arditis % 60 0 .0001 SR (SD) 92.2 (31.1) 57.1 (40.9) .0001 RP mg/L (SD) 106.7 (83.5) 22.6 (44.1) .0001 SO IU (SD) 1011 (1573) 889 (733) NS ositive throat culture % 77% 76% NS nterval from pharyngitis to arthritis, days (SD)
15 (9.2) 14.6 (10.1) NS
esponse to treatment, days (SD)
2.2 (1.7) 6.9 (5.9) .0001
elapse % 7 21 0.013
reatment; relapse, relapse of joint symptoms after cessation of anti-inflammatory treat- ent; NS, not significant.
emographic characteristics. The age of onset was 10.2 3.0 t
ifferentiation of Post-Streptococcal Reactive Arthritis from Acute Rheu
ears for ARF and 9.3 3.6 years for PSRA. A total of 63% of atients with ARF and 54% of patients with PSRA were male, nd the number of persons in the household was 5.9 1.5 for RF and 6.5 2.1 for the patients with PSRA. A family history f ARF in first- or second-degree relatives was found in 7.2% of he patients with ARF and 7.5% of the patients with PSRA.
The clinical and laboratory characteristics are summa- ized in Table I. Fever 38°C was recorded in 46 patients ith ARF (66%) and 25 patients with PSRA (16%). The
rythrocyte sedimentation rate and the C-reactive protein evel were significantly higher in the ARF group. The 2 roups did not differ in the proportion with positive results of hroat cultures at onset of joint disease, and no significant ifference was found in the levels of antistreptolysin O that ere markedly increased in both groups.
The patients with ARF had significantly more active oints (P .0004), with 79% of the patients having migratory rthritis, in contrast to 33% of the patients in the PSRA group P .004). The distribution of involved joints (Figure) did ot differ in the groups, except large joints in the upper xtremities were more frequently involved in ARF (P 0002). Arthritis was symmetrical in 40% of patients with RF and 22% of the patients with PSRA (P .05). Axial
oint involvement was not documented in either group. A total of 41 patients with ARF (60%) had carditis by
valuation of a qualified pediatric cardiologist. None of the atients with PSRA had proven carditis. Two patients with SRA had prolonged P-R intervals with electrocardiography, nd 3 patients with PSRA had a trace of mitral regurgitation n echocardiogram, which was not considered pathologic. he interval from onset of pharyngitis to the onset of arthritis as 15.1 9.2 days (documented in 76% of the patients) for
igure. The distribution in percent with active joints in patients with RF and PSRA. Large LE, Large joint lower extremity; small LE, small
oint lower extremity; large UE, large joint upper extremity; small UE, mall joint upper extremity. *P .0002.
he patients with ARF, versus 14.6 10.1 days for the
matic Fever 697
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atients with PSRA (documented in 70% of the patients; P ot significant).
The time required for resolution of joint symptoms in esponse to anti-inflammatory treatment was significantly horter in patients with ARF as compared with patients with SRA (2.18 1.71 days versus 6.73 5.89, respectively; .0001). Resolution of joint symptoms was defined at the
ate stated by the attending physician that no arthritis or rthralgia was noted on physical examination. Only 7% of atients with ARF sustained a relapse after cessation of anti- nflammatory therapy, compared with 21% of patients with SRA (P .013) requiring repeated anti-inflammatory treat- ent. The relapse of joint complaints suggests a longer nat-
ral course of arthritis. Twenty-two percent of the patients with PSRA did not
eceive anti-inflammatory treatment, and their joint disease as treated only with rest, compared with only 1 patient in
he ARF group. A total of 87% of patients with ARF received long-term
rophylactic antibiotic treatment, compared with 50% of pa- ients with PSRA; 50% of the patients with ARF received ntramuscular penicillin versus 4% of the patients with PSRA.
espite more intensive antibiotic prophylaxis in patients with RF, 12% had a recurrence, compared with 8% of patients in
he PSRA group. The 2 most significant variables differentiating ARF
rom PSRA on univariate analysis were the time required for esolution of joint symptoms in response to anti-inflamma- ory therapy and the number of patients who had a relapse of oint disease after cessation of anti-inflammatory treatment.
By using multivariate, backward, stepwise logistic regres- ion, we found 4 variables to be significant diagnostic discrimi- ators between ARF and PSRA: erythrocyte sedimentation rate, -reactive protein, duration of joint symptoms in response to
reatment with anti-inflammatory medications, and relapse of oint symptoms after cessation of anti-inflammatory treatment Table II). By using discriminant analysis, we calculated this rediction equation: 1.568 0.015 sedimentation rate .02 CRP – 0.162 days to resolution of joint symptoms – .04 return of joint symptom (yes 1, no 0).
If the value was 0, the patient was classified as having RF; otherwise, the patient was classified as having PSRA. his prediction gave 79% sensitivity rate (correct classification
s ARF) and 87.5% specificity rate (correct classification as
able II. Significant predictors of acute rheumatic ever by using stepwise logistic regression
Variable Odds ratio 95% CI Significance
SR 1.015 1.000-1.031 0.043 RP 1.016 1.004-1.028 0.007 ays to disappearance of joint symptoms
0.565 0.389-0.820 0.003
0.026 0.002-0.390 0.008
DISCUSSION Two recent studies attempted to answer whether ARF
nd PSRA are distinct entities and to validate the diagnostic riteria proposed by Ayoub and Ahmed.6 Tutar et al9 com- ared 24 children with PSRA with 20 patients with ARF. he latency period from upper respiratory tract infection was
ignificantly shorter in patients with PSRA; however, 25% of he patients with ARF also had a short latency period. Un- esponsiveness of articular symptoms to salicylate therapy was ore frequent in PSRA, but also 45% of the patients with RF with joint symptoms did not respond during the first 72 ours. The authors concluded that because there was consid- rable overlap between PSRA and ARF, these 2 entities could ot easily be distinguished.
In 2004, Mackie and Keat10 addressed the same issue by onducting a systematic search on Medline using strict inclu- ion criteria. They identified 188 cases of PSRA published in he literature between 1982 and 2002. One hundred of these ases were in adults 18 years old. The authors concluded hat PSRA is a heterogeneous group of clinical entities, some f which share features of ARF and others with HLA B27- elated spondyloarthropathies and that the assumed causal ole of streptococcal infection is far from proven.
There are several studies addressing the association of RF and PSRA with class II HLA-DR antigens. Ahmed
t al11 found an increased frequency of HLA DRB1*01 in atients with PSRA compared with healthy control subjects nd to patients with ARF. In patients with ARF, there was an ncreased frequency of HLA DRB1*16 allele compared with ontrol subjects. This association may suggest that the patho- enesis of PSRA, like that of ARF, may be related to the nheritance of certain class II HLA alleles. In 2004, Simo- ini12 published a different observation on genotyping of the LA-DRB1 locus in 25 patients with ARF, 34 patients with SRA, and healthy control subjects. The frequency of RB1*01 and DRB1*16 in patients with PSRA and ARF did
ot show any statistical significance when compared with each ther or with that of the control subjects. The conclusion in his study was that the 2 diseases are not genetically different n these alleles.
The presence of a non-HLA B cell alloantigen D8/17 n a significantly greater percentage of patients with ARF and heir first-degree relatives compared with control subjects has een shown by Khanna.13 In a study of Israeli patients, arel14 has found a significantly higher percentage of B cells
xpressing the D8/17 antigen in patients with a history of RF than in control subjects. Later the same author investi-
ated the presence of D8/17 alloantigen on B cells from atients with PSRA compared with control subjects.15 There as a small difference between the expression of the antigen
n patients with PSRA and subjects in the control group, but ith significant overlap in the 2 groups. Moreover, there was weak negative correlation between the percentage of D8/17 ositive cells and the time elapsed from diagnosis. It was
uggested previously that this expression is regulated by the
The Journal of Pediatrics • November 2008
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1 s 2 K A J 3 c 4 s l 5 R 6 i 7 P n O 8 Y 9 r 1 k 1 a 1 1 a a 1 P m 1 D 2 1 D 2 1 2 1
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nfection, so it is questionable whether it is a true genetic arker.
In this study, we have shown that we were able to ifferentiate between ARF and PSRA in 80% of the cases n the basis of 4 criteria: the sedimentation rate and CRP at nset, the number of days before resolution of joint symptoms fter starting anti-inflammatory therapy, and the presence or bsence of a recurrence of arthritis after discontinuation of nti-inflammatory therapy. Other variables proposed as dif- erentiating factors in the 2 entities, including the latency eriod between development of pharyngitis and joint symp- oms which was approximately 3 to 10 days for PSRA in arlier studies,9,11,12 did not differ between ARF and PSRA n our population. This observation in our cohort is not easily xplained; 1 possibility is that there was a parental recall bias nd that possibly the parents, in response to this question, eferred to an earlier upper respiratory illness and not neces- arily to the one that caused the arthritis.
Although not significant in multivariate analysis, more atients with ARF had involvement of 1 joint, symmetrical nd migratory arthritis. There are some similarities and a few ifferences in the characteristics of the arthritis in our patients as ompared with patients in earlier studies. There were more joints nvolved and significantly more patients with migratory arthritis n our study and in the earlier studies. Contrary to the other tudies, none of our patients had axial involvement, and there ere more patients with symmetrical arthritis in the ARF group.
Because our analysis revealed that more patients with RF had fever and markedly elevated erythrocyte sedimen-
ation rate, we reexamined the charts of all patients classified s having PSRA who had fever, sedimentation rate of 60 m/hour, and at least 2 active joints. Ten of the 11 patients ith PSRA we found with these features had positive results n a throat culture. We assume that the high erythrocyte edimentation rate and fever in these patients represented the cute streptococcal illness in some or most of these cases.
On the basis of the results of this study, ARF and PSRA ppear to be 2 distinct entities. Although ARF has a more acute resentation, with fever, acute phase response, a greater number f joints, and frequency of cardiac involvement, the response to reatment is much quicker and the course of arthritis is shorter han in PSRA. If PSRA was a milder form of the spectrum of RF, we would not expect a slower response to treatment or a
onger course of the arthritis. We suggest that our equation might be used by clini-
ians to correctly classify their patients, at least until there are ore accurate and easier to use guidelines. However, this
quation will need to be validated in a prospective study. hen there is doubt about the diagnosis, we suggest to favor
he diagnosis of ARF and administer the usual antibiotic
rophylactic treatment.
t V
ifferentiation of Post-Streptococcal Reactive Arthritis from Acute Rheu
There is a growing need for guidelines about the ne- essity for and duration of anti-streptococcal prophylaxis in atients in whom PSRA is diagnosed. This study was not esigned to answer that question. Shulman and Ayoub,16 the merican Heart Association, and the Red Book of the AP17 suggest that antibiotic prophylaxis be given for 1 year,
nd if no carditis is observed, then prophylaxis should be iscontinued.
Our retrospective data are subject to parental recall and hysician diagnostic biases, but the large size of this series ay help to diminish these concerns.
We conclude that ARF and PSRA are different enti- ies, although both are consequences of group A streptococcal nfection and involve the joints. Different approaches to an- ibiotic prophylaxis…
Differentation of Post-Streptococcal Reactive Arthritis from Acute Rheumatic Fever
JUDITH BARASH, MD, ERAN MASHIACH, MD, PNINA NAVON-ELKAN, MD, YACKOV BERKUN, MD, LIORA HAREL, MD, TSIVIA TAUBER, MD, SHAI PADEH, MD, PHILIP J. HASHKES, MD, MSC, AND YOSEF UZIEL, MD, FOR THE PEDIATRIC RHEUMATOLOGY STUDY GROUP OF ISRAEL
bjective To perform a retrospective study comparing clinical and laboratory aspects of patients with acute rheumatic fever ARF) and patients with post-streptococcal reactive arthritis (PSRA), to discern whether these are 2 separate entities or varying linical manifestations of the same disease.
tudy design We located the records of 68 patients with ARF and 159 patients with PSRA, whose diseases were diagnosed ith standardized criteria and treated by 8 pediatric rheumatologists in 7 medical centers, using the Israeli internet-based ediatric rheumatology registry. The medical records of these patients were reviewed for demographic, clinical, and laboratory ariables, and the data were compared and analyzed with univariate, multivariate, and discriminatory analysis.
esults Four variables were found to differ significantly between ARF and PSRA and serve also as predictors: sedimentation ate, C-reactive protein, duration of joint symptoms after starting anti-inflammatory reatment, and relapse of joint symptoms after cessation of treatment. A discriminative quation was derived that enabled us to correctly classify >80% of the patients.
onclusion On the basis of simple clinical and laboratory variables, we were able to ifferentiate ARF from PSRA and correctly classify >80% of the patients. It appears that RF and PSRA are distinct entities. (J Pediatr 2008;153:696-9)
ost-streptococcal reactive arthritis (PSRA) is defined as arthritis of 1 joints, associated with a recent group A streptococcal infection in a patient who does not fulfill the Jones criteria for the diagnosis of acute rheumatic fever (ARF).1,2
lthough other definitions have been suggested, mainly for adult cases, this definition is he most accepted and used by most investigators. Some authors consider PSRA to be part f the spectrum of ARF, whereas other authors consider it to be a different entity.
Authors who consider PSRA to be part of the ARF spectrum refer mainly to a small umber of cases in which PSRA has been diagnosed and in which carditis suggestive of RF subsequently developed.3,4
In 1993, Deighton5 proposed the following as distinguishing features of PSRA: ) onset within 10 days of group A streptococcal infection, as opposed to 2 to 3 weeks in RF; 2) Prolonged or recurrent arthritis, in contrast to ARF, in which the arthritis lasts
few days to 3 weeks; 3) Slow and partial response to aspirin, whereas in ARF the esponse to aspirin is usually dramatic.
The following diagnostic criteria for PSRA have been proposed by Ayoub and hmed based on these clinical features6: 1) Arthritis of acute onset, symmetric or
symmetric, usually non-migratory, can affect any joint, persistent or recurrent. The rthritis is at best only poorly responsive to salicylates or nonsteroidal anti-inflammatory rugs; 2) Evidence of antecedent group A streptococcal infection; and 3) Failure to fulfill he modified Jones criteria for the diagnosis of ARF.2
The question whether PSRA is a distinct entity from ARF has not yet been nswered. Our objective was to search for differences in these 2 entities in a well-defined, arge cohort. We attempted to discern whether they are 2 separate entities or varying
From the Pediatric Day Care and Pediatric Rheumatology service (J.B.), and Depart- ment of Pediatrics (E.M.), Kaplan Medical Center, Rehovot, affiliated to the Hadassah Medical School, the Hebrew University Jerusalem, Israel; Pediatric Day Hospital, Shaarei Zedek Medical Center, Jerusalem, af- filiated to the Hadassah Medical School, the Hebrew University, Jerusalem Israel (P.N.-E.); Department of Pediatrics, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (Y.B., S.P.); Schneider Chil- dren Hospital, Petah Tikva, affiliated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (L.H.); Pediatric Day Care, Assaf Harofeh Medical Center, Zrifin, affili- ated to the Sackler Medical School, Tel Aviv University, Tel Aviv, Israel (T.T.); Section of Pediatric Rheumatology, Cleveland Clinic, affiliated to the Cleveland Clinic Lerner School of Medicine of Case Western Uni- versity, Cleveland, OH (P.H.); and Depart- ment of Pediatrics, Meir Medical Center, Kfar Saba, affiliated to the Sackler Medical School Tel Aviv University, Tel Aviv, Israel (Y.U.).
Drs Hashkes and Uziel have contributed equally to this study.
The authors declare no potential conflict of interest.
Submitted for publication Dec 2, 2007; last revision received Mar 31, 2008; accepted May 21, 2008.
Reprint requests: Judith Barash, MD, Pediatric Day Care, Kaplan Medical Center, PO Box 1, Rehovot 76100, Israel. E-mail: judith_b@ clalit.org.il; [email protected].
0022-3476/$ - see front matter
RF Acute rheumatic fever PSRA Post-streptococcal reactive arthritis
d f p w t 2 a a
c v c m p w w a b m e s
d
r w e l g t d w
j a ( n e . A j
e p P a o T w
F A j s
R
R
D
linical manifestations of the same disease and, if possible, to ffer a simple clinical tool to differentiate between them.
METHODS We located patients, 16 years old, who received a
iagnosis and were treated by 8 pediatric rheumatologists rom 7 centers who participated in the Israeli internet-based ediatric rheumatology registry.7 We searched for patients in hom ARF was diagnosed with joint involvement and pa-
ients with a diagnosis of PSRA between the years 1996 and 005 (most after 2001). A total of 159 patients with PSRA nd 68 patients with ARF for whom there was sufficient nalyzable data were found.
ARF was diagnosed according to the revised Jones riteria,2 and PSRA was diagnosed in cases of arthritis in- olving 1 joints associated with proven group A streptococ- al infection in a patient not fulfilling the Jones criteria. The edical charts of these patients were reviewed by a single
hysician, and all demographic, clinical, and laboratory data ere summarized. The characteristics of ARF and PSRA ere compared with 2-sample t tests (for continuous vari-
bles) and 2 tests (for categorical variables). Multivariate ackwards stepwise logistic regression analysis was used to odel the probability of ARF versus PSRA. A prediction
quation was calculated by using discriminant analysis.8 The tudy was approved by each center’s ethical committee.
RESULTS There was no significant difference in the 2 groups in
able I. Clinical and laboratory data of patients ith acute rheumatic fever and post-streptococcal
eactive arthritis
P value
ever °C (SD) 38.3 (0.4) 38.3 (0.5) NS with Fever 38 66 16 .0004 umber of active joints (SD)
2.5 (1.2) 1.8 (1.3) .0004
igratory arthritis % 79 33 .004 ymetrical arthritis % 40 22 .05 arditis % 60 0 .0001 SR (SD) 92.2 (31.1) 57.1 (40.9) .0001 RP mg/L (SD) 106.7 (83.5) 22.6 (44.1) .0001 SO IU (SD) 1011 (1573) 889 (733) NS ositive throat culture % 77% 76% NS nterval from pharyngitis to arthritis, days (SD)
15 (9.2) 14.6 (10.1) NS
esponse to treatment, days (SD)
2.2 (1.7) 6.9 (5.9) .0001
elapse % 7 21 0.013
reatment; relapse, relapse of joint symptoms after cessation of anti-inflammatory treat- ent; NS, not significant.
emographic characteristics. The age of onset was 10.2 3.0 t
ifferentiation of Post-Streptococcal Reactive Arthritis from Acute Rheu
ears for ARF and 9.3 3.6 years for PSRA. A total of 63% of atients with ARF and 54% of patients with PSRA were male, nd the number of persons in the household was 5.9 1.5 for RF and 6.5 2.1 for the patients with PSRA. A family history f ARF in first- or second-degree relatives was found in 7.2% of he patients with ARF and 7.5% of the patients with PSRA.
The clinical and laboratory characteristics are summa- ized in Table I. Fever 38°C was recorded in 46 patients ith ARF (66%) and 25 patients with PSRA (16%). The
rythrocyte sedimentation rate and the C-reactive protein evel were significantly higher in the ARF group. The 2 roups did not differ in the proportion with positive results of hroat cultures at onset of joint disease, and no significant ifference was found in the levels of antistreptolysin O that ere markedly increased in both groups.
The patients with ARF had significantly more active oints (P .0004), with 79% of the patients having migratory rthritis, in contrast to 33% of the patients in the PSRA group P .004). The distribution of involved joints (Figure) did ot differ in the groups, except large joints in the upper xtremities were more frequently involved in ARF (P 0002). Arthritis was symmetrical in 40% of patients with RF and 22% of the patients with PSRA (P .05). Axial
oint involvement was not documented in either group. A total of 41 patients with ARF (60%) had carditis by
valuation of a qualified pediatric cardiologist. None of the atients with PSRA had proven carditis. Two patients with SRA had prolonged P-R intervals with electrocardiography, nd 3 patients with PSRA had a trace of mitral regurgitation n echocardiogram, which was not considered pathologic. he interval from onset of pharyngitis to the onset of arthritis as 15.1 9.2 days (documented in 76% of the patients) for
igure. The distribution in percent with active joints in patients with RF and PSRA. Large LE, Large joint lower extremity; small LE, small
oint lower extremity; large UE, large joint upper extremity; small UE, mall joint upper extremity. *P .0002.
he patients with ARF, versus 14.6 10.1 days for the
matic Fever 697
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atients with PSRA (documented in 70% of the patients; P ot significant).
The time required for resolution of joint symptoms in esponse to anti-inflammatory treatment was significantly horter in patients with ARF as compared with patients with SRA (2.18 1.71 days versus 6.73 5.89, respectively; .0001). Resolution of joint symptoms was defined at the
ate stated by the attending physician that no arthritis or rthralgia was noted on physical examination. Only 7% of atients with ARF sustained a relapse after cessation of anti- nflammatory therapy, compared with 21% of patients with SRA (P .013) requiring repeated anti-inflammatory treat- ent. The relapse of joint complaints suggests a longer nat-
ral course of arthritis. Twenty-two percent of the patients with PSRA did not
eceive anti-inflammatory treatment, and their joint disease as treated only with rest, compared with only 1 patient in
he ARF group. A total of 87% of patients with ARF received long-term
rophylactic antibiotic treatment, compared with 50% of pa- ients with PSRA; 50% of the patients with ARF received ntramuscular penicillin versus 4% of the patients with PSRA.
espite more intensive antibiotic prophylaxis in patients with RF, 12% had a recurrence, compared with 8% of patients in
he PSRA group. The 2 most significant variables differentiating ARF
rom PSRA on univariate analysis were the time required for esolution of joint symptoms in response to anti-inflamma- ory therapy and the number of patients who had a relapse of oint disease after cessation of anti-inflammatory treatment.
By using multivariate, backward, stepwise logistic regres- ion, we found 4 variables to be significant diagnostic discrimi- ators between ARF and PSRA: erythrocyte sedimentation rate, -reactive protein, duration of joint symptoms in response to
reatment with anti-inflammatory medications, and relapse of oint symptoms after cessation of anti-inflammatory treatment Table II). By using discriminant analysis, we calculated this rediction equation: 1.568 0.015 sedimentation rate .02 CRP – 0.162 days to resolution of joint symptoms – .04 return of joint symptom (yes 1, no 0).
If the value was 0, the patient was classified as having RF; otherwise, the patient was classified as having PSRA. his prediction gave 79% sensitivity rate (correct classification
s ARF) and 87.5% specificity rate (correct classification as
able II. Significant predictors of acute rheumatic ever by using stepwise logistic regression
Variable Odds ratio 95% CI Significance
SR 1.015 1.000-1.031 0.043 RP 1.016 1.004-1.028 0.007 ays to disappearance of joint symptoms
0.565 0.389-0.820 0.003
0.026 0.002-0.390 0.008
DISCUSSION Two recent studies attempted to answer whether ARF
nd PSRA are distinct entities and to validate the diagnostic riteria proposed by Ayoub and Ahmed.6 Tutar et al9 com- ared 24 children with PSRA with 20 patients with ARF. he latency period from upper respiratory tract infection was
ignificantly shorter in patients with PSRA; however, 25% of he patients with ARF also had a short latency period. Un- esponsiveness of articular symptoms to salicylate therapy was ore frequent in PSRA, but also 45% of the patients with RF with joint symptoms did not respond during the first 72 ours. The authors concluded that because there was consid- rable overlap between PSRA and ARF, these 2 entities could ot easily be distinguished.
In 2004, Mackie and Keat10 addressed the same issue by onducting a systematic search on Medline using strict inclu- ion criteria. They identified 188 cases of PSRA published in he literature between 1982 and 2002. One hundred of these ases were in adults 18 years old. The authors concluded hat PSRA is a heterogeneous group of clinical entities, some f which share features of ARF and others with HLA B27- elated spondyloarthropathies and that the assumed causal ole of streptococcal infection is far from proven.
There are several studies addressing the association of RF and PSRA with class II HLA-DR antigens. Ahmed
t al11 found an increased frequency of HLA DRB1*01 in atients with PSRA compared with healthy control subjects nd to patients with ARF. In patients with ARF, there was an ncreased frequency of HLA DRB1*16 allele compared with ontrol subjects. This association may suggest that the patho- enesis of PSRA, like that of ARF, may be related to the nheritance of certain class II HLA alleles. In 2004, Simo- ini12 published a different observation on genotyping of the LA-DRB1 locus in 25 patients with ARF, 34 patients with SRA, and healthy control subjects. The frequency of RB1*01 and DRB1*16 in patients with PSRA and ARF did
ot show any statistical significance when compared with each ther or with that of the control subjects. The conclusion in his study was that the 2 diseases are not genetically different n these alleles.
The presence of a non-HLA B cell alloantigen D8/17 n a significantly greater percentage of patients with ARF and heir first-degree relatives compared with control subjects has een shown by Khanna.13 In a study of Israeli patients, arel14 has found a significantly higher percentage of B cells
xpressing the D8/17 antigen in patients with a history of RF than in control subjects. Later the same author investi-
ated the presence of D8/17 alloantigen on B cells from atients with PSRA compared with control subjects.15 There as a small difference between the expression of the antigen
n patients with PSRA and subjects in the control group, but ith significant overlap in the 2 groups. Moreover, there was weak negative correlation between the percentage of D8/17 ositive cells and the time elapsed from diagnosis. It was
uggested previously that this expression is regulated by the
The Journal of Pediatrics • November 2008
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1 s 2 K A J 3 c 4 s l 5 R 6 i 7 P n O 8 Y 9 r 1 k 1 a 1 1 a a 1 P m 1 D 2 1 D 2 1 2 1
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nfection, so it is questionable whether it is a true genetic arker.
In this study, we have shown that we were able to ifferentiate between ARF and PSRA in 80% of the cases n the basis of 4 criteria: the sedimentation rate and CRP at nset, the number of days before resolution of joint symptoms fter starting anti-inflammatory therapy, and the presence or bsence of a recurrence of arthritis after discontinuation of nti-inflammatory therapy. Other variables proposed as dif- erentiating factors in the 2 entities, including the latency eriod between development of pharyngitis and joint symp- oms which was approximately 3 to 10 days for PSRA in arlier studies,9,11,12 did not differ between ARF and PSRA n our population. This observation in our cohort is not easily xplained; 1 possibility is that there was a parental recall bias nd that possibly the parents, in response to this question, eferred to an earlier upper respiratory illness and not neces- arily to the one that caused the arthritis.
Although not significant in multivariate analysis, more atients with ARF had involvement of 1 joint, symmetrical nd migratory arthritis. There are some similarities and a few ifferences in the characteristics of the arthritis in our patients as ompared with patients in earlier studies. There were more joints nvolved and significantly more patients with migratory arthritis n our study and in the earlier studies. Contrary to the other tudies, none of our patients had axial involvement, and there ere more patients with symmetrical arthritis in the ARF group.
Because our analysis revealed that more patients with RF had fever and markedly elevated erythrocyte sedimen-
ation rate, we reexamined the charts of all patients classified s having PSRA who had fever, sedimentation rate of 60 m/hour, and at least 2 active joints. Ten of the 11 patients ith PSRA we found with these features had positive results n a throat culture. We assume that the high erythrocyte edimentation rate and fever in these patients represented the cute streptococcal illness in some or most of these cases.
On the basis of the results of this study, ARF and PSRA ppear to be 2 distinct entities. Although ARF has a more acute resentation, with fever, acute phase response, a greater number f joints, and frequency of cardiac involvement, the response to reatment is much quicker and the course of arthritis is shorter han in PSRA. If PSRA was a milder form of the spectrum of RF, we would not expect a slower response to treatment or a
onger course of the arthritis. We suggest that our equation might be used by clini-
ians to correctly classify their patients, at least until there are ore accurate and easier to use guidelines. However, this
quation will need to be validated in a prospective study. hen there is doubt about the diagnosis, we suggest to favor
he diagnosis of ARF and administer the usual antibiotic
rophylactic treatment.
t V
ifferentiation of Post-Streptococcal Reactive Arthritis from Acute Rheu
There is a growing need for guidelines about the ne- essity for and duration of anti-streptococcal prophylaxis in atients in whom PSRA is diagnosed. This study was not esigned to answer that question. Shulman and Ayoub,16 the merican Heart Association, and the Red Book of the AP17 suggest that antibiotic prophylaxis be given for 1 year,
nd if no carditis is observed, then prophylaxis should be iscontinued.
Our retrospective data are subject to parental recall and hysician diagnostic biases, but the large size of this series ay help to diminish these concerns.
We conclude that ARF and PSRA are different enti- ies, although both are consequences of group A streptococcal nfection and involve the joints. Different approaches to an- ibiotic prophylaxis…
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