# Differentiation of PSRA due to Group A and due to Nongroup A Streptococci in Patients with Early Arthritis and Elevated Antisteptolysin-O at Presentation

Authors: T. L. Th. A. Jansen
Journal: International Journal of Rheumatology
 (2009)

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## Abstract

A study was performed of consecutive patients presenting to a Dutch
early arthritis clinic with a primary suggested diagnosis of reactive
arthritis due to streptococci between April 1998 and January 2003, in a
well-defined reference population consisting of 600 000 inhabitants. At
1 year after presentation out of 45 acute arthritis patients with
initially an elevated antistreptolysin-O and without an alternative
rheumatic diagnosis only 9 patients (20%) were not diagnosed as PSRA; 16
cases (36%) were due to NGAS, 20 cases (44%) due to GAS. The estimate of the annual incidence rate of PSRA in the Netherlands during the study was 1.26 per 100 000: 0.70 GAS-related. A diagnostic set of criteria was formulated based on the original Ayoub&Ahmed criteria by adding a
serological criterium ASO/antiDNaseB ratio <1.4 and excluding a clinical criterium on
chronicity/recurrency of arthritis: likelihood ratio for a positive test 7.9 [95%
confidence interval (95%CI: 2.7–22.7)], for a negative test 0.06 [95%CI: 0.009–0.39].


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## Body

## 1. Introduction

Streptococci in man are responsible for a variety of infections, ranging from relatively mild
illnesses, such as pharyngitis and impetigo, to clinically severe pathologies
such as pneumonia, septicaemia, necrotizing fasciitis or myositis. Streptococci
may evoke not only bacterial/purulent but also sterile sequelae. Classically,
arthritis secondary to group A streptococcal (GAS) pharyngitis is attributed to acute rheumatic fever (ARF) [1], but  nowadays post-streptococcal reactive arthritis (PSRA)
must be considered as well [2–5]. Dissimilarities between ARF and PSRA may
exist genetically [6], on the level of humoral hyperresponsiveness [7–9], and on the level of clinical characteristics [10–16]. In individual cases diagnostic criteria may be
helpful for diagnosing probably GAS-induced PSRA in particular. In 1997, Ayoub and
Ahmed have proposed a set of clinical and serological criteria for the
diagnosis of PSRA [17]: (A) acute-onset arthritis, symmetric or asymmetric, usually nonmigratory, (B) a protracted course or a recurrent type of
arthritis, (C) poor responsiveness to salicylates/nonsteroidals, (D) evidence of
antecedent streptococcal infection, (E) absence of any Jones major manifestation.
Though these criteria were meant for classification and not meant for
diagnostic use, they can be applied as a starter for diagnostic use for
clinicians: particularly criterion
(B) is unclear from the onset. Clinically, rheumatologists need to homogenize
groups of PSRA patients as so far literature describes a heterogeneous spectrum
of PSRA without proven prognostic implications [18]. This study reflects
all new patients presenting in a five-year period with early arthritis and at
presentation elevated streptococcal antibody titre suggestive of a recent
streptococcal infection, and not known with a previous rheumatic condition.


## 2. Materials and Methods

### 2.1. Study Design

A cohort of
patients was studied comprising consecutive patients with early and acute onset
of arthritis and at presentation a serological suggestion of a recent infection
withβ-haemolytic streptococci, presenting to our outpatient clinics of
rheumatology from April 1998 until January 2003: a period of 57 months. Before
inclusion, other causes of arthritis were excluded: septic arthritis,
rheumatoid arthritis, connective tissue disease, crystal deposition disease,
reactive arthritis attributable to parvovirus B19/salmonella/shigella/campylobacter/chlamydia/gonococ-ci/spirochetes, and arthritis secondary to
inflammatory bowel disease. An elevated antistreptolysin-O and/or antideoxy-ribonuclease-B
titre with/without tonsillopharyngitis was a prerequisite for inclusion into
the present study. All patients were according to Good Clinical Practice regularly
seen on outpatient basis for followup. There was no strict study protocol for
PSRA patients, but the following tests were obtained on routine basis in these
patients: full blood count, erythrocyte sedimentation rate, serum creatinine,
alkaline phosphatase, gamma-glutamyltranspeptidase, aspartate amino or alanine
aminotranspeptidase, uric acid, IgM rheumatoid factor (IgM RF), antinuclear
antibodies (ANA), C reactive protein, and urine microscopy. An electrocardiogram
was obtained of all patients. An echocardiogram was obtained in cases with a
cardiac murmur or with a conduction block on the electrocardiogram. Clinical
evaluation was performed by a rheumatologist, that is, the number of joints
involved was counted
according the 36 swollen joint index (SJI).During follow-up visits (t = 0, 6
weeks, 12 weeks, and every 3 month afterwards), the diagnosis was reevaluated
by patient’s own rheumatologist, and when after one year no alternative
explanation for the arthritis had been presented, the diagnosis of PSRA became definite. This
procedure was checked by an experienced clinician before entrance into this
study.


### 2.2. Serological Measurements

In all patients
antistreptolys-in-O (ASO) and antideoxyribonuclease-B (antiDNaseB) titres were
measured simultaneously and sequentially, at least at three time points: at
presentation, at 4–10 weeks after
pharyngitis, and once afterwards. When a sore throat was not recollected, the
titres of ASO and antiDNaseB were measured every 4 weeks during a period of 3
months. The suggestion of a recent streptococcal infection was accepted when an
increased titre of ASO and/or antiDNaseB and subsequently
decrease/normalization of titres were found: (1) ASO >200 U/L in adults,
ASO >300 U/L in adolescents; antiDNaseB >200 U/L irrespective of age; (2)
one or both titres must primarily show a significant rise and subsequent
decrease: critical difference between consecutive ASO values 26% and between
consecutive antiDNaseB values 14% [5]. Titres were determined by
nephelometry kit from Behring (Marburg, Germany).PSRA was diagnosed by the patient’s
own rheumatologist when after at least one year no alternative diagnosis could
be made. Definite PSRA patients were subdivided into two separate groups, based
on the ASO/antiDNaseB ratio taken at 4–10 weeks after
pharyngitis/tonsillitis: ratio <1.40 a plea for GAS-induced reactive arthritis,
whereas ratio >1.5, a plea for NGAS-induced PSRA [5]. Patients
diagnosed by their own rheumatologist or the experienced clinician as non-PSRA
are grouped together into a third separate group.


### 2.3. Analysis of Criteria

Ayoub and Ahmed
have proposed criteria for the classification of PSRA which may be quite
applicable for clinical use [17]: a triad regarding characteristics of
arthritis, one regarding evidence of antecedent streptococcal infection, and a
duplet regarding the exclusion of acute rheumatic fever: (A) acute onset of,
symmetric or asymmetric, nonmigratory arthritis, (B) protracted course of
arthritis or recurrent arthritis, (C) poor response of arthritis to
salicylates/nonsteroidals, (D) serological evidence of antecedent streptococcal
infection, (E) not fulfilling any modified Jones major criterion. The combination of this quintet
of criteria is tested in our study groups. Criterion (B) is however difficult to score prospectively in
a diagnostic phase from the onset in an individual patient.A previous study from the region of
Arnhem, in the central region of the Netherlands, revealed that the higher
ASO/antiDNaseB ratios plea for PSRA types not due to GAS, that is, ratios >1.5  plea for nongroup A streptococcal (NGAS) infection which may be helpful
particularly in cases with a negative throat culture; ratios <1.4 plea for
GAS-induced reactive arthritis [5]. Therefore a serological criterion which is clear
from the beginning at the diagnostic phase, is formulated for presumably
GAS-induced PSRA: (F) ASO/antiDNB ratio at 4–10 weeks <1.4.  A further serological criterion
is formulated as (G) antiDNaseB >400 U/L which is twice above the upper limit
of normal range (normal range: <200 U/L in adults)The presented patient population is
fitted into five sets of several combinations of criteria: starting with  the five ((A), (B), (C), (D), plus (E)) criteria
adapted from Ayoub and Ahmed, versus modification 1, that is, a sextet
consisting of the aforementioned quintet plus (F), versus modification 2, that
is, a sextet consisting of criteria by Ayoub and Ahmed plus (G) and modifications 3 and 4
consisting of the sextets minus (B):  (A),
(C),  (D), (E), plus (F), and (A), (C), (D), (E),
plus (G), respectively.Using the aforementioned tests, the
following test characteristics are calculated: sensitivity (Se), specificity
(Sp), positive predictive value (PPV), likelihood ratio of a positive test
(LR+) measured as the ratio between probability on a positive test result in
GAS-induced PSRA patients versus nonindex patients ideally reaching to
infinite, and likelihood ratio of a negative test (LR−) which is measured as
the ratio between probability on a negative test result in GAS-induced PSRA
versus nonindex patients ideally reaching to nil: using a2×2 table with
GAS-induced PSRA diagnosed by a rheumatologist at classification time 1 year
after presentation as the golden standard, and using several combinations of
criteria as index test, and in which a = true test positive, b = false test
positive, c = false test negative, and d = true test negative:  (legend: V[x] =
square root of x; EXP[x] = 2.7182818284x)(1)
Se =a/(a + c) with 95% confidence interval: Se +/− (95%CI) 1.96*V[ac/(a + c)3];(2)
Sp =d/(b + d) with 95%CI: Sp +/− 1.96*V[bd/(b + d)3];(3)
PPV =a/(a + b) with 95%CI: PPV +/−  1.96*V[ab/(a + b)3];(4)
NPV =d/(c + d) with 95%CI: NPV +/− 1.96*V[cd/(c + d)3];(5)
LR+ =
Se/(1 − Sp) with 95%CI: EXP[LN(LR+) +/− 1.96*V[1/a − 1/(a + c) + 1/b – 1/(b + d)]];(6)
LR− =
(1 − Se)/Sp with 95%CI: EXP[LN(LR−) +/−  1.96*V[1/c − 1/(a + c) + 1/d − 1/(b + d)]].


### 2.4. Statistics

Intergroup
comparison between probable GAS and NGAS patients was done by Mann-Whitney's two-sample test. Nonparametric
Spearman's rho correlations are calculated between ESR, CRP, ASO/ADB ratio,
number of arthritic joints, and number of weeks arthritis persists.P-values
<.05 are considered statistically significant.


## 2.1. Study Design

A cohort of
patients was studied comprising consecutive patients with early and acute onset
of arthritis and at presentation a serological suggestion of a recent infection
withβ-haemolytic streptococci, presenting to our outpatient clinics of
rheumatology from April 1998 until January 2003: a period of 57 months. Before
inclusion, other causes of arthritis were excluded: septic arthritis,
rheumatoid arthritis, connective tissue disease, crystal deposition disease,
reactive arthritis attributable to parvovirus B19/salmonella/shigella/campylobacter/chlamydia/gonococ-ci/spirochetes, and arthritis secondary to
inflammatory bowel disease. An elevated antistreptolysin-O and/or antideoxy-ribonuclease-B
titre with/without tonsillopharyngitis was a prerequisite for inclusion into
the present study. All patients were according to Good Clinical Practice regularly
seen on outpatient basis for followup. There was no strict study protocol for
PSRA patients, but the following tests were obtained on routine basis in these
patients: full blood count, erythrocyte sedimentation rate, serum creatinine,
alkaline phosphatase, gamma-glutamyltranspeptidase, aspartate amino or alanine
aminotranspeptidase, uric acid, IgM rheumatoid factor (IgM RF), antinuclear
antibodies (ANA), C reactive protein, and urine microscopy. An electrocardiogram
was obtained of all patients. An echocardiogram was obtained in cases with a
cardiac murmur or with a conduction block on the electrocardiogram. Clinical
evaluation was performed by a rheumatologist, that is, the number of joints
involved was counted
according the 36 swollen joint index (SJI).During follow-up visits (t = 0, 6
weeks, 12 weeks, and every 3 month afterwards), the diagnosis was reevaluated
by patient’s own rheumatologist, and when after one year no alternative
explanation for the arthritis had been presented, the diagnosis of PSRA became definite. This
procedure was checked by an experienced clinician before entrance into this
study.


## 2.2. Serological Measurements

In all patients
antistreptolys-in-O (ASO) and antideoxyribonuclease-B (antiDNaseB) titres were
measured simultaneously and sequentially, at least at three time points: at
presentation, at 4–10 weeks after
pharyngitis, and once afterwards. When a sore throat was not recollected, the
titres of ASO and antiDNaseB were measured every 4 weeks during a period of 3
months. The suggestion of a recent streptococcal infection was accepted when an
increased titre of ASO and/or antiDNaseB and subsequently
decrease/normalization of titres were found: (1) ASO >200 U/L in adults,
ASO >300 U/L in adolescents; antiDNaseB >200 U/L irrespective of age; (2)
one or both titres must primarily show a significant rise and subsequent
decrease: critical difference between consecutive ASO values 26% and between
consecutive antiDNaseB values 14% [5]. Titres were determined by
nephelometry kit from Behring (Marburg, Germany).PSRA was diagnosed by the patient’s
own rheumatologist when after at least one year no alternative diagnosis could
be made. Definite PSRA patients were subdivided into two separate groups, based
on the ASO/antiDNaseB ratio taken at 4–10 weeks after
pharyngitis/tonsillitis: ratio <1.40 a plea for GAS-induced reactive arthritis,
whereas ratio >1.5, a plea for NGAS-induced PSRA [5]. Patients
diagnosed by their own rheumatologist or the experienced clinician as non-PSRA
are grouped together into a third separate group.


## 2.3. Analysis of Criteria

Ayoub and Ahmed
have proposed criteria for the classification of PSRA which may be quite
applicable for clinical use [17]: a triad regarding characteristics of
arthritis, one regarding evidence of antecedent streptococcal infection, and a
duplet regarding the exclusion of acute rheumatic fever: (A) acute onset of,
symmetric or asymmetric, nonmigratory arthritis, (B) protracted course of
arthritis or recurrent arthritis, (C) poor response of arthritis to
salicylates/nonsteroidals, (D) serological evidence of antecedent streptococcal
infection, (E) not fulfilling any modified Jones major criterion. The combination of this quintet
of criteria is tested in our study groups. Criterion (B) is however difficult to score prospectively in
a diagnostic phase from the onset in an individual patient.A previous study from the region of
Arnhem, in the central region of the Netherlands, revealed that the higher
ASO/antiDNaseB ratios plea for PSRA types not due to GAS, that is, ratios >1.5  plea for nongroup A streptococcal (NGAS) infection which may be helpful
particularly in cases with a negative throat culture; ratios <1.4 plea for
GAS-induced reactive arthritis [5]. Therefore a serological criterion which is clear
from the beginning at the diagnostic phase, is formulated for presumably
GAS-induced PSRA: (F) ASO/antiDNB ratio at 4–10 weeks <1.4.  A further serological criterion
is formulated as (G) antiDNaseB >400 U/L which is twice above the upper limit
of normal range (normal range: <200 U/L in adults)The presented patient population is
fitted into five sets of several combinations of criteria: starting with  the five ((A), (B), (C), (D), plus (E)) criteria
adapted from Ayoub and Ahmed, versus modification 1, that is, a sextet
consisting of the aforementioned quintet plus (F), versus modification 2, that
is, a sextet consisting of criteria by Ayoub and Ahmed plus (G) and modifications 3 and 4
consisting of the sextets minus (B):  (A),
(C),  (D), (E), plus (F), and (A), (C), (D), (E),
plus (G), respectively.Using the aforementioned tests, the
following test characteristics are calculated: sensitivity (Se), specificity
(Sp), positive predictive value (PPV), likelihood ratio of a positive test
(LR+) measured as the ratio between probability on a positive test result in
GAS-induced PSRA patients versus nonindex patients ideally reaching to
infinite, and likelihood ratio of a negative test (LR−) which is measured as
the ratio between probability on a negative test result in GAS-induced PSRA
versus nonindex patients ideally reaching to nil: using a2×2 table with
GAS-induced PSRA diagnosed by a rheumatologist at classification time 1 year
after presentation as the golden standard, and using several combinations of
criteria as index test, and in which a = true test positive, b = false test
positive, c = false test negative, and d = true test negative:  (legend: V[x] =
square root of x; EXP[x] = 2.7182818284x)(1)
Se =a/(a + c) with 95% confidence interval: Se +/− (95%CI) 1.96*V[ac/(a + c)3];(2)
Sp =d/(b + d) with 95%CI: Sp +/− 1.96*V[bd/(b + d)3];(3)
PPV =a/(a + b) with 95%CI: PPV +/−  1.96*V[ab/(a + b)3];(4)
NPV =d/(c + d) with 95%CI: NPV +/− 1.96*V[cd/(c + d)3];(5)
LR+ =
Se/(1 − Sp) with 95%CI: EXP[LN(LR+) +/− 1.96*V[1/a − 1/(a + c) + 1/b – 1/(b + d)]];(6)
LR− =
(1 − Se)/Sp with 95%CI: EXP[LN(LR−) +/−  1.96*V[1/c − 1/(a + c) + 1/d − 1/(b + d)]].


## 2.4. Statistics

Intergroup
comparison between probable GAS and NGAS patients was done by Mann-Whitney's two-sample test. Nonparametric
Spearman's rho correlations are calculated between ESR, CRP, ASO/ADB ratio,
number of arthritic joints, and number of weeks arthritis persists.P-values
<.05 are considered statistically significant.


## 3. Results

During a period
of nearly five years 45 patients with a sterile acute arthritis with at
presentation a positive streptococcal serology presented to our outpatient department. All cases were
sporadic, and clustering of cases was not seen. In 36 patients a significant
change in streptococcal serology was observed, and in 16 a probability of PSRA due
to group A streptococci could not be confirmed as they had group C or G
streptococci in throat culture (n = 2) and a compatible high serological ratio
suggestive of nongroup A streptococci (NGAS), that is,  ASO/antiDNaseB >1.5. Suspicion rose in a
group of 20 patients during followup that indeed group A streptococci (GAS)
were the causative organisms. This indicates an estimated annual incidence rate
for PSRA of 36 in our Dutch population, that is, 1.26/100 000: GAS-related
PSRA (n = 20) indicates an annual incidence rate of 0.70/100 000, with
NGAS-related PSRA (n = 16) 0.56/100 000.A group
consisting of 9 patients presented with arthritis plus elevated ASO but did not
have a significant increase nor decrease in streptococcal antibody titres; and
during followup an alternative diagnosis had to be be made. Therefore these patients
are categorized into a third group of non-PSRA. During followup they were
diagnosed as coincidental streptococcal carriers in rheumatoid arthritis (n = 3),
psoriatic arthritis (n = 3), reactive arthritis due to Chlamydia (n = 1), Löfgren
syndrome (n = 1), and Lyme arthritis (n = 1).In GAS-induced
PSRA, 4 out of 20 patients had positive antinuclear antibodies, without any
specificity. By definition all PSRA patients have an increased ASO titre at 4–10 weeks after a
sore throat/pharyngitis, since seronegative cases were excluded. In the 20
presumed GAS-induced PSRA we obtained 7 positive throat cultures (35%): all
indeed consisted GAS; whereas in the 16 presumed NGAS cases 2 positive throat
cultures (12%) were found: once group C and once group G streptococci. The
number of arthritic joints according to the 36 swollen joint count (SJC36) is
higher in the presumed GAS- than in the presumed NGAS-induced cases: means (SD)
5.2 (1.3) versus 1.9 (0.4). In GAS-related PSRA the following systemic
involvement was encountered: pericarditis (1 out of 20 patients), and
pneumonitis (1 out of 20 patients), whereas in NGAS-related PSRA similar extraarticular
manifestations were not seen.GAS-related
PSRA patients all presented with a nonmigratory type of arthritis; 45% had
arthritis which persisted for more than 3 months (by our definition protracted
course), and in 10% arthritis recurred. Arthritis with characteristics
protractedor recurrent occurred in
50%. Good response to salicilates/nonsteroidals was seen in 1 out of 20
patients. All patients had proof of recent streptococcal infection in serology,
either in ASO and/or in antiDNaseB. None of the patients presented with a major
Jones’ criterion
other than arthritis, nor fulfilled Jones’ criteria on ARF. By definition all
GAS-related cases presented with a low ASO/antiDNaseB ratio. Altogether 95% of
GAS-induced PSRA patients fulfilled the criteria A +  C + D  +  E + F, by including criterion B this
percentage dropped to 50%. When criterion B is excluded, 75% of NGAS-induced patients meet criteria set
A + C + D+  E. In the 9 non-PSRA cases criteria set A  + C + D + E + F is met in 33% still.In 45 patients
with acute arthritis consisting of GAS-induced PSRA in 20, NGAS-induced PSRA in
16, and other cases
in 9, the following test characteristics for finding GAS-induced PSRA are
calculated: sensitivity (Se), specificity (Sp), predictive value of a positive
test result, that is, positive predictive value (PPV), predictive value of a
negative test result, that is, negative predictive value (NPV) with 95%
confidence intervals (95%CI). Also likelihood ratio of positive test (LR+) and
likelihood ratio of negative test (LR−) are calculated. Prevalence of index cases, that
is, GAS-induced PSRA in this population is 44%. Only 50% of patients meet  A + B + C + D + E, which
represents Se, 76% Sp, with predictive values: 62.5% PPV and 65.5% NPV, and likelihood
ratio for a positive test 2.1 LR+. By adding additional criterion F specificity increases to 88%
and LR+ increases to 4.2. By eliminating criterion B a significant improvement is obtained
of sensitivity and likelihood ratios: LR+ 7.9 and LR− 0.06. The additional
serological criteria (F) or (G) give similar results regarding their additive
diagnostic value. For further data see Table2.Table 1
Overview of 45 patients with acute arthritis
subdivided into post-streptococcal reactive arthritis (PSRA) probably due to
group A streptococci (GAS) in 20, probably due to nongroup A streptococci
(NGAS) in 16, and 9 non-PSRA patients. Clinical data are taken at presentation;
maximum serological data are tabulated. Legend: IgM-RF = rheumatoid factor (IgM type), ANA = antinuclear antibodies.
PSRAPresumed
GASPresumed NGASNon-PSRANumber of
females/males11/97/96/3Mean age (SD)
in year [range]33 (11) [17–54]37 (17) [12–55]40 (16) [14–70]Positivity forHLA-B271 (5%)0
(0%)0 (0%)IgM-RF1 (5%)0 (0%)5 (55%)ANA5
(25%)0 (0%)2 (22%)Antistreptolysin-O (ASO)>20020 (100%)16 (100%)6 (67%)mean value (SEM)1390 (235)1055 (130)1088 (360)Antideoxyribonuclease-B
(ADB)>20020 (100%)2 (12.5%)6  (67%)mean value (SEM)2730 (450)295 (67)340 (90)ASO/ADB ratio<1.420 (100%)0 (0%)3 (33%)mean value (SEM)0.62 (0.06)6.2 (1.2)9.4 (5.0)Positive throat
culture7x GAS2x NGAS1x NGASArthritic
joints; mean number (SEM)5.2 (1.3)*1.9 (0.4)3.4 (1.2)monoarthritis8 (40%)10 (63%)3 (33%)oligoarthritis7 (35%)5 (32%)3 (33%)polyarthritis5 (25%)1 (6%)3 (33%)Mean duration in weeks (SD)25 (10)*5 (2.5)—exceeding 2 months10 (50%)5 (31%)—exceeding 6 months5 (25%)0 (0%)—Pericarditis1 (5%)0 (0%)0 (0%)Pneumonitis1 (5%)0 (0%)0 (0%)Erythema
nodosum/multiforme1 (5%)0
(0%)1 (11%)Cholestatic
hepatitis2
(10%)0 (0%)0 (0%)Tenosynovitis4 (20%)0 (0%)3 (33%)P*-value <.05 for
comparison presumed GAS-induced and presumed NGAS-induced PSRA patients. GAS no.
is presumed as the causative organism if the ASO/antiDNaseB ratio is <1.4;
NGAS is presumed if ASO/antiDNaseB ratio >1.5.Table 2
Test
characteristics of three sets applied as diagnostic criteria in 45 patients
consisting of 36 patients with definite post-streptococcal reactive arthritis
(PSRA) due to group A streptococci (GAS:n = 20) and due to nongroup A streptococci
(NGAS: n = 16), and 9 non-PSRA patients: calculations represent values of a screening
test aiming to find GAS-related PSRA only. Legend: Sensitivity (Se);
Specificity (Sp); Positive Predictive Value (PPV); Negative Predictive Value
(NPV); Likelihood ratio (LR+) in an ideal test is optimal when ad infinitum, as
it gives a ratio between probability on a positive test result in GAS-induced
PSRA patients versus nonindex patients; Likelihood ratio negative test (LR−) in
an ideal test is optimal when it reaches nil, as it gives a ratio between
probability on a negative test result in GAS-induced PSRA versus nonindex
patients. In the second line 95% confidence intervals (95%CI) are given. For
criteria (A), (B), (C), and so forth see also text in Materials and
Methods section.
SetOriginal quintetSextet
1Sextet 2Novel quintet 1Novel quintet 2Ayoub and AhmedModification
1Modification 2Modification 3Modification
4A,B, C, D, EA,B, C, D, E,  FA,B, C, D, E,  GA, C, D, E,FA, C, D, F,GSe50%50%50%95%95%95%CI28–72%28–72%28–72%85–100%85–100%Sp76%88%92%88%80%95%CI59–93%75–100%81–100%75–100%64–96%PPV63%77%83%86%79%95%CI 39–86%54–100%62–100%72–100%63–95%NPV66%69%70%96%95%95%CI48–83%53–85%54–85%87–100%86–100%LR+2.14.26.37.94.895%CI0.9–4.71.3–13.21.5–25.32.7–23.02.9–7.7LR-0.660.570.540.060.0695%CI0.40–1.080.36–0.900.35–0.860.008–0.390.009–0.42


### 3.1. Correlations

Spearman's rho
in the 36 PSRA patients between period arthritis persists, mean (SD) 17 (35) weeks and swollen joint count
(SJC) 3.5 (4.5) joints, is 0.55 (P < .001). In the 20 GAS-induced cases
Spearman's correlation between period of persisting arthritis and SJC is 0.66 (P < .005),
versus 0.26 (P > .05) in NGAS-induced cases. Other correlations are
insignificant between the period arthritis persists on the one hand and erythrocyte sedimentation
rate(ESR)/C-reactive protein(CRP) on the other.


## 3.1. Correlations

Spearman's rho
in the 36 PSRA patients between period arthritis persists, mean (SD) 17 (35) weeks and swollen joint count
(SJC) 3.5 (4.5) joints, is 0.55 (P < .001). In the 20 GAS-induced cases
Spearman's correlation between period of persisting arthritis and SJC is 0.66 (P < .005),
versus 0.26 (P > .05) in NGAS-induced cases. Other correlations are
insignificant between the period arthritis persists on the one hand and erythrocyte sedimentation
rate(ESR)/C-reactive protein(CRP) on the other.


## 4. Discussion

Lancefield group A streptococci
(GAS) [2–5], but also nongroup A streptococci, group C and group G [19], are supposed to be capable to evoke reactive arthritis, though proof is lacking
in literature [18]. Post-streptococcal reactive arthritis (PSRA) due to GAS may well be considered
part of the spectrum or possibly a forme fruste of acute rheumatic fever (ARF)
which currently seems to have vanished from welfaring communities. The clinical
significance of a more benign PSRA secondary to NGAS remains unclear: it is not
known whether carditis and/or chorea risks in NGAS-induced PSRA are similar to the risks
in patients who developed full-blown rheumatic fever. It is a challenge for
clinicians to separate these entities in a prospective manner. Previously ARF
and PSRA have been differentiated and correctly classified by paediaticians
applying simple clinical and laboratory variables [20]. In this paper similar
variables are used to define clusters of criteria to differentiate subtypes of
PSRA, which enables homogeneity of studied cohorts in future. Of course some
circularity in reasoning cannot be ruled out completely as most patients
referred have already been diagnosed using serological criteria which are
generally applied in the Netherlands
due to previous publications [4, 5, 10].A resurgence over the last decades
of other post-streptococcal syndromes has been related to the spread of
different possibly more virulent clones of streptococci, higher number of
patients with conditions interfering with immunity, and alterations in patterns
of child care [21]. In our region of the Netherlands we find a low estimated
annual incidence for PSRA, only 0.70 per 100 000 inhabitants for GAS-induced PSRA.
Despite the resurgence of post-streptococcal syndromes as claimed, these low
incidence rates on GAS-induced PSRA stress the importance of multicentre
cooperation in order to increase insight into risk profiles for developing
severe sequelae such as carditis, and may increase our insight into long term
prognosis.Next to pyogenic sequelae, GAS
infections are known for their molecular mimicry resulting in non-pyogenic,
sterile but potentially devastating sequelae such as in acute rheumatic fever
(ARF). Patients may also develop a more benign manifestation of post-streptococcal
reactive arthritis (PSRA), particularly when caused by nongroup A streptococci
(NGAS) a predictor for benign courses [19]. In children probably more
than in adults, GAS-induced PSRA should be considered a potential predecessor
of rheumatic heart disease, which is reflected in penicillin prophylaxis
regimens [22]. Currently, clinicians should be capable to separate
GAS-induced PSRA from NGAS-induced PSRA, and this may be relevant as presently
more specific risk factors for developing a subsequent carditis are lacking. A
recent analysis of PSRA cases from literature revealed a significant clinical
heterogeneity of the term PSRA [18]. Prior to an evidence-based advice
of therapy clarity is needed of the clinical entity of the PSRA diagnosis.Only a weak
genetic difference between patients with ARF and PSRA has been demonstrated:
ARF being possibly associated with HLA DRB1*16, and PSRA with HLA DRB1*01 [6]. This could not be confirmed by Simonini et al. [23]. It is
therefore doubtful whether genetics are responsible for an individual's genetic
susceptibility for developing the type of post-streptococcal syndrome. Humoral
hyperresponsiveness then might be hypothesized to explain the specificity of
response following streptococcal infection. A high frequency of in vitro elevated D8/17 binding to B
lymphocytes has been found as a susceptibility marker for developing ARF more
than PSRA [7, 8, 24]. Another explanation could be in an individual’s defense,
for example, dependent on Toll-like receptors. Next to host factors,
microbacterial factors may be important: in GAS-induced PSRA so far, the
M-serotypes 9, 11, and 28 have been found, and these are M-serotypes not known
from acute rheumatic fever [25].Clear diagnostic criteria for
GAS-induced PSRA may be helpful for clinicians. There is a need for criteria
considering the clinical heterogeneity in the PSRA diagnosis in current
literature [18]. More homogeneity may result form an additional
serological criterion
of high ASO titres with lower ASO/antiDNaseB ratios, to exclude nongroup A
streptococci. Already in 1997 Ayoub and Ahmed proposed a set of criteria for
PSRA [17].  However, some of these cannot be applied at the patient’s presentation,
which thwarts diagnostic applicability. In the present study, a retrospective
evaluation of the potential clinical applicability of these criteria was modified from Ayoub and
Ahmed based on Dutch experience. Half of the presented GAS-induced PSRA
patients, however, do not fulfil the previously proposed criteria by Ayoub and Ahmed
on PSRA. Particularly the criterion
of a protracted course of arthritis is met in only half of presumably
GAS-induced PSRA patients. It is unclear yet whether this GAS-related PSRA
patient group without protracted arthritis bears a higher risk than the other
PSRA subgroups to develop, for example, carditis. On the other hand, one cannot
apply this feature for diagnosing purposes at presentation as clearly a certain
delay in time is needed to meet this criterion. Interestingly, a protracted course was not present in
any of our NGAS-induced patients, diagnosed by serological data.Epidemiologically, in adulthood PSRA
due to GAS is estimated to occur in 0.7 per 100 000 inhabitants. There may be
some underdiagnosis as clearly not all suspected patients will have been
referred to our department. In childhood these epidemiologic data may be quite
different, probably higher. Epidemiological reasoning to prove that PSRA really
exists cannot be done by using the presented data. Such proof needs to be
derived from immunology. Immunologically, the classic paradigm for molecular
mimicry in GAS-induced PSRA is similar as in acute rheumatic fever after
infection with GAS, underscoring the existence of PSRA. However, the presence
of antibodies to an antigen in the membrane of the organism, the type 5
streptococcal M protein cross-reacting with tissue, has not been convincingly
demonstrated in PSRA. The assumed causal role of streptococcal infection therefore
remains to be demonstrated pathogenetically.Ayoub  and Ahmed have originally proposed criteria
that are applicable only in full-blown clinical situations, not specifically
for diagnostic purposes from the onset; as these appear to exclude half of our
presumably GAS-induced PSRA patients [17]. An additional serological criterion, that is,
either the elevated antideoxyribonuclease-B or the lower antistreptolysin-O/antideoxyribonuclease-B ratio (<1.4), as described previously [5], may
be applied elegantly and leads to an improved criteria set in our presented
population. Also the criterion
on a protracted course, resulting in excluding all NGAS-induced cases, may
become abundant. In order to homogenize the PSRA patient group one might study:
(A) acute onset and nonmigratory type of arthritis, (C) poor responsiveness of
arthritis to salicylates/nonsteroidals, (D) evidence of antecedent streptococcal
infection, (E) not fulfilling modified Jones criteria, plus (F)
antistreptolysin-O/antiDNaseB ratio <1.4, or (G) antiDNase-B  >400 U/L.
Prospective studies in other GAS-induced PSRA patient groups are needed for
validation and proving their
prognostic value. For purposes of homogeneity in studies the aforementioned
criteria may have some merits. For practical purposes in an individual during
the diagnostic phase a serological criterion plus (A) and (C) seem to be quite applicable.



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