rheumatic€¦ · rheumatic fever (1, 2). theresults indicated that most clinical rebounds were not...

EXPERIMENTALREACTIVATION OF SUBSIDING RHEUMATICFEVER

By ALVANR. FEINSTEIN AND MARIO SPAGNUOLO*

(From Irvington House, Irvington-on-Hudson, N. Y., and Department of Medicine,New York University School of Medicine, New York, N. Y.)

(Submitted for publication April 27, 1961; accepted June 15, 1961)

When anti-inflammatory therapy is reduced ordiscontinued in patients with acute rheumatic fe-ver, a flare-up of disease activity frequently oc-curs, manifested by clinical abnormalities or bychanges only in laboratory tests. The nature ofthis rebound phenomenon was recently analyzedin a retrospective survey of 265 patients with acuterheumatic fever (1, 2). The results indicated thatmost clinical rebounds were not due to any of thethree possible causes to which they have been at-tributed in the past: 1) polycyclic rheumatic ac-tivity, 2) an insufficient duration of therapy or 3)relative hypoadrenalism. Instead, the data stronglysuggested that these rebounds represented the ap-pearance of the inflammation that had been sup-pressed during the antirheumatic therapy. Thishypothesis was based on the findings that the in-cidence of clinical rebounds increased with greaterseverity of cardiac involvement, that rebounds weremore frequent in patients treated with steroidsalone than in those treated with salicylates, that re-bounds were more likely to occur after long coursesof steroid therapy than after short courses, thatthey were rare after long courses of salicylates,and finally, that the incidence of post-steroid re-bounds could be reduced by adding salicylateswhen the steroid reduction began, and by continu-ing salicylates for several weeks after steroids werestopped.

This new hypothesis has important implicationsregarding the natural history of rheumatic feverand has practical significance for its treatment.One of the implications has been used in the pres-ent study to provide a method of testing the valid-ity of the theory. If the hypothesis is correct, itshould be possible to "create" a rebound by givinganti-inflammatory therapy at a time when the con-valescent rheumatic patient has no clinical abnor-malities but is still in a subclinical inflammatory

* Work performed in part during tenure of a Fellow-ship from the New York State Department of Health.

state. The use of profoundly suppressive therapyat this time might permit the remaining sup-pressed inflammation to reach an amount largeenough so that clinical abnormalities occur whenthe treatment is discontinued. The occurrence ofsuch an event had been noted previously (2) inone asymptomatic patient who was inadvertentlygiven a short course of steroid therapy severalweeks after his previous treatment had been dis-continued and who had a clinical rebound whenthe steroid treatment was stopped.

The present work was undertaken as a pros-pective study of these phenomena in an effort toconfirm or reject the proposed theory. The re-sults, as noted below, confirm the new hypothesis.

CLINICAL MATERIAL AND METHODS

The patients ranged in age from 4 to 18 years and hadall been admitted to Irvington House during the periodbeginning April 1959 for either acute or convalescentcare of an attack of rheumatic fever which, in each in-stance, fulfilled the modified Jones diagnostic criteria(3). Because the initial course of anti-inflammatorytherapy was usually begun elsewhere, the patients hadbeen treated in different ways and for different lengthsof time. Some had received only salicylates and someonly steroids. Some had received "overlap" therapy inwhich salicylates were added to steroids and continuedafter the steroids were stopped, while others had re-ceived "combined" treatment in which steroids and salicy-lates were used together in a variety of ways other thanthe "overlap" technique.

After admission to Irvington House, anti-inflammatorytreatment was begun, altered or concluded according tothe individual clinical situation. In general, treatmentwas concluded within 12 weeks after onset of the acuterheumatic attack. In addition, the patients received oralprophylaxis daily, with sulfadiazine, 1.0 g, or with potas-sium penicillin G, 200,000 U, to prevent streptococcal in-fections. The absence of such infections during the pres-ent study was assured by periodic throat cultures andmeasurement of streptococcal antibodies.

After their initial treatment was stopped, some pa-tients may have had a reappearance of rheumatic ac-tivity with laboratory or clinical abnormalities, and the

1891

ALVAN R. FEINSTEIN AND MARIO SPAGNUOLO

latter sometimes received additional treatment beforethese derangements subsided. Patients became eligiblefor the present study after they had been without any

anti-inflammatory therapy for 1 month. Although theymay have had rebounds during that interval, they in-variably had no clinical symptoms or signs of rheumaticactivity when the experimental study began. The1-month interval was chosen because of previous demon-strations (1) that post-therapeutic rebounds usually oc-

curred within 2 weeks and were rare beyond 4 weeksafter cessation of therapy. Therefore, when the experi-mental study was begun, all patients were beyond the"clinical rebound period" of their initial course of therapy.They were convalescent, asymptomatic and free of clinicalevidence of acute rheumatic activity.

The plan of the experiment is shown in Figure 1. Theexperimental treatment was begun exactly 1 month afterthe previous anti-inflammatory treatment was stopped,and was continued for 2 weeks with one of the follow-

ing regimens: 1) prednisone, 60 mg per day for 1 weekand 40 mg per day for the second week; 2) aspirin, 3/4grain per lb per day for 1 week and M grain per lb perday for the second week; 3) no therapy (control group).

For allocation into the experimental therapeutic groups,the patients were divided into three clinical categories.One group was considered to have "no valvular in-volvement" because they lacked significant cardiac mur-murs, according to criteria which have been describedelsewhere (1, 4, 5). The second group of patients had"valvular involvement" with no significant cardiac en-largement, i.e., no chamber more than 1 + enlarged.The third group had "valvular involvement" with sig-nificant cardiac enlargement. After classification intoone of the three cardiac categories, each patient wasallocated consecutively to one of the three experimentaltherapeutic groups. Because the number of patients wasrelatively small and because the consecutive order of al-location to the three therapeutic groups was followedrigorously within the clinical categories, the use of sta-tistical random-number tables was not considered neces-sary. The plan for assignment of experimental therapydid not classify patients according to their previous treat-ment because the variations in its agent(s) and durationwere too great. The most effective randomization seemedto be provided by considering the cardiac status and bymaintaining the common property of being therapy-freefor 1 month before onset of experimental treatment.

During the study the patients were observed for changesin clinical status and vital signs. Laboratory measure-ments were made of hematocrit, white blood cell count.sedimentation rate (Westergren and Wintrobe, uncor-rected), serum C-reactive protein, and occult blood in

BLE I

Status of patients before experimental treatment

Types of post-therapeutic reboundsNo. of

Cardiac status Previous treatment patients None Laboratory Clinical

No valvular Steroids or "combined" 18 3 11 4involvement Salicylate 12 10 1 1

"Overlap" 2 1 1 0

Subtotal 32 14 13 5

Valvular in- Steroids or "combined" 14 5 5 4volvement Salicylate 14 6 5 3without "Overlap" 7 2 4 1significantcardiomegaly Subtotal 35 13 14 8

Valvular in- Steroids or "combined" 11 1 4 6volvement Salicylate 5 1 2 2with "Overlap" 5 1 4 0significantcardiomegaly Subtotal 21 3 10 8

Entire group Steroids or "combined" 43 9 20 14Salicylate 31 17 8 6"Overlap" 14 4 9 1

Total 88 30 37 21

Clinic: rebounds No evidence ofmcy have occurred acute clinical

activity ot thist me

InitIal course.......of suppressivee Euri.e. otreatment withsteroids Off Re-tre.me ator salloltes

VARYING MONTH WEEKS-"

DURATIONS

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TABLE II

Relationship of clinical status and types of rebounds after 2 weeks of experimental suppressivetherapy in patients with subsiding rheumatic fever *

Types of rebounds after experimental therapy

Experimental No. of No Laboratory ClinicalClinical status therapy patients rebound rebound rebound

No valvular Prednisone 11 3 5 3involvement Aspirin 10 10 0 0

Control 11 10 1 0

Subtotal 32 23 6 3

VaIvular in- Prednisone 11 4 5 2volvement Aspirin 12 11 1 0without Control 12 10 2 0significantcardiomegaly Subtotal 35 25 8 2

Valvular in- Prednisone 7 0 3 4volvement Aspirin 7 4 2 1with Control 7 7 0 0significantcardiomegaly Subtotal 21 11 5 5

Entire group Prednisone 29 7 13 9Aspirin 29 25 3 1Control 30 27 3 0

Total 88 59 19 10

* Treatment given 1 month after cessation of previous therapy.

the stools (by guaiac test). These observations weremade before, during, and after the experimental periodof therapy. Three-position chest X-rays with bariumwere taken before and after the experimental therapy.

The criteria used for post-therapeutic clinical and lab-oratory rebounds have been defined elsewhere (1, 2) andwill be reviewed here only briefly: A laboratory reboundconsisted of an elevation either in sedimentation rate(over 20 mmper hour) or in C-reactive protein (traceor higher), without any clinical abnormalities. A clini-cal rebound was a laboratory rebound with associatedclinical abnormalities. These could be manifested byfever, sleeping tachycardia, joint symptoms, or newfeatures of carditis.

RESULTS

Status of patients before experimental therapy(Table I). Table I shows the situation of thepresent group before the beginning of experi-mental treatment. In the entire group, the initialtreatment was followed by clinical rebounds in 6of 31 patients who received salicylate, in 14 of 43who received steroids or "combined" treatment,and in 1 of 14 treated with the "overlap" regi-men. The incidence of clinical rebounds increasedwith increasing severity of cardiac damage. Lab-oratory rebounds were common, and bore some-what similar relationships to the clinical state

and the therapeutic agent. The results noted inthis group are almost identical with those observedin other patients during earlier surveys (1, 2) ofrebound phenomena and demonstrate that whileno initial course of suppressive treatment wasentirely able to avoid post-therapeutic clinical re-bounds, the latter were more frequent after ster-oids and less frequent when salicylates were givenalone or in such a way as to "overlap" the ster-oids.

Incidence of rebounds after experimental ther-apy (Table II). There were 88 patients in thestudy. Of the 29 who were experimentally treatedwith prednisone, 9 had clinical rebounds and 13had laboratory rebounds after prednisone was dis-continued. Of the 29 patients treated with aspirin,1 had a post-therapeutic clinical rebound and 3 hadlaboratory rebounds. In the 30 control patients,there were no clinical rebounds and 3 laboratoryrebounds.

Within the cardiac categories, the incidence ofpost-prednisone rebounds was the same in patientswith no valvular involvement as in those who hadvalvular involvement without significant cardio-megaly (3 of 11 in the first group and 2 of 11 inthe second). No clinical rebounds occurred in the

1893


salicylate or control groups for either of these two

clinical categories. In the group with significantcardiomegaly, the short course of salicylate was

followed by a clinical rebound in 1 of 7 patients,while prednisone therapy provoked a clinical re-

bound in 4 of 7 patients. No clinical rebound oc-

curred in the untreated group.

Within the experimentally treated prednisonegroup, therefore, the incidence of clinical reboundswas greater in patients with cardiomegaly thanin those with no or slight heart damage. Aspirintherapy had effects significantly different fromthose in the control group only in patients withsignificant cardiac enlargement.

It is apparent that the short course of experi-mental therapy was able to induce clinical re-

bounds in patients who might otherwise havecontinued their course without complication if leftuntreated. The features of these clinical re-

bounds and the number of patients in whom theyoccurred were as follows: fever, 5; tachycardia, 1;fever and tachycardia, 1; fever, tachycardia anderythema marginatum, 1; arthralgia, 1; congestiveheart failure, 1. All these manifestations subsidedspontaneously without retreatment except for thecongestive failure. The latter occurred in a pa-

tient with cardiomegaly who received prednisone;its clinical features disappeared with digitalis anddiuretics.

Correlation between the previous post-thera-peutic rebounds and those which followed the ex-

perimental course of therapy (Table III). TableIII shows the relationship between the events inthe 1-month interval which preceded experimentaltherapy and the events which followed it. In pa-

tients who had no rebound after their previouscourse of treatment, experimental therapy was notable to provoke a clinical rebound, although labo-ratory rebounds occurred in 6 of the 13 patientswho received prednisone, in 1 of 8 who receivedsalicylate and in 1 of the 9 controls. In patientswhose previous therapy was followed by a labora-tory rebound, the experimental course of salicylatesproduced essentially the same results as those seen

in the control group: no clinical rebounds occurredand only 2 of the 26 patients had laboratory re-

bounds after the experimental period. By con-

trast, 6 of the 11 patients in this category whowere treated with steroids had clinical reboundsand the other 5 had laboratory rebounds.

In the group of patients whose previous course

of therapy was followed by a clinical rebound,there were no clinical rebounds in the controls.Subsequent clinical rebounds occurred in 1 ofthe 9 who were experimentally treated with salicy-lates, and in 3 of the 5 patients who receivedsteroids.

These data show that the experimental re-

treatment with prednisone provoked either a

laboratory rebound or a clinical rebound in all pa-

tients who had had evidence of rheumatic activityafter their previous course of therapy. It pro-

TABLE III

Correlation between rebounds which followed the initial course of therapy and those whichfollowed the experimental 2-week course of therapy 1 month later

Nature of rebound Types of rebounds after experimental therapyafter initial course Experimental No. of

of therapy therapy patients None Laboratory Clinical

None Prednisone 13 7 6 0Aspirin 8 7 1 0None 9 8 1 0

Total 30 22 8 0

Laboratory Prednisone 11 0 5 6Aspirin 12 11 1 0None 14 13 1 0

Total 37 24 7 6

Clinical Prednisone 5 0 2 3Aspirin 9 7 1 1None 7 6 1 0

Total 21 13 4 4

Total 88 59 19 10

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TABLE IV

Relationship of previous therapy to experimental therapy and the rebounds after experimental therapy

Types of postexperimental reboundsExperimental No. of

Previous therapy therapy patients None Laboratory Clinical

Steroids or "combined" Prednisone 16 3 5 8Aspirin 14 12 1 1None 13 12 1 0

Subtotal 43 27 7 9

Aspirin Prednisone 9 3 6 0Aspirin 10 9 1 0None 12 10 2 0

Subtotal 31 22 9 0

"Overlap" Prednisone 4 1 2 1Aspirin 5 4 1 0None 5 5 0 0

Subtotal 14 10 3 1

Total 88 59 19 10

voked a clinical rebound in more than half of thepatients whose first course of treatment was fol-lowed by only a laboratory rebound. These ef-fects did not appear after the experimental treat-ment with salicylate. In this group, laboratoryrebounds occurred in only 3 patients and clinicalrebound in only 1. With the exception of thelatter patient, the results of the experimental treat-ment with salicylate did not differ significantlyfrom those of the control group. By contrast,none of the experimental therapeutic regimens wasable to alter the course of the disease when rheu-matic activity had subsided completely withoutrebound after the previous course of therapy.

Relationship of previous therapy to experi-mental therapy and postexperimental rebounds(Table IV). This table shows the occurrence ofrebounds after experimental therapy in relationto the therapy which had been given before theexperimental period. The three experimentalregimens were divided about equally among thepatients in each of the three "previous therapy"groups. Of the 43 patients who had been previ-ously treated with steroid or "combined" therapy,9 had clinical rebounds after the experimentaltreatment. The only salicylate-induced clinicalrebound in this study occurred in 1 of these pa-tients. Of the 31 patients treated with salicylateonly, none developed clinical rebounds in responseto experimental treatment. One of the 14 "over-

lap" patients had a clinical rebound after the sub-sequent course of prednisone.

Table I shows that clinical or laboratory re-bounds may have occurred after the initial courseof therapy in all three types of therapeutic regi-mens, less frequently in the salicylate group.Table IV shows that patients treated initially withsalicylate failed to develop clinical rebounds afterexperimental therapy and that the greatest sus-ceptibility to the experimental rebounds was inpatients treated initially with steroids or "non-overlapping" combined therapy.

Effect of experimental treatment upon theerythrocyte sedimentation rate (Figure 2). Withminor numerical differences, the Westergren anduncorrected Wintrobe sedimentation rates showedidentical variations. For convenience of illustra-tion the Wintrobe rates have been used in Figure 2.

Using a value of 20 mmper hour as the upperlimit of normal, the sedimentation rates in the"no valvular involvement" group were abnormallyelevated before experimental therapy in 3 of 11controls, in 4 of 10 patients who received aspirin,and in 3 of 11 treated with prednisone. In thepatients with noncardiomegalic "valvular involve-ment," the pretreatment sedimentation rate waselevated as follows: controls, 5 of 12; aspirin, 6of 12; prednisone, 4 of 11. In the group withsignificant cardiomegaly, an abnormal pretreat-ment sedimentation rate was found as follows:

1895


controls, 5 of 7; aspirin, 4 of 7; prednisone, 4of 7.

The pretherapeutic values of the sedimentationrate and the response to experimental treatmentare shown in Figure 2. In all three clinical cate-gories of the control group, the erythrocyte sedi-mentation rate (ESR) remained the same or

showed only slight changes. During the experi-mental salicylate treatment, the ESR rose in 9patients and fell when treatment was discontinued;in the other patients it remained the same or de-clined slightly. [This paradoxical rise in sedimen-tation rate with aspirin has been noted in the past(6). It appeared mainly in patients who showedsome gastric intolerance of the drug. Its mecha-nism is obscure; it may be related to gastritis or

to occult bleeding.] By contrast, the ESR fellduring treatment in all prednisone patients, re-

gardless of its initial value. In almost every in-

stance, the ESR after treatment was higher thanits pre-prednisone value. These data suggest thatsteroid therapy suppresses inflammation pro-foundly (as measured by sedimentation rate) andis followed by recrudescence of the inflammationto levels greater than those which existed previ-ously.

The heavy black lines in Figure 2 show thecourse of the patients who developed clinical re-

bounds after the experimental therapy was stopped.In 6 of these 10 patients the sedimentation ratewas above 20 before experimental treatment andin 8 it was above 20 at the time of the clinicalrebound. The 2 patients without a high sedimen-tation rate at that time had abnormal values forserum C-reactive protein. The variations in reac-

tion of these parameters presumably reflect the

ERYTHROCYTE RESPONSE TO EXPERIMENTAL THERAPEUTIC AGENTSCLINICAL EUINENTATION CONTROLS ASPIRIN PREONISONECARDIAC RATE TREATMENT T RETKATMENT TREATMI1TSTATUS hmm/r. before during after before during after before during ofier

40-

NO 30-VALVOLARINVOLVEMENT 20 X

10.

C-O _ _/50-

VALVULAR 40DFt

INVOLVEMENTWITHOUT 30'

SIGNIFICANTCARDIAC 20-

ENLARGEMENT10-

~~~~(CAP 20)

CR40-

VALVULARUINVOLVEMENT 3O -

WITH cRSIGNIFICANT 20r

CARDIACENLARGEMENT I

~~~~~~~~~~~~~CRICRP641

FIG. 2. RESPONSEOF SEDIMENTATION RATE TO EXPERIMENTAL THERAPY AND

APPEARANCEOF POST-THERAPEUTIC CLINICAL REBOUNDSIN PATIENTS CONVALES-

CENT FROMRHEUMATICFEVER. Sedimentation rate is the uncorrected Wintrobevalue. CR= clinical rebound. Heavy black lines used for patients with clini-cal rebounds. CRP= serum C-reactive protein value, shown for patients whosesedimentation rate was below 20 at time of clinical rebound.

1896


different capacities with which they measure theexistence of inflammation in different patients.

Effect of experimental treatment upon the se-

rumn C-reactive protein (Table V). The valuesfound here parallel those observed with the sedi-mentation rate. Of the 29 patients receivingprednisone, 2 had an abnormal value before theexperimental therapy, none had an abnormal valueduring therapy and 6 had abnormal tests after-ward. Five patients on salicylate treatment hada pretherapy elevation in C-reactive protein whichbecame normal thereafter. In 7 patients, abnormalvalues for C-reactive protein appeared during ther-apy but were negative previously and afterward.The effect of salicylate in elevating this acutephase reactant is consistent with its effects, notedsimultaneously, upon sedimentation rate and withthose noted in earlier experiments with serum

transaminase (7). In the control group, 3 patientshad abnormal values before treatment, 1 duringtreatment and none thereafter.

Changes in hematocrit during and after ex-

perimental treatment (Table VI). The hemato-crit values during and after treatment were com-

pared in all patients with those which were pres-

ent before the experimental treatment began. Thechanges are listed in Table VI. In the controlgroup there was no essential difference during or

after treatment. The mean hematocrit of thesalicylate group fell during treatment while thatof the prenisone group rose. Both mean changes,compared with those of the control group were

statistically significant. Within 1 to 2 weeks afterstopping the experimental treatment, the hemato-crit returned to its previous levels with no sig-

TABLE V

Behavior of C-reactive protein in relation to experimentaltherapy

No. of patients withabnormal C-reactive

protein

Experimental No. of Before During Aftertherapy patients therapy therapy therapy

Prednisone 29 2 0 6Aspirin 29 5* 7t 1Control 30 3 1 0

* The 5 patients with pretherapy elevations in C-re-active protein had no abnormalities thereafter.

t The 7 patients whose abnormal C-reactive proteinappeared during therapy did not have it previously.

TABLE VI

Changes in hematocrit during and after experimental treat-ment, compared with pretreatment value

Mean changes in hematocritNo. of

Treatment patients During treatment After treatment

Prednisone 29 +3.3* + 3.2 -0.2t i 3.3Aspirin 29 -1.4* + 3.1 +-O.t ± 2.1Controls 30 0 + 2.1 -0.1 ± 1.5

* The difference between these means and that of thecontrols is more than twice the standard error of thesampling.

t The difference between these means and that of thecontrols is not more than twice the standard error of thesampling.

nificant difference between the treatment groupsand the controls.

Changes in white blood cell count during experi-mental treatment; other changes. As was ex-pected (8), all patients receiving the experimentalcourse of prednisone had an elevation in whiteblood cell count during the 2-week treatment pe-riod; the white counts returned to their previouslevels shortly after treatment was stopped. Sa-licylate had no effect upon the white count.

The stool guaiac test became positive in 2 pa-tients who received salicylate therapy and be-came negative after treatment was stopped. Therewere no abnormalities in the stool guaiac tests ofpatients who received prednisone or in the con-trol group. There were no significant changes inthe cardiac size of any patients, during or aftertherapy, as measured by three-position chestX-rays.

DISCUSSION

These data provide the first evidence that re-bounds of clinical activity in rheumatic fever canbe deliberately produced by the use of an ap-parently benign therapeutic procedure. A 2-weekcourse of anti-inflammatory therapy, given toasymptomatic rheumatic patients in a convales-cent state after an acute attack, was followed bya recrudescence of clinical activity in 9 of 29 pa-tients who received prednisone and in 1 of 29 whoreceived aspirin. The untreated control groupremained asymptomatic. Clinical rebounds afterthe experimental therapy occurred only in patientswho had shown some clinical or laboratory evi-dence of rheumatic activity following their originalcourse of suppressive treatment and only in pa-

1897


tients whose original treatment included steroids.The results have several sets of implications:A. They help confirm, and can be explained only

by, the hypothesis that a rheumatic post-thera-peutic rebound represents the reappearance of theinflammation which was previously suppressed.The alternative explanations for the events notedin the present study and the evidence against themare as follows: 1) Recurrent episodes of rheu-matic fever did not cause the flare-ups becausethere had been no associated streptococcal infec-tions. 2) Polycyclic rheumatic activity was un-likely, since it did not appear in the control groupand because the flare-ups noted here were soheavily localized in the prednisone group. 3) Anonspecific reaction, perhaps hypoadrenalistic, tosteroid cessation is an unlikely explanation forthese reasons: a) a clinical rebound occurred in asalicylate-treated patient; b) the rebounds weremore frequent in patients with more severe heartdisease; c) in two patients the rebounds had clini-cal features characteristic of acute rheumatic fever-erythema marginatum and congestive heartfailure-and were not merely nonspecific inflam-matory responses; and d) the experimental post-steroid symptoms did not occur randomly butappeared only in patients who had had some formof rebound previously after their initial course oftherapy. Patients who had had no evidence ofrheumatic activity after their initial therapy wereclinically unresponsive to the experimental steroidtreatment.

B. The explanation which best fits these andprevious (1, 2) data is that an attack of rheu-matic fever is associated with a stimulus or sub-stance which produces inflammation and which isthen consumed or dispersed in the inflammatoryprocess. The usual course is for the inflammationto create clinical manifestations at first, to be-come subclinical later, and finally to cease. Inmost attacks of rheumatic fever, there seems to bea finite amount of this hypothetical substance; itcreates a finite amount of inflammatory reactionand is dispersed by it in a finite length of time.The amount of this substance, and hence of theinflammation, will vary with individual rheumaticattacks and with individual patients, and will de-termine the severity of the attack, the residualcardiac damage, and the duration of measurableabnormalities (9) in laboratory tests.

Therapy with steroids or salicylates or bothwill generally suppress the inflammation and willreduce the severity of its clinical and laboratorymanifestations. Although the expression of in-flammation may be suppressed, the underlying dis-ease remains active and the production of the hy-pothetical substance continues. The salicylates orsubtherapeutic doses of steroids will suppressinflammation only partially, so that it is mani-fested by laboratory abnormalities without as-sociated clinical features. During the period ofpartial suppression, some of the hypothetical sub-stance can be dispersed as the subclinical inflam-mation proceeds. When the suppression of in-flammation is total, as with large doses of steroids,little or no dispersion occurs and the substanceaccumulates. When the total or partial suppres-sion ceases, the clinical or laboratory magnitudeof the inflammation which then appears will de-pend upon how much of the substance remains tobe dispersed.

This hypothesis explains the types of reboundsseen in earlier surveys (1, 2) of initial treatmentof rheumatic fever. It also explains the presentfindings that profound suppression of rheumaticinflammation, at a time when it has reached sub-clinical levels but has not yet ceased, may be fol-lowed by clinical manifestations later when the in-flammatory reaction resumes. These concepts ap-pear to apply equally well to the rebound eventsnoted in treatment of acute thyroiditis (10) andinvite analogy regarding autoimmune phenomenain rheumatic fever.

C. These concepts do not apply to a small per-centage of severely ill patients with rheumatic fe-ver who show "chronic" or unusually prolongedclinical rheumatic activity (11) with spontaneousremissions and recrudescences unrelated to pre-ceding therapy. There were no such patients inthe present study.

D. Finally, the data indicate that anti-inflam-matory drugs, particularly steroids, should not begiven to patients with rheumatic fever who do notshow acute clinical abnormalities, since the ther-apy itself may provoke a recrudescence of clinicalactivity and iatrogenic "chronicity" of the disease.This is particularly pertinent in situations whereresumption of therapy is contemplated because itsinitial cessation was followed by abnormalitiesonly in acute phase reactants. Previous work has

1898


shown that these "laboratory rebounds" subsidespontaneously (1, 2) and the present data showthat their treatment may provoke clinical rebounds.

SUMMARY

A 2-week course of treatment with prednisoneor aspirin was given experimentally to clinicallyasymptomatic patients who were convalescingfrom acute rheumatic fever. The experimentaltreatment was begun exactly 1 month after theinitial course of suppressive treatment was ended.When the experimental therapy was stopped, arecrudescence of clinical rheumatic activity oc-curred in 9 of 29 patients treated with prednisone,in 1 of 29 treated with aspirin and in none of 30controls. The experimental clinical rebounds,which were more frequent in patients with severecardiac damage, occurred only in patients whohad shown clinical or laboratory evidence of rheu-matic activity after their previous course of treat-ment and only in those whose previous treatmentincluded steroids.

The experimental treatment with prednisonecaused a fall in the sedimentation rate of all pa-tients (regardless of its initial value) and its dis-continuation was followed by a rise, often togreater than pretreatment levels. It elevated thewhite blood cell count in all patients and causeda statistically significant rise in mean hemato-crit values. The experimental treatment withaspirin caused paradoxical rises in sedimentationrate and C-reactive protein in about one-fourthof the patients; it produced positive stool guaiactests in 2 of 29 patients and a statistically signifi-cant fall in mean hematocrit of the group.

The data are consistent with, and help confirm,the hypothesis that the post-therapeutic reboundphenomenon in rheumatic fever occurs becausesuppressive therapy, in preventing or inhibitingthe inflammatory process, also prevents or in-hibits the dispersion of the stimulus that causesinflammation. The subsequent removal of the sup-pressive agent is followed by the resumption ofinflammation in magnitude proportional to theremaining causative stimulus.

The results indicate that anti-inflammatorytreatment should not be begun or resumed forpatients with rheumatic fever whose acute abnor-malities are only in laboratory tests.

ACKNOWLEDGAIENT

The authors gratefully acknowledge the assistance ofthe nursing staff of Irvington House, headed by Mrs.Mary Culver.

REFERENCES

1. Feinstein, A. R., Spagnuolo, M., and Gill, F. A. Therebound phenomenon in acute rheumatic fever. I.Incidence and significance. Yale J. Biol. Med.1961, 33, 259.

2. Spagnuolo, M., and Feinstein, A. R. The reboundphenomenon in acute rheumatic fever. II. Treat-ment and prevention. Yale J. Biol. Med. 1961, 33,279.

3. American Heart Association. (Report of Committeeon Standards and Criteria for Programs of Care,of the Council on Rheumatic Fever.) Jones cri-teria (modified) for guidance in diagnosis of rheu-matic fever. Mod. Conc. cardiov. Dis. 1955, 24,291.

4. Feinstein, A. R., and Di Massa, R. The prognosticsignificance of valvular involvement in acute rheu-matic fever. New Engl. J. Med. 1959, 260, 1001.

5. Feinstein, A. R. Standards, stethoscopes, steroidsand statistics: The problem of evaluating treatmentin acute rheumatic fever. Pediatrics 1961, 27, 819.

6. Jager, B. V., and Alway, R. The treatment of acuterheumatic fever with large doses of sodium sa-licylate; with special reference to dose managementand toxic manifestations. Amer. J. med. Sci. 1946,211, 273.

7. Manso, C., Taranta, A., and Nydick, I. Effect ofaspirin administration on serum glutamic oxalo-acetic and glutamic pyruvic transaminases inchildren. Proc. Soc. exp. Biol. (N. Y.) 1956, 93,84.

8. Harris, T. N., and Vandegrift, H. N. Leukocytosisas a complication of prednisone therapy in rheu-matic fever. Pediatrics 1960, 25, 80.

9. Feinstein, A. R., and Spagnuolo, M. The durationof activity in acute rheumatic fever. J. Amer. med.Ass. 1961, 175, 1117.

10. Werner, S. C. ACTH and cortisone therapy ofacute nonsuppurative (subacute) thyroiditis. J.clin. Endocr. 1953, 13, 1332.

11. Taranta, A., Spagnuolo, M., and Feinstein, A. R."Chronic" rheumatic fever (abstract). Arth.Rheum. 1960, 3, 466.

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rheumatic€¦ · rheumatic fever (1, 2). theresults indicated that most clinical rebounds were not...

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