COMMENTARY
THE
ROLE
OF
HORMONES
IN TREATMENT
OF
RHEUMATIC
FEVER
By Albert Dorfman, M.D.*
I
NQIEASED diSseminatloll of informationregarding medical research and rapid
and effective marketing of new remedies
has created considerable pressure for the immediate use of new drugs. Dangers of
lack of critical evaluation of therapeutic
procedures have been dramatically
illus-trated by the discovery of the relationship
between use of atmospheres of high oxygen
concentration in the treatment of
prema-tures and development of retrolental
fibro-piasia.
The evaluation of’ the effect of
adreno-cortical and adrenocorticotropic hormones
in rheumatic fever poses a problem not
sub-ject to simple solution. Difficulties center
around characteristics both of the disease
and of the drugs. Since rheumatic fever has
not been reproduced in any species other
than man, testing of therapy must occur at
the clinical level. It is clear, however, that
if any agents were available which brought
about a prompt and complete cessation of rheumatic activity, this would become quickly apparent. In the absence of such a
drug, studies of rheumatic fever must give
due consideration to variability of
mani-festations, severity, duration and residual
structural damage. Problems are
encoun-tered because of lack of specific methods
for either diagnosis or measurement of
rheu-rnatic activity. Meaningful conclusions can
only be drawn when studies are planned so as to be sure that comparisons are being made between like groups of patients and
tile therapeutic trial is carried out in such
From the Department of Pediatrics, University
of Chicago, and La Rahida Jackson Park
Sani-tarium, Chicago.
0 ADDRESS: Bobs Roberts Niemorial Hospital for Children, 920 East 59th Street, Chicago .37, Ill.
a way as to be certain that the difference
in therapeutic agents represents the only
difference between groups.
There are certain difficulties that derive
from the nature of hormone therapy of
in-flammatory disease. It is now quite
ap-parent that when used systemically these
are agents of low therapeutic index,
con-trolling few diseases except in dosages
sufficient to produce evidences of
hyper-adrenalism. Although the sequeiae of the
use of reasonable doses of hormones are less
severe than originally feared, they are of
sufficient magnitude to restrain the
unquali-fled use of massive doses. The use of
adrenal hormones in the treatment of
in-fiammatory disease must still be regarded as
an empirical procedure. No unequivocal
evidence has established adrenal
insuffici-ency in diseases responsive to adrenal
hor-mone therapy, although Seeley et al. has
suggested that cortisone acts as replacement
therapy for a selective adrenal insufficiency
in rheumatic fever. This view is difficult to
reconcile with the finding of acute
maui-festations of rheumatic fever in the presence
of high blood levels of
17-hydroxycorticos-teroids during the early phase of the
dis-ease. Additional evidence against this idea
is the increase in blood
17-hydroxycorticos-teroids upon administration of ACTH to
patients with rheumatic fever, as well as
the fact that doses of cortisone or
hydro-cortisone sufficient for the maintenance of
adrenalectomized patients have little
thera-peutic value in most inflammatory diseases.
Similarly, the oft repeated suggestion that
the antirheumatic effect of salicylates is
mediated via the adrenals is not reasonable.
Manifestations of Cushing’s syndrome are
salicyl-fiOfi DOBFMAN FIORMONE TREATMENT OF RHEUMATIC FEVER
ates are efll)loyed altllough indications of
therapeutic effects of adrenal hormones in
rheumatic fever are not usually observed in the absence of hperadrenalism. Further evidence against this view of the
mecha-flIsIfl of action of salicylates is the lack of
effect of these compounds On various other
diseases which are strikingly influenced by
adrenal hormones (e. g., asthma).
On the basis of present knowledge it
seems probable that the therapeutic effects of the adrenal hormones derive from their
)harrnacological effects Oil such phenomena
as antibody formation, vascular reaction,
and effects on connective tissue, although
exact mechanisms are unknown. Further
clarification may come from the unraveling
of the complex interactions of the various
a(ireflal hormones. Of considerable interest
will be the amplification of knowledge
re-garding the effects of aidosterone, particu-iarly with respect to its role in congestive
failure in acute rheumatic fever, andi the
dietermiliation of its effects upon acute
in-flammatory reactions. The effect of
electro-lyte changes induced by adrenal hormones
upon inflammatory disease is not yet clear.
The discovery by Hench et al.2 of the
dramatic response of rheumatoid arthritis
to cortisone therapy was followed quickly
by a report of striking effects of cortisone on
rheumatic fever. In view of the frequent
self-limited nature of rheumatic fever, this
finding aroused hope that suppression of
the acute disease might restilt in prevention of cardiac damage.
Since that time, a large number of studies
have been published which are concerned
with the efficacy of hormone therapy in
rheumatic fever. Because of the obvious
difficulties of any one clinic accumulating
sufficient patients with rheumatic fever for
a properly controlled study, a Cooperative
Study was initiated in 1950 under the
auspices of the National Heart Institute of
the United States Public Health Service, the Medlical Research Council of Great Britain,
and the American Council on Rheumatic
Fever and Congenital Heart Disease of the
American Heart Association. This study was
diesigned to compare the effects of cortisone
(intramuscular), ACTH, and acetylsalicylic
acid on both the acute course of rheumatic
fever and the incidence of residual cardiac
damage. Patients were treated for a period
of 6 weeks and are being followed for a
period of 5 years. The results obtained
dur-ing the period of treatment and the status of
the patients 1 year after therapy have
re-cently been reported.3 A review of most of
the other individual studies has been
re-cently prepared by Massell.I
From these reports it is apparent that
different conclusions have been reached by
various investigators. It is not possible to
reconcile these variations because of the
marked diversity of criteria for selection of
patients and for evaluation of results, and
the striking range of dosage schedules
which have been used. On certain points
there seems, however, to be substantial
agreement. No one has claimed that
hor-mone therapy results in complete
termina-tion of rheumatic fever in all patients, or
the reversal of pre-existing structural
de-fects.
There is some diversity of opinion
regard-ing the effect of hormone therapy on the
natural history of the disease. The most
extreme view in this respect has been
pre-sented by Wilson et al.5 who have been
im-pressed by the capacity of hormone therapy
to terminate an attack of rheumatic fever
when administered early in the course of
the disease, for relatively short periods of
time, in large doses. The experience of these
investigators has been uncontrolled and
is not comparable to other reports because
of difference in criteria for evaluation of
activity. Most investigators have regarded
the effects of hormones as suppressive
rather than curative. This has been based
on the oft repeated observation of the
re-currences of certain manifestations upon
withdrawal of therapy; a phenomenon
which has been widely designated as the
“rebound phenomenon.” It is not clear
COMMENTARY 607
continuing rheumatic activity independent
of hormone therapy, or is a consequence of
pituitary or adrenal suppression induced by
hormone therapy. That the latter
interpre-tation is correct is suggested by more
strik-ing evidlence of “reboundi” in the hormone treated patients than in those treated with acetvisaiicylic acid in the Cooperative
Studiy. Such a conclusion is not, however,
unequivocal since no information was
avail-able regarding the behavior of a compar-able group of untreated patients. While it
is clear that hormone therapy does not bring about cessation of rheumatic activity in patients with chronic disease, the effect of sucil therapy on the dluration of an at-tack of rheumatic fever, when administered early, is not settled. It should be pointed
out that evidences of “rebound” usually
subsidle spontaneously aIld are most fre-quently mild, although occasionally severe.
Certain effects of hormone therapy on
some manifestations of the disease are quite
definite and probably do not require further
documentation. It is quite clear both from
the results of the Cooperative Study and other investigations that fever, elevated pulse rates during sleep, and joint
involve-ment readily return to normal on treatment
with ACTH and cortisone; however, equally
striking effects on these manifestations are
apparently prodluced by adequate salicylate therapy. The few attempts at controlled
studies utilizing salicylates as compared
with 110 treatment (see Iilingwortha)
sug-gests that these effects are the result of
therapy with all 3 agents.
Available studies also indlicate that
hor-inone therapy results in a more prompt
depression of sedimentation rate and
de-creased conduction time than is usually
ob-served consequent to salicylate therapy. Such appeared to be the case in the
corn-parison between treatment groups in the
Cooperative Study.
The effects of hormone therapy on
erythema marginatum and chorea are
con-fusing. Although claims of favorable effects
have been made, these do not occur
uni-formly as evidenced by the results of both
the Cooperative Study and those of a
num-ber of individual investigators.
Considerable interest attaches to the
ef-feet of hormone therapy on subcutaneous
nodules since this finding is so frequently
correlated with carditis. Massell’ has
re-centiy presented evidence that nodules
dis-appear more rapidly on hormone therapy
than in a group of patients otherwise
treated. The control group, however, was
selected from the past records so that there
is no assurance that these patients were
comparable, either in initial characteristics
or in treatment other than hormones.
How-ever, somewhat similar results were
ob-served in the Cooperative Study, that is,
nodules disappear more promptly in
pa-tients treated with ACTH or cortisone than
in those receiving salicyiates.
Various attempts to study the effects of
cortisone on the histology of rheumatic
nodules have led to conflicting conclusions.
Of particular interest, however, is the
re-cent report of Robies Gil, Rodriguez, and
Ibarra7 that pretreatment with cortisone of
patients undergoing commissurotomy
re-suited in a decrease in evidence of active
rheumatic lesions in auricular biopsies.
The evaluation of hormone therapy upon
manifestations of cardiac involvement is
difficult in view of the cnideness of
avail-able measurements and the prol)lems of
dis-tinguishing phenomena dependent upon
pre-existing structural deformities from
those dependent upon acute inflammatory
disease. A number of investigators have
at-tempted to study the result of hormone
therapy on congestive failure and
pen-carditis. Massell4 has combined the results
of a number of studies and reached the
conclusion that the hormones exert a more
beneficial effect than is observed with other
forms of therapy. The results of the
Go-operative Study did not afford any support
for this view, but even in the large number
of cases involved in this study only a
rela-tively small number exhibited congestive
608 DORFMAN HORMONE TREATMENT OF RHEUMATIC FEVER
percentage had pre-existing heart disease. The evaluation of congestive failure as well
as heart size is further complicated by the
salt and water retaining properties of the adrenal hormones.
Possibly the most critical assessment of the value of any therapeutic regimen must
depend on tile course of valvular disease as
evidenced by murmurs. Conclusions
regard-ing the capacity of hormone therapy to
i)ning about prevention of valvular disease in the absence of controlled experiments
must be viewed critically because they re-fleet both changes in the course of acute (lisease as well as valvular deformity. In
addition, evaluation of prevention of
valvu-lan disease in the absence of controlled
cx-periments is difficult due to the marked
variability of the outcome of an attack of
rheumatic fever and the undoubted
impor-tailce of prevention of repeated attacks. The results of the Cooperative Study show that
only in the case of the least striking mur-murs was there evidence of a more rapid dhsappearance as a result of hormone
ther-apy. The significance of this difference
dis-appeared when the groups were compared
at the end of one year, primarily because an
increasing number of patients who had i)een treated with salicylates had lost mur-murs by this time. Comparisons between patients with louder grades of murmurs afford no support for the notion that hor-inone therapy had prevented valvular de-formity. Special mention should be made of those patients with no murmurs at the on-set of therapy. Irrespective of therapy, such
patients have a small probability of having
residual murmurs after an attack of acute
rheumatic fever. it is obvious that the study
of such patients affords a poor test of the
capacity of hormones to prevalent valvular
disease.
In contrast to the results of the
Coopera-tive Study, has been the claim of some in-vestigators that hormone therapy prevents rheumatic heart disease in a very substantial percentage of patients. Most striking in this respect have been the reports of Greenman8
and Done et al,9 These workers,
particu-larly Greenman, have used considerably
larger doses of hormone for longer periods
of time than were used in the Coopera-tive Study. It is possible that better results may have been achieved for this reason, but
these studies were not adequately controlled
and the effects of selection of patients on the
results obtained cannot be assessed.
This abbreviated review of the status of
studies on hormone therapy makes it
obvi-ous that the results obtained are not
clear-cut, suggesting that much is to be desired in
the improvement of available remedies for
rheumatic fever. It is also apparent that
further controlled investigations will be
necessary to reach any final evaluation of
hormone therapy. Nevertheless, it is
neces-sary to attempt some over-all evaluation as
a guide to the ever present need for
de-cision regarding treatment. The weight of
evidence would seem to indicate that
treat-ment with cortisone, hydrocortisone, or
ACTH results in a more prompt response of
certain manifestations of rheumatic fever,
including some that are indicative of
carditis. It would seem reasonable to treat
patients with acute severe carditis with
adequate doses of these substances.
Hor-mone treatment of chronically active
pa-tients or those with severe damage has so
far been unrewarding, and treatment of
patients with little or no cardiac
involve-ment would seem unnecessary in view of
the excellent prognosis of such patients
‘ hen treated with salicylates. Although the
use of very large doses of hormones for long
periods of time may offer some promise,
the potential dangers are sufficiently great
as to cast doubt on the application of such
a regimen except in highly restricted
cir-cumstances.
REFERENCES
1. Seely,
J.
R., Ely, R. S., Done, A. K., Ainger, L. E., and Kelley, V. C. : Effects ofthen-apy on concentration of
17-hydroxy-corti-costeroids in the plasma of patients with
rheumatic fever. PEDIATRICS, 15:543, 1955.
2. Hench, P. S., Kendall, E. C., Slocumb, C.
COMMENTARY 609
of adrenal cortex (17-hydroxy-dehydro-corticosterone: compound E) and of
pitui-tary adrenocorticotrophic hormone on
rheumatoid arthritis. Proc. Staff Meet.,
Mayo Clin., 24:181, 1949.
3. Subcommittee of Principal Investigators American Council on Rheumatic Fever and Congenital Heart Disease and the Rheumatic Fever Working Party of the Medical Research Council of Great Britain : Treatment of acute rheumatic fever in children, a cooperative clinical trial of A.C.T.H., cortisone, and aspirin. Circulation, 1 1 :343, 1955; Brit. M.
J.,
1:555, 1955.
4. NIassell, B. F. : ACTH and cortisone therapy
of rheumatic fever and rheumatic carditis.
New England
J.
Med., 251:183, 221, 263,1954.
5. Wilson, M. C., Helper, H. N., Lubschez, R.,
Ham, K. and Epstein, N. : Effect of
short-term administration of corticotropin in
active rheumatic carditis. Am.
J.
Dis.Child., 86:131, 1953.
6. Illingworth, R. S., Burke,
J.,
Doxiadis, S. A.,Lorber,
J.,
Philpott, M. G., and Stone,D. C. H. : Salicylates in rheumatic fever:
An attempt to assess their value. Quart.
J.
Med., 23:177, 1954.7. Robles Gil,
J.,
Rodriguez, H. and Ibarra,J.
J.
: A histopathological and clinicalstudy of cardiac lesions in patients
sub-jected to mitral commissurotomy; the
effect of cortisone on such lesions. Proc.
2nd World Cong. Card., p. 189, 1954. 8. Greenman, L., Weigand, F. A. and
Danow-ski, T. S.: Cortisone therapy in initial
attacks of rheumatic carditis. Ann.
Rheum. Dis., 12:342, 1953
9. Done, A. K., Ely, R. S., Ainger, L. E., Seely,
J.
R., and Kelley, V. C. : Therapy of acuterheumatic fever. PEDIATRICS, 15:522,
